Research Annual Report 2009

Research Annual Report 2009 Molecular Medicine (MM) Clinical and experimental neuroendocrinology Regulation of calcium and bone metabolism Regulation of the bioactivity of thyroid hormone Signalling in reproduction and ageing Localisation, detection and radionuclide therapy of various diseases Regulation of follicle development, oocyte and endometrial embryo quality Pathophysiology of pediatric endocrine, metabolic and renal diseases Malignant transformation of hematopoietic stem cells: pathophysiology and development of therapy Hematopoiesis: regulation of the proliferation and differentiation of hematopoietic progenitor cells Molecular determinants of therapy response and outcome in childhood cancer Lymphoid differentiation and immunodeficiencies Immune regulation and autoimmunity Diagnosis, classification and treatment evaluation of leukemias and malignant lymphomas Solid tumors between bench and bed Improving accuracy and therapeutic ratio in radiation oncology 10599, B&T Ontwerp en advies (http://www.b-en-t.nl)

Research Annual Report 2009 Molecular Medicine (MM) Hyperthermia: a treatment for cancer Photodynamic therapy Neuro-oncology and pain Pathophysiological aspects and treatment of gastro-intestinal diseases Innovative tumor model development/tumor vasculature/tumor targeting/locoregional control Clinical and experimental aspects of urological tumors Gynaecological oncology; basics, epidemiology and clinical aspects Developmental biology; pathophysiology of the newborn Experimental therapeutical approaches in inflammatory dermatoses and cutaneous oncology Translational genomics and proteomics of cancer Translational pharmacology Translational tumor immunology Neoplastic lesions and chronic inflammatation of the gastrointestinal tract Liverspecific immunopathology; mechanism and therapeutic modulation Human virus infections: immunity, therapy and epidemiology 10599, B&T Ontwerp en advies (http://www.b-en-t.nl)

Research Annual Report 2009 Molecular Medicine (MM) Infections due to bacteria, fungi and parasites: diagnosis, molecular mechanisms, epidemiology, therapy and prevention Clinical research in infectious diseases in adults Renal insufficiency and organ transplantation Cell biological and pathophysiological investigations on pulmonary diseases Neuromuscular and Neuroinflammatory Disorders Organ transplantation Genitourinary tract disorders in children Disorders of the gastrointestinal tract in childhood Clinical, epidemiological and basic research of infectious diseases and immunological diseases in children 10599, B&T Ontwerp en advies (http://www.b-en-t.nl)

EMC MM-01-39-01 - Clinical and experimental neuroendocrinology Programme design in brief A. Studies on the regulation of hormone secretion by the normal pituitary gland as well as by human pituitary tumours in vivo and in vitro. B. An integrative approach to the endocrinology of ageing. Hormonal factors related to the ageing process are investigated in population studies. Intervention studies with hormones (growth hormone, dehydroepiandrosterone) are carried out. C. An integrative approach to factors determining glucocorticoid sensitivity in man. Molecular studies of mutations in the glucocorticoid receptor and in the translational regulation of glucocorticoid action are carried out in cells obtained from patients with glucocorticoid resistance and from patients with transient changes in glucocorticoid sensitivity. D. Studies on the expression of growth factor and peptide receptors in cancer and in immune cells. E. The regulation of the growth and activity of immune and of tumour cells in vitro by manipulation of the expression of peptide receptors is studied in relation with the potential endocrine manipulation of immune diseases and cancer growth in vivo. F. An integrative approach of clinical and surgical endocrinology is used in studies aimed at improving patient care. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 1,8 0,82 1,15 2,25 6,02 reproduction and development 0,1 0 0 0 0,1 surgery 0,1 0 0 0 0,1 Total 2 0,82 1,15 2,25 6,22 2 0 0 2 53 1 2 58 Thesis Bruin, C. de (2009, juli 01). Somatostatin and dopamine receptors as molecular targets for the medical treatment of Cushing's disease. EUR (170 pag.). Prom./coprom.: Prof.Dr. S.W.J. Lamberts & Dr. L.J. Hofland. Rietveld, I. (2009, december 16). The role of a CA repeat polymorphism in the promoter region of the insulin-like growth factor gene in psyciology and the pathophysiology of diabetes mellitus. EUR (126 pag.). Prom./coprom.: Prof.Dr. S.W.J. Lamberts, Prof.Dr.Ir. C.M. van Duijn & Dr. J.A.M.J.L. Janssen. Article/Letter to the editor Akerstrom, G, Falconi, M, Kianmanesh, R., Ruszniewski, P. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pre- and Perioperative Therapy in Patients with Neuroendocrine Tumors. Neuroendocrinology, 90(2), 203-208. Akker, E.L.T. van den, Koper, J.W., Joosten, K.F.M., Jong, F.H. de, Hazelzet, J.A., Lamberts, S.W.J. & Hokken-Koelega, A.C.S. (2009). Glucocorticoid receptor mrna levels are selectively decreased in neutrophils of children with sepsis. Intensive Care Medicine, 35, 1247-1254. Arnold, R., Chen, YJ, Costa, F, Falconi, M, Gross, D, Grossman, A.B., Hyrdel, R., Kos-Kudla, B, Salazar, R. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Follow-Up and Documentation. Neuroendocrinology, 90(2), 227-233. Brugts, M.P., Luermans, JGLM, Lentjes, EGWM, Vrouwerff, NJ van Trooyen-van, Horst, FAL van der, Slee, PHTJ, Lamberts, S.W.J. & Janssen, JAML (2009). Heterophilic antibodies may be a cause of falsely low total IGF1 levels. European Journal of Endocrinology, 161(4), 561-565. Bruin, C. de, Pereira, AM, Feelders, R.A., Romijn, J.A., Roelfsema, F, Sprij-Mooij, D.M., Aken, M.O. van, Lelij, A.J. van der, Herder, W.W. de, Lamberts, S.W.J. & Hofland, L.J. (2009). Coexpression of Dopamine and Somatostatin Receptor Subtypes in Corticotroph Adenomas. Journal of Clinical Endocrinology and Metabolism, 94(4), 1118-1124. Bruin, C. de, Meij, BP, Kooistra, HS, Hanson, JM, Lamberts, S.W.J. & Hofland, L.J. (2009). Cushing's Disease in Dogs and Humans. Hormone Research, 71, 140-143. Bruin, C. de, Feelders, R.A., Waaijers, A.M., Koetsveld, P.M. van, Sprij-Mooij, D.M., Lamberts, S.W.J. & Hofland, L.J. (2009). Differential regulation of human dopamine D-2 and somatostatin receptor subtype expression by glucocorticoids in vitro. Journal of Molecular Endocrinology, 42(1-2), 47-56. Bruin, C. de, Feelders, R.A., Lamberts, S.W.J. & Hofland, L.J. (2009). Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome. Reviews in Endocrine & Metabolic Disorders, 10(2), 91-102. Caraglia, M, Marra, M, Tagliaferri, P, Lamberts, S.W.J., Zappavigna, S, Misso, G, Cavagnini, F., Facchini, G, Abbruzzese, A, Hofland, L.J. & Vitale, G. (2009). Emerging Strategies to Strengthen the Anti-Tumour Activity of Type I Interferons: Overcoming Survival Pathways. Current Cancer Drug Targets, 9(5), 690-704. Casteren, N.J. van, Pieters, R., Dohle, G.R., Baalen, M. van, Neggers, S & Heuvel-Eibrink, M.M. van den (2009). Cranial irradiation does not result in pituitary-gonadal axis dysfunction in very long-term male survivors of childhood acute lymphoblastic leukemia. Leukemia, 23(12), 2310-2313. Dekker, M.J.H.J., Akker, E.L.T. van den, Koper, F.J.W., Manenschijn, L., Geleijns, K, Ruts, L., Rijs, W. van, Tio-Gillen, A.P., Doorn, P.A. van, Lamberts, S.W.J. & Jacobs, B.C. (2009). Effect of glucocorticoid receptor gene polymorphisms in Guillain- Barre syndrome. Journal of the Peripheral Nervous System, 14(2), 75-83.

Eriksson, B., Annibale, B, Bajetta, E, Mitry, E, Pavel, M, Platania, M, Salazar, R. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Chemotherapy in Patients with Neuroendocrine Tumors. Neuroendocrinology, 90(2), 214-219. Feelders, R.A., Hofland, L.J., Aken, M.O. van, Neggers, SJ, Lamberts, S.W.J., Herder, W.W. de & Lely, A.J. van der (2009). Medical Therapy of Acromegaly Efficacy and Safety of Somatostatin Analogues. Drugs, 69(16), 2207-2226. Ferone, D., Montella, L, Chiara, A De, Hofland, L.J., Lamberts, S.W.J. & Palmieri, G (2009). Somatostatin receptor expression in thymic tumors. Frontiers in Bioscience, 14, 3304-3309. Forrer, F., Krenning, E.P., Kooij, P.P., Bernard, H.F., Konijnenberg, M.W., Bakker, W.H., Teunissen, J.J.M., Jong, M. de, Lom, K. van, Herder, W.W. de & Kwekkeboom, D.J. (2009). Bone marrow dosimetry in peptide receptor radionuclide therapy with [Lu- 177-DOTA(0),Tyr(3)]octreotate. European Journal of Nuclear Medicine and Molecular Imaging, 36(7), 1138-1146. Froberg, A.C., Jong, M. de, Nock, B.A., Breeman, W.A.P., Erion, J.L., Maina, T, Verdijsseldonck, M.C.C., Herder, W.W. de, Lugt, A. van der, Kooij, P.P.M. & Krenning, E.P. (2009). Comparison of three radiolabelled peptide analogues for CCK-2 receptor scintigraphy in medullary thyroid carcinoma. European Journal of Nuclear Medicine and Molecular Imaging, 36(8), 1265-1272. Hoek, J. van der, Hoorn, E.J., Jong, GMT de, Janssens, ENW & Herder, W.W. de (2009). Severe Hyponatremia with High Urine Sodium and Osmolality. Clinical Chemistry, 55(11), 1905-1908. Hoek, M. van, Hofland, L.J., Rijke, Y.B. de, Nederveen, F.H. van, Krijger, R.R. de, Koetsveld, P.M. van, Lamberts, S.W.J., Lely, A.J. van der, Herder, W.W. de & Feelders, R.A. (2009). Effects of Somatostatin Analogs on a Growth Hormone-Releasing Hormone Secreting Bronchial Carcinoid, in Vivo and in Vitro Studies. Journal of Clinical Endocrinology and Metabolism, 94(2), 428-433. Horst-Schrivers, ANA van der, Ieperen, E van, Wymenga, ANM, Boezen, H.M., Weijmar-Schultz, WCM, Kema, I.P., Meijer, W.G., Herder, W.W. de, Willemse, P.H.B., Links, T.P. & Vries, E.G.E. de (2009). Sexual Function in Patients with Metastatic Midgut Carcinoid Tumours. Neuroendocrinology, 89(2), 231-236. Janssen, J.A.M.J.L. (2009). Advantages and disadvantages of GH/IGF-I combination treatment. Reviews in Endocrine & Metabolic Disorders, 10(2), 157-162. Kiewiet, R.M., Aken, M.O. van, Weerd, K. van der, Uitterlinden, P., Themmen, A.P.N., Hofland, L.J., Rijke, Y.B. de, Delhanty, P.J.D., Ghigo, E., Abribat, T. & Lely, A.J. van der (2009). Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes. European Journal of Endocrinology, 161(4), 567-573. Kloppel, G., Couvelard, A, Perren, A, Komminoth, P., McNicol, AM, Nilsson, O., Scarpa, A, Scoazec, JY, Wiedenmann, B., Papotti, M., Rindi, G. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Towards a Standardized Approach to the Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors and Their Prognostic Stratification (vol 90, pg 162, 2009). Neuroendocrinology, 90(4), 432-432. Kumsta, R., Moser, D, Streit, F, Koper, F.J.W., Meyer, J. & Wust, S (2009). Characterization of a Glucocorticoid Receptor Gene (GR, NR3C1) Promoter Polymorphism Reveals Functionality and Extends a Haplotype With Putative Clinical Relevance. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 150B(4), 476-482. Kwekkeboom, D.J., Krenning, E.P., Lebtahi, R, Komminoth, P., Kos-Kudla, B, Herder, W.W. de & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogs. Neuroendocrinology, 90(2), 220-226. Kwekkeboom, D.J., Krenning, E.P., Scheidhauer, K, Lewington, V, Lebtahi, R, Grossman, A., Vitek, P, Sundin, A & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Somatostatin Receptor Imaging with In-111-Pentetreotide. Neuroendocrinology, 90(2), 184-189. Lamberts, S.W.J. & Uitterlinden, A.G. (2009). Genetic Testing in Clinical Practice. Annual Review of Medicine, 60, 431-442. Lely, A.J. van der (2009). Ghrelin and New Metabolic Frontiers. Hormone Research, 71, 129-133. Manenschijn, L., Akker, E.L.T. van den, Lamberts, S.W.J. & Rossum, E.F.C. van (2009). Clinical Features Associated with Glucocorticoid Receptor Polymorphisms An Overview. Annals of the New York Academy of Sciences, 179-198. Melmed, S., Colao, A., Barkan, A, Molitch, M, Grossman, A.B., Kleinberg, D, Clemmons, D, Chanson, P., Laws, E, Schlechte, J, Vance, M.L., Ho, K & Giustina, A (2009). Guidelines for Acromegaly Management: An Update. Journal of Clinical Endocrinology and Metabolism, 94(5), 1509-1517. Messidoro, C., Elte, JWF, Cabezas, MC, Agteren, M. van, Lacroix, A. & Herder, W.W. de (2009). Food-dependent Cushing's syndrome. Netherlands Journal of Medicine, 67(5), 187-190. Mulder, RL, Kremer, LCM, Santen, HM van, Ket, JL, Trotsenburg, A.S.P. van, Koning, CCE, Meeteren, AYN Schouten-van, Caron, H.N., Neggers, S.J.C.M.M. & Dalen, EC van (2009). Prevalence and risk factors of radiation-induced growth hormone deficiency in childhood cancer survivors: A systematic review. Cancer Treatment Reviews, 35(7), 616-632. Muller, M., Beld, A.W. van den, Grobbee, D.E., Jong, F.H. de & Lamberts, S.W.J. (2009). Sex hormones and cognitive decline in elderly men. Psychoneuroendocrinology, 34(1), 27-31.

Nederveen, F.H. van, Gaal, J., Favier, J, Korpershoek, E., Oldenburg, R.A., Bruyn, E.M.C.A. de, Sleddens, H.F.B.M., Derkx, P., Riviere, J, Dannenberg, H., Petri, B.J., Komminoth, P., Pacak, K., Hop, W.C.J., Pollard, PJ, Mannelli, M, Bayley, JP, Perren, A, Niemann, S, Verhofstadt, AA, Bruine, AP de, Maher, ER, Tissier, F, Meatchi, T, Badoual, C, Bertherat, J, Amar, L, Alataki, D, Marck, E. van, Ferrau, F., Francois, J, Herder, W.W. de, Peeters, MPFMV, Linge, A. van, Lenders, J.W.M., Gimenez-Roqueplo, AP, Krijgert, RR de & Dinjens, W.N.M. (2009). An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncology, 10(8), 764-771. Neggers, S.J.C.M.M., Herder, W.W. de, Janssen, J.A.M.J.L., Feelders, R.A. & Lely, A.J. van der (2009). Combined treatment for acromegaly with long-acting somatostatin analogs and pegvisomant: long-term safety for up to 4.5 years (median 2.2 years) of follow-up in 86 patients. European Journal of Endocrinology, 160(4), 529-533. Neggers, S.J.C.M.M. & Lely, A.J. van der (2009). Somatostatin analog and pegvisomant combination therapy for acromegaly. Nature Reviews Endocrinology, 5(10), 546-552. Oberg, K, Ferone, D., Kaltsas, G., Knigge, UP, Taal, B & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biotherapy. Neuroendocrinology, 90(2), 209-213. O'Toole, D, Grossman, A., Gross, D, Fave, G. delle, Barkmanova, J, O'Connor, J, Pape, U.F. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers. Neuroendocrinology, 90(2), 194-202. Peeters, R.P., Hagendorf, A., Vanhorebeek, I, Visser, T.J., Klootwijk, W., Mesotten, D, Wouters, PJ, Koper, F.J.W., Jong, F.H. de, Feelders, R.A., Lamberts, S.W.J. & Berghe, G. van den (2009). Tissue mrna expression of the glucocorticoid receptor and its splice variants in fatal critical illness. Clinical Endocrinology, 71(1), 145-153. Petri, B.J., Eijck, C.H.J. van, Herder, W.W. de, Wagner, A. & Krijger, R.R. de (2009). Phaeochromocytomas and sympathetic paragangliomas. British Journal of Surgery, 96(12), 1381-1392. Pivonello, R., Martino, M.C. de, Cappabianca, P, Leo, M De, Faggiano, A, Lombardi, G., Hofland, L.J., Lamberts, S.W.J. & Colao, A. (2009). The Medical Treatment of Cushing's Disease: Effectiveness of Chronic Treatment with the Dopamine Agonist Cabergoline in Patients Unsuccessfully Treated by Surgery. Journal of Clinical Endocrinology and Metabolism, 94(1), 223-230. Plockinger, U, Wiedenmann, B. & Herder, W.W. de (2009). ENETS Consensus Guidelines for the Standard of Care in Neuroendocrine Tumors. Neuroendocrinology, 90(2), 159-161. Plockinger, U, Gustafsson, B, Ivan, D, Szpak, W & Davar, J (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Echocardiography. Neuroendocrinology, 90(2), 190-193. Siiskonen, S.J., Visser, L.E., Tiemeier, H.W., Hofman, A., Lamberts, S.W.J., Uitterlinden, A.G. & Stricker, B.H.C. (2009). BclI glucocorticoid receptor polymorphism and smoking in the general population. Addiction Biology, 14(3), 349-355. Spijker, AT, Rossum, E.F.C. van, Hoencamp, E, DeRijk, RH, Haffmans, J, Blom, M., Manenschijn, L., Koper, F.J.W., Lamberts, S.W.J. & Zitman, F.G. (2009). Functional polymorphism of the glucocorticoid receptor gene associates with mania and hypomania in bipolar disorder. Bipolar Disorders, 11(1), 95-101. Spijker, AT & Rossum, E.F.C. van (2009). Glucocorticoid Receptor Polymorphisms in Major Depression Focus on Glucocorticoid Sensitivity and Neurocognitive Functioning. Annals of the New York Academy of Sciences, 199-215. Stolk, L., Zhai, G., Meurs, J.B.J. van, Verbiest, M.M.P.J., Visser, J.A., Estrada, K, Rivadeneira, F., Williams, FM, Cherkas, L, Deloukas, P, Soranzo, N, Keyzer, J.J., Pop, VJM, Lips, P., Lebrun, C.E.I., Schouw, Y.T. van der, Grobbee, D.E., Witteman, J.C.M., Hofman, A., Pols, H.A.P., Laven, J.S.E., Spector, T.D. & Uitterlinden, A.G. (2009). Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nature Genetics, 41(6), 645-647. Sundin, A, Vullierme, M.P., Kaltsas, G. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological Examinations. Neuroendocrinology, 90(2), 167-183. Teunissen, J.J.M., Krenning, E.P., Jong, F.H. de, Rijke, Y.B. de, Feelders, R.A., Aken, M.O. van, Herder, W.W. de & Kwekkeboom, D.J. (2009). Effects of therapy with [Lu-177-DOTA(0),Tyr(3)]octreotate on endocrine function. European Journal of Nuclear Medicine and Molecular Imaging, 36(11), 1758-1766. Vila, G, Riedl, M, Resl, M, Lely, A.J. van der, Hofland, L.J., Clodi, M & Luger, A (2009). Systemic administration of oxytocin reduces basal and lipopolysaccharide-induced ghrelin levels in healthy men. Journal of Endocrinology, 203(1), 175-179. Vitale, G., Koetsveld, P.M. van, Herder, W.W. de, Wansem, K. van der, Janssen, J.A.M.J.L., Colao, A., Lombardi, G., Lamberts, S.W.J. & Hofland, L.J. (2009). Effects of type I interferons on IGF-mediated autocrine/paracrine growth of human neuroendocrine tumor cells. American Journal of Physiology, Endocrinology and Metabolism, 296(3), E559-E566. Vitale, G., Caraglia, M, Koetsveld, P.M. van, Maroni, P, Marra, M, Colao, A., Lamberts, S.W.J., Cavagnini, F. & Hofland, L.J. (2009). Potential role of type I interferons in the treatment of pituitary adenomas. Reviews in Endocrine & Metabolic Disorders, 10(2), 125-133. Voorhoeve, P.G., Akker, E.L.T. van den, Lamberts, S.W.J., Delemarre- van de Waal, H.A. & Hokken-Koelega, A.C.S. (2009). Glucocorticoid receptor gene polymorphism is less frequent in children born small for gestational age without catch-up growth. Hormone Research, 71, 162-166.

Voorhoeve, P.G., Akker, E.L.T. van den, Rossum, E.F.C. van, Koper, F.J.W., Mechelen, W. van, Lamberts, S.W.J. & Waal, HA Delemarre-Van D (2009). Glucocorticoid receptor gene variant is associated with increased body fatness in youngsters. Clinical Endocrinology, 71(4), 518-523. Winsen, LML van, Manenschijn, L., Rossum, E.F.C. van, Crusius, BA, Koper, F.J.W., Polman, C.H. & Uitdehaag, B.M.J. (2009). A Glucocorticoid Receptor Gene Haplotype (TthIII1/ER22/23EK/9 beta) Is Associated with a More Aggressive Disease Course in Multiple Sclerosis. Journal of Clinical Endocrinology and Metabolism, 94(6), 2110-2114. Part of book - abstract Janssen, J.A.M.J.L. (2009). Combination of GH and IGF=I makes the difference! In DR Clemmons & AF Attanasio (Eds.), Hypothalamic-pituitary disease and obesity (pp. 161-175). Bristol: Bioscientifica. Neggers, S.J.C.M.M., Lamberts, S.W.J. & Lely, A.J. van der (2009). Long-term treatment. In JAH Wass (Ed.), Acromegaly. a handbook of history, current therapy and future prospects (pp. 181-188). Bristol: Bioscientifica.

EMC MM-01-39-02 - Regulation of calcium and bone metabolism Programme design in brief Research focus is skeletal and calcium homeostasis and development and progression of related disorders with particular emphasis on ageing. Increasing life span is accompanied by an increase in age-related diseases such as osteoporosis. Osteoporosis is an important common disease with a large impact on quality of life as well as health care budget. Development of pharmaceutical and life style interventions as prevention or as treatment is important and requires an optimal knowledge in aetiology and mechanisms of development of osteoporosis. Current therapies for osteoporosis are directed to inhibit bone loss and thereby its progression. There is, however, a major need for anabolic therapies, which stimulate bone formation because bone loss has already occurred when the consequences of osteoporosis have become overt. Directly coupled to this is improvement in early diagnostics. The overall aim of this research line is to develop better diagnostics and therapies for skeletal disorders and disturbances in calcium homeostasis by a combination of molecular, cellular, animal, epidemiological and eventually clinical studies. Four integrated lines of research can be identified. 1) Characterisation of molecular mechanisms of bone cell differentiation and of bone formation and degradation using human bone cell models by bioinformatic and systems biological analyses of gene, protein and enzyme activity profiles. 2) Identification of risk determinants for osteoporosis and osteoarthritis on basis of genetic epidemiological and serum proteomic studies within a.o. the Rotterdam Study. 3) Calcium homeostasis and skeletal metabolism in relation to ageing by analyses of experimental animal models, e.g. premature ageing mice, as well as human population research. 4) Development of medium/high throughput screenings procedures to quickly screen therapeutic targets and to evaluate novel therapeutic compounds. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 6,23 7,53 0 1,8 15,56 Total 6,23 7,53 0 1,8 15,56 4 0 0 4 35 1 2 42 Thesis Baars, G.J.A. (2009, oktober 30). Factors related to student achievement in medical school. EUR. Prom./coprom.: T.A.W. Splinter & Prof.Dr. T. Stijnen. Sniekers, Y.H. (2009, september 24). Estrogen effects on cartilage and bone changes in models for osteoarthritis. EUR (125 pag.). Prom./coprom.: Prof.Dr.Ir. H.H. Weinans, Prof.dr. J.P.T.M. van Leeuwen & Dr. G.J.V.M. van Osch. Stolk, L. (2009, december 01). Genetics of estrogen-related traits; from candidate genes to GWAS. EUR (187 pag.). Prom./coprom.: Prof.dr. A.G. Uitterlinden. Zillikens, M.C. (2009, oktober 07). The interplay of genes and diet in metabolic diseases and aging. EUR (216 pag.). Prom./coprom.: Prof.dr. A.G. Uitterlinden, Prof.Dr. B.A. Oostra & Prof.Dr.Ir. C.M. van Duijn. Article/Letter to the editor Alexander, RT, Woudenberg-Vrenken, TE, Buurman, J, Dijkman, H., Eerden, B.C.J. van der, Leeuwen, J.P.T.M. van, Bindels, RJ & Hoenderop, JG (2009). Klotho Prevents Renal Calcium Loss. Journal of the American Society of Nephrology, 20(11), 2371-2379. Allikmets, R., Dean, M, Hageman, G.S., Baird, PN, Klaver, C.C., Bergen, AA & Weber, B.H. (2009). The SERPING1 gene and age-related macular degeneration. Lancet (UK), 374(9693), 875-876. Aulchenko, Y.S., Ripatti, S, Lindqvist, I, Boomsma, D, Heid, IM, Pramstaller, P.P., Penninx, BWJH, Janssens, A.C.J.W., Wilson, JF, Spector, T., Martin, NG, Pedersen, NL, Kyvik, KO, Kaprio, J, Hofman, A., Freimer, N.B., Jarvelin, MR, Gyllensten, U, Campbell, H, Rudan, I, Johansson, A, Marroni, F, Hayward, C, Vitart, V, Jonasson, I, Pattaro, C, Wright, A, Hastie, N, Pichler, I, Hicks, AA, Falchi, M, Willemsen, G, Hottenga, J.J., Geus, E.J.C. de, Montgomery, GW, Whitfield, J, Magnusson, P, Saharinen, J, Perola, M, Silander, K, Isaacs, A.J., Sijbrands, E.J.G., Uitterlinden, A.G., Witteman, J.C.M., Oostra, B.A., Elliott, P, Ruokonen, A, Sabatti, C, Gieger, C, Meitinger, T, Kronenberg, F, Doring, A, Wichmann, HE, Smit, J.H., McCarthy, MI, Duijn, C.M. van & Peltonen, L. (2009). Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nature Genetics, 41(1), 47-55. Becker, M.L., Visser, L.E., Newton-Cheh, C, Hofman, A., Uitterlinden, A.G., Witteman, J.C.M. & Stricker, B.H.C. (2009). A common NOS1AP genetic polymorphism is associated with increased cardiovascular mortality in users of dihydropyridine calcium channel blockers. British Journal of Clinical Pharmacology, 67(1), 61-67. 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EMC MM-01-39-03 - Regulation of the bioactivity of thyroid hormone Programme design in brief The prohormone T4 is converted by outer ring deiodination to the active hormone T3 and by inner ring deiodination to the inactive metabolite rt3. The three deiodinases (D1-3) involved are expressed in different tissues, where they play different roles in systemic and local control of T3 levels. The deiodinases are located in cell membranes with their active site exposed to the cytoplasm, while the T3 receptors (TRs) reside in the nucleus. Uptake of thyroid hormone across the plasma membrane is thus required for thyroid hormone action and metabolism, and is mediated by specific transporters. Recently, our group identified an important T3 transporter (MCT8) which was shown to be mutated in patients with severe psychomotor retardation and grossly elevated serum T3 levels. This project concerns the characterization of the deiodinases and transporters in human tissues as well as their importance in the regulation of the bioactivity of thyroid hormone in health and disease. In addition, the specific role of the alpha-type TR (TRa) in the tissue-specific action of thyroid hormone, particularly in the brain, is investigated. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 0,5 4,27 0 0 4,77 nuclear medicine 0,2 0 0 0 0,2 Total 0,7 4,27 0 0 4,97 1 0 0 1 17 0 0 18 Thesis Deure, W.M. van der (2009, januari 14). Inter-individual differences in thyroid hormone bioactivity: the effect of genetic variation. EUR. Prom./coprom.: Prof.Dr.Ir. T.J. Visser. Article/Letter to the editor Cooper-Kazaz, R, Deure, W.M. van der, Medici, M., Visser, T.J., Alkelai, A, Glaser, B., Peeters, R.P. & Lerer, B (2009). Preliminary evidence that a functional polymorphism in type 1 deiodinase is associated with enhanced potentiation of the antidepressant effect of sertraline by triiodothyronine. Journal of Affective Disorders, 116(1-2), 113-116. Deure, W.M. van der, Peeters, R.P., Uitterlinden, A.G., Hofman, A., Breteler, M.M.B., Witteman, J.C.M. & Visser, T.J. (2009). Impact of thyroid function and polymorphisms in the type 2 deiodinase on blood pressure: the Rotterdam Study and the Rotterdam Scan Study. Clinical Endocrinology, 71(1), 137-144. Deure, W.M. van der, Hansen, PS, Peeters, R.P., Uitterlinden, A.G., Fenger, M, Kyvik, KO, Hegedus, L & Visser, T.J. (2009). The effect of genetic variation in the type 1 deiodinase gene on the interindividual variation in serum thyroid hormone levels: an investigation in healthy Danish twins. Clinical Endocrinology, 70(6), 954-960. Heemstra, KA, Hoftijzer, HC, Deure, W.M. van der, Peeters, R.P., Fliers, E., Appelhof, BC, Wiersinga, W.M., Corssmit, EPM, Visser, T.J. & Smit, J.W.A. (2009). Thr92Ala polymorphism in the type 2 deiodinase is not associated with T4 dose in athyroid patients or patients with Hashimoto thyroiditis. Clinical Endocrinology, 71(2), 279-283. Heemstra, KA, Soeters, MR, Fliers, E., Serlie, MJ, Burggraaf, J., Doorn, MB van, Klaauw, AA van der, Romijn, J.A., Smit, J.W., Corssmit, EP & Visser, T.J. (2009). Type 2 Iodothyronine Deiodinase in Skeletal Muscle: Effects of Hypothyroidism and Fasting. Journal of Clinical Endocrinology and Metabolism, 94(6), 2144-2150. Hes, FJ, Madan, K., Rombout-Liem, IS, Szuhai, K, Sorensen, H, Amstel, H.K.P. van, Bakker, EM, Visser, T.J., Smit, J.W. & Hansson, K. (2009). Multiple Genomic Aberrations in a Patient With Mental Retardation and Hypogonadism: 45,X/46,X,psu dic(y) Karyotype, Thyroid Hormone Receptor Beta (THRB) Mutation and Heterozygosity for Wilson Disease. American Journal of Medical Genetics Part A, 149A(10), 2231-2235. Heuer, H. & Visser, T.J. (2009). Minireview: Pathophysiological Importance of Thyroid Hormone Transporters. Endocrinology, 150(3), 1078-1083. Kester, M.H.A., Toussaint, MJM, Punt, CA, Matondo, R, Aarnio, A.M., Darras, V.M., Everts, M.E., Bruin, A. & Visser, T.J. (2009). Large Induction of Type III Deiodinase Expression After Partial Hepatectomy in the Regenerating Mouse and Rat Liver. Endocrinology, 150(1), 540-545. Mebis, L., Debaveye, Y, Ellger, B, Derde, S, Ververs, EJ, Langouche, L, Darras, V.M., Fliers, E., Visser, T.J. & Berghe, G. van den (2009). Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness. Critical Care, 13(5). Mebis, L., Paletta, D, Debaveye, Y, Ellger, B, Langouche, L, D'Hoore, A, Darras, V.M., Visser, T.J. & Berghe, G. van den (2009). Expression of thyroid hormone transporters during critical illness. European Journal of Endocrinology, 161(2), 243-250. Peeters, R.P., Hagendorf, A., Vanhorebeek, I, Visser, T.J., Klootwijk, W., Mesotten, D, Wouters, PJ, Koper, F.J.W., Jong, F.H. de, Feelders, R.A., Lamberts, S.W.J. & Berghe, G. van den (2009). Tissue mrna expression of the glucocorticoid receptor and its splice variants in fatal critical illness. Clinical Endocrinology, 71(1), 145-153. Ven, LTM van der, Kuil, T van de, Leonards, PEG, Slob, W, Lilienthal, H, Litens, S, Herlin, M, Hakansson, H, Canton, RF, Berg, M. van den, Visser, T.J., Loveren, H. van, Vos, J.G. & Piersma, AH (2009). Endocrine effects of hexabromocyclododecane (HBCD) in a one-generation reproduction study in Wistar rats. Toxicology Letters, 185(1), 51-62. Visser, W.E., Philp, NJ, Dijk, T.B. van, Klootwijk, W., Friesema, E.C.H., Jansen, J., Beesley, PW, Ianculescu, AG & Visser, T.J. (2009). Evidence for a Homodimeric Structure of Human Monocarboxylate Transporter 8. Endocrinology, 150(11), 5163-5170.

Visser, W.E., Jansen, J., Friesema, E.C.H., Kester, M.H.A., Mancilla, E, Lundgren, J, Knaap, M.S. van der, Lunsing, RJ, Brouwar, OF & Visser, T.J. (2009). Novel Pathogenic Mechanism Suggested by Ex Vivo Analysis of MCT8 (SLC16A2) Mutations. Human Mutation, 30(1), 29-38. Visser, W.E., Heemstra, KA, Swagemakers, S.M.A., Ozgur, Z., Corssmit, EP, Burggraaf, J., Ijcken, W.F.J. van, Spek, P.J. van der, Smit, J.W.A. & Visser, T.J. (2009). Physiological Thyroid Hormone Levels Regulate Numerous Skeletal Muscle Transcripts. Journal of Clinical Endocrinology and Metabolism, 94(9), 3487-3496. Visser, W.E., Friesema, E.C.H. & Visser, T.J. (2009). Transport of Thyroxine and 3,3 ',5-Triiodothyronine in Human Umbilical Vein Endothelial Cells. Endocrinology, 150(3), 1552-1557. Vujovic, M, Nordstrom, K, Gauthier, K, Flamant, F, Visser, T.J., Vennstrom, B & Mittag, J. (2009). Interference of a Mutant Thyroid Hormone Receptor alpha 1 with Hepatic Glucose Metabolism. Endocrinology, 150(6), 2940-2947.

EMC MM-01-39-04 - Signalling in reproduction and ageing Programme design in brief Glycoprotein hormones and members of the TGF /activin family of growth and differentiation factors play a central role in development and functioning of the organism throughout life. This program focuses on the effect of variations in signal transduction of hormones (including LH, hcg, FSH, ghrelin and unacylated ghrelin) and TGF- family members (including anti- Müllerian hormone, BMPs, inhibins and activins) during foetal and postnatal development and subsequent functioning and ageing of the organism. Furthermore, effects of mutations or single nucleotide polymorphisms in enzymes involved in biosynthesis or catabolism of steroid hormones are investigated. Variations in signaling through these pathways affect the early make-up of physiological response systems that can have effects during adult life and in the ageing process. Variations in signal transduction of ligand-receptor interaction, gene expression, proliferation and apoptosis are studied; not only at the molecular and cellular level, but also at the level of the whole body in animal models of ageing, in patients and in populations of ageing men and women. Specific areas are: 1.The role of TGF- family members in female ageing, oestrogen effects and age at menopause 2.The role of LH and LH receptor variations in female ageing 3.The influence of gene variants in female and male physiology 4.Development of animal models for the study of the role of genetic variations in the pathophysiology of ageing. 5.Causes and effects of changes in steroid biosynthetic pathways. 6.Evaluation of the (metabolic) role of natural and synthetic growth hormone secretatogues in peripheral tissues in vitro and in vivo Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 2,14 0 0 0,85 2,99 Total 2,14 0 0 0,85 2,99 0 0 0 0 29 1 3 33 Article/Letter to the editor Akker, E.L.T. van den, Koper, J.W., Joosten, K.F.M., Jong, F.H. de, Hazelzet, J.A., Lamberts, S.W.J. & Hokken-Koelega, A.C.S. (2009). Glucocorticoid receptor mrna levels are selectively decreased in neutrophils of children with sepsis. Intensive Care Medicine, 35, 1247-1254. Alwani, R.A., Neggers, S.J.C.M.M., Klift, M. van der, Baggen, M.G.A., Leenders, G.J.L.H. van, Aken, M.O. van, Lely, A.J. van der, Herder, W.W. de & Feelders, R.A. (2009). Cushing's syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma. Pituitary, 12(3), 280-283. Bannink, E.M.N., Sassen, C van, Buuren, S. van, Jong, F.H. de, Lequin, M.H., Mulder, P.G.H. & Muinck Keizer-Schrama, S.M.P.F. (2009). Puberty induction in Turner syndrome: results of oestrogen treatment on development of secondary sexual characteristics, uterine dimensions and serum hormone levels. Clinical Endocrinology, 70(2), 265-273. Elfferich, P., Juniarto, A.Z., Dubbink, H.J., Royen, M.E. van, Molier, M., Hoogerbrugge, J.W., Houtsmuller, A.B., Trapman, J., Santosa, A, Jong, F.H. de, Drop, S.L.S., Faradz, SMH, Bruggenwirth, H & Brinkmann, A.O. (2009). Functional Analysis of Novel Androgen Receptor Mutations in a Unique Cohort of Indonesian Patients with a Disorder of Sex Development. Sexual Development, 3(5), 237-244. Feelders, R.A., Hofland, L.J., Aken, M.O. van, Neggers, SJ, Lamberts, S.W.J., Herder, W.W. de & Lely, A.J. van der (2009). Medical Therapy of Acromegaly Efficacy and Safety of Somatostatin Analogues. Drugs, 69(16), 2207-2226. Goossens, K., Juniarto, A.Z., Timmerman, M.A., Faradz, SMH, Wolffenbuttel, K.P., Drop, S.L.S. & Jong, F.H. de (2009). Lack of correlation between phenotype and genotype in untreated 21-hydroxylase-deficient Indonesian patients. Clinical Endocrinology, 71, 628-635. Hoek, M. van, Hofland, L.J., Rijke, Y.B. de, Nederveen, F.H. van, Krijger, R.R. de, Koetsveld, P.M. van, Lamberts, S.W.J., Lely, A.J. van der, Herder, W.W. de & Feelders, R.A. (2009). Effects of Somatostatin Analogs on a Growth Hormone-Releasing Hormone Secreting Bronchial Carcinoid, in Vivo and in Vitro Studies. Journal of Clinical Endocrinology and Metabolism, 94(2), 428-433. Kaay, D.C.M. van der, Jong, F.H. de, Rose, S.R., Odink, R.J.H., Bakker-van Waarde, W.M., Sulkers, E.J. & Hokken-Koelega, A.C.S. (2009). Overnight levels of luteinizing hormone, collicle-stimulating hormone and growth hormone before and during gonadotropin-releasing hormone analogue treatment in short boys born small for gestational age. Hormone Research, 71, 260-267. Kaay, D.C.M. van der, Jong, F.H. de, Laven, J.S.E. & Hokken-Koelega, A.C.S. (2009). Overnight Luteinizing and Follicle Stimulating Hormone Profiles During GnRHa Treatment in Short Girls Born Small for Gestational Age. Journal of Pediatric Endocrinology & Metabolism, 22(2), 161-169. Kerkhof, G.F., Leunissen, R.W.J., Willemsen, R.H., Jong, F.H. de, Stijnen, T. & Hokken-Koelega, A.C.S. (2009). Influence of preterm birth and birth size on gonadal function in young men. Journal of Clinical Endocrinology and Metabolism, 94(11), 4243-4250. Kevenaar, M.E., Themmen, A.P.N., Kerkwijk, A.J. van, Valkenburg, O., Uitterlinden, A.G., Jong, F.H. de, Laven, J.S.E. & Visser, J.A. (2009). Variants in the ACVR1 gene are associated with AMH levels in women with polycystic ovary syndrome. Human Reproduction, 24(1), 241-249.

Kiewiet, R.M., Aken, M.O. van, Weerd, K. van der, Uitterlinden, P., Themmen, A.P.N., Hofland, L.J., Rijke, Y.B. de, Delhanty, P.J.D., Ghigo, E., Abribat, T. & Lely, A.J. van der (2009). Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes. European Journal of Endocrinology, 161(4), 567-573. Knauff, E.A.H., Eijkemans, M.J.C., Lambalk, C.B., Kate-Booij, M.J. ten, Hoek, A., Beerendonk, CCM, Laven, J.S.E., Goverde, A.J., Broekmans, F.J.M., Themmen, A.P.N., Jong, F.H. de & Fauser, B.C.J.M. (2009). Anti-Mullerian Hormone, Inhibin B, and Antral Follicle Count in Young Women with Ovarian Failure. Journal of Clinical Endocrinology and Metabolism, 94(3), 786-792. Kuijper, T.M., Ritstier, K., Verhoef-Post, M., Piersma, D., Bruysters, M.W.P., Berns, P.M.J.J. & Themmen, A.P.N. (2009). LH receptor gene expression is essentially absent in breast tumor tissue: Implications for treatment. Molecular and Cellular Endocrinology, 302(1), 58-64. Lely, A.J. van der (2009). Ghrelin and New Metabolic Frontiers. Hormone Research, 71, 129-133. Lie Fong, S., Laven, J.S.E., Hakvoort-Cammel, F.G.A.J., Schipper, I., Visser, J.A., Themmen, A.P.N., Jong, F.H. de & Heuvel- Eibrink, M.M. van den (2009). Assessment of ovarian reserve in adult childhood cancer survivors using anti-mullerian hormone. Human Reproduction, 24(4), 982-990. Lind van Wijngaarden, R.F.A. de, Joosten, K.F.M., Berg, S. van den, Otten, B.J., Jong, F.H. de, Sweep, C.G.J., Weerd, A.W. de & Hokken-Koelega, A.C.S. (2009). The relationship between central adrenal insufficiency and sleep-related breathing disorders in children with Prader-Willi Syndrome. Journal of Clinical Endocrinology and Metabolism, 94(7), 2387-2393. Muller, M., Beld, A.W. van den, Grobbee, D.E., Jong, F.H. de & Lamberts, S.W.J. (2009). Sex hormones and cognitive decline in elderly men. Psychoneuroendocrinology, 34(1), 27-31. Neggers, S.J.C.M.M., Herder, W.W. de, Janssen, J.A.M.J.L., Feelders, R.A. & Lely, A.J. van der (2009). Combined treatment for acromegaly with long-acting somatostatin analogs and pegvisomant: long-term safety for up to 4.5 years (median 2.2 years) of follow-up in 86 patients. European Journal of Endocrinology, 160(4), 529-533. Neggers, S.J.C.M.M. & Lely, A.J. van der (2009). Somatostatin analog and pegvisomant combination therapy for acromegaly. Nature Reviews Endocrinology, 5(10), 546-552. Peeters, R.P., Hagendorf, A., Vanhorebeek, I, Visser, T.J., Klootwijk, W., Mesotten, D, Wouters, PJ, Koper, F.J.W., Jong, F.H. de, Feelders, R.A., Lamberts, S.W.J. & Berghe, G. van den (2009). Tissue mrna expression of the glucocorticoid receptor and its splice variants in fatal critical illness. Clinical Endocrinology, 71(1), 145-153. Perry, JRB, Stolk, L., Franceschini, N, Lunetta, KL, Zhai, GJ, McArdle, PF, Smith, AV, Aspelund, T, Bandinelli, S, Boerwinkle, E., Cherkas, L, Eiriksdottir, G, Estrada, K, Ferrucci, L, Folsom, A.R., Garcia, M, Gudnason, V, Hofman, A., karasik, D., Kiel, DP, Launer, L.J., Meurs, J.B.J. van, Nalls, MA, Rivadeneira Ramirez, F., Shuldiner, AR, Singleton, A., Soranzo, N, Tanaka, T, Visser, J.A., Weedon, MN, Wilson, S.G., Zhuang, V, Streeten, EA, Harris, T.B., Murray, A, Spector, T.D., Demerath, EW, Uitterlinden, A.G. & Murabito, JM (2009). Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nature Genetics, 41(6), 648-650. Pierik, F.H., Deddens, J.A., Muinck Keizer-Schrama, S.M.P.F., Jong, F.H. de, Weber, R.F.A. & Burdorf, A. (2009). Response: the hypothalamus-pituitary-testis axis in cryptorchid boys. International Journal of Andrology, 32, 90. Pierik, F.H., Deddens, J.A., Burdorf, A., Muinck Keizer-Schrama, S.M.P.F., Jong, F.H. de & Weber, R.F.A. (2009). The hypothalamus-pituitary-testis axis in boys during the first six months of life: a comparison of cryptorchidism and hypospadias cases with controls. International Journal of Andrology, 32(5), 453-461. Ronde, W. de, Kulve, J ten, Woerdeman, J, Kaufman, J.M. & Jong, F.H. de (2009). Effects of oestradiol on gonadotrophin levels in normal and castrated men. Clinical Endocrinology, 71(6), 874-879. Stolk, L., Zhai, G., Meurs, J.B.J. van, Verbiest, M.M.P.J., Visser, J.A., Estrada, K, Rivadeneira, F., Williams, FM, Cherkas, L, Deloukas, P, Soranzo, N, Keyzer, J.J., Pop, VJM, Lips, P., Lebrun, C.E.I., Schouw, Y.T. van der, Grobbee, D.E., Witteman, J.C.M., Hofman, A., Pols, H.A.P., Laven, J.S.E., Spector, T.D. & Uitterlinden, A.G. (2009). Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nature Genetics, 41(6), 645-647. Teunissen, J.J.M., Krenning, E.P., Jong, F.H. de, Rijke, Y.B. de, Feelders, R.A., Aken, M.O. van, Herder, W.W. de & Kwekkeboom, D.J. (2009). Effects of therapy with [Lu-177-DOTA(0),Tyr(3)]octreotate on endocrine function. European Journal of Nuclear Medicine and Molecular Imaging, 36(11), 1758-1766. Urlings-Strop, LC, Stijnen, T., Themmen, A.P.N. & Splinter, T.A.W. (2009). Selection of medical students: a controlled experiment. Medical Education, 43(2), 175-183. Valkenburg, O., Uitterlinden, A.G., Piersma, D., Hofman, A., Themmen, A.P.N., Jong, F.H. de, Fauser, B.C.J.M. & Laven, J.S.E. (2009). Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome. Human Reproduction, 24(8), 2014-2022. Vila, G, Riedl, M, Resl, M, Lely, A.J. van der, Hofland, L.J., Clodi, M & Luger, A (2009). Systemic administration of oxytocin reduces basal and lipopolysaccharide-induced ghrelin levels in healthy men. Journal of Endocrinology, 203(1), 175-179. Part of book - abstract Jong, F.H. de & Ronde, W. de (2009). Productie en afbraak van geslachtshormonen. In R Abs, MA Bex, RA Feelders, AJ van der lely, FRE Nobels & APN Themmen (Eds.), Erasmus Endocrinologie Cursus 2009 (pp. 35-38). Rotterdam: ErasmusMC.

Themmen, A.P.N. & Leeuwen, J.P.T.M. van (2009). Stamcellen komen klinisch steeds dichterbij. In R Abs, MA bex, RA Feelders, AJ van der Lely, F Nobels & APN Themmen (Eds.), Erasmus Endocrinologie Cursus. Rotterdam: ErasmusMC. Other output Jong, F.H. de (2009). De prognostische (on)mogelijkheden van SNP-gegevens. Tros Radar optreden: (2009, maart 02).

EMC MM-01-40-01 - Localisation, detection and radionuclide therapy of various diseases Programme design in brief Detection of disease: (Pre)clinical development and use of radiolabeled pharmaceuticals (e.g. peptides, anti-sense molecules, 18F-deoxy-glucose (FGD)) to localize and detect various diseases (e.g. tumour and heart imaging). Comparison of results with those of conventional imaging modalities (e.g. MRI, CT, US) and cost-benefit analyses. Investigation of predictive value of scintigraphy for success of various treatment modalities, e.g. unlabelled peptides versus cytostatic drugs. New radiolabelled peptide-analogues, such as of Bombesine, CCK, Substance P, neurotensin and adhesion molecules have been introduced for lesion visualization. As tumour cells have receptors on their surface for different peptides, many receptorpositive tumours may then be localized, possibly followed by therapy with unlabelled compound or by radionuclide therapy. Treatment of disease: As a new modality of cancer treatment, we introduced radionuclide therapy of somatostatin receptor-positive lesions by repeated administration of chelated somatostatin analogues (octreotide, [Tyr3]octreotide, [Tyr3]octreotate) radiolabelled with high doses of therapeutic radionuclides, like the auger electron emitter 111In, the high energy beta particle emitter 90Y and the low energy beta particle emitter 177Lu. Different phase1 studies have been started on radionuclide therapy of human tumours using these radiolabelled peptide analogues. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot nuclear medicine 2,75 0 0 1,35 4,1 surgery 0,1 0 0 0 0,1 Total 2,85 0 0 1,35 4,2 0 0 0 0 21 1 0 22 Article/Letter to the editor Akerstrom, G, Falconi, M, Kianmanesh, R., Ruszniewski, P. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pre- and Perioperative Therapy in Patients with Neuroendocrine Tumors. Neuroendocrinology, 90(2), 203-208. Arnold, R., Chen, YJ, Costa, F, Falconi, M, Gross, D, Grossman, A.B., Hyrdel, R., Kos-Kudla, B, Salazar, R. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Follow-Up and Documentation. Neuroendocrinology, 90(2), 227-233. Beek, R.D. van, Heuvel-Eibrink, M.M. van den, Cammel, F.G.A.J., Bos, C. van den, Pal, HJH van der, Krenning, E.P., Rijke, Y.B. de, Pieters, R. & Muinck Keizer-Schrama, S.M.P.F. (2009). Bone mineral density, growth, and thyroid function in long-term survivors of pediatric Hodgkin's Lymphoma treated with chemotherapy only. Journal of Clinical Endocrinology and Metabolism, 94(6), 1904-1909. Boot, A.M., Sluis, I.M. van der, Krenning, E.P. & Muinck Keizer-Schrama, S.M.P.F. (2009). Bone Mineral Density and Body Composition in Adolescents with Childhood-Onset Growth Hormone Deficiency. Hormone Research, 71(6), 364-371. Eriksson, B., Annibale, B, Bajetta, E, Mitry, E, Pavel, M, Platania, M, Salazar, R. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Chemotherapy in Patients with Neuroendocrine Tumors. Neuroendocrinology, 90(2), 214-219. Essen, M. van, Krenning, E.P., Kam, B.L.R., Jong, M. de, Valkema, R. & Kwekkeboom, D.J. (2009). Peptide-receptor radionuclide therapy for endocrine tumors. NATURE REVIEWS ENDOCRINOLOGY, 5(7), 382-393. Forrer, F., Krenning, E.P., Kooij, P.P., Bernard, H.F., Konijnenberg, M.W., Bakker, W.H., Teunissen, J.J.M., Jong, M. de, Lom, K. van, Herder, W.W. de & Kwekkeboom, D.J. (2009). Bone marrow dosimetry in peptide receptor radionuclide therapy with [Lu- 177-DOTA(0),Tyr(3)]octreotate. European Journal of Nuclear Medicine and Molecular Imaging, 36(7), 1138-1146. Froberg, A.C., Jong, M. de, Nock, B.A., Breeman, W.A.P., Erion, J.L., Maina, T, Verdijsseldonck, M.C.C., Herder, W.W. de, Lugt, A. van der, Kooij, P.P.M. & Krenning, E.P. (2009). Comparison of three radiolabelled peptide analogues for CCK-2 receptor scintigraphy in medullary thyroid carcinoma. European Journal of Nuclear Medicine and Molecular Imaging, 36(8), 1265-1272. Jong, M. de, Breeman, W.A.P., Kwekkeboom, D.J., Valkema, R. & Krenning, E.P. (2009). Tumor Imaging and Therapy Using Radiolabeled Somatostatin Analogues. Accounts of Chemical Research, 42(7), 873-880. Kloppel, G., Couvelard, A, Perren, A, Komminoth, P., McNicol, AM, Nilsson, O., Scarpa, A, Scoazec, JY, Wiedenmann, B., Papotti, M., Rindi, G. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Towards a Standardized Approach to the Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors and Their Prognostic Stratification (vol 90, pg 162, 2009). Neuroendocrinology, 90(4), 432-432. Kwekkeboom, D.J., Krenning, E.P., Lebtahi, R, Komminoth, P., Kos-Kudla, B, Herder, W.W. de & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogs. Neuroendocrinology, 90(2), 220-226. Kwekkeboom, D.J., Krenning, E.P., Scheidhauer, K, Lewington, V, Lebtahi, R, Grossman, A., Vitek, P, Sundin, A & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Somatostatin Receptor Imaging with In-111-Pentetreotide. Neuroendocrinology, 90(2), 184-189.

Lhommel, R., Goffette, P., Eynde, M. van den, Jamar, F., Pauwels, S., Bilbao, J.I. & Walrand, S.H.M. (2009). Yttrium-90 TOF PET scan demonstrates high-resolution biodistribution after liver SIRT. European Journal of Nuclear Medicine and Molecular Imaging, 36, 1696-1696. Melis, M.L., Bijster, M., Visser, M., Konijnenberg, M.W., Swart, J. de, Rolleman, E.J., Boerman, O.C., Krenning, E.P. & Jong, M. de (2009). Dose-response effect of Gelofusine on renal uptake and retention of radiolabelled octreotate in rats with CA20948 tumours. European Journal of Nuclear Medicine and Molecular Imaging, 36(12), 1968-1976. Muller, C.M., Mindt, TL, Jong, M. de & Schibli, R (2009). Evaluation of a novel radiofolate in tumour-bearing mice: promising prospects for folate-based radionuclide therapy. European Journal of Nuclear Medicine and Molecular Imaging, 36(6), 938-946. Oberg, K, Ferone, D., Kaltsas, G., Knigge, UP, Taal, B & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biotherapy. Neuroendocrinology, 90(2), 209-213. O'Toole, D, Grossman, A., Gross, D, Fave, G. delle, Barkmanova, J, O'Connor, J, Pape, U.F. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers. Neuroendocrinology, 90(2), 194-202. Plockinger, U, Gustafsson, B, Ivan, D, Szpak, W & Davar, J (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Echocardiography. Neuroendocrinology, 90(2), 190-193. Schroeder, R.P.J., Weerden, W.M. van, Bangma, C., Krenning, E.P. & Jong, M. de (2009). Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues. Methods-A Companion to Methods in Enzymology, 48(2), 200-204. Sundin, A, Vullierme, M.P., Kaltsas, G. & Plockinger, U (2009). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological Examinations. Neuroendocrinology, 90(2), 167-183. Teunissen, J.J.M., Krenning, E.P., Jong, F.H. de, Rijke, Y.B. de, Feelders, R.A., Aken, M.O. van, Herder, W.W. de & Kwekkeboom, D.J. (2009). Effects of therapy with [Lu-177-DOTA(0),Tyr(3)]octreotate on endocrine function. European Journal of Nuclear Medicine and Molecular Imaging, 36(11), 1758-1766. Yim, CB, Boerman, O.C., Visser, M., Jong, M. de, Dechesne, AC, Rijkers, DTS & Liskamp, RMJ (2009). Versatile Conjugation of Octreotide to Dendrimers by Cycloaddition ("Click") Chemistry to Yield High-Affinity Multivalent Cyclic Peptide Dendrimers. Bioconjugate Chemistry, 20(7), 1323-1331.

EMC MM-01-52-07 - Regulation of follicle development, oocyte and endometrial embryo quality Programme design in brief General objectives: The ability of a primordial follicle to undergo folliculogenesis constitutes the very foundation of the expression of the menstrual cycle. During its growth important changes occur within the oöcyte, as well as in its granulose- and theca-cells. These changes include proliferation, differentiation and as well as growth and apoptosis. Hormones (steroid as well proteins) and growth factors control the early (gonadotropin-independent) and late (gonadotropin-dependent) follicle development. Regulation of follicle recruitment and dominant follicle selection as well as ovarian dysfunction is studied in the human model both in-vivo and in-vitro using morphometric, molecular and genetic techniques. Clinical studies involve a) Genetic (genotype - phenotype association) and environmental determinants of anovulatory infertility, especially polycystic ovary syndrome (PCOS) and premature ovarian failure (POF). b) Development of new ovulation induction strategies and optimization of fertility treatment and outcome in patients with ovarian dysfunction. c) Prevention of long-term health implications of reproductive, metabolic and cardiovascular components of ovarian dysfunction especially PCOS and POF. d) Gamete and embryo quality using genetic (preimplantation genetic aneuploidy screening) and molecular techniques in subfertile patients as well as in patients with anovulatory dysfunction Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot gynaecology/obstetrics 3,07 0 0 1,53 4,6 urology 1,8 0 0 0 1,8 Total 4,87 0 0 1,53 6,4 1 0 0 1 26 0 3 30 Thesis Gaast, M.H. van der (2009, mei 12). Ovarian stimulation and the endometrium. EUR. Prom./coprom.: Prof.Dr. B.C.J.M. Fauser & N.S. Macklon. Article/Letter to the editor Berg, I.M. van den, Laven, J.S.E., Stevens, M., Jonkers, I., Galjaard, R.J.H., Gribnau, J. & Doorninck, J.H. van (2009). X Chromosome Inactivation Is Initiated in Human Preimplantation Embryos. American Journal of Human Genetics, 84(6), 771-779. Boxmeer, J.C., Macklon, N.S., Lindemans, J., Beckers, N.G.M., Eijkemans, M.J.C., Laven, J.S.E., Steegers, E.A.P. & Steegers- Theunissen, R.P.M. (2009). IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid. Human Reproduction, 24(5), 1059-1066. Boxmeer, J.C., Smit, M., Utomo, E., Romijn, J.C., Eijkemans, M.J.C., Lindemans, J., Laven, J.S.E., Macklon, N.S., Steegers, E.A.P. & Steegers-Theunissen, R.P.M. (2009). Low folate in seminal plasma is associated with increased sperm DNA damage. Fertility & Sterility, 92(2), 548-556. Casteren, N.J. van, Pieters, R., Dohle, G.R., Baalen, M. van, Neggers, S & Heuvel-Eibrink, M.M. van den (2009). Cranial irradiation does not result in pituitary-gonadal axis dysfunction in very long-term male survivors of childhood acute lymphoblastic leukemia. Leukemia, 23(12), 2310-2313. Casteren, N.J. van, Linden, G.H.M. van der, Hakvoort-Cammel, F.G.A.J., Hahlen, K., Dohle, G.R. & Heuvel-Eibrink, M.M. van den (2009). Effect of childhood cancer treatment on fertility markers in adult male long-term survivors. Pediatric Blood & Cancer, 52, 108-112. Casteren, N.J. van, Jong, J., Stoop, H., Steyerberg, E.W., Bekker- Grob, E.W. de, Dohle, G.R., Oosterhuis, J.W. & Looijenga, L.H.J. (2009). Evaluation of testicular biopsies for carcinoma in situ: immunohistochemistry is mandatory. International Journal of Andrology, 32(6), 666-674. Casteren, N.J. van, Stoop, H., Dohle, G.R., Wit, R. de, Oosterhuis, J.W. & Looijenga, L.H.J. (2009). Noninvasive detection of testicular carcinoma in situ in semen using OCT3/4 reply tot Klau-Pieter Dieckmann's letter. European Urology, 55, 65-66. Casteren, N.J. van, Looijenga, L.H.J. & Dohle, G.R. (2009). Testicular microlithiasis and carcinoma in situ overview and proposed clinical guideline. International Journal of Andrology, 32(4), 279-287. Devroey, P., Fauser, B.C.J.M. & Diedrich, K. (2009). Approaches to improve the diagnosis and management of infertility. Human Reproduction Update, 15(4), 391-408. Dijk, G. van & Laven, J.S.E. (2009). De willekeur voorbij. Medisch Contact, 64, 328-330. Fleischer, K., Vliet, HA van, Rosendaal, F.R., Rosing, J., Tchaikovski, S & Helmerhorst, F.M. (2009). Effects of the contraceptive patch, the vaginal ring and an oral contraceptive on APC resistance and SHBG: A cross-over study. Thrombosis Research, 123(3), 429-435. Gaast, M.H. van der, Macklon, N.S., Beier-Hellwig, K., Krusche, CA, Fauser, B.C.J.M., Beier, H.M. & Classen-Linke, I (2009). The feasibility of a less invasive method to assess endometrial maturation-comparison of simultaneously obtained uterine secretion and tissue biopsy. Bjog-An International Journal of Obstetrics and Gynaecology, 116(2), 304-312. Heijden, G.W. van der, Berg, I.M. van den, Baart, E.B., Derijck, AAHA, Martini, E. & Boer, P. (2009). Parental Origin of Chromatin in Human Monopronuclear Zygotes Revealed by Asymmetric Histone Methylation Patterns, Differs Between IVF and ICSI. Molecular Reproduction and Development, 76(1), 101-108.

Kaay, D.C.M. van der, Jong, F.H. de, Laven, J.S.E. & Hokken-Koelega, A.C.S. (2009). Overnight Luteinizing and Follicle Stimulating Hormone Profiles During GnRHa Treatment in Short Girls Born Small for Gestational Age. Journal of Pediatric Endocrinology & Metabolism, 22(2), 161-169. Kevenaar, M.E., Themmen, A.P.N., Kerkwijk, A.J. van, Valkenburg, O., Uitterlinden, A.G., Jong, F.H. de, Laven, J.S.E. & Visser, J.A. (2009). Variants in the ACVR1 gene are associated with AMH levels in women with polycystic ovary syndrome. Human Reproduction, 24(1), 241-249. Knauff, E.A.H., Eijkemans, M.J.C., Lambalk, C.B., Kate-Booij, M.J. ten, Hoek, A., Beerendonk, CCM, Laven, J.S.E., Goverde, A.J., Broekmans, F.J.M., Themmen, A.P.N., Jong, F.H. de & Fauser, B.C.J.M. (2009). Anti-Mullerian Hormone, Inhibin B, and Antral Follicle Count in Young Women with Ovarian Failure. Journal of Clinical Endocrinology and Metabolism, 94(3), 786-792. Knauff, E.A.H., Franke, L, Es, MA van, Berg, L.H. van den, Schouw, Y.T. van der, Laven, J.S.E., Lambalk, C.B., Hoek, A., Goverde, A.J., Christin-Maitre, S., Hsueh, AJ, Wijmenga, C. & Fauser, B.C.J.M. (2009). Genome-wide association study in premature ovarian failure patients suggests ADAMTS19 as a possible candidate gene. Human Reproduction, 24(9), 2372-2378. Korfage, I.J., Pluijm, S., Roobol-Bouts, M.J., Dohle, G.R., Schroder, F.H. & Essink-Bot, M.L. (2009). Erectile Dysfunction and Mental Health in a General Population of Older Men. Journal of Sexual Medicine, 6(2), 505-512. Laven, J.S.E. (2009). Zwanger na kunst en vliegwerk. Kleine Maatjes, 31, 5-7. Lie Fong, S., Laven, J.S.E., Hakvoort-Cammel, F.G.A.J., Schipper, I., Visser, J.A., Themmen, A.P.N., Jong, F.H. de & Heuvel- Eibrink, M.M. van den (2009). Assessment of ovarian reserve in adult childhood cancer survivors using anti-mullerian hormone. Human Reproduction, 24(4), 982-990. Olivennes, F., Howles, C, Borini, A, Germond, M, Trew, G, Wikland, M, Zegers-Hochschild, F, Saunders, H & Alam, V (2009). Individualizing FSH dose for assisted reproduction using a novel algorithm: the CONSORT study. Reproductive Biomedicine OnLine, 18(2), 195-204. Pierik, F.H., Deddens, J.A., Burdorf, A., Muinck Keizer-Schrama, S.M.P.F., Jong, F.H. de & Weber, R.F.A. (2009). The hypothalamus-pituitary-testis axis in boys during the first six months of life: a comparison of cryptorchidism and hypospadias cases with controls. International Journal of Andrology, 32(5), 453-461. Schoenmakers, S., Wassenaar, E., Hoogerbrugge, J.W., Laven, J.S.E., Grootegoed, J.A. & Baarends, W.M. (2009). Female Meiotic Sex Chromosome Inactivation in Chicken. PLoS Genetics, 5(5). Schouten, B.W.V., Bohnen, A.M., Dohle, G.R., Groeneveld, F.P.M.J., Willemsen, S.P., Thomas, S. & Bosch, J.L.H.R. (2009). Risk factors for deterioration of erectile function: the Krimpen study. International Journal of Andrology, 32(2), 166-175. Stolk, L., Zhai, G., Meurs, J.B.J. van, Verbiest, M.M.P.J., Visser, J.A., Estrada, K, Rivadeneira, F., Williams, FM, Cherkas, L, Deloukas, P, Soranzo, N, Keyzer, J.J., Pop, VJM, Lips, P., Lebrun, C.E.I., Schouw, Y.T. van der, Grobbee, D.E., Witteman, J.C.M., Hofman, A., Pols, H.A.P., Laven, J.S.E., Spector, T.D. & Uitterlinden, A.G. (2009). Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nature Genetics, 41(6), 645-647. Valkenburg, O., Uitterlinden, A.G., Piersma, D., Hofman, A., Themmen, A.P.N., Jong, F.H. de, Fauser, B.C.J.M. & Laven, J.S.E. (2009). Genetic polymorphisms of GnRH and gonadotrophic hormone receptors affect the phenotype of polycystic ovary syndrome. Human Reproduction, 24(8), 2014-2022. Verberg, MFG, Eijkemans, M.J.C., Macklon, N.S., Heijnen, E.M.E.W., Baart, E.B., Hohmann, F.P., Fauser, B.C.J.M. & Broekmans, FJ (2009). The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis. Human Reproduction Update, 15(1), 5-12. Vujkovic, M., Vries, J.H. de, Dohle, G.R., Bonsel, G.J., Lindemans, J., Macklon, N.S., Spek, P.J. van der, Steegers, E.A.P. & Steegers-Theunissen, R.P.M. (2009). Associations between dietary patterns and semen quality in men undergoing IVF/ICSI treatment. Human Reproduction, 24(6), 1304-1312. Book editorship Dohle, G.R., Jungwirth, A., Colpi, G., Giwercman, A., Diemer, T. & Hargreave, TB (Eds.). (2009). European association of urology guidelines on male infertility. --: --.

EMC MM-01-54-01 - Pathophysiology of pediatric endocrine, metabolic and renal diseases Programme design in brief Human growth and development including sexual differentiation and puberty and individual organ systems such as the kidney and bone are regulated by the concerted action of a large number of endocrine, paracrine and autocrine factors. This programme aims at: a. Studying normal growth and development and the role of growth hormone and growth factors in congenital and acquired growth disorders by means of epidemiological investigations and clinical trials as well as laboratory studies using various in vitro techniques. b. Long term goals are to unravel in molecular detail the factors involved in the etiology of type 1 diabetes. We want to develop techniques to predict and prevent this disease, eventually applicable in the general population. Immunological, genetic and beta-cell factors are studied. These aims and goals should allow to develop concomitant strategies to cure or improve the current treatment of those who have already developed the disease. The search for the pathogenesis of type 1 diabetes mellitus the optimal treatment and ultimately its prevention is highly relevant for longterm morbidity, prognosis and socioeconomic consequences at adulthood. c. Studying normal and abnormal renal development as well as therapeutic options by means of multicenter clinical trials. d. Studying intermediary metabolism of patients with inborn errors of aminoacids, organic acids, lipids and defects of cellular organelles, some of them by newborn screening. Development of therapeutic options by dietary intervention or enzyme replacement therapy in nationwide and international collaboration. Special attention is focused on congenital defects of glycosylation, a recently detected group of inborn errors. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot pediatrics 0,83 5,45 4 7,89 18,17 Total 0,83 5,45 4 7,89 18,17 6 0 0 6 60 4 1 71 Thesis Ester, W.A. (2009, januari 21). Genetic and environmental factors in pre- en postnatal growth disorders. EUR (224 pag.) (Enschede: PrintPartners Ipskamp). Prom./coprom.: Prof.Dr. A.C.S. Hokken-Koelega. Geelhoed, J.J.M. (2009, december 11). Early influences on cardiovascular and renal development. The Generation R Study. EUR (299 pag.). Prom./coprom.: Prof.Dr. A. Hofman, Prof.Dr. A.J. van der Heijden & Dr. V.W.V.K. Jaddoe. Kort, S.W.K. de (2009, oktober 14). Metabolic health of children born SGA. EUR (239 pag.) (Rotterdam: Optima Grafische Communicatie). Prom./coprom.: Prof.Dr. A.C.S. Hokken-Koelega. Leunissen, R.W.J. (2009, mei 06). Growth patterns and adult diseases. EUR. Prom./coprom.: Prof.Dr. A.C.S. Hokken-Koelega. Lind van Wijngaarden, R.F.A. de (2009, juni 24). Prader-Willi Syndrome. New perspectives and effects of growth hormone treatment in children. EUR (248 pag.) (Enschede: Ipskamp Drukkers). Prom./coprom.: Prof.Dr. A.C.S. Hokken-Koelega. Prince, F.H.M. (2009, december 11). Etanercept in juvenile idiopathic arthritis results from the Dutch national ABC register. EUR (232 pag.) (Enschede: Ipskamp Drukkers B.V.). Prom./coprom.: Prof.Dr. A.J. van der Heijden. Article/Letter to the editor Akker, E.L.T. van den, Koper, J.W., Joosten, K.F.M., Jong, F.H. de, Hazelzet, J.A., Lamberts, S.W.J. & Hokken-Koelega, A.C.S. (2009). Glucocorticoid receptor mrna levels are selectively decreased in neutrophils of children with sepsis. Intensive Care Medicine, 35, 1247-1254. Ay, L., Houten, V.A.A. van, Steegers, E.A.P., Hofman, A., Witteman, J.C.M., Jaddoe, V.W.V. & Hokken-Koelega, A.C.S. (2009). Fetal and Postnatal Growth and Body Composition at 6 Months of Age. Journal of Clinical Endocrinology and Metabolism, 94(6), 2023-2030. Ay, L., Kruithof, C.J., Bakker, R., Steegers, E.A.P., Witteman, J.C.M., Moll, H.A., Hofman, A., Mackenbach, J.P., Hokken- Koelega, A.C.S. & Jaddoe, V.W.V. (2009). Maternal anthropometrics are associated with fetal size in different periods of pregnancy and at birth. The Generation R Study. Bjog-An International Journal of Obstetrics and Gynaecology, 116(7), 953-963. Bannink, E.M.N., Palen, R.L.F. van der, Mulder, P.G.H. & Muinck Keizer-Schrama, S.M.P.F. (2009). Long-term follow-up of GHtreated girls with Turner Syndrome: BMI, blood pressure, body proportions. Hormone Research, 71, 336-342. Bannink, E.M.N., Palen, R.L.F. van der, Mulder, P.G.H. & Muinck Keizer-Schrama, S.M.P.F. (2009). Long-term follow-up of GHtreated girls with Turner Syndrome: metabolic consequences. Hormone Research, 71, 343-349. Bannink, E.M.N., Sassen, C van, Buuren, S. van, Jong, F.H. de, Lequin, M.H., Mulder, P.G.H. & Muinck Keizer-Schrama, S.M.P.F. (2009). Puberty induction in Turner syndrome: results of oestrogen treatment on development of secondary sexual characteristics, uterine dimensions and serum hormone levels. Clinical Endocrinology, 70(2), 265-273. Beek, N.A.M.E. van der, Hagemans, M.L.C., Reuser, A.J.J., Hop, W.C.J., Ploeg, A.T. van der, Doorn, P.A. van & Wokke, J.H.J. (2009). Rate of disease progression during long-term follow-up of patients with late-nset Pompe disease. Neuromuscular Disorders, 19, 113-117. Beek, R.D. van, Heuvel-Eibrink, M.M. van den, Cammel, F.G.A.J., Bos, C. van den, Pal, HJH van der, Krenning, E.P., Rijke, Y.B. de, Pieters, R. & Muinck Keizer-Schrama, S.M.P.F. (2009). Bone mineral density, growth, and thyroid function in long-term

survivors of pediatric Hodgkin's Lymphoma treated with chemotherapy only. Journal of Clinical Endocrinology and Metabolism, 94(6), 1904-1909. Bergen, M, Takken, T., Engelbert, R.H.H., Groothoff, J.W., Nauta, J., Hoeck, K Van, Helders, P.J.M. & Lilien, M (2009). Exercise training in pediatric patients with end-stage renal disease. Pediatr Nephrol, 24, 619-622. Bever, Y. van, Gischler, S.J., Hoeve, L.J., Smit, L.S., Nauta, J. & Dooijes, D. (2009). Obstructive apneas and severe dysphagia in a girl with Townes-Brocks syndrome and atypical feet involvement. European Journal of Medical Genetics, 52(6), 426-429. Blijdorp, K., Cransberg, K., Wildschut, E.D., Gischler, S.J., Houmes, R.J., Wolff, E.D. & Tibboel, D. (2009). Haemofiltration in newborns treated with extracorporeal membrane oxygenation: a case-comparison study. Critical Care, 13(2). Boot, A.M., Sluis, I.M. van der, Krenning, E.P. & Muinck Keizer-Schrama, S.M.P.F. (2009). Bone Mineral Density and Body Composition in Adolescents with Childhood-Onset Growth Hormone Deficiency. Hormone Research, 71(6), 364-371. Cools, M.B.C., Looijenga, L.H.J., Wolffenbuttel, K.P. & Drop, S.L.S. (2009). Disorders of sex development: update on the genetic background, terminology and risk for the develoment of germ cell tumors. World Journal of Pediatrics, 5(2), 93-102. Dalinghaus, M., Balk, A.H.M.M., Hoog, M. de, Osch-Gevers, M. van, Maat, A.P.W.M., Cransberg, K., Houmes, R.J.M., Helbing, W.A. & Bogers, A.J.J.C. (2009). Harttransplantatie bij kinderen. Nederlands Tijdschrift voor Geneeskunde, 153, 168-173. Dekker, M.J.H.J., Akker, E.L.T. van den, Koper, F.J.W., Manenschijn, L., Geleijns, K, Ruts, L., Rijs, W. van, Tio-Gillen, A.P., Doorn, P.A. van, Lamberts, S.W.J. & Jacobs, B.C. (2009). Effect of glucocorticoid receptor gene polymorphisms in Guillain- Barre syndrome. Journal of the Peripheral Nervous System, 14(2), 75-83. Dommelen, P van, Grote, F.K., Oostdijk, W., Muinck Keizer-Schrama, S.M.P.F., Bouquet, J., Hendriks, J.J.E., Kouwenberg, J.M., Verkerk, P.H., Buuren, S. van & Wit, J.M. (2009). Growth monitoring to detect children with Cystic Fibrosis. Hormone Research, 72, 218-224. Elfferich, P., Juniarto, A.Z., Dubbink, H.J., Royen, M.E. van, Molier, M., Hoogerbrugge, J.W., Houtsmuller, A.B., Trapman, J., Santosa, A, Jong, F.H. de, Drop, S.L.S., Faradz, SMH, Bruggenwirth, H & Brinkmann, A.O. (2009). Functional Analysis of Novel Androgen Receptor Mutations in a Unique Cohort of Indonesian Patients with a Disorder of Sex Development. Sexual Development, 3(5), 237-244. Ester, W.A., Meurs, J.B.J. van, Arends, N.J.T., Uitterlinden, A.G., Ridder, M.A.J. de & Hokken-Koelega, A.C.S. (2009). Birth size, postnatal growth and growth during growth hormone treatment in small-for-gestational-age children: associations with IGF1 gene polymorphisms and haplotypes? Hormone Research, 72, 15-24. Ester, W.A., Meurs, J.B. van, Arends, N.J.T., Uitterlinden, A.G., Ridder, M.A.J. de & Hokken-Koelega, A.C.S. (2009). The - G1245A IGF1 polymorphism is related with small head size and less brain sparing in small for gestational age born children. European Journal of Endocrinology, 160(4), 549-555. Ester, W.A., Duyvenvoorde, H.A. van, Wit, C.C. de, Broekman, A.J., Ruivenkamp, C.A.L., Govaerts, L.C.P., Wit, J.M., Hokken- Koelega, A.C.S. & Losekoot, M. (2009). Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the hetereogeneity of its phenotype. Journal of Clinical Endocrinology and Metabolism, 94(12), 4717-4727. Geelhoed, J.J.M., Steegers, E.A.P., Osch-Gevers, M. van, Verburg, B.O., Hofman, A., Witteman, J.C.M., Heijden, A.J. van der, Helbing, W.A. & Jaddoe, V.W.V. (2009). Cardiac structures track during the first 2 years of life and are associated with fetal growth and hemodynamics: The Generation R Study. American Heart Journal, 158(1), 71-77. Geelhoed, J.J.M., Kleyburg-Linkers, V.E., Snijders, S.P.E., Lequin, M., Nauta, J., Steegers, E.A.P., Heijden, A.J. van der & Jaddoe, V.W.V. (2009). Reliability of renal ultrasound measurements in children. Pediatric Nephrology, 24(7), 1345-1353. Geelhoed, J.J.M., Verburg, B.O., Nautal, J, Lequin, M., Hofman, A., Moll, H.A., Witteman, J.C.M., Heijden, A.J. van der, Steegers, E.A.P. & Jaddoe, V.W.V. (2009). Tracking and Determinants of Kidney Size From Fetal Life Until the Age of 2 Years: The Generation R Study. American Journal of Kidney Diseases, 53(2), 248-258. Giezeman-Smits, K.M., Nauta, J., Bruijn, I.A. de & Palache, A.M. (2009). Trivalent inactivated subunit influenza vaccine Influvac: 25-year experience of safety and immunogenicity. Vaccine, 27, 2414-2417. Goossens, K., Juniarto, A.Z., Timmerman, M.A., Faradz, SMH, Wolffenbuttel, K.P., Drop, S.L.S. & Jong, F.H. de (2009). Lack of correlation between phenotype and genotype in untreated 21-hydroxylase-deficient Indonesian patients. Clinical Endocrinology, 71, 628-635. Graaff, L.C.G. de, Bellis, A. de, Bellastella, A. & Hokken-Koelega, A.C.S. (2009). Antipituitary antibodies in Dutch patients with idiopathic hypopituitarism. Hormone Research, 71, 22-27. Graaff, L.C.G. de, Argente, J., Veenma, D.C.M., Herrebout, M.A.C., Friesema, E.C.H., Uitterlinden, A.G., Drent, M., Campos- Barros, A. & Hokken-Koelega, A.C.S. (2009). Genetic screening of a Dutch population with isolated GH deficiency (IGHD). Clinical Endocrinology, 70, 742-750. Harkel, A.D.J. ten, Cransberg, K., Osch-Gevers, M. van & Nauta, J. (2009). Diastolic dysfunction in paediatric patients on peritoneal dialysis and after renal transplantation. Nephrology Dialysis Transplantation, 24, 1987-1991.

Hartman, A, Winkel, M.L. te, Beek, R.D. van, Muinck Keizer-Schrama, S.M.P.F., Kemper, H.C.G., Hop, W.C.J., Heuvel-Eibrink, M.M. van den & Pieters, R. (2009). A randomized trial investigating an exercise program to prevent reduction of bone mineral density and impairment of motor performance during treatment for childhood acute lymphoblastic leukemia. Pediatric Blood & Cancer, 53, 64-71. Hersmus, R., Leeuw, H.C.G.M. de, Stoop, H., Bernard, P., Doorn, H.C. van, Bruggenwirth, H.T., Drop, S.L.S., Oosterhuis, J.W., Harley, V.R. & Looijenga, L.H.J. (2009). A novel SRY missense mutation affecting nuclear import in a 46,XY female patient with bilateral gonadoblastoma. European Journal of Human Genetics, 17, 1642-1649. Holzhauer, S., Hokken-Koelega, A.C.S., Ridder, M de, Hofman, A., Moll, H.A., Steegers, E.A.P., Witteman, J.C.M. & Jaddoe, V.W.V. (2009). Effect of birth weight and postnatal weight gain on body composition in early infancy The Generation R Study. Early Human Development, 85(5), 285-290. Horster, F., Garbade, S.F., Zwickler, T., Aydin, H.I., Bodamer, O.A., Burlina, A., Das, A.M., Klerk, J.B.C. de, Dionisi-Vici, C., Geb, S., Gokcay, G., Guffon, N., Maier, E.M., Morava, E., Walter, J.H., Schwan, B., Wijburg, F.A., Lindner, M., Grunewald, S., Baumgartner, MR & Kolker, S. (2009). Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters. Journal of Inherited Metabolic Disease, 32, 630-639. Johnston, L.B., Ester, W.A., Caliebe, J, Molinas, C, Wollmann, H., Fryklund, L., Clark, A.J., Ranke, MB, Tauber, M., Hokken- Koelega, A.C.S. & Savage, M.O. (2009). Network of European Studies of Genes in Growth (NESTEGG). Hormone Research, 71(suppl 2), 48-54. Kaay, D.C.M. van der, Hendriks, A.E.J., Ester, W.A., Leunissen, R.W.J., Willemsen, R.H., Kort, S.W.K. de, Paquette, J., Hokken-Koelega, A.C.S. & Deal, C. (2009). Genetic and epigeneti variability in the gene for IGFBP-3 (IGFBP3): Correlation with serum IGFBP-3 levels and growth in short children born small for gestational age. Growth Hormone and IGF Research, 19, 198-205. Kaay, D.C.M. van der, Deal, C., Kort, S.W.K. de, Willemsen, R.H., Leunissen, R.W.J., Ester, W.A., Paquette, J., Doorn, J. van & Hokken-Koelega, A.C.S. (2009). Insulin-like growth factor-binding protein-1: serum levels, promoter polymorphism, and associations with components of the metabolic syndrome in short subjects born small for gestational age. Endocrine Research, 94(4), 1386-1392. Kaay, D.C.M. van der, Jong, F.H. de, Rose, S.R., Odink, R.J.H., Bakker-van Waarde, W.M., Sulkers, E.J. & Hokken-Koelega, A.C.S. (2009). Overnight levels of luteinizing hormone, collicle-stimulating hormone and growth hormone before and during gonadotropin-releasing hormone analogue treatment in short boys born small for gestational age. Hormone Research, 71, 260-267. Kaay, D.C.M. van der, Jong, F.H. de, Laven, J.S.E. & Hokken-Koelega, A.C.S. (2009). Overnight Luteinizing and Follicle Stimulating Hormone Profiles During GnRHa Treatment in Short Girls Born Small for Gestational Age. Journal of Pediatric Endocrinology & Metabolism, 22(2), 161-169. Kaay, D.C.M. van der, Rose, S.R., Dijk, M. van, Noordam, C., Rheenen, E. van & Hokken-Koelega, A.C.S. (2009). Reduced levels of GH during GnRH analogue treatment in pubertal short girls born small of gestational age (SGA). Clinical Endocrinology, 70, 914-919. Kerkhof, G.F., Leunissen, R.W.J., Willemsen, R.H., Jong, F.H. de, Stijnen, T. & Hokken-Koelega, A.C.S. (2009). Influence of preterm birth and birth size on gonadal function in young men. Journal of Clinical Endocrinology and Metabolism, 94(11), 4243-4250. Kort, S.W.K. de, Willemsen, R.H., Kaay, D.C.M. van der, Duivenvoorden, H.J. & Hokken-Koelega, A.C.S. (2009). Does preterm birth influence the response to growth hormone treatment in short, small for gestational age children? Clinical Endocrinology, 70, 582-587. Kort, S.W.K. de, Willemsen, R.H., Kaay, D.C.M. van der & Hokken-Koelega, A.C.S. (2009). The effect of growth hormone treatment on metabolic and cardiovascula risk factors is similar in priterm and term short, small for gestational age children. Clinical Endocrinology, 71, 65-73. Leunissen, R.W.J., Stijnen, T. & Hokken-Koelega, A.C.S. (2009). Influence of birth size on body composition in early adulthood: the programming factors for growth and metabolism (PROGRAM)-study. Clinical Endocrinology, 70, 245-251. Leunissen, R.W.J., Kerkhof, G.F., Stijnen, T. & Hokken-Koelega, A.C.S. (2009). Timing and tempo of first-year rapid growth in relation to cardiovascular and metabolic risk profile in early adulthood. Jama - Journal of the American Medical Association, 301(21), 2234-2242. Lind van Wijngaarden, R.F.A. de, Festen, D.A.M., Otten, B.J., Mil, EGAH van, Rotteveel, J.J., Odink, RJ, Leeuwen, M. van, Haring, A.J.P., Bocca, G., Houdijk, M. & Hokken-Koelega, A.C.S. (2009). Bone mineral density and effects of growth hormone treatment in prepubertal children with Prader-Willi Syndrome: a randomized controlled trial. Journal of Clinical Endocrinology and Metabolism, 94, 3763-3771. Lind van Wijngaarden, R.F.A. de, Siemensma, E.P.C., Festen, D.A.M., Otten, B.J., Mil, EGAH van, Rotteveel, J.J., Odink, R.J.H., Heus, G.C.B. de, Leeuwen, M. van, Haring, A.J.P., Bocca, G., Houdijk, E.C.A.M., Hoorweg-Nijman, J.J.G., Vreuls, R.C.F.M., Jira, P.E., Trotsenburg, A.S.P. van, Bakker, B., Schroor, E.J., Pilon, J.W., Wit, J.M., Drop, S.L.S. & Hokken-Koelega, A.C.S. (2009). Efficacy and safety of long-term continuous growth hormone treatment in children with Prader-Willi Syndrome. Journal of Clinical Endocrinology and Metabolism, 94(11), 4205-4215.

Lind van Wijngaarden, R.F.A. de, Klerk, L.W.L. de, Festen, D.A.M., Duivenvoorden, H.J., Otten, B.J. & Hokken-Koelega, A.C.S. (2009). Randomized controlled trial to investigate the effects of growth hormone treatment on scoliosis in children with Prader- Willi Syndrome. Journal of Clinical Endocrinology and Metabolism, 94(4), 1274-1280. Lind van Wijngaarden, R.F.A. de, Joosten, K.F.M., Berg, S. van den, Otten, B.J., Jong, F.H. de, Sweep, C.G.J., Weerd, A.W. de & Hokken-Koelega, A.C.S. (2009). The relationship between central adrenal insufficiency and sleep-related breathing disorders in children with Prader-Willi Syndrome. Journal of Clinical Endocrinology and Metabolism, 94(7), 2387-2393. Manenschijn, L., Akker, E.L.T. van den, Lamberts, S.W.J. & Rossum, E.F.C. van (2009). Clinical Features Associated with Glucocorticoid Receptor Polymorphisms An Overview. Annals of the New York Academy of Sciences, 179-198. Mook-Kanamori, D.O., Kort, S.W.K. de, Duijn, C.M. van, Uitterlinden, A.G., Hofman, A., Moll, H.A., Steegers, E.A.P., Hokken- Koelega, A.C.S. & Jaddoe, V.W.V.K. (2009). Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies. BMC Medical Genetics, 10, 67-67. Muinck Keizer-Schrama, S.M.P.F. (2009). Pediatric meet the professors: Introduction. Hormone Research, 71(suppl 1), 21. Oostdijk, W., Grote, F.K., Muinck Keizer-Schrama, S.M.P.F. & Wit, J.M. (2009). Diagnostic approach in children with short stature. Hormone Research, 72, 206-217. Pierik, F.H., Deddens, J.A., Muinck Keizer-Schrama, S.M.P.F., Jong, F.H. de, Weber, R.F.A. & Burdorf, A. (2009). Response: the hypothalamus-pituitary-testis axis in cryptorchid boys. International Journal of Andrology, 32, 90. Pierik, F.H., Deddens, J.A., Burdorf, A., Muinck Keizer-Schrama, S.M.P.F., Jong, F.H. de & Weber, R.F.A. (2009). The hypothalamus-pituitary-testis axis in boys during the first six months of life: a comparison of cryptorchidism and hypospadias cases with controls. International Journal of Andrology, 32(5), 453-461. Schreuder, M.F., Navis, G.J. & Nauta, J. (2009). Minder zout op de kinderleeftijd. Nederlands Tijdschrift voor Geneeskunde, 153(5), 186-189. Segers, H., Heyden, J.C. van der, Akker, E.L.T. van den, Krijger, R.R. de, Zwaan, C.M. & Heuvel-Eibrink, M.M. van den (2009). Cushing syndrome as a presenting symptom of renal tumors in children. Pediatric Blood & Cancer, 53, 211-213. Spiekerkoetter, U., Lindner, M., Santer, R, Grotzke, M., Baumgartner, MR, Boehles, H., Das, A., Haase, C., Hennermann, J.B., Karall, D., Klerk, J.B.C. de, Knerr, I., Koch, H.G., Plecko, B., Roschinger, W., Schwab, K.O., Scheible, D., Wijburg, F.A., Zschocke, J., Mayatepek, E. & Wendel, U. (2009). Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. Journal of Inherited Metabolic Disease, 32, 488-497. Spiekerkoetter, U., Lindner, M., Santer, R, Grotzke, M., Baumgartner, MR, Boehles, H., Das, A., Haase, C., Hennermann, J.B., Karall, D., Klerk, J.B.C. de, Knerr, I., Koch, H.G., Plecko, B., Roschinger, W., Schwab, K.O., Scheible, D., Wijburg, F.A., Zschocke, J., Mayatepek, E. & Wendel, U. (2009). Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. Journal of Inherited Metabolic Disease, 32, 498-505. Spronsen, F.J. van, Rijn, M. van, Dorgelo, B., Hoeksma, M., Bosch, A.M., Mulder, F.M., Klerk, J.B.C. de, Koning, T. de, Estela Rubio-Gozalbo, M., Vries, M. de & Verkerk, P.H. (2009). Phenylalanine tolerance can already reliably be assessed at the age of 2 years in patients with PKU. Journal of Inherited Metabolic Disease, 32, 27-31. Takken, T., Engelbert, R.H.H., Bergen, M., Groothoff, J.W., Nauta, J., Hoeck, K Van, Lilien, M & Helders, P.J.M. (2009). Sixminute walking test in children with ESRD: discrimination validity and construct validity. Pediatr Nephrol, 24, 2217-2223. Tauber, M., Hokken-Koelega, A.C.S., Hauffa, B.P. & Goldstone, A.P. (2009). About the benefits of growth hormone treatment in children with Prader-Willi syndrome. Journal of Pediatrics, May 2009, 778. Voorhoeve, P.G., Akker, E.L.T. van den, Lamberts, S.W.J., Delemarre- van de Waal, H.A. & Hokken-Koelega, A.C.S. (2009). Glucocorticoid receptor gene polymorphism is less frequent in children born small for gestational age without catch-up growth. Hormone Research, 71, 162-166. Voorhoeve, P.G., Akker, E.L.T. van den, Rossum, E.F.C. van, Koper, F.J.W., Mechelen, W. van, Lamberts, S.W.J. & Waal, HA Delemarre-Van D (2009). Glucocorticoid receptor gene variant is associated with increased body fatness in youngsters. Clinical Endocrinology, 71(4), 518-523. Walvoord, E.C., Pena, A. de la, Park, S., Silverman, B., Cuttler, L., Rose, S.R., Cutler, G., Drop, S.L.S. & Chipman, J.J. (2009). Inhaled Growth Hormone )(GH) compared with subcutaneous GH in children with GH deficiency: pharmacokinetics, pharmacodynamics and safety. Journal of Clinical Endocrinology and Metabolism, 94(6), 2052-2059. Willemsen, R.H., Leunissen, R.W.J., Stijnen, T. & Hokken-Koelega, A.C.S. (2009). Prematurity is not associated with reduced insulin sensitivity in adulthood. Journal of Pediatric Endocrinology & Metabolism, 94(5), 1695-1700. Part of book - abstract Dessens, A.B., Cools, M.B.C., Richter - Unruh, A., Looijenga, L.H.J., Grootegoed, J.A. & Drop, S.L.S. (2009). Genetic defects of female sexual differentiation. In D.W. Pfaff & A.P. Arnold (Eds.), Hormones, Brain and Behavior (pp. 3207-3234). San Diego: Elsevier.

EMC MM-02-41-03 - Malignant transformation of hematopoietic stem cells: pathophysiology and development of therapy Programme design in brief In this project we investigate abnormalities in the cellular responsiveness to hematopoietic growth factors, the expression, structure and function of hematopoie tic growth factor receptors as well as alterations of signal transduction and transcripti on that may contribute to the develop ment of hematological malignancies. The abnormalities may influence the survival, cell cycle regulation, commitment or maturation of hematopoietic progenitor cells. The investiga ti ons on the genetic abnormalities of hemato-oncologic diseases extend towards the development of a specific diagnosis and the detection of minimal residual disease, as well as new therapeutic interventions of hematological malignancies. With respect to the development of new treatment strategies aimed at eradicating malignant hematopoietic progenitor cells, we address questions related to their sensitivity to chemotherapy, the response to novel drugs that target specific genes and the clinical development of stem cell transplantation. The modalities are explored in relevant animal models as well as in clinical studies. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot hematology 3,3 3,5 5,8 6,75 19,35 internal medicine 0,8 0 0 0 0,8 Total 4,1 3,5 5,8 6,75 20,15 1 0 0 1 39 0 0 40 Thesis Wouters, B.J. (2009, mei 20). Genomic and epigenomic studies of acute myeloid leukemia with CEPBA abnormalities. EUR (240 pag.). Prom./coprom.: Prof.Dr. B. Lowenberg & Prof. H.R. Delwel. Article/Letter to the editor Bruin, M.L. de, Burgers, J.A., Baas, P., Veer, M.B. van t, Noordijk, E.M., Louwman, MWJ, Zijlstra, JM, Berg, H., Aleman, B.M.P. & Leeuwen, F.E. van (2009). Malignant mesothelioma after radiation treatment for Hodgkin lymphoma. Blood, 113(16), 3679-3681. Cornelissen, J.J., Holt, B. van der, Verhoef, G.E.G., Veer, M.B. van t, Oers, M.H.J. van, Schouten, H.C., Ossenkoppele, G., Sonneveld, P., Maertens, J., Kooy, MV, Schaafsma, M.R., Wijermans, P.W., Biesma, D.H., Wittebol, S., Voogt, P.J., Baars, J.W., Zachee, P, Verdonck, L.F., Lowenberg, B. & Dekker, A.W. (2009). Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus nodonor comparison. Blood, 113(6), 1375-1382. Deenik, W., Beverloo, H.B., Luytgaarde, SCPAM van der Poel-va, Wattel, M.M., Esser, J.W.J. van, Valk, P.J.M. & Cornelissen, J.J. (2009). Rapid complete cytogenetic remission after upfront dasatinib monotherapy in a patient with a NUP214-ABL1- positive T-cell acute lymphoblastic leukemia. Leukemia, 23(3), 627-629. Dijkstra, M.K., Lom, K. van, Tielemans, D., Elstrodt, F., Langerak, A.W., Veer, M.B. van t & Jongen-Lavrencic, M. (2009). 17p13/TP53 deletion in B-CLL patients is associated with microrna-34a downregulation. Leukemia, 23(3), 625-627. Dimopoulos, M, Terpos, E, Comenzo, RL, Tosi, P, Beksac, M., Sezer, O, Siegel, D., Lokhorst, H., Kumar, S., Rajkumar, SV, Niesvizky, R, Moulopoulos, LA & Durie, BGM (2009). International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma. Leukemia, 23(9), 1545-1556. Dispenzieri, A, Kyle, R, Merlini, G, Miguel, JS, Ludwig, H., Hajek, R., Palumbo, A., Jagannath, S, Blade, J., Lonial, S, Dimopoulos, M, Comenzo, R., Einsele, H, Barlogie, B, Anderson, K., Gertz, M, Harousseau, JL, Attal, M, Tosi, P, Sonneveld, P., Boccadoro, M., Morgan, G., Richardson, P., Sezer, O, Mateos, M.V., Cavo, M., Joshua, D., Turesson, I., Chen, W., Shimizu, K., Powles, R., Rajkumar, SV & Durie, BGM (2009). International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia, 23(2), 215-224. Figueroa, ME, Wouters, B.J., Skrabanek, L, Glass, J, Li, YS, Erpelinck - Verschuren, C.A.J., Langerak, A.W., Lowenberg, B., Fazzari, M, Greally, JM, Valk, P.J.M., Melnick, A & Delwel, R. (2009). Genome-wide epigenetic analysis delineates a biologically distinct immature acute leukemia with myeloid/t-lymphoid features. Blood, 113(12), 2795-2804. Forrer, F., Krenning, E.P., Kooij, P.P., Bernard, H.F., Konijnenberg, M.W., Bakker, W.H., Teunissen, J.J.M., Jong, M. de, Lom, K. van, Herder, W.W. de & Kwekkeboom, D.J. (2009). Bone marrow dosimetry in peptide receptor radionuclide therapy with [Lu- 177-DOTA(0),Tyr(3)]octreotate. European Journal of Nuclear Medicine and Molecular Imaging, 36(7), 1138-1146. Giralt, S, Stadtmauer, E.A., Harousseau, JL, Palumbo, A., Bensinger, W, Comenzo, RL, Kumar, S., Munshi, NC, Dispenzieri, A, Kyle, R, Merlini, G, Miguel, J San, Ludwig, H., Hajek, R., Jagannath, S, Blade, J., Lonial, S, Dimopoulos, MA, Einsele, H, Barlogie, B, Anderson, KC, Gertz, M, Attal, M, Tosi, P, Sonneveld, P., Boccadoro, M., Morgan, G., Sezer, O, Mateos, M.V., Cavo, M., Joshua, D., Turesson, I., Chen, W., Shimizu, K., Powles, R., Richardson, PG, Niesvizky, R, Rajkumar, SV & Durie, BGM (2009). International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia, 23(10), 1904-1912. Harousseau, JL, Martinelli, G, Jedrzejczak, WW, Brandwein, JM, Bordessoule, D, Masszi, T, Ossenkoppele, G.J., Alexeeva, JA, Beutel, G, Maertens, J., Vidriales, M.B., Dombret, H., Thomas, X, Burnett, AK, Robak, T., Khuageva, NK, Golenkov, AK, Tothova, E, Mollgard, L, Park, YC, Bessems, A, Porre, P De & Howes, AJ (2009). A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood, 114(6), 1166-1173.

Heuser, M, Sly, LM, Argiropoulos, B, Kuchenbauer, F, Lai, C, Weng, A, Leung, M, Lin, G, Brookes, C, Fung, S, Valk, P.J.M., Delwel, H.R., Lowenberg, B., Krystal, G & Humphries, RK (2009). Modeling the functional heterogeneity of leukemia stem cells: role of STAT5 in leukemia stem cell self-renewal. Blood, 114(19), 3983-3993. Heutte, N, Flechtner, HH, Mounier, N, Mellink, WAM, Meerwaldt, J.H., Eghbali, H, Veer, M.B. van t, Noordijk, E.M., Kluin- Nelemans, J.C., Lampka, E, Thomas, J., Lugtenburg, P.J., Viterbo, L, Carde, P., Hagenbeek, A., Maazen, R.W.M. van der, Smit, W.G.J.M., Brice, P, Kooy, MV, Baars, J.W., Poortmans, P, Tirelli, U., Leeksma, OC, Tomsic, R., Feugier, P, Salles, G, Gabarre, J, Kersten, MJ, Neste, E Van den, Creemers, GJM, Gaillard, I, Meijnders, P, Tertian, G, Reman, O, Muller, HP, Troncy, J, Blanc, M, Schroyens, W., Voogt, P.J., Wijermans, P., Rieux, C, Ferme, C & Henry-Amar, M. (2009). Quality of life after successful treatment of early-stage Hodgkin's lymphoma: 10-year follow-up of the EORTC-GELA H8 randomised controlled trial. Lancet Oncology, 10(12), 1160-1170. Hochhaus, A., O'Brien, SG, Guilhot, F., Druker, B.J., Branford, S, Foroni, L, Goldman, J.M., Muller, MC, Radich, J.P., Rudoltz, M, Mone, M, Gathmann, I., Hughes, TP & Larson, R.A. (2009). Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia, 23(6), 1054-1061. Jonge, HJM de, Bont, E.S.J.M. de, Valk, P.J.M., Schuringa, JJ, Kies, M, Woolthuis, CM, Delwel, H.R., Veeger, NJGM, Vellenga, E., Lowenberg, B. & Huls, G (2009). AML at older age: age-related gene expression profiles reveal a paradoxical downregulation of p16(ink4a) mrna with prognostic significance. Blood, 114(14), 2869-2877. Kumar, S., Giralt, S, Stadtmauer, E.A., Harousseau, JL, Palumbo, A., Bensinger, W, Comenzo, RL, Lentzsch, S, Munshi, N, Niesvizky, R, Miguel, JS, Ludwig, H., Bergsagel, L, Blade, J., Lonial, S, Anderson, KC, Tosi, P, Sonneveld, P., Sezer, O, Vesole, D, Cavo, M., Einsele, H, Richardson, PG, Durie, BGM & Rajkumar, SV (2009). Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomibcontaining regimens. Blood, 114(9), 1729-1735. Lowenberg, B., Ossenkoppele, G.J., Putten, W.L.J. van, Schouten, H.C., Graux, C., Ferrant, A., Sonneveld, P., Maertens, J., Jongen-Lavrencic, M., Lilienfeld-Toal, M von, Biemond, BJ, Vellenga, E., Kooy, MV, Verdonck, L.F., Beck, J., Dohner, H., Gratwohl, A., Pabst, T & Verhoef, G. (2009). High-Dose Daunorubicin in Older Patients with Acute Myeloid Leukemia. New England Journal of Medicine, 361(13), 1235-1248. Montesinos, P, Diaz-Mediavilla, J, Deben, G, Prates, V, Tormo, M, Rubio, V, Perez, I, Fernandez, I, Viguria, M, Rayon, C, Gonzalez, J, Serna, J de la, Esteve, J, Bergua, JM, Rivas, C, Gonzalez, M., Gonzalez, JD, Negri, S, Brunet, S, Lowenberg, B. & Sanz, M.A. (2009). Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy without intrathecal prophylaxis. Haematologica, 94(9), 1242-1249. Montesinos, P, Bergua, JM, Vellenga, E., Rayon, C, Parody, R, Serna, J de la, Leon, A, Esteve, J, Milone, G, Deben, G, Rivas, C, Gonzalez, M., Tormo, M, Diaz-Mediavilla, J, Gonzalez, JD, Negri, S, Amutio, E, Brunet, S, Lowenberg, B. & Sanz, M.A. (2009). Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood, 113(4), 775-783. Palumbo, A., Sezer, O, Kyle, R, Miguel, JS, Orlowski, RZ, Moreau, P, Niesvizky, R, Morgan, G., Comenzo, R., Sonneveld, P., Kumar, S., Hajek, R., Giralt, S, Bringhen, S, Anderson, KC, Richardson, PG, Cavo, M., Davies, F, Blade, J., Einsele, H, Dimopoulos, MA, Spencer, A., Dispenzieri, A, Reiman, T, Shimizu, K., Lee, J.H. v.d., Attal, M, Boccadoro, M., Mateos, M, Chen, W., Ludwig, H., Joshua, D., Chim, J, Hungria, V., Turesson, I., Durie, BGM & Lonial, S (2009). International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation. Leukemia, 23(10), 1716-1730. Palumbo, A., Dimopoulos, M, Miguel, JS, Harousseau, JL, Attal, M, Hussein, M, Knop, S, Ludwig, H., Lilienfeld-Toal, M von & Sonneveld, P. (2009). Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma. Blood Reviews, 23(2), 87-93. Qian, Z, Mao, L, Fernald, AA, Yu, H., Luo, R., Jiang, Y., Anastasi, J, Valk, P.J., Delwel, R. & Beau, MM Le (2009). Enhanced expression of FHL2 leads to abnormal myelopoiesis in vivo. Leukemia, 23(9), 1650-1657. Rao, AV, Valk, P.J.M., Metzeler, KH, Acharya, CR, Tuchman, SA, Stevenson, MM, Rizzieri, DA, Delwel, H.R., Buske, C, Bohlander, SK, Potti, A & Lowenberg, B. (2009). Age-Specific Differences in Oncogenic Pathway Dysregulation and Anthracycline Sensitivity in Patients With Acute Myeloid Leukemia. Journal of Clinical Oncology, 27(33), 5580-5586. Richardson, PG, Sonneveld, P., Schuster, MW, Stadtmauer, E.A., Facon, T., Harousseau, JL, Ben-Yehuda, D, Lonial, S, Goldschmidt, H., Reece, D, Blade, J., Boccadoro, M., Cavenagh, JD, Boral, AL, Esseltine, DL, Wen, PY, Amato, AA, Anderson, KC & Miguel, J San (2009). Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. British Journal of Haematology, 144(6), 895-903. Sanz, M, Burnett, A., Lo-Coco, F & Lowenberg, B. (2009). FLT3 inhibition as a targeted therapy for acute myeloid leukemia. Current Opinion in Oncology, 21(6), 594-600. Sanz, M.A., Grimwade, D., Tallman, M.S., Lowenberg, B., Fenaux, P, Estey, E.H., Naoe, T, Lengfelder, E, Buchner, T, Dohner, H., Burnett, AK & Lo-Coco, F (2009). Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood, 113(9), 1875-1891. Schwieger, M., Schuler, A, Forster, M, Engelmann, A, Arnold, MA, Delwel, R., Valk, P.J., Lohler, J, Slany, RK, Olson, E.N. & Stocking, C. (2009). Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C. Blood, 114(12), 2476-2488.

Silva, FPG, Swagemakers, S.M.A., Erpelinck-Verschueren, C, Wouters, B.J., Delwel, H.R., Vrieling, H., Spek, P.J. van der, Valk, P.J.M. & Giphart-Gassler, M (2009). Gene expression profiling of minimally differentiated acute myeloid leukemia: M0 is a distinct entity subdivided by RUNX1 mutation status. Blood, 114(14), 3001-3007. Silva, FPG, Almeida, I, Morolli, B., Brouwer-Mandema, G, Wessels, H, Vossen, R., Vrieling, H., Marijt, EWA, Valk, P.J.M., Kluin- Nelemans, H.C., Sperr, WR, Ludwig, WD & Giphart-Gassler, M (2009). Genome wide molecular analysis of minimally differentiated acute myeloid leukemia. Haematologica, 94(11), 1546-1554. Slobbe, L., Waal, L. de, Jongman, L.R., Lugtenburg, P.J. & Rijnders, B.J.A. (2009). Three-day treatment with imipenem for unexplained fever during prolonged neutropaenia in haematology patients receiving fluoroquinolone and fluconazole prophylaxis: A prospective observational safety study. European Journal of Cancer, 45(16), 2810-2817. Sonneveld, P. (2009). Thalidomide/dexamethasone in myeloma: a double-edged sword. Blood, 113(15), 3394-3394. Terpos, E, Sezer, O, Croucher, PI, Garcia-Sanz, R., Boccadoro, M., Miguel, J San, Ashcroft, J, Blade, J., Cavo, M., Delforge, M., Dimopoulos, MA, Facon, T., Macro, M, Waage, A & Sonneveld, P. (2009). The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Annals of Oncology, 20(8), 1303-1317. Veer, M.B. van t, Jong, DD de, MacKenzie, M, Kluin-Nelemans, H.C., Oers, M.H.J. van, Zijlstra, J., Hagenbeek, A. & Putten, W.L.J. van (2009). High-dose Ara-C and beam with autograft rescue in R-CHOP responsive mantle cell lymphoma patients. British Journal of Haematology, 144(4), 524-530. Verhaak, R.G.W., Wouters, B.J., Erpelinck - Verschuren, C.A.J., Abbas, S., Beverloo, H.B., Lugthart, S., Lowenberg, B., Delwel, R. & Valk, P.J.M. (2009). Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profiling. Haematologica, 94(1), 131-134. Vogl, DT, Stadtmauer, E.A., Richardson, PG, Sonneveld, P., Schuster, MW, Irwin, D, Facon, T., Harousseau, JL, Boral, A, Neuwirth, R & Anderson, KC (2009). Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma. British Journal of Haematology, 147(4), 531-534. Wondergem, M.J., Grunberg, K, Wittgen, BPH, Sonneveld, P. & Zweegman, S. (2009). Interstitial pneumonitis caused by Pneumocystis jirovecii pneumonia (PCP) during bortezomib treatment. Histopathology, 54(5), 631-633. Wouters, B. & Delwel, R. (2009). CEBPA promoter hypermethylation in a subset of myeloid/t-lymphoid leukemias with a distinct gene expression profile Response. Blood, 113(8), 1866-1866. Wouters, B.J., Lowenberg, B. & Delwel, R. (2009). A decade of genome-wide gene expression profiling in acute myeloid leukemia: flashback and prospects. Blood, 113(2), 291-298. Wouters, B.J., Lowenberg, B., Erpelinck - Verschuren, C.A.J., Putten, W.L.J. van, Valk, P.J.M. & Delwel, R. (2009). Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood, 113(13), 3088-3091. Yin, B, Delwel, R., Valk, P.J., Wallace, M.R., Loh, M.L., Shannon, KM & Largaespada, DA (2009). A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene. Blood, 113(5), 1075-1085.

EMC MM-02-41-04 - Hematopoiesis: regulation of the proliferation and differentiation of hematopoietic progenitor cells Programme design in brief In this program we investigate the regulation of blood cell formation, i.e. hematopoiesis, in health and disease. Hematopoiesis is differentially regulated at the levels of primitive stem cells and more differentiated progenitor cell subsets and we study specifically the intrinsic characteristics of hematopoietic stem/progenitor cells and the extrinsic interactions with cells of the tissue microenvironment. The studies on hematopoietic and lymphoid development and intrinsic characteristics of stem/progenitor cells include the analysis of genetic determinants that control replication, replicative senescence, differentiation commitment, maturation, cellular dependence on humoral and stromal regulators and expression of specific hematopoietic growth factor receptors and differentiation specific genes. The focus of the experimental stem cell transplantation program is on improving immune reconstitution and induction of allo-antigen specific tolerance following transplantation. Specific projects deal with the development of tools and conditions that allow efficient gene transfer into the most primitive stem cells with long-term in vivo repopulation ability, eventually for the development of gene therapy, presently focused on inherited disorders, including immunodeficiencies, inherited anemias and metabolic diseases. In direct connection to the studies on hematopoiesis in healthy circumstances, the program has a focus on hematopoiesis in disease conditions. These diseases are characterized by quantitatively insufficient hematopoiesis resulting from disturbances at intrinsic or extrinsic levels of regulation in stem/progenitor cells. Conditions studied include idiopathic and congenital neutropenia and accelerated aging of stem cells following cytotoxic treatment. Models that include transgenic mice and subhuman primates have been developed to allow for the dissection of these conditions at the molecular level. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot hematology 6,8 7,25 1 1,8 16,85 Total 6,8 7,25 1 1,8 16,85 0 0 0 0 11 1 0 12 Article/Letter to the editor Avivi, I, Montoto, S, Canals, C, Maertens, J., Al-Ali, H, Mufti, GJ, Finke, J., Schattenberg, A., Fanin, R, Cornelissen, J.J., Vernant, J.P., Russell, N, Beguin, Y, Thomson, K, Verdonck, L.F., Kobbe, G, Tilly, H, Socie, G & Sureda, A (2009). Matched unrelated donor stem cell transplant in 131 patients with follicular lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. British Journal of Haematology, 147(5), 719-728. Bij, A van der, Betjes, M., Weening, J.J., Cornelissen, J., Mes, T., Osterhaus, A. & Beersma, M. (2009). BK virus nephropathy in an immunodeficient patient with chronic lymphocytic leukemia. Journal of Clinical Virology, 45(4), 341-344. Boehm, B., Steinert, M., Dietrich, J., Peter, R., Belyi, D., Wagemaker, G., Rosinger, S., Fliedner, T.M. & Weiss, M. (2009). Thyroid examination in highly radiation-exposed workers after the Chernobyl accident. European Journal of Endocrinology, 160, 625-630. Bruinsma, M., Soest, P.L. van, Leenen, P.J.M., Lowenberg, B., Cornelissen, J.J. & Braakman, E. (2009). Keratinocyte Growth Factor Improves Allogeneic Bone Marrow Engraftment through a CD4(+)Foxp3(+) Regulatory T Cell-Dependent Mechanism. Journal of Immunology, 182(12), 7364-7369. Cupedo, T., Crellin, NK, Papazian, N., Rombouts, EJ, Weijer, K., Grogan, JL, Fibbe, W.E., Cornelissen, J.J. & Spits, H. (2009). Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127(+) natural killer-like cells. Nature Immunology, 10(1), 66-74. Holler, E, Kolb, H.J., Greinix, H, Perrotin, D, Campilho, F, Aversa, F, Gil, L, Cornelissen, J., Varanese, L, Schacht, A, Friese, A & Rustige, J (2009). Bleeding events and mortality in SCT patients: a retrospective study of hematopoietic SCT patients with organ dysfunctions due to severe sepsis or GVHD. Bone Marrow Transplantation, 43(6), 491-497. Kheradmand Kia, S., Kartalaei, P.S., Farahbakhshian, E., Pourfarzad, F., Lindern, M.M. von & Verrijzer, C.P. (2009). EZH2- dependent chromatin looping controls INK4a and INK4b, but not ARF, during human progenitor cell differentiation and cellular senescence. Epigenetics & Chromatin, 2, 16. Lent, AU van, Dontje, W, Nagasawa, M, Siamari, R, Bakker, A.Q., Pouw, SA, Maijoor, KA, Weijer, K., Cornelissen, J.J., Blom, B., Santo, J.P. di, Spits, H. & Legrand, N (2009). IL-7 Enhances Thymic Human T Cell Development in "Human Immune System" Rag2(-/-)IL-2R gamma(-/-)(c) Mice without Affecting Peripheral T Cell Homeostasis. Journal of Immunology, 183(12), 7645-7655. Meenhuis, A, Irandoust, M., Wolfler, A., Roovers, O., Valkhof, M. & Touw, I.P. (2009). Janus kinases promote cell-surface expression and provoke autonomous signalling from routing-defective G-CSF receptors. Biochemical Journal, 417, 737-746. Robin, C.I., Bollerot, K., Mendes, S., Haak, E., Crisan, M., Cerisoli, F., Lauw, I, Kaimakis, P., Jorna, R.J.J., Vermeulen, M.W.G., Kayser, M., Linden, R. van der, Imanirad, P., Verstegen, M.M.A., Nawaz-Yousaf, H, Papazian, N., Steegers, E.A.P., Cupedo, T. & Dzierzak, E.A. (2009). Human Placenta Is a Potent Hematopoietic Niche Containing Hematopoietic Stem and Progenitor Cells throughout Development. Cell Stem Cell, 5(4), 385-395. Vivier, E, Spits, H. & Cupedo, T. (2009). Interleukin-22-producing innate immune cells: new players in mucosal immunity and tissue repair? Nature Reviews Immunology, 9(4), 229-234. Wolfler, A., Irandoust, M., Meenhuis, A, Gits, J., Roovers, O. & Touw, I.P. (2009). Site-Specific Ubiquitination Determines Lysosomal Sorting and Signal Attenuation of the Granulocyte Colony-Stimulating Factor Receptor. Traffic, 10(8), 1168-1179.

EMC MM-02-54-03 - Molecular determinants of therapy response and outcome in childhood cancer Programme design in brief This translational research programme is focussed on the role of molecular genetic abnormalities on leukemogensis and outcome in childhood malignancies, especially leukemia. Specific goals are: Molecular classification of childhood leukemias to redefine leukemias into biological subclasses. This is done by genome-wide screening techniques at the DNA level, extensive gene expression profiling by micro-array analysis and protein expression profiling. Identification of (epi)genetic abnormalities important for develoment of childhood leukemias and lymphomas. Expression of tumor suppressor genes and oncogenes in various types of childhood leukemias and lymphomas are studied. The value of epigenetic silencing mechanisms such as methylation are studied. Identification of molecules associated with cellular drug resistance and clinical therapy response. New resistance genes for specific classes of cytotoxic drugs are identified by micro-array analyses of drug resistant and sensitive patients and confirmed by other techniques. New strategies to modulate these new resistance genes are developed. Identification of new targets for therapeutic intervention. New specific targets are detected in specific genetic subgroups of childhood leukemia by micro-array expression analysis. The presence of potential new drug targets is confirmed by other techniques and validation studies are performed. RNAi is being developed for ALL cells for this purpose. New agents directed against the newly discovered targets are evaluated in preclinical models for their activity in childhood leukemias. Development of new treatment protocols: the targets and new compounds studied in the preclinical setting as described above are used in phase I/II studies. Central goal of the clinical program is the development of targeted therapies for children with hematological malignancies. The clinical part of the research programme also studies: (1) Effectiveness of therapy in paediatric oncology, which are mainly done in national and international collaborations; (2) Improvements in supportive care in paediatric oncology, which are essential because of the high intensity of most treatment protocols; (3) Late effects of disease and treatment, which is important in the light of the improved cure rates of children with cancer. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot pediatrics 6,73 3 27,23 2,89 39,85 Total 6,73 3 27,23 2,89 39,85 1 1 0 2 49 2 6 59 Thesis Dome, J.F. (2009, september 10). Identification and management of high risk Wilms tumors. EUR. Prom./coprom.: Prof.Dr. R. Pieters & Prof. Dr. M.J. Coppes. Hartman, A (2009, januari 21). Motor performance following chemotherapy for childhood cancer. EUR (139 pag.) (Rotterdam: Optima Grafische Communicatie). Prom./coprom.: Prof.Dr. R. Pieters. Article/Letter to the editor Aarsen, F.K., Paquier, P.F., Arts, W.F.M., Veelen, M.L.C. van, Michiels, E.M.C., Lequin, M.H. & Catsman-Berrevoets, C.E. (2009). Cognitive deficits and predictors 3 years after diagnosis of a pilocytic astrocytoma in childhood. Journal of Clinical Oncology, 27, 3526-3532. Akagi, T., Yin, D., Kawamata, N., Bartram, C.R., Hofmann, WK, Song, J.H., Miller, C.W., Boer, M.L. den & Koeffler, H.P. (2009). Functional analysis of a novel DNA polymorphism of a tandem repeated sequence in the asparagine synthetase gene in acute lymphoblastig leukemia cells. Leukemia Research, 33, 991-996. Bakker, M.A. den, Beverloo, H.B., Heuvel-Eibrink, M.M. van den, Meeuwis, C.A., Tan, LM, Johnson, LA, French, CA & Leenders, G.J.L.H. van (2009). NUT Midline Carcinoma of the Parotid Gland With Mesenchymal Differentiation. American Journal of Surgical Pathology, 33(8), 1253-1258. Balgobind, B.V., Raimondi, S.C., Harbott, J., Zimmermann, M., Alonzo, T.A., Auvrignon, A., Beverloo, H.B., Chang, M., Dworzak, M, Forestier, E., Gibson, BES, Hasle, H., Harrison, C.J., Heerema, N.A., Kaspers, G.J.L., Leszl, A., Litvinko, N., Nigro, L.L., Motimoto, A., Perot, C., Pieters, R., Reinhardt, D., Rubnitz, J.E., Smith, F.O., Stary, J., Stasevich, I., Strehl, S, Taga, T., Tomizawa, D., Webb, D., Zemanova, Z, Zwaan, C.M. & Heuvel-Eibrink, M.M. van den (2009). Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood, 114(12), 2489-2496. Balgobind, B.V., Zwaan, C.M., Meyer, C., Marschalek, R, Pieters, R., Beverloo, H.B. & Heuvel-Eibrink, M.M. van den (2009). NRIP3: a novel translocation partner of MLL detected in a pediatric acute myeloid leukemia with complex chromosome 11 rearrangements. Haematologica, 94(7), 1033-1034. Beek, R.D. van, Heuvel-Eibrink, M.M. van den, Cammel, F.G.A.J., Bos, C. van den, Pal, HJH van der, Krenning, E.P., Rijke, Y.B. de, Pieters, R. & Muinck Keizer-Schrama, S.M.P.F. (2009). Bone mineral density, growth, and thyroid function in long-term survivors of pediatric Hodgkin's Lymphoma treated with chemotherapy only. Journal of Clinical Endocrinology and Metabolism, 94(6), 1904-1909. Beishuizen, A., Diepstraten, A.F.M. & Nowak, P.J.C.M. (2009). Nieuwe behandelingen in de kinderoncologie ter voorkoming van (latere) functionele en cosmetische problemen. IKR-bulletin (Rotterdam), april 2009, 12-16. Bekkering, W.P., Vliet Vlietland, Th., Koopman, H.M., Schaap, G.R., Schreuder, H.W.B., Beishuizen, A., Tissing, W.J.E., Hoogerbrugge, P.M., Anninga, J.K. & Taminiau, AHM (2009). The Bt-DUX: development of a subjective measure of health -

related quality of life in patients who underwent surgery of lower extremity malignant bone tumor. Pediatric Blood & Cancer, 53, 348-355. Blink, M., Buitenkamp, T.D., Wouwe, J.P. van der, Wering, E.R. van, Velden, V.H.J. van der & Zwaan, C.M. (2009). Ontwikkelingen in de diagnostiek en behandeling van leukemie bij kinderen met downsyndroom. Tijdschrift voor Kindergeneeskunde, 77(2), 52-58. Boer, M.L. den, Slegtenhorst, M.A. van, Menezes, R.X. de, Cheok, M.H., Gladdines, J.G.C.A.M., Peters, T.C.J.M., Zutven, L.J.C.M. van, Beverloo, H.B., Spek, P.J. van der, Escherich, G, Horstmann, M.A., Janka-Schaub, G.E., Kamps, W.A., Evans, W.E. & Pieters, R. (2009). A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncology, 10, 125-134. Bont, J.M. de (2009). Biologische markers in hersentumoren bij kinderen. Nederlands Tijdschrift voor Oncologie, 6(3), 167-169. Boot, A.M., Sluis, I.M. van der, Krenning, E.P. & Muinck Keizer-Schrama, S.M.P.F. (2009). Bone Mineral Density and Body Composition in Adolescents with Childhood-Onset Growth Hormone Deficiency. Hormone Research, 71(6), 364-371. Casteren, N.J. van, Pieters, R., Dohle, G.R., Baalen, M. van, Neggers, S & Heuvel-Eibrink, M.M. van den (2009). Cranial irradiation does not result in pituitary-gonadal axis dysfunction in very long-term male survivors of childhood acute lymphoblastic leukemia. Leukemia, 23(12), 2310-2313. Casteren, N.J. van, Linden, G.H.M. van der, Hakvoort-Cammel, F.G.A.J., Hahlen, K., Dohle, G.R. & Heuvel-Eibrink, M.M. van den (2009). Effect of childhood cancer treatment on fertility markers in adult male long-term survivors. Pediatric Blood & Cancer, 52, 108-112. Catsman-Berrevoets, C.E., Aarsen, F.K., Hemsbergen, M.L.C. van, Noesel, M.M. van, Hakvoort-Cammel, F.G.A.J. & Heuvel- Eibrink, M.M. van den (2009). Improvement of neurological status and quality of life in children with opsoclonus myoclonus syndrome at long-term follow-up. Pediatric Blood & Cancer, 53, 1048-1053. Cnossen, M.H., Ommen, C.H. van & Appel, I.M. (2009). Etiology and treatment of perinatal stroke: a role for prothrombotic coagulation factors? Seminars in Fetal & Neonatal Medicine, 14, 311-317. Dongen, J.C.A. van, Dalinghaus, M., Kroon, A.A., Vries, A.C.H. de & Heuvel-Eibrink, M.M. van den (2009). Succesful treatment of congenital acute myeloid leukemia (AML-M6) in a premature infant. Journal of Pediatric Hematology Oncology, 31(11), 853-854. Eden, T.O.B., Pieters, R. & Richards, S. (2009). Beneficial and harmful effects of anthracyclines in the treatment of childhood acute lymphoblastic leukaemia: a systematic review and meta-analysis. British Journal of Haematology, 145, 376-388. Faber, J, Krivtsov, A.V., Stubbs, M.C., Wright, R., Davis, T.N., Heuvel-Eibrink, M.M. van den, Zwaan, C.M., Kung, A.L. & Armstrong, S.A. (2009). HOXA9 is required for sirvival in human MLL-rearranged acute leukemias. Blood, 113(11), 2375-2385. Goemans, BF, Tamminga, R, Corbijn, C.M., Hahlen, K. & Kaspers, G.J.L. (2008). Outcome for children with relapsed acute myeloid leukemia in the Netherlands following initial treatment between 1980 and 1998: survival after chemotherapy only? Haematologica, 93(9), 1418-1420. Hartman, A, Winkel, M.L. te, Beek, R.D. van, Muinck Keizer-Schrama, S.M.P.F., Kemper, H.C.G., Hop, W.C.J., Heuvel-Eibrink, M.M. van den & Pieters, R. (2009). A randomized trial investigating an exercise program to prevent reduction of bone mineral density and impairment of motor performance during treatment for childhood acute lymphoblastic leukemia. Pediatric Blood & Cancer, 53, 64-71. Heide, R., Zuidema, E., Beishuizen, A., Hollander, J.C. den, Gysel, D. van, Seyger, M.M.B., Pasmans, S.G.M.A., Kahourou, T. & Oranje, A.P. (2009). Clinical aspects of diffuse cutaneous mastocytis in children: two variants. Dermatology, 219, 309-315. Heide, R., Doorn, K. van, Mulder, P.G.H., Toorenenbergen, A.W. van, Beishuizen, A., Groot, H. de, Tank, B. & Oranje, A.P. (2009). Serum tryptase and SCORMA (SCORing MAstocytosis) index as disease severity parameters in childhood and adult cutaneous mastocytosis. Clinical & Experimental Dermatology, 34, 462-468. Hempel, G., Relling, M.V., Rossi, G. de, Stary, J., Lorenzo, P de, Valsecchi, M.G., Barisone, E., Boos, J. & Pieters, R. (2009). Pharmacokinetics of Daunorubicin and Daunorubicinol in infants with leukemia treated in the Interfant 99 protocol. Pediatric Blood & Cancer, 54, 355-360. Hoek, J. van den, Krijger, R.R. de, Ven, C.P. van de, Lequin, M.H. & Heuvel-Eibrink, M.M. van den (2009). Cystic nephroma, cystic partially differentiated nephroblastoma and cystic Wilm's tumor in children: a spectrum with therapeutic dilemmas. Urologia Internationalis, 82, 65-70. Hollink, I.H.I.M., Heuvel-Eibrink, M.M. van den & Zwaan, C.M. (2009). CEBPA resembles Roman god Janus. Blood, 113(26), 6501-6502. Hollink, I.H.I.M., Heuvel-Eibrink, M.M. van den, Zimmermann, M., Balgobind, B.V., Peters, T.C.J.M., Alders, M., Willasch, A.M., Kaspers, G.J.L., Trka, J., Baruchel, A, Graaf, S.S.N. de, Creutzig, U., Pieters, R., Reinhardt, D. & Zwaan, C.M. (2009). Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia. Blood, 113(23), 5951-5960. Hollink, I.H.I.M., Zwaan, C.M., Zimmermann, M., Peters, T.C.J.M., Pieters, R., Cloos, J, Kaspers, G.J.L., Graaf, S.S.N. de, Harbott, J., Creutzig, U., Reinhardt, D., Heuvel-Eibrink, M.M. van den & Thiede, C (2009). Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML. Leukemia, 23, 262-270.

Hulleman, E., Kazemier, K.M., Holleman, A., VanderWeele, D.J., Rudin, C.M., Broekhuis, M.J.C., Evans, W.E., Pieters, R. & Boer, M.L. den (2009). Inhibition of glycosis modulates prednisolone resistance in acute lymphoblastic leukemia cells. Blood, 113(9), 2014-2021. Hulleman, E., Broekhuis, M.J.C., Pieters, R. & Boer, M.L. den (2009). Pyruvate kinase M2 and prednisolone resistance in acute lymphoblastic leukemia. Haematologica, 94(9), 1322-1324. Jonge, R. de, Tissing, W.J.E., Hooijberg, J.H., Jansen, G., Kaspers, G.J.L., Lindemans, J., Peters, G.J. & Pieters, R. (2009). Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia. Blood, 113(10), 2284-2289. Kotani, A., Ha, D., Hsieh, J., Rao, P.K., Schotte, D., Boer, M.L. den, Armstrong, S.A. & Lodish, H.F. (2009). mir-128b is a potent glucocorticoid sensitizer in MLL-AF4 acute lymphocytic leukemia cells and exerts cooperative effects with mir-221. Blood, 114(19), 4169-4178. Lie Fong, S., Laven, J.S.E., Hakvoort-Cammel, F.G.A.J., Schipper, I., Visser, J.A., Themmen, A.P.N., Jong, F.H. de & Heuvel- Eibrink, M.M. van den (2009). Assessment of ovarian reserve in adult childhood cancer survivors using anti-mullerian hormone. Human Reproduction, 24(4), 982-990. Linden, M.H. van der, Valsecchi, M.G., Lorenzo, P de, Moricke, A., Janka, G., Leblanc, T.M., Felice, M., Biondi, A., Campbell, M., Hann, I., Rubnitz, J.E., Stary, J., Szczepanski, T., Vora, A., Ferster, A., Hovi, L., Silverman, L.B. & Pieters, R. (2009). Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol. Blood, 114(18), 3764-3768. Loh, M.L., Sakai, D.S., Flotho, C., Kang, M., Fliegauf, M., Archambeault, S., Mullighan, C.G., Chen, L., Bergstraesser, E., Bueso-Ramos, C.E., Emanuel, P.D., Hasle, H., Issa, J.M., Heuvel-Eibrink, M.M. van den, Locatelli, F., Stary, J., Trebo, M., Wlodarski, M., Zecca, M., Shannon, KM & Niemeyer, C.M. (2009). Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood, 114(9), 1859-1863. Lonnerholm, G., Valsecchi, M.G., Lorenzo, P de, Schrappe, M., Hovi, L., Campbell, M., Mann, G., Janka-Schaub, G., Li, C.K, Stary, J., Hann, I. & Pieters, R. (2009). Pharmacokinetics of high-dose methotrexate in infants treated for acute lymphoblastic leukemia. Pediatric Blood & Cancer, 52, 596-601. Meijerink, J.P.P., Boer, M.L. den & Pieters, R. (2009). New genetic abnormalities and treatment response in acute lymphoblastic leukemia. Seminars in Hematology, 46(1), 16-23. Meyer, C., Hofmann, J., Renneville, A., Zuna, J., Trka, J., Ben Abdelali, R., Macintyre, E., De Braekeleer, E., De Braekeleer, M., Delabesse, E., Oliveira, M.P. de, Cave, H., Clappier, E, Dongen, J.J.M. van, Balgobind, B.V., Heuvel-Eibrink, M.M. van den, Beverloo, H.B., Panzer-Grumayer, R., Teigler-Schlegel, A, Harbott, J., Kjeldsen, E., Schnittger, S., Koehl, U., Gruhn, B., Heidenreich, O., Chan, L.C., Yip, S.F., Krzywinski, M., Eckert, C., Moricke, A., Schrappe, M., Alonso, C.N., Schafer, B.W., Krauter, J, Lee, D.A., Stadt, U zur, Te Kronnie, G., Sutton, R., Izraeli, S, Trakhtenbrot, L., Lo Nigro, L., Tsaur, G., Fechina, L., Szczepanski, T., Strehl, S, Ilencikova, D., Molkentin, M., Burmeister, T., Dingermann, T., Klingebiel, T. & Marschalek, R (2009). New insights to the MLL recombinome of acute leukemias. Leukemia, 23, 1490-1499. Ouedraogo, AL, Bousema, T, Schneider, P., Vlas, S.J. de, Ilboudo-Sanogo, E, Cuzin-Ouattara, N, Nebie, I, Roeffen, W., Verhave, JP, Luty, AJF & Sauerwein, R (2009). Substantial Contribution of Submicroscopical Plasmodium falciparum Gametocyte Carriage to the Infectious Reservoir in an Area of Seasonal Transmission. PLoS One, 4(12). Peters, M., Appel, I.M., Cnossen, M.H., Breuning-Boers, J.M. & Heijboer, H. (2009). Sikkelcelziekte in de hielprikscreening. l. Nederlands Tijdschrift voor Geneeskunde, 153, B359. Raadt, B. de, Wijers, E. & Beishuizen, A. (2009). Ouders en een ernstig ziek kind - 'coping ' bij hoge en langdurige stress. Ouderschap en Ouderbegeleiding, 12, 12-18. Real, P.J., Tosello, V., Palomero, T., Castillo, M., Hernando, E., Stanchina, E. de, Sulis, M.L., Barnes, K., Sawai, C., Homminga, I., Meijerink, J.P.P., Aifantis, I., Basso, G., Cordon-Cardo, C., Ai, W. & Ferrando, A.A. (2009). y-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nature Medicine, 15(1), 50-58. Schotte, D., Chau, J.C.K., Sylvester, G., Liu, G., Chen, C, Velden, V.H.J. van der, Broekhuis, M.J.C., Peters, T.C.J.M., Pieters, R. & Boer, M.L. den (2009). Identification of new microrna genes and aberrant microrna profiles in childhood acute lymphoblastic leukemia. Leukemia, 23, 313-322. Segers, H., Heyden, J.C. van der, Akker, E.L.T. van den, Krijger, R.R. de, Zwaan, C.M. & Heuvel-Eibrink, M.M. van den (2009). Cushing syndrome as a presenting symptom of renal tumors in children. Pediatric Blood & Cancer, 53, 211-213. Simonis, M.J., Klous, P.M., Homminga, I., Galjaard, R.J.H., Rijkers, EJ, Grosveld, F.G., Meijerink, J.P.P. & Laat, W.L. de (2009). High-resolution identification of balanced and complex chromosomal rearrangements by 4C technology. Nature Methods, 6(11), 837-842. Stumpel, D.J.P.M., Schneider, P., Roon, E.H.J. van, Boer, J.M., Lorenzo, P de, Valsecchi, M.G., Menezes, R.X. de, Pieters, R. & Stam, R.W. (2009). Specific promoter methylation identifies different subgroups of MLL-rearranged infant acure lymphoblastic leukemia, influences clinical outcome, and provides therapeutic options. Blood, 114(27), 5490-5498. Stutterheim, J., Gerritsen, A., Zappeij-Kannegieter, L., Yalcin, B., Dee, R., Noesel, M.M. van, Berthold, F., Versteeg, R., Caron, H.N., Schoot, C.E. van der & Tytgat, G.A.M. (2009). Detecting minimal residual disease in neuroblastoma: the superiority of a panel of real-time quantitative PCR markers. Clinical Chemistry, 55(7), 1316-1326.

Tallen, G., Dworzak, M, Gadner, H., Masera, G., Schrappe, M., Biondi, A., Vassal, G, Pieters, R., Jazbec, J., Morland, B. & Creutzig, U. (2009). Imperatieve continual support by the European Community for future advances in paediatric oncology in Europe: meeting report of the EC-funded science-communication project DIRECT "Overcoming Cancer with Research. Magazine of European Medical Oncology, 2, 234-245. Tosello, V., Mansour, MR, Barnes, K., Paganin, M, Sulis, M.L., Jenkinson, S., Allen, C.G., Gale, RE, Linch, DC, Palomero, T., Real, P., Murty, VVVS, Yao, X., Richards, S.M., Goldstone, A., Rowe, J., Basso, G., Wiernik, P.H., Paietta, E., Pieters, R., Horstmann, M, Meijerink, J.P.P. & Ferrando, A.A. (2009). WT1 mutations in T-ALL. Blood, 114(5), 1038-1045. Veerman, A.J., Kamps, W.A., Berg, H., Berg, E. van den, Bokkerink, JPM, Bruin, M.C.A., Heuvel-Eibrink, M.M. van den, Korbijn, C.M., Korthof, ET, Pal, K. van der, Stijnen, Th., Weel-Sipman, M.H. van, Weerden, J.F. van, Wering, E.R. van & Does - van den Berg, A. van der (2009). Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004). Lancet Oncology, 10, 957-966. Velden, V.H.J. van der, Corral, L., Valsecchi, M.G., Jansen, M.W.J.C., Lorenzo, P de, Gazzaniga, G., Panzer-Grümayer, E.R., Schrappe, M., Schrauder, A, Meyer, C., Marschalek, R, Nigro, L.L., Metzler, M., Basso, G., Mann, G., Boer, M.L. den, Biondi, A., Pieters, R. & Dongen, J.J.M. van (2009). Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia, 23, 1073-1079. Vlaardingerbroek, H., Flier, M. van der, Borgstein, J.A., Lequin, M.H. & Sluis, I.M. van der (2009). Fatal Aspergillus Rhinosinusitis During Induction Chemotherapy in a Child With Acute Lymphoblastic Leukemia. Journal of Pediatric Hematology Oncology, 31(5), 367-369. Vries, A. de, Bredius, R.G.M., Lankester, A.C., Trebo, M., Sedlacek, P., Niemeyer, C.M., Zecca, M., Locatelli, F. & Heuvel- Eibrink, M.M. van den (2009). HLA-indentical umbilical cord blood transplantaton from a sibling donor in juvenile myelomonocytic leukemia. Haematologica, 94(2), 302-304. Vries, M.C. de & Zwaan, C.M. (2009). Mogelijkheden tot uitbreiden van geneesmiddelenonderzoek bij kinderen. Tijdschrift voor Kindergeneeskunde, 77(2), 59-66. Willasch, A.M., Gruhn, B., Kalinova, M., Schneider, G., Kreyenberg, H., Steinbach, D., Weber, G., Hollink, I.H.I.M., Zwaan, C.M., Biondi, A., Velden, V.H.J. van der, Reinhardt, D., Gazzaniga, G., Bader, P. & Trka, J. (2009). Standardization of WT1 mrna quantitation for minimal residual disease monitoring in childhood AML and implications of WT1 gene mutations: a European multicenter study. Leukemia, 23, 1472-1479. Zuna, J., Prouzova, Z., Kalina, T., Lizcova, L., Zemanova, Z, Muzikova, K, Rahmatova, S., Meijerink, J.P.P. & Trka, J. (2009). Backtracking of ALL to cord blood. Leukemia Research, 33, e107-e108. Part of book - abstract Pieters, R. & Caron, H.N. (2009). Nieuwsvormingen. In J.L. Van den Brande & G. Derksen-Lubsen (Eds.), Leerboek Kindergeneeskunde (pp. 500-516). Utrecht: de Tijdstroom.

EMC MM-02-72-01 - Lymphoid differentiation and immunodeficiencies Programme design in brief One of the most intriguing features of the specific immune system is the generation of mature B and T lymphocytes that carry immunoglobulin (Ig) molecules and T-cell receptors (TCR), which are highly specific for antigens, even when these cells have not encountered the antigens before. The generation and selection of a diverse and flexible specificity repertoire by lymphocytes is dependent on a series of developmental cell fate decisions, including the induction and regulation of Ig and TCR gene rearrangements. These decisions are implemented by the activity of specific transcription factors and enzyme systems and occur at specific checkpoints, controlled by signaling pathways downstream of antigen receptors and their immature forms. In particular, the research aims of this program comprise: - To study the role of lymphoid-specific transcription factors that control the in vivo developmental program of lymphoid cells. - To investigate signal transduction routes that are crucial to stem cell self-renewal and differentiation into lymphoid cells. - To unravel the essential steps in the induction and execution of Ig/TCR gene rearrangements in precursor-b and -T cells, e.g. using immunodeficiencies as model. - To characterize the signal transduction pathways downstream of the antigen receptors, which are essential for survival, selection and developmental progression of lymphoid cells. - To investigate how defects in the regulation of differentiation and proliferation steps during lymphoid development result in immunodeficiencies or lymphoid malignancies. - To translate the obtained knowledge on normal lymphoid differentiation and gene defects into novel diagnostics and opportunities for gene therapy in patients with primary immunodeficiencies (PID). Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot immunology 8,47 2,06 1,25 1 12,78 pediatrics 0,06 0 0 0 0,06 Total 8,53 2,06 1,25 1 12,84 1 0 1 2 42 1 13 58 Thesis Mitalas, E. (2009, november 11). Identification of factors affecting the outcome of transanal advancement flap repair for high transsphincteric fistulas. EUR. Prom./coprom.: Prof.Dr. R. Benner, Prof.Dr. H.W. Tilanus & Dr. W.R. Schouten. Wolf, MG (2009, maart 20). Understanding amyloidogenesis through computer simulations. Tackling the sampling problem by using replica exchange umbrella sampling and hydrogen bond biasing potentials. extern. Prom./coprom.: SW de Leeuw, Prof.Dr. J.D. Laman & JA Jongejan. Article/Letter to the editor Berg, J.W. van den, Dik, W.A., Khan, N.A., Bonthuis, F., Holten-Neelen, J.C.P.A., Ijzermans, J.N.M., Benner, R. & Bruin, R.W.F. de (2009). The synthetic human chorionic gonadotropin (HCG) related oligopeptide LQGV reduces CLP induced mortality and inflammation. Shock, 32, 9-9. Bruinsma, M., Soest, P.L. van, Leenen, P.J.M., Lowenberg, B., Cornelissen, J.J. & Braakman, E. (2009). Keratinocyte Growth Factor Improves Allogeneic Bone Marrow Engraftment through a CD4(+)Foxp3(+) Regulatory T Cell-Dependent Mechanism. Journal of Immunology, 182(12), 7364-7369. Burg, M. van der, Ijspeert, H., Verkaik, N.S., Turul, T., Wiegant, W.W., Morotomi-Yano, K, Mari, PO, Tezcan, I., Chen, DJ, Zdzienicka, M.Z., Dongen, J.J.M. van & Gent, D.C. van (2009). A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. Journal of Clinical Investigation, 119(1), 91-98. Burg, M. van der, Dongen, J.J.M. van & Gent, D.C. van (2009). DNA-PKcs deficiency in human: long predicted, finally found. Current Opinion in Allergy and Clinical Immunology, 9(6), 503-509. Burg, M. van der, Zelm, M.C. van & Dongen, J.J.M. van (2009). Molecular Diagnostics of Primary Immunodeficiencies Benefits and Future Challenges. Advances in Experimental Medicine and Biology, 634, 231-241. Daele, P.L.A. van (2009). Commentary: Think anaphylaxis. British Medical Journal (International Edition), 338. Daele, P.L.A. van, Beukenkamp, B.S., Kleinekoort, W.M.C., Valk, P.J.M., Laar, J.A.M. van, Hagen, P.M. van & Velden, V.H.J. van der (2009). Immunophenotyping of mast cells: a sensitive and specific diagnostic tool for systemic mastocytosis. Netherlands Journal of Medicine, 67(4), 142-146. Denollet, J, Schiffer, AA, Kwaijtaal, M, Hooijkaas, H., Hendriks, EH, Widdershoven, JW & Kupper, N (2009). Usefulness of Type D Personality and Kidney Dysfunction as Predictors of Interpatient Variability in Inflammatory Activation in Chronic Heart Failure. American Journal of Cardiology, 103(3), 399-404. Duijts, L., Bakker-Jonges, L.E., Labout, J.A.M., Jaddoe, V.W.V., Hofman, A., Steegers, E.A.P., Dongen, J.J.M. van, Hooijkaas, H. & Moll, H.A. (2009). Fetal Growth Influences Lymphocyte Subset Counts at Birth: The Generation R Study. Neonatology, 95(2), 149-156. Duijts, L., Bakker-Jonges, L.E., Mook, D.O., Labout, J.A.M., Hofman, A., Duijn, C.M. van, Dongen, J.J.M. van, Hooijkaas, H., Moll, H.A. & Jaddoe, V.W.V.K. (2009). Variation in the IGF-1 gene is associated with lymphocyte subset counts in neonates: The Generation R study. Clinical Endocrinology, 70, 53-59.

Epker, J.L., Biezen, P. van, Daele, P.L.A. van, Gelder, T. van, Vossen, A.C.T.M. & Saase, J.L.C.M. van (2009). Progressive multifocal leukoencephalopathy, a review and an extended report of five patients with different immune compromised states. European Journal of Internal Medicine, 20(3), 261-267. Ham, S.M. van, Samsom, J.N., Bos, N.A., Damoiseaux, J., Laman, J.D. & Wauben, M.H.M. (2009). Vaccination immunology: Prevention and beyond. NVVI-Dutch society for immunology course Lunteren, 2008, April 3-4. Immunology Letters, 122, 101-103. Hamburg, J.P. van, Bruijn, J.W. de, Ribeiro de Almeida, C.A., Dingjan, G.M. & Hendriks, R.W. (2009). Gene expression profiling in mice with enforced Gata3 expression reveals putative targets of Gata3 in double positive thymocytes. Molecular Immunology, 46(16), 3251-3260. Huizinga, H.G., Hintzen, R.Q., Assink, K., Meurs, M. van & Amor, S. (2009). T-cell responses to neurofilament light protein are part of the normal immune repertoire. International Immunology, 21(4), 433-441. Ionita, MG, Vink, A., Dijke, I.E., Laman, J.D., Peeters, W, Kraak, PH van der, Moll, F.L., Vries, JPPM de, Pasterkamp, G. & Kleijn, D.P.V. de (2009). High Levels of Myeloid-Related Protein 14 in Human Atherosclerotic Plaques Correlate With the Characteristics of Rupture-Prone Lesions. Arteriosclerosis Thrombosis & Vascular Biology, 29(8), 1220-1227. Jhunjhunwala, S, Zelm, M.C. van, Peak, MM & Murre, C. (2009). Chromatin Architecture and the Generation of Antigen Receptor Diversity. Cell, 138(3), 435-448. Kap, Y.S., Meurs, M. van, Driel, N van, Koopman, G, Melief, J.A.M., Brok, H.P.M., Laman, J.D. & Hart, B.A. 't (2009). A Monoclonal Antibody Selection for Immunohistochemical Examination of Lymphoid Tissues From Non-human Primates. Journal of Histochemistry & Cytochemistry, 57(12), 1159-1167. Khan, N.A., Susa, D., Berg, J.W. van den, Huisman, M., Ameling, M.H., Engel, S. van den, Roest, H.P., Ijzermans, J.N.M., Dik, W.A., Benner, R. & Bruin, R.W.F. de (2009). Amelioration of renal ischaemia-reperfusion injury by synthetic oligopeptides related to human chorionic gonadotropin. Nephrology Dialysis Transplantation, 24(9), 2701-2708. Kim, BS, Miyagawa, F, Cho, YH, Bennett, CL, Clausen, B.E. & Katz, SI (2009). Keratinocytes Function as Accessory Cells for Presentation of Endogenous Antigen Expressed in the Epidermis. Journal of Investigative Dermatology, 129(12), 2805-2817. Koeijvoets, K.C.M.C., Mooijaart, SP, Dallinga-Thie, G.M., Defesche, J.C., Steyerberg, E.W., Westendorp, R.G.J., Kastelein, J.J.P., Hagen, P.M. van & Sijbrands, E.J.G. (2009). Complement factor H Y402H decreases cardiovascular disease risk in patients with familial hypercholesterolaemia. European Heart Journal, 30(5), 618-623. Kool, M., Nimwegen, M. van, Willart, M.A.M., Muskens, A.M., Boon, L., Smit, J.J., Coyle, A, Clausen, B.E., Hoogsteden, H.C., Lambrecht, B.N. & Hammad, H. (2009). An Anti-Inflammatory Role for Plasmacytoid Dendritic Cells in Allergic Airway Inflammation. Journal of Immunology, 183(2), 1074-1082. Krop, M., Veghel, R. van, Garrelds, I.M., Bruin, R.J.A. de, Gool, J.M.G. v., Meiracker, A.H. van den, Thio, M, Daele, P.L.A. van & Danser, A.H.J. (2009). Cardiac Renin Levels Are Not Influenced by the Amount of Resident Mast Cells. Hypertension, 54(2), 315-321. Lanjouw, E., Daele, P.L.A. van, Raes, M.P.E. & Meijden, W.I. van der (2009). Consecutively Acquired Sexually Transmitted Infections Mimicking Crohn's Disease. American Journal of Gastroenterology, 104(2), 532-533. Loomans, C.J.M., Haperen, M.J. van, Duijs, J.M., Verseyden, C., Crom, R. de, Leenen, P.J.M., Drexhage, H.A., Boer, H.C. de, Koning, E.J.P. de, Rabelink, T.J., Staal, F.J.T. & Zonneveld, A.J. van (2009). 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Rakhmanov, M., Keller, B., Gutenberger, S, Foerster, C., Hoenig, M, Driessen, G.J.A., Burg, M. van der, Dongen, J.J.M. van, Wiech, E., Visentini, M., Quinti, I, Prasse, A., Voelxen, N., Salzer, U, Goldacker, S, Fisch, P., Eibel, H., Schwarz, K., Peter, HH & Warnatz, K (2009). Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells. Proceedings of the National Academy of Sciences of the United States of Ame, 106(32), 13451-13456. Ribechini, E, Leenen, P.J.M. & Lutz, M.B. (2009). Gr-1 antibody induces STAT signaling, macrophage marker expression and abrogation of myeloid-derived suppressor cell activity in BM cells. European Journal of Immunology, 39(12), 3538-3551. Ribeiro de Almeida, C.A., Heath, H.E., Krpic, S., Dingjan, G.M., Hamburg, J.P. van, Bergen, I.M., Nobelen, S. van de, Sleutels, F., Grosveld, F., Galjart, N. & Hendriks, R.W. (2009). Critical Role for the Transcription Regulator CCCTC-Binding Factor in the Control of Th2 Cytokine Expression. Journal of Immunology, 182(2), 999-1010.

Rossum, AP van, Vlasveld, LT, Vlasveld, IN, Jansen, P.M., Dik, W.A., Hooijkaas, H. & Castel, A (2009). Granulocytosis and thrombocytosis in renal cell carcinoma: a pro-inflammatory cytokine response originating in the tumour. Netherlands Journal of Medicine, 67(5), 191-194. Schouten, O., Boersma, E., Hoeks, S.E., Benner, R., Urk, H. van, Sambeek, M.R.H.M. van, Verhagen, H.J.M., Khan, N.A., Dunkelgrun, M., Bax, J.J. & Poldermans, D. (2009). Fluvastatin and Perioperative Events in Patients Undergoing Vascular Surgery. New England Journal of Medicine, 361(10), 980-989. Tanaka, H., Matsushima, H, Nishibu, A, Clausen, B.E. & Takashima, A (2009). Dual Therapeutic Efficacy of Vinblastine as a Unique Chemotherapeutic Agent Capable of Inducing Dendritic Cell Maturation. Cancer Research, 69(17), 6987-6994. Timmermans, F, Velghe, I, Vanwalleghem, L, Smedt, M. de, Coppernolle, S Van, Taghon, T., Moore, HD, Leclercq, G., Langerak, A.W., Kerre, T, Plum, J. & Vandekerckhove, B (2009). 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EMC MM-02-72-02 - Immune regulation and autoimmunity Programme design in brief The Dept. Immunology focuses on lymphatic and myeloid differentiation, immune regulation and inflammation. Chronic inflammation and autoimmune disease are leading causes of morbidity, psychosiocal burden and economic loss in Western societies. In view of the central role of innate and adaptive immunity in these diseases, detailed insight into immune regulation is a requirement for elucidation of immunopathogenesis, and the rational development of diagnosis and (immuno)therapy. The Postgraduate School Molecular Medicine has an extensive and active program in immune regulation and autoimmunity, consisting of a close collaboration between clinical and pre-clinical departments. Chronic inflammatory diseases of interest are type I diabetes, thyroiditis, affective disorders and schizophrenia (all having a major immuno-neuro-endocrine component), rheumatoid arthritis (RA) and the related disorder Sjögren s syndrome, psoriasis, and the demyelinating diseases multiple sclerosis (MS) and Guillain-Barré syndrome (GBS). The general premise is that the immune mechanisms driving the multifactorial pathophysiology in these different diseases of interest are highly analogous. The fundamental immunological concepts we address within the frame of these diseases are: - immune (de)regulation by antigen presenting cells, notably dendritic cells and macrophages - functional T and B lymphocyte subsets - influences of the neuroendocrine system on leukocyte-target organ interaction - microbial compounds driving chronic inflammation - molecular mimicry and antibody neurotoxicity Development of innovative animal models including conditional and cell type-specific transgenesis is integral part of this approach. Research topics include basic immunopathogenic mechanisms (e.g. molecular mimicry in GBS and MS); immune-endocrine interactions (e.g. in the pathogenesis of postpartum thyroiditis and post partum psychosis and in the linked amelioration of MS, thyroiditis and RA during pregnancy); molecular signaling pathways in chronic autoimmune inflammation (e.g. transcription factors in psoriasis and major psychiatric diseases, inflammatory gene signature expressions in monocytes in major psychiatric diseases, epi-genetic regulation of these various genes); experimental immunotherapy (e.g. antibodies against costimulatory molecules and cytokines); immune regulation by external factors (e.g. UV irradiation and skin inflammation, infection and MS activity); immune function and disease activity in MS; and an immune deregulation by an aberrant development and activity of antigen presenting cells (e.g. in diabetes, Sjögren s syndrome, thyroiditis, atherosclerosis, affective disorders, schizophrenia and histiocytosis). Close collaboration with clinical researchers who are well-trained in immunology allows joint elaboration of scientifically relevant research questions, construction of well-characterized patient cohorts, and evaluation of experimental (immuno)therapy. Specifically, the departments of Neurology (workgroup leaders Prof. Dr. R.Q. Hintzen, Dr. B.C. Jacobs, Prof. Dr. P.A. van Doorn), Dermatology (Prof. Dr. H.A.M. Neuman, Prof. Dr. E.P. Prens), Rheumatology (Prof. Dr. J.M.W. Hazes, Dr. E. Lubberts, Dr. R.J.E.M. Dolhain) and Internal Medicine (Dr. P.M. van Hagen) have structurally integrated their immune research groups within the department of Immunology. There is additional close collaboration on the role of microbial compounds in immune regulation with the departments of Virology (Prof. Dr. A.D.M.E. Osterhaus), Medical Microbiology and Infectious Diseases (Prof. Dr. H.A. Verbrugh, Dr. H.P. Endtz, Prof. Dr. A. van Belkum). Furthermore, the departments of Internal Medicine (Prof. Dr. A.J. van der Lelij, Prof. Dr. T.J. Visser) and Immunology collaborate on thyroid autoimmune disease and diabetes in schizophrenia, and the department of Psychiatry (Prof. Dr. M.W. Hengeveld, Prof. Dr. S. Kushner, Dr. V. Bergink, Dr. J.M. van Beveren) and Immunology on immune aberrancies in major affective disorders and schizophrenia. Combining researchers with different backgrounds (e.g. the clinic, molecular biology, cellular immunology) working on these different diseases in a single integrated team significantly stimulates scientific discussion and output. The joint expertise allows coverage of a broad area of approaches and technology, ranging from patient cohort studies via functional in vitro and genetic analyses of patient material to several animal disease models in rodents and non-human primates. The MS research is organized in the MS Centre ErasMS (head Prof. Dr. R.Q. Hintzen), supported by a 4 year program grant from the Dutch MS Research Foundation. The Biomedical Primate Research Centre (Dr. B.A. `t Hart and colleagues, Rijswijk) participates in this MS Centre. The research on inflammation as one of the causal factors of major psychiatric disorders is supported by a large scale EU-KP-7 grant (MOODINFLAME, 19 partners in 11 countries, coordinator ErasmusMC) and a NWO-TOP program grant. In this work there is extensive collaboration with Prof. Dr. W.A. Nolen (Dept of Psychiatry, Groningen) en Prof. Dr. R.S. Kahn (Dept of Psychiatry, Utrecht). Diabetes research is supported by a grant from the DFN and the JDRF. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot dermatology 0,03 0 0 0 0,03 immunology 5,34 3 1,3 0,03 9,67 neurology 0,09 0 0,4 0 0,49 rheumatology 0,09 0 0 0 0,09 Total 5,55 3 1,7 0,03 10,28 4 0 0 4 29 4 2 39 Thesis Geijn, F.E. van de (2009, december 17). Mannose-binding lectin in pregnancy course and outcome. Studies in healthy women and rheumatoid arthritis patients. EUR. Prom./coprom.: Prof.Dr. J.M.W. Hazes, Prof.Dr. J.D. Laman & R.J.E.M. Dolhain. Padmos, R.C. (2009, februari 25). Inflammatory monocytes in bipolar disorder and related endocrine autoimmune diseases. EUR. Prom./coprom.: Prof.Dr. H.A. Drexhage. Racz, E. (2009, november 19). Molecular targets of narrow-band UVB phototherapy in psoriasis. EUR. Prom./coprom.: Prof.Dr. E.P. Prens, Prof.Dr. J.D. Laman & Drs. C.T.E. van der Fits. Zwam, M. van (2009, februari 04). Immunological function of draining lymph nodes in multiple sclerosis and animal models. EUR. Prom./coprom.: Prof.Dr. J.D. Laman & Dr. L.A. Boven.

Article/Letter to the editor Aksentijevich, I, Masters, SL, Ferguson, PJ, Dancey, P, Frenkel, J, Royen-Kerkhoff, A van, Laxer, R., Tedgard, U, Cowen, EW, Pham, TH, Booty, M, Estes, JD, Sandler, NG, Plass, N, Stone, D.L., Turner, ML, Hill, S, Butman, JA, Schneider, R, Babyn, P, El-Shanti, HI, Pope, E, Barron, K, Bing, XY, Laurence, A, Lee, CCR, Chapelle, D, Clarke, GI, Ohson, K, Nicholson, M, Gadina, M, Yang, B, Korman, BD, Gregersen, P.K., Hagen, P.M. van, Hak, A.E., Huizing, M, Rahman, P, Douek, DC, Remmers, E.F., Kastner, DL & Goldbach-Mansky, R (2009). An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist. New England Journal of Medicine, 360(23), 2426-2437. Belkum, A. van, Jacobs, B.C., Beek, E. van, Louwen, R., Rijs, W. van, Debruyne, L, Gilbert, M., Li, J., Jansz, A, Megraud, F & Endtz, H.P. (2009). Can Campylobacter coli induce Guillain-Barre syndrome? European Journal of Clinical Microbiology & Infectious Diseases, 28(5), 557-560. Bergh, K. van den, Hooijkaas, H., Blockmans, D, Westhovens, R, Beeck, KO De, Verschueren, P, Dufour - van den Goorbergh, B.C.M., Merwe, J.P. van de, Fijak, M, Klug, J, Michiels, G, Devogelaere, B, Smedt, H De, Derua, R, Waelkens, E, Blanckaert, N & Bossuyt, X. (2009). Heterogeneous Nuclear Ribonucleoprotein H1, a Novel Nuclear Autoantigen. Clinical Chemistry, 55(5), 946-954. Cornelissen, F., Hamburg, J.P. van & Lubberts, E. (2009). The IL-12/IL-23 axis and its role in Th17 cell development, pathology and plasticity in arthritis. Current Opinion in Investigational Drugs, 10(5), 452-462. Daele, P.L.A. van, Kappen, J.H., Hagen, P.M. van & Laar, J.A.M. van (2009). Managing Behçet's disease: an update on current and emerging treatment options. Therapeutics and clinical risk management, 5, 385-390. Damoiseaux, J., Tervaert, JWC, Derksen, R, Hamann, D., Hooijkaas, H., Klasen, I, Kallenberg, C, Limburg, P & Smeenk, R (2009). Autoantibody Standardization in the Netherlands The Past, the Present, and the Future. Annals of the New York Academy of Sciences, 1173, 10-14. Dekker, M.J.H.J., Akker, E.L.T. van den, Koper, F.J.W., Manenschijn, L., Geleijns, K, Ruts, L., Rijs, W. van, Tio-Gillen, A.P., Doorn, P.A. van, Lamberts, S.W.J. & Jacobs, B.C. (2009). Effect of glucocorticoid receptor gene polymorphisms in Guillain- Barre syndrome. Journal of the Peripheral Nervous System, 14(2), 75-83. Fits, C.T.E. van der, Mourits, S., Voerman, J.S.A., Kant, M., Laman, J.D., Boon, L., Cornelissen, F.H.J., Mus, A.M.C., Florencia, E.F.I.I.I., Prens, E.P. & Lubberts, E. (2009). Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL- 23/IL-17 axis. Journal of Immunology, 182, 5836-5845. Hamburg, J.P. van, Mus, A.M., Bruijn, J.W. de, Vogel, L.L. de, Boon, L., Cornelissen, F., Asmawidjaja, P., Hendriks, R.W. & Lubberts, E. (2009). GATA-3 Protects Against Severe Joint Inflammation and Bone Erosion and Reduces Differentiation of Th17 Cells During Experimental Arthritis. Arthritis & Rheumatism, 60(3), 750-759. Hart, B.A. 't & Massacesi, L. (2009). Clinical, Pathological, and Immunologic Aspects of the Multiple Sclerosis Model in Common Marmosets (Callithrix jacchus). Journal of Neuropathology and Experimental Neurology, 68(4), 341-355. Hart, B.A. 't, Hintzen, R.Q. & Laman, J.D. (2009). Multiple sclerosis - a response-to-damage model. Trends in Molecular Medicine, 15(6), 235-244. Houliston, RS, Jacobs, B.C., Tio-Gillen, A.P., Verschuuren, J.J., Khieu, NH, Gilbert, M. & Jarrell, HC (2009). STD-NMR Used To Elucidate the Fine Binding Specificity of Pathogenic Anti-Ganglioside Antibodies Directly in Patient Serum. Biochemistry, 48(2), 220-222. Islam, Z., Belkum, A. van, Wagenaar, J.A., Cody, AJ, Boer, A.G. de, Tabor, H, Jacobs, B.C., Talukder, KA & Endtz, H.P. (2009). Comparative Genotyping of Campylobacter jejuni Strains from Patients with Guillain-Barre Syndrome in Bangladesh. PLoS One, 4(9). Islam, Z., Belkum, A. van, Cody, AJ, Tabor, H, Jacobs, B.C., Talukder, KA & Endtz, H.P. (2009). Pigs as Source for Toxigenic Corynebactedum ulcerans. Emerging Infectious Diseases, 15(8), 1316-1317. Jacobs, B.C., Wijnans, E.G., Sturkenboom, M.C.J.M. & Maas, N.A.T. van der (2009). Guillain-barré-syndroom en het nieuwe influenza A(H1N1)-virus. Nederlands Tijdschrift voor Geneeskunde, 153, 1490. Jacobs, B.C. & Willison, H.J. (2009). Peripheral neuropatheis. Biomarkers for axonal damage in immune-mediated neuropathy. Nature Reviews Neurology, 5(11), 584-585. Kappen, J.H., Dik, W.A., Dingjan, G.M., Daele, P.L.A. van, Hooijkaas, H., Hagen, P.M. van & Laar, J.A.M. van (2009). Cytokines in the colon of a patient with Behcet's disease. Arthritis Research & Therapy, 11(4). Kappen, J.H., Wallace, GR, Stolk, L., Rivadeneira Ramirez, F., Uitterlinden, A.G., Daele, P.L.A. van, Laman, J.D., Kuijpers, R.W.A.M., Baarsma, G.S., Stanford, MR, Fortune, F, Madanat, W, Hagen, P.M. van & Laar, J.A.M. van (2009). Low prevalence of NOD2 SNPs in Behcet's disease suggests protective association in Caucasians. Rheumatology, 48(11), 1375-1377. Kuijf, M.L., Eurelings, M., Tio-Gillen, A.P., Doorn, P.A. van, Berg, L.H. van den, Hooijkaas, H., Stork, J, Notermans, N.C. & Jacobs, B.C. (2009). Detection of anti-mag antibodies in polyneuropathy associated with IgM monoclonal gammopathy. Neurology, 73(9), 688-695.

Kuitwaard, K., Gelder, J. van, Tio-Gillen, A.P., Hop, W.C.J., Gelder, T. van, Toorenenbergen, A.W. van, Doorn, P.A. van & Jacobs, B.C. (2009). Pharmacokinetics of Intravenous Immunoglobulin and Outcome in Guillain-Barre Syndrome. Annals of Neurology, 66(5), 597-603. Kuitwaard, K., Koningsveld, R. van, Ruts, L., Jacobs, B.C. & Doorn, P.A. van (2009). Recurrent Guillain-Barre syndrome. Journal of Neurology Neurosurgery and Psychiatry, 80(1), 56-59. Laar, J.A.M. van, Kappen, J.H., Daele, P.L.A. van & Hagen, P.M. van (2009). Do synovial biopsies help to support evidence for involvement of innate immunity in the immunopathology of Behcet's disease? Arthritis Research & Therapy, 11(2). Mortensen, NP, Kuijf, M.L., Ang, C.W., Schiellerup, P, Krogfelt, KA, Jacobs, B.C., Belkum, A. van, Endtz, H.P. & Bergman, M.P. (2009). Sialylation of Campylobacter jejuni lipo-oligosaccharides is associated with severe gastro-enteritis and reactive arthritis. Microbes and Infection, 11(12), 988-994. Neuteboom, R.F., Verbraak, E., Voerman, J.S.A., Meurs, M. van, Steegers, E.A.P., Groot, C.J.M. de, Laman, J.D. & Hintzen, R.Q. (2009). First trimester interleukin 8 levels are associated with postpartum relapse in multiple sclerosis. Multiple Sclerosis, 15(11), 1356-1358. Neuteboom, R.F., Verbraak, E., Voerman, J.S.A., Meurs, M. van, Steegers, E.A.P., Groot, C.J.M. de, Laman, J.D. & Hintzen, R.Q. (2009). Serum leptin levels during pregnancy in multiple sclerosis. Multiple Sclerosis, 15(8), 907-912. Nikolic, T., Coppens, J.M.C., Leenen, P.J.M., Drexhage, H.A. & Versnel, M.A. (2009). Plasmacytoid dendritic cells in autoimmune diabetes - Potential tools for immunotherapy. Immunobiology, 214(9-10), 791-799. Padmos, R.C., Baal, GCM van, Vonk, R., Wijkhuijs, J.M., Kahn, R.S., Nolen, W.A. & Drexhage, H.A. (2009). Genetic and Environmental Influences on Pro-Inflammatory Monocytes in Bipolar Disorder A Twin Study. Archives of General Psychiatry, 66(9), 957-+. Pluchino, S, Gritti, A, Blezer, E., Amadio, S, Brambilla, E, Borsellino, G, Cossetti, C, Carro, U Del, Comi, G., Hart, B.A. 't, Vescovi, A & Martino, G. (2009). Human Neural Stem Cells Ameliorate Autoimmune Encephalomyelitis in Non-human Primates. Annals of Neurology, 66(3), 343-354. Putten, C. van, Zuiderwijk-Sick, EA, Straalen, L van, Geus, E.D. de, Boven, L.A., Kondova, I, IJzerman, AP & Bajramovic, J.J. (2009). Differential Expression of Adenosine A(3) Receptors Controls Adenosine A(2A) Receptor-Mediated Inhibition of TLR Responses in Microglia. Journal of Immunology, 182(12), 7603-7612. Steensel, L. van, Paridaens, A.D.A., Schrijver, B., Dingjan, G.M., Daele, P.L.A. van, Hagen, P.M. van, Bosch, W.A. van den, Drexhage, H.A., Hooijkaas, H. & Dik, W.A. (2009). Imatinib Mesylate and AMN107 Inhibit PDGF-Signaling in Orbital Fibroblasts: A Potential Treatment for Graves' Ophthalmopathy. Investigative Ophthalmology & Visual Science, 50(7), 3091-3098. Wildenberg, M.E., Coppens, J.M.C., Helden - Meeuwsen, C.G. van, Bootsma, H, Vissink, A, Rooijen, N. van, Merwe, J.P. van de, Drexhage, H.A. & Versnel, M.A. (2009). Increased frequency of CD16+monocytes and the presence of activated dendritic cells in salivary glands in primary Sjogren syndrome. Annals of the Rheumatic Diseases, 68(3), 420-426. Zwam, M. van, Huizinga, H.G., Melief, J.A.M., Wierenga-Wolf, A.F., Meurs, M. van, Voerman, J.S.A., Biber, KPH, Boddeke, H.W.G.M., Hopken, UE, Meisel, C, Meisel, A, Bechmann, I, Hintzen, R.Q., Hart, B.A. 't, Amor, S., Laman, J.D. & Boven, L.A. (2009). Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE. Journal of Molecular Medicine-Jmm, 87(3), 273-286. Zwam, M. van, Huizinga, H.G., Heijmans, N, Meurs, M. van, Wierenga-Wolf, A.F., Melief, J.A.M., Hintzen, R.Q., Hart, B.A. 't, Amor, S., Boven, L.A. & Laman, J.D. (2009). Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing experimental autoimmune encephalomyelitis. Journal of Pathology, 217(4), 543-551. Part of book - abstract Kallenberg, C.G.M. & Drexhage, H.A. (2009). Auto-immuniteit. In GT Rijkers, FGM Kroese, CGM Kallenberg & RHWM Derksen (Eds.), Immunologie (pp. 293-326). Houten: Bohn Stafleu van Loghum. Book editorship Pekelharing, J.M., Hooijkaas, H., Punt, J.M.H.M., Smeets, L.C. & Souverijn, J.H.M. (Eds.). (2009). Handboek Medische laboratoriumdiagnostiek. Houten: Prelum uitgevers.

EMC MM-02-72-03 - Diagnosis, classification and treatment evaluation of leukemias and malignant lymphomas Programme design in brief This research program focusses on the diagnosis and classification of leukemias and malignant lymphomas as well as on the evaluation of treatment effectiveness during follow-up via detection of low frequencies of malignant cells, i.e. detection of `minimal residual disease (MRD). The research program combines molecular and cellular studies on normal and malignant hematopoiesis, particularly focusing on immature lymphoid differentiation. The research program consists of three main projects: Normal and aberrant V(D)J recombination in leukemias and malignant lymphomas: basic aspects and diagnostic applications. Project leader: A.W. Langerak. One of the key processes during early lymphoid differentiation concerns the rearrangements of the immunoglobulin (Ig) and T-cell receptor (TCR) genes. This so-called V(D)J recombination process is tightly regulated. Nevertheless, aberrant V(D)J recombination activity can induce aberrant Ig/TCR gene rearrangements, which involve oncogenes. Insight into normal and oncogenic rearrangements can be translated into better diagnosis and classification of lymphoid malignancies. Immunobiology of acute leukemia and treatment evaluation. Project leader: V.H.J. van der Velden. Although most patients with acute leukemia achieve remission according to cytomorphological and clinical criteria, many patients relapse and die from their disease. Therefore sensitive techniques are needed to monitor the patients for the presence of MRD during and after treatment in order to obtain better insight into the in vivo effectiveness of treatment, with flow cytometric immunophenotyping using aberrant marker expression and detection of tumor-associated proteins or with molecular MRD techniques via PCR analysis of Ig/TCR gene rearrangements and chromosome aberrations. Gene expression profiles in immature lymphoid cells and acute lymphoblastic leukemias. Project leader: F.J.Th. Staal. Gene expression profiles determine the differentiation lineage, developmental stage, and activation stage of the involved cells. Just like in any other cell type, regulation of gene expression in lymphocytes is largely controlled at the level of transcriptional initiation by transcription factors and transcriptional repressors. The study focusses on transcription factors and signaling routes that are controlling the most immature steps of lymphoid differentiation. In parallel, the abnormal regulation of gene expression in acute lymphoblastic leukemias is extensively studied and compared to corresponding normal immature T and B cell subpopulations. Results of these comparative studies will be exploited for developing new diagnostic tools. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot immunology 0,58 1 0,8 0 2,38 Total 0,58 1 0,8 0 2,38 0 0 0 0 12 0 10 22 Article/Letter to the editor Blink, M., Buitenkamp, T.D., Wouwe, J.P. van der, Wering, E.R. van, Velden, V.H.J. van der & Zwaan, C.M. (2009). Ontwikkelingen in de diagnostiek en behandeling van leukemie bij kinderen met downsyndroom. Tijdschrift voor Kindergeneeskunde, 77(2), 52-58. Brugge, P.J. ter, Ta, T.B.V., Bruijn, J.W. de, Keijzers, G., Maas, A., Gent, D.C. van & Hendriks, R.W. (2009). A mouse model for chronic lymphocytic leukemia based on expression of the SV40 large T antigen. Blood, 114(1), 119-127. Cilloni, D, Renneville, A., Hermitte, F, Hills, RK, Daly, S, Jovanovic, JV, Gottardi, E., Fava, M, Schnittger, S., Weiss, T, Jansen, J.H., Izzo, B, Nomdedeu, J, Heijden, A van der, Reijden, B.A. van der, Velden, V.H.J. van der, Ommen, H, Preudhomme, C, Saglio, G. & Grimwade, D. (2009). Real-Time Quantitative Polymerase Chain Reaction Detection of Minimal Residual Disease by Standardized WT1 Assay to Enhance Risk Stratification in Acute Myeloid Leukemia: A European LeukemiaNet Study. Journal of Clinical Oncology, 27(31), 5195-5201. Csinady, E, Velden, V.H.J. van der, Joas, R, Fischer, S, Vries, J.F. de, Beverloo, H.B., Konig, M, Potschger, U, Dongen, J.J.M. van, Mann, G., Haas, O.A. & Panzer-Grumayer, ER (2009). Chromosome 14 copy number-dependent IGH gene rearrangement patterns in high hyperdiploid childhood B-cell precursor ALL: implications for leukemia biology and minimal residual disease analysis. Leukemia, 23(5), 870-876. Dijkstra, M.K., Lom, K. van, Tielemans, D., Elstrodt, F., Langerak, A.W., Veer, M.B. van t & Jongen-Lavrencic, M. (2009). 17p13/TP53 deletion in B-CLL patients is associated with microrna-34a downregulation. Leukemia, 23(3), 625-627. Figueroa, ME, Wouters, B.J., Skrabanek, L, Glass, J, Li, YS, Erpelinck - Verschuren, C.A.J., Langerak, A.W., Lowenberg, B., Fazzari, M, Greally, JM, Valk, P.J.M., Melnick, A & Delwel, R. (2009). Genome-wide epigenetic analysis delineates a biologically distinct immature acute leukemia with myeloid/t-lymphoid features. Blood, 113(12), 2795-2804. Goessel, H von, Jacobs, U, Semper, S, Krumbholz, M, Langer, T, Keller, T, Schrauder, A, Velden, V.H.J. van der, Dongen, J.J.M. van, Harbott, J., Panzer-Grumayer, ER, Schrappe, M., Rascher, W. & Metzler, M. (2009). Cluster analysis of genomic ETV6-RUNX1 (TEL-AML1) fusion sites in childhood acute lymphoblastic leukemia. Leukemia Research, 33(8), 1082-1088. Loosdrecht, AA van de, Alhan, C, Bene, M.C., Porta, MG Della, Drager, AM, Feuillard, J, Font, P, Germing, U, Haase, D, Homburg, CH, Ireland, R, Jansen, J.H., Kern, W., Malcovati, L, Marvelde, J.G. te, Mufti, GJ, Ogata, K, Orfao, A., Ossenkoppele, G.J., Porwit, A., Preijers, FW, Richards, SJ, Schuurhuis, G.J., Subira, D., Valent, P, Velden, V.H.J. van der, Vyas, P, Westra, A.H., Witte, T.M. de, Wells, DA, Loken, M.R. & Westers, TM (2009). Standardization of flow cytometry in myelodysplastic syndromes: report from the first European LeukemiaNet working conference on flow cytometry in myelodysplastic syndromes. Haematologica, 94(8), 1124-1134. Meyer, C., Hofmann, J., Renneville, A., Zuna, J., Trka, J., Ben Abdelali, R., Macintyre, E., De Braekeleer, E., De Braekeleer, M., Delabesse, E., Oliveira, M.P. de, Cave, H., Clappier, E, Dongen, J.J.M. van, Balgobind, B.V., Heuvel-Eibrink, M.M. van den, Beverloo, H.B., Panzer-Grumayer, R., Teigler-Schlegel, A, Harbott, J., Kjeldsen, E., Schnittger, S., Koehl, U., Gruhn, B.,

Heidenreich, O., Chan, L.C., Yip, S.F., Krzywinski, M., Eckert, C., Moricke, A., Schrappe, M., Alonso, C.N., Schafer, B.W., Krauter, J, Lee, D.A., Stadt, U zur, Te Kronnie, G., Sutton, R., Izraeli, S, Trakhtenbrot, L., Lo Nigro, L., Tsaur, G., Fechina, L., Szczepanski, T., Strehl, S, Ilencikova, D., Molkentin, M., Burmeister, T., Dingermann, T., Klingebiel, T. & Marschalek, R (2009). New insights to the MLL recombinome of acute leukemias. Leukemia, 23, 1490-1499. Niemeijer, ND, Lugtenburg, P.J., Ermens, A.A.M., Langerak, A.W., Kam, K.H. & Esser, J.W.J. van (2009). Subcutaan 'panniculitis-like' T-cellymfoom. Nederlands Tijdschrift voor Hematologie, 6, 321-328. Schotte, D., Chau, J.C.K., Sylvester, G., Liu, G., Chen, C, Velden, V.H.J. van der, Broekhuis, M.J.C., Peters, T.C.J.M., Pieters, R. & Boer, M.L. den (2009). Identification of new microrna genes and aberrant microrna profiles in childhood acute lymphoblastic leukemia. Leukemia, 23, 313-322. Velden, V.H.J. van der, Corral, L., Valsecchi, M.G., Jansen, M.W.J.C., Lorenzo, P de, Gazzaniga, G., Panzer-Grümayer, E.R., Schrappe, M., Schrauder, A, Meyer, C., Marschalek, R, Nigro, L.L., Metzler, M., Basso, G., Mann, G., Boer, M.L. den, Biondi, A., Pieters, R. & Dongen, J.J.M. van (2009). Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia, 23, 1073-1079. Weerkamp, F., Dekking, E, Ng, Y.Y., Velden, V.H.J. van der, Wai, H, Bottcher, S, Bruggemann, M, Sluijs, AJ van der, Koning, A.H.J., Boeckx, N., Poecke, N Van, Lucio, P., Mendonca, A. De, Sedek, L, Szczepanski, T., Kalina, T., Kovac, M, Hoogeveen, P.G., Flores-Montero, J, Orfao, A., Macintyre, E., Lhermitte, L, Chen, R, Brouwer - de Cock, K.A.J., Linden, A. van der, Noordijk, A.L., Comans-Bitter, W.M., Staal, F.J.T. & Dongen, J.J.M. van (2009). Flow cytometric immunobead assay for the detection of BCR-ABL fusion proteins in leukemia patients. Leukemia, 23(6), 1106-1117. Willasch, A.M., Gruhn, B., Kalinova, M., Schneider, G., Kreyenberg, H., Steinbach, D., Weber, G., Hollink, I.H.I.M., Zwaan, C.M., Biondi, A., Velden, V.H.J. van der, Reinhardt, D., Gazzaniga, G., Bader, P. & Trka, J. (2009). Standardization of WT1 mrna quantitation for minimal residual disease monitoring in childhood AML and implications of WT1 gene mutations: a European multicenter study. Leukemia, 23, 1472-1479. Part of book - abstract Dongen, J.J.M. van & Velden, V.H.J. van der (2009). Minimal residual disease (MRD) bij hematologische maligniteiten. In JM Pekelharing, H Hooijkaas, JHMH Punt, LC Smeets & JHM Souverijn (Eds.), Handboek Medische laboratoriumdiagnostiek (pp. 383-386). Houten: Prelum uitgevers. Langerak, A.W. (2009). From the patient to the sequence: selection of material, primers and PCR protocol, clonality analysis, and sequencing protocols. In P Ghia, R Rosenquist & F Davi (Eds.), Immunoglobulin gene analysis in chronic lymphocytic leukemia (pp. 23-31). Milan: GECA SpA Cesano Boscone. Langerak, A.W. & Velden, V.H.J. van der (2009). Molecular diagnostics in leukemia and lymphoma. In WB van Leeuwen & C Vink (Eds.), Molecular Diagnostics, techniques and applications (pp. 295-320). Rotterdam: IVA GROEP BV. Langerak, A.W. & Dongen, J.J.M. van (2009). Moleculaire classificatie van hematologische maligniteiten. In JM Pekelharing, H Hooijkaas, HMHM Punt, LC Smeets & JHM Souverijn (Eds.), Handboek Medische laboratoriumdiagnostiek (pp. 387-388). Houten: Prelum uitgevers. Langerak, A.W. & Dongen, J.J.M. van (2009). Moleculaire klonaliteitsdiagnostiek van lymfoproliferaties. In JM Pekelharing, H Hooijkaas, JMHM Punt, LC Smeets & JHM Souverijn (Eds.), Handboek Medische laboratoriumdiagnostiek (pp. 389-392). Houten: Prelum uitgevers. Velden, V.H.J. van der & Dongen, J.J.M. van (2009). MRD detection in acute lymphoblatic leukemia patients using Ig/TCR gene rearrangements as targets for real-time quantitative PCR. In CWE So (Ed.), Leukemia. Methods in Molecular Biology (pp. 115-150). Humana Press. Velden, V.H.J. van der & Dongen, J.J.M. van (2009). Immunofenotypische analyse van hematologische maligniteiten. In JM Pekelharing, H Hooijkaas, JMHM Punt, LC Smeets & JHM Souverijn (Eds.), Handboek Medische laboratoriumdiagnostiek (pp. 297-304). Houten: Prelum uitgevers. Patent Staal, F.J.T. & Dongen, J.J.M. van (25-02-2009). Method for detecting low levels of a fusion protein. no EP20040774869.

EMC MM-03-24-01 - Solid tumors between bench and bed Programme design in brief The department of Pathology is the backbone of the Josephine Nefkens Institute (JNI), and thereby committed to translational research of human solid tumors. The focus of the department is to unravel the pathogenesis of solid cancers combining advanced morphological and molecular methods on human tumor material, and animal models. Leading themes are the molecular and (epi)genetic basis of cancer, tumor stem cell biology, and tumor-host interactions. Results are used to develop objective criteria for diagnosis, response prediction and prognosis of human cancers, which will then be implemented in topreferral and routine clinical pathology. This is implemented and stimulated by coupling basic scientists with clinical pathologists around specific cancer types. These activities are also meant to facilitate other Erasmus MC departments- research programs by making available its morphologic expertise and giving access to human pathology specimens through the Erasmus MC tissue bank (Dr. P.H. Riegman). The research program of the department forms a substantial part of Main Theme 3, -Solid Tumors- of the Postgraduate Schools Molecular Medicine. Collaborations within Erasmus MC are formalized in the Postgraduate Schools Molecular Medicine, MGC and NIHES. Here below, the research program of the Department of Pathology is briefly summarized per research group: - Group Dr. W.N.M. Dinjens: molecular diagnosis of solid cancers; - Group Prof.dr. R. Fodde: Cancer stemness in tumor onset, progression and metastasis. - Group Dr. A.B. Houtsmuller: kinetics of molecules involved in DNA-repair, and (androgen dependent) transcription, studied in vivo using fluorescent-labeled proteins; - Group Prof.dr. J.M. Kros: molecular markers for diagnosis and response prediction in gliomas; - Group Dr. R.R. De Krijger: molecular markers for diagnosis and progression in pheochromocytoma; - Group Prof.dr. L.H.J. Looijenga and Prof.dr. J.W. Oosterhuis: pathogenesis of germ cell tumors, and cancer risk of various types of gonadal dysgenesis; - Group Prof.dr. J. Trapman and Dr. G.J.L.H. van Leenders: molecular mechanisms of origin and progression of prostate cancer; role of prostate (cancer) stem cells; - Group Prof.dr. E.C. Zwarthoff: biology and molecular diagnosis of bladder cancer; function of the leukemia-associated MN1TEL fusion gene; molecular pathogenesis of meningioma. For more extensive descriptions of the work carried out in our department, the reader is referred to the -Application for Renewal of the Erasmus Postgraduate School Molecular Medicine 2003- (www.molmed.nl), -Oncological Research at the Erasmus MC University Medical Center Rotterdam, Annual Reports 2000-2004-, and recent issues of -Daniel den Hoed Cancer News-. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot genetics 0 0,75 0 0 0,75 pathology 11,23 5,34 5,2 2,24 24,01 Total 11,23 6,09 5,2 2,24 24,76 6 1 0 7 94 8 0 109 Thesis Aa, M.N.M. van der (2009, februari 25). Surveillance of bladder cancer. EUR. Prom./coprom.: Prof.Dr. T.H. van der Kwast, Prof.Dr. E.C. Zwarthoff & Prof.Dr. E.W. Steyerberg. Gaspar, C.S. (2009, februari 26). Signaling pathways in cancer: a matter of dosage. EUR. Prom./coprom.: Prof.Dr. R. Fodde. Hermans, K.G.L. (2009, januari 28). Unraveling of the major genetic defects in prostate cancer. EUR. Prom./coprom.: Prof.Dr. J. Trapman. Meester-Smoor, M.A. (2009, oktober 30). Molecular analysis of the MN1 oncogene and the leukemia-associated fusion gene MN1-TEL. EUR. Prom./coprom.: Prof.Dr. E.C. Zwarthoff. Mustafa, D.A.M. (2009, november 10). Identifying proteins involved in glioma angiogenesis: a proteomics approach. EUR. Prom./coprom.: Prof.Dr. J.M. Kros & Dr. T.M. Luider. Nagel, CR (2009, november 27). Shedding light on microrna function. EUR. Prom./coprom.: Prof.Dr. R. Agami. Wijngaart, D.J. van de (2009, april 01). Peptides and proteins interacting with the androgen receptor. EUR (170 pag.). Prom./coprom.: Prof.Dr. J. Trapman. Article/Letter to the editor Aa, M.N.M. van der, Bekker, MD, Kwast, T.H. van der, Essink-Bot, M.L., Steyerberg, E.W., Zwarthoff, E.C., Sen, FEF & Elzevier, HW (2009). Sexual function of patients under surveillance for bladder cancer. Bju International, 104(1), 35-40. Agthoven, T. van, Sieuwerts, A.M., Veldscholte, J., Meijer-Gelder, M.E. van, Smid, M., Brinkman, A., Dekker, A.T. den, Leroy, I.M., Ijcken, W.F.J. van, Sleijfer, S., Foekens, J.A. & Dorssers, L.C.J. (2009). CITED2 and NCOR2 in anti-oestrogen resistance and progression of breast cancer. British Journal of Cancer, 101(11), 1824-1832. Agthoven, T. van, Veldscholte, J., Smid, M., Agthoven, TLA van, Vreede, L., Broertjes, M., Vries, I. de, Jong, D. de, Sarwari, R. & Dorssers, L.C.J. (2009). Functional identification of genes causing estrogen independence of human breast cancer cells. Breast Cancer Research and Treatment, 114(1), 23-30. Agthoven, T. van, Sieuwerts, A.M., Meijer-Gelder, M.E. van, Look, M.P., Smid, M., Veldscholte, J., Sleijfer, S., Foekens, J.A. & Dorssers, L.C.J. (2009). Relevance of Breast Cancer Antiestrogen Resistance Genes in Human Breast Cancer Progression and Tamoxifen Resistance. Journal of Clinical Oncology, 27(4), 542-549.

Bakker, M.A. den, Goemaere, N.N.T., Severin, J.A., Nouwen, J.L. & Verhagen, P.C.M.S. (2009). Histoplasma-associated inflammatory pseudotumour of the kidney mimicking renal carcinoma. Virchows Archiv. An International Journal of Pathology, 454(2), 229-232. Bakker, M.A. den, Beverloo, H.B., Heuvel-Eibrink, M.M. van den, Meeuwis, C.A., Tan, LM, Johnson, LA, French, CA & Leenders, G.J.L.H. van (2009). NUT Midline Carcinoma of the Parotid Gland With Mesenchymal Differentiation. American Journal of Surgical Pathology, 33(8), 1253-1258. Bakker, M.A. den & Oosterhuis, J.W. (2009). Tumours and tumour-like conditions of the thymus other than thymoma; a practical approach. Histopathology, 54(1), 69-89. Been, J.V., Kornelisse, R.F., Rours, G.I.J.G., Lima Passos, V., Krijger, R.R. de & Zimmermann, L.J.I. (2009). Early postnatal blood pressure in preterm infants: effects of chorioamnionitis and timing of antenatal steriods. Pediatric Research, 66(5), 571-576. Been, J.V., Rours, G.I.J.G., Kornelisse, R.F., Lima Passos, V., Kramer, B.W., Schneider, T.A.J., Krijger, R.R. de & Zimmermann, L.J.I. (2009). Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants. American Journal of Obstetrics and Gynecology, 201, 587.e1-587.e8. Bekker- Grob, E.W. de, Aa, M.N.M. van der, Zwarthoff, E.C., Eijkemans, M.J.C., Rhijn, B.W.G. van, Kwast, T.H. van der & Steyerberg, E.W. (2009). Non-muscle-invasive bladder cancer surveillance for which cystoscopy is partly replaced by microsatellite analysis of urine: a cost-effective alternative? Bju International, 104(1), 41-47. Bent, M.J. van den, Dubbink, H.J., Sanson, M, Lee-Haarloo, CR van der, Hegi, M, Jeuken, J.W.M., Ibdaih, A, Brandes, A.A., Taphoorn, M.J.B., Frenay, M., Lacombe, D., Gorlia, T., Dinjens, W.N.M. & Kros, J.M. (2009). 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Body mass index as a prognostic marker for biochemical recurrence in Dutch men treated with radical prostatectomy. Bju International, 104(3), 321-325. Rolleman, E.J., Weening, J.J. & Betjes, M.G.H. (2009). Acute nephritic syndrome after anti-vegf therapy for renal cell carcinoma. Nephrology Dialysis Transplantation, 24(6), 2002-2003. Roon, A.H.C. van, Borg, P.C.J. ter, Zondervan, P.E., Stoop, H. & Man, R.A. de (2009). A patient with an alpha-foetoprotein producing tumour. Nederlands Tijdschrift voor Geneeskunde, 153, 364. Royen, M.E. van, Farla, P., Mattern, K.A., Geverts, B., Trapman, J. & Houtsmuller, A.B. (2009). Fluorescence reecovery after photobleaching (FRAP) to study nuclear protein dynamics in living cells. Methods in Molecular Biology, 464, 363-385. Royen, M.E. van, Dinant, C., Farla, P., Trapman, J. & Houtsmuller, A.B. (2009). FRAP and FRET methods to study nuclear receptors in living cells. Methods in Molecular Biology, 505, 69-96. Saelens, I.E.Y., Bartels, M.C., Rij, G. van, Dinjens, W.N.M. & Mooy, C.M. (2009). Introduction of Epithelial Cells in the Flap-Graft Interface During Descemet Stripping Automated Endothelial Keratoplasty. Archives of Ophthalmology, 127(7), 936-937. Schaart, M.W., Bruijn, A.C.J.M. de, Bouwman, D.M., Krijger, R.R. de, Goudoever, J.B. van, Tibboel, D. & Renes, I.B. (2009). Epithelial functions of the residual bowel after surgery for necrotising enterocolitis in human infants. Journal of Pediatric Gastroenterology and Nutrition, 49, 31-41. Scheithauer, B.W., Erdogan, S, Rodriguez, FJ, Burger, P.C., Woodruff, JM, Kros, J.M., Gokden, M & Spinner, RJ (2009). Malignant Peripheral Nerve Sheath Tumors of Cranial Nerves and Intracranial Contents A Clinicopathologic Study of 17 Cases. American Journal of Surgical Pathology, 33(3), 325-338. Schroder, F.H., Hugosson, J., Roobol-Bouts, M.J., Tammela, T.L.J., Ciatto, S., Nelen, V., Kwiatkowski, M, Lujan, M, Lilja, H., Zappa, M., Denis, L.J., Recker, F, Berenguer, A., Maattanen, L, Bangma, C.H., Aus, G, Villers, A., Rebillard, X, Kwast, T.H. van

der, Blijenberg, B.G., Moss, S.M., Koning, H.J. de & Auvinen, A. (2009). Screening and Prostate-Cancer Mortality in a Randomized European Study. New England Journal of Medicine, 360(13), 1320-1328. Segers, H., Heyden, J.C. van der, Akker, E.L.T. van den, Krijger, R.R. de, Zwaan, C.M. & Heuvel-Eibrink, M.M. van den (2009). Cushing syndrome as a presenting symptom of renal tumors in children. Pediatric Blood & Cancer, 53, 211-213. Snaathorst, J., Sewnaik, A., Paridaens, A.D.A., Krijger, R.R. de & Meij, E.H. van der (2009). Primary epithelial tumors of the lacrimal gland; a retrospective analysis of 22 patients. International Journal of Oral and Maxillofacial Surgery, 38(7), 751-757. Snoek, E.M. van der, Amelink, A., Ende, M.E. van der, Hollander, J.C. den, Hollander, J.G. den, Kroon, F.P., Vriesendorp, R., Neumann, H.A.M. & Robinson, D.J. (2009). Photodynamic Therapy With Topical Metatetrahydroxychlorin (Fosgel) Is Ineffective for the Treatment of Anal Intraepithelial Neoplasia, Grade III. Jaids. Journal of Acquired Immune Deficiency Syndromes, 52(1), 141-143. Soest, G. van, Goderie, TPM, Gonzalo Lopez, M.N., Koljenovic, S., Leenders, G.J.L.H. van, Regar, E.S., Serruys, P.W.J.C. & Steen, A.F.W. van der (2009). Imaging atherosclerotic plaque composition with intracoronary optical coherence tomography. Cardiologie (Hoogland), 17(11), 448-450. Takkenberg, J.J.M., Klieverik, L.M.A., Schoof, P.H., Suylen, R.J. van, Herwerden, L.A. van, Zondervan, P.E., Roos-Hesselink, J.W., Eijkemans, M.J.C., Yacoub, M.H. & Bogers, A.J.J.C. (2009). The Ross Procedure A Systematic Review and Meta- Analysis. Circulation, 119(2), 222-228. Tilborg, AAG van, Bangma, C.H. & Zwarthoff, E.C. (2009). Bladder cancer biomarkers and their role in surveillance and screening. International Journal of Urology, 16(1), 23-30. Umar, A., Kang, H., Timmermans, A.M., Look, M.P., Meijer-Gelder, M.E. van, Bakker, M.A. den, Jaitly, N, Martens, J.W.M., Luider, T.M., Foekens, J.A. & Pasa-Tolic, L (2009). Identification of a Putative Protein Profile Associated with Tamoxifen Therapy Resistance in Breast Cancer. Molecular & Cellular Proteomics, 8(6), 1278-1294. Verkerk, A.J.M.H., Schot, R., Dumee, B.C., Schellekens, K.P.C., Swagemakers, S.M.A., Bertoli Avella, A.M., Lequin, M.H., Dudink, J., Govaert, P., Zwol, A.L. van, Hirst, J., Wessels, M.W., Catsman-Berrevoets, C.E., Verheijen, F.W., Graaff, E. de, Coo, I.F.M. de, Kros, J.M., Willemsen, R., Spek, P.J. van der & Mancini, G.M.S. (2009). Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. American Journal of Human Genetics, 85, 40-52. Wang, YY, Hanifi Moghaddam, P., Hanekamp, E.E., Kloosterboer, H.J., Franken, P., Veldscholte, J., Doorn, H.C. van, Ewing, PC, Kim, JJ, Grootegoed, J.A., Burger, C.W., Fodde, R. & Blok, L.J. (2009). 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EMC MM-03-32-04 - Improving accuracy and therapeutic ratio in radiation oncology Programme design in brief A key field of research in radiotherapy is the clinical application of conformal radiotherapy, and intensity modulated radiotherapy (IMRT), where the treated volume is made to conform to the target volume, thereby limiting the volume of irradiated normal critical tissue. By reducing the probability of normal tissue toxicity, this approach allows for sparing of critical organs and/or radiation dose escalation and improved local tumor control. In collaboration with the AvL in Amsterdam, a randomized clinical trial of dose escalation for prostate cancer is currently underway. Phase II studies of intensity modulated conformal radiotherapy are underway for long cancer and head and neck cancer (to limit damage to the salivary glands and escalate dose). Studies of stereotactic irradiation for eye and brain tumors have been activated. The intraoperative brachytherapy research is focused on the treatment of tumors of the rectum, head and neck, and lung. A program of Ultrasound and CT-assisted bbrachytherapy for prostate cancer is underway. In collaboration with the Toraxcenter of the University Hospital Rotterdam, patients are being treated with endovascular brachytherapy in the context of ongoing clinical trials. In addition, two trials of radiotherapy for peripheral vascular disease and arteriovenous shunts are rapidly accruing patients. Finally for a number of clinical tumor sites radiation with concomitant chemotherapy radiation protectors is being studied. The current research in clinical physics is focused on the development and application of tools for conformal intensity modulated therapy. Improved electronic portal imaging (EPI) techniques are being developed and EPI has been clinical implemented for patient set-up verification and correction, in-vivo dosimetry during conformal treatments and for quality assurance measurements of intensity modulated photon beams produced with dynamic multileaf collimation. A program has been started to use implanted radio opaque markers for set-up verification instead of the bony anatomy. The optimization of dose distributions by intensity modulated radiotherapy beams is being actively pursued and algorithm is being developed for automated beam orientation selection. The research activities of molecular radiobiology are geared gaining an improved understanding of the mechanisms and biology relevance of double-strand. DNA breaks repair in relation to genomic instability, carcinogenisis and DNA end joining. In a Dutch Cancer Society funded project, the phenotype of mice with defective homologous recombination repair is currently being analyzed. Recently, dr. Kanaar has been granted a subsidy in the prestigious Pioneer program coordinated by the Netherlands Research Council. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot genetics 0,5 0 0 0 0,5 radiotherapy 5,99 0,5 1 3,23 10,72 Total 6,49 0,5 1 3,23 11,22 1 0 0 1 35 2 4 42 Thesis Nijdam, W.M. (2009, december 16). Treatment modalities, quality of life and costs in head and neck cancer. A quest for priorization. EUR. Prom./coprom.: Prof.Dr. P.C. Levendag & G.C. van Rhoon. Article/Letter to the editor Al Uwini, S., Antonini, N, Poortmans, PM, Boersma, L., Hurkmans, C, Leer, J.W., Horiot, JC, Struikmans, H. & Bartelink, H. (2009). The influence of the use of CT-planning on the irradiated boost volume in breast conserving treatment. Radiotherapy and Oncology, 93(1), 87-93. Al-Mamgani, A., Tans, L., Rooij, P.H.E. van, Noever-Smit, I., Baatenburg de Jong, R.J. & Levendag, P.C. (2009). Hypofractionated radiotherapy denoted as the Christie scheme: An effective means of palliating patients with head and neck cancers not suitable for curative treatment. Acta Oncologica, 48(4), 562-570. Al-Mamgani, A., Heemsbergen, W.D., Peeters, STH & Lebesque, J.V. (2009). Role of intensity-modulated radiotherapy in reducing toxicity in dose escalation for localized prostate cancer. International Journal of Radiation Oncology Biology Physics, 73(3), 685-691. Bhagwat, N, Olsen, AL, Wang, AT, Hanada, K., Stuckert, P, Kanaar, R., D'Andrea, A, Niedernhofer, L.J. & McHugh, PJ (2009). XPF-ERCC1 Participates in the Fanconi Anemia Pathway of Cross-Link Repair. Molecular and Cellular Biology, 29(24), 6427-6437. Bin Kassim, I., Dirkx, M.L.P. & Heijmen, B.J.M. (2009). Evaluation of the dosimetric impact of non-exclusion of the rectum from the boost PTV in IMRT treatment plans for prostate cancer patients. Radiotherapy and Oncology, 92(1), 62-67. Breedveld, S., Storchi, P.R.M. & Heijmen, B.J.M. (2009). The equivalence of multi-criteria methods for radiotherapy plan optimization. Physics in Medicine and Biology, 54(23), 7199-7209. Brugmans, L., Verkaik, N.S., Kunen, M., Drunen, E. van, Williams, BR, Petrini, JHJ, Kanaar, R., Essers, J. & Gent, D.C. van (2009). NBS1 cooperates with homologous recombination to counteract chromosome breakage during replication. DNA Repair, 8(12), 1363-1370. Bruin, M.L. de, Sparidans, J, Veer, M.B. van t, Noordijk, E.M., Louwman, MWJ, Zijlstra, JM, Berg, H., Russell, N.S., Broeks, A., Baaijens, M.H.A., Aleman, B.M.P. & Leeuwen, F.E. van (2009). Breast Cancer Risk in Female Survivors of Hodgkin's Lymphoma: Lower Risk After Smaller Radiation Volumes. Journal of Clinical Oncology, 27(26), 4239-4246. Budzowska, M. & Kanaar, R. (2009). Mechanisms of Dealing with DNA Damage-Induced Replication Problems. Cell Biochemistry and Biophysics, 53(1), 17-31.

Dols, L.F.C., Verhoef, C., Eskens, F.A.L.M., Schouten, O., Nonner, J., Hop, W.C.J., Mendez Romero, A.M., Man, R.A. de, Linden, E. van der, Dwarkasing, R.S. & Ijzermans, J.N.M. (2009). Improvement of 5 year survival rate after liver resection for colorectal metastases between 1984-2006. Nederlands Tijdschrift voor Geneeskunde, 153, 490-495. Gibbs, IC, Levendag, P.C., Fariselli, L, Bondiau, PY, Lartigau, E, Loo, BW, Gagnon, GJ & Koong, A (2009). Re: "The safety and efficacy of robotic image-guided radiosurgery system treatment for intra- and extracranial lesions: A systematic review of the literature" [Radiotherapy and Oncology 89 (2009) 245-253]. Radiotherapy and Oncology, 93(3), 656-657. Grigorescu, AA, Vissers, JHA, Ristic, D., Pigli, YZ, Lynch, TW, Wyman, C. & Rice, PA (2009). Inter-subunit interactions that coordinate Rad51s activities. Nucleic Acids Research, 37(2), 557-567. Hoogeman, M.S., Prevost, J.G.H.G., Nuyttens, J.J.M.E., Poll, J., Levendag, P.C. & Heijmen, B. (2009). Clinical accuracy of the respiratory tumor tracking system of the cyberknife: assessment by analysis of log files. International Journal of Radiation Oncology Biology Physics, 74(1), 297-303. Huang, K, Sneed, P.K., Kunwar, S., Kragten, A.T., Larson, D.A., Berger, M.S., Chan, A.J.K., Pouliot, J. & McDermott, M.W. (2009). Surgical resection and permanent iodine-125 brachytherapy for brain metastases. Journal of Neuro-Oncology, 91(1), 83-93. Kinoshita, E., Linden, E. van der, Sanchez, H & Wyman, C. (2009). RAD50, an SMC family member with multiple roles in DNA break repair: how does ATP affect function? Chromosome Research, 17(2), 277-288. Kirshner, M, Rathavs, M, Nizan, A, Essers, J., Kanaar, R., Shiloh, Y & Barzilai, A (2009). Analysis of the relationships between ATM and the Rad54 paralogs involved in homologous recombination repair. DNA Repair, 8(2), 253-261. Kragten, A.T., Wilt, J.H.W. de, Schmitz, P.I.M., Bontenbal, M. & Levendag, P.C. (2009). Multimodality treatment for anaplastic thyroid carcinoma - Treatment outcome in 75 patients. Radiotherapy and Oncology, 92(1), 100-104. Linden, E. van der, Sanchez, H, Kinoshita, E., Kanaar, R. & Wyman, C. (2009). RAD50 and NBS1 form a stable complex functional in DNA binding and tethering. Nucleic Acids Research, 37(5), 1580-1588. Loenhout, MTJ van, Heijden, T van der, Kanaar, R., Wyman, C. & Dekker, C. (2009). Dynamics of RecA filaments on singlestranded DNA. Nucleic Acids Research, 37(12), 4089-4099. Mameren, J van, Modesti, M., Kanaar, R., Wyman, C., Peterman, EJG & Wuite, GJL (2009). Counting RAD51 proteins disassembling from nucleoprotein filaments under tension. Nature, 457(7230), 745-748. Mazeron, JJ, Ardiet, JM, Haie-Meder, C, Kovacs, G., Levendag, P.C., Peiffert, D, Polo, A, Rovirosa, A & Strnad, V (2009). GEC- ESTRO recommendations for brachytherapy for head and neck squamous cell carcinomas. Radiotherapy and Oncology, 91(2), 150-156. Mendez Romero, A.M., Zinkstok, R.T., Wunderink, W., Os, RM van, Joosten, P.J., Seppenwoolde, Y., Nowak, P.J.C.M., Brandwijk, R.P., Verhoef, C., Ijzermans, J.N.M., Levendag, P.C. & Heijmen, B.J.M. (2009). Stereotactic body radiation therapy for liver tumors: impact of daily setup corrections and day- to day anatomic anatomic variations on dose in target and organs at risk. International Journal of Radiation Oncology Biology Physics, 75(4), 1201-1208. Morak, M.J.M., Hermans, J.J., Smeenk, H.G., Renders, W.M., Nuyttens, J.J.M.E., Kazemier, G. & Eijck, C.H.J. van (2009). Staging for locally advanced pancreatic cancer. European Journal of Surgical Oncology, 35(9), 963-968. Muller, K., Nowak, P.J.C.M., Naus, N.C., Pan, C. de, Santen, C.A. van, Levendag, P.C. & Luyten, G.P.M. (2009). Lacrimal gland radiosensitivity in vueal melanoma pateints. International Journal of Radiation Oncology Biology Physics, 74(2), 497-502. Munoz, IM, Hain, K, Declais, AC, Gardiner, M., Toh, GW, Sanchez-Pulido, L, Heuckmann, JM, Toth, R, Macartney, T, Eppink, B., Kanaar, R., Ponting, CP, Lilley, DMJ & Rouse, J (2009). Coordination of Structure-Specific Nucleases by Human SLX4/BTBD12 Is Required for DNA Repair. Molecular Cell, 35(1), 116-127. Nout, RA, Putter, H., Jurgenliemk-Schulz, IM, Jobsen, J.J., Lutgens, L.C.H.W., Steen-Banasik, E.M. van de, Mens, J.W.M., Slot, A., Kroese, MCS, Bunningen, BNFM van, Smit, VTHBM, Nijman, HW, Tol, PP van den & Creutzberg, C.L. (2009). Quality of Life After Pelvic Radiotherapy or Vaginal Brachytherapy for Endometrial Cancer: First Results of the Randomized PORTEC-2 Trial. Journal of Clinical Oncology, 27(21), 3547-3556. Osman, S.O.S., Boer, J.C.J. de, Astreinidou, E., Gangsaas, A., Heijmen, B.J.M. & Levendag, P.C. (2009). On-line cone beam CT image guidance for vocal cord tumor targeting. Radiotherapy and Oncology, 93(1), 8-13. Penninkhof, J.J., Quint, S., Boer, H, Mens, J.W.M., Heijmen, B. & Dirkx, M (2009). Surgical clips for position verification and correction of non-rigid breast tissue in simultaneously integrated boost (SIB) treatments. Radiotherapy and Oncology, 90(1), 110-115. Soria, G, Belluscio, L, Cappellen, W.A. van, Kanaar, R., Essers, J. & Gottifredi, V (2009). DNA damage induced Pol eta recruitment takes place independently of the cell cycle phase. Cell Cycle, 8(20), 3340-3348. Teguh, D.N., Levendag, P.C., Noever-Smit, I., Voet, P.W.J., Est, J.G.H. van der, Rooij, P.H.E. van, Dumans, A.G., Boer, M.F. de, Huls, MPC van der, Sterk, W. & Schmitz, P.I.M. (2009). Early hyperbaric oxygen therapy for reducing radiotherapy side effects: early results of a randomized trial in oropharyngeal and nasopharyngeal cancer. International Journal of Radiation Oncology Biology Physics, 75(3), 711-716.

Teguh, D.N., Levendag, P.C., Kolkman-Deurloo, I.K.K., Rooij, P.H.E. van & Schmitz, P.I.M. (2009). Quality of life of oropharyngeal cancer patients treated with brachytherapy. Current Oncology Reports, 11(2), 143-150. Vasquez Osorio, E.M., Hoogeman, M.S., Bondar, M.L., Levendag, P.C. & Heijmen, B.J.M. (2009). A novel flexible framework with automatic feature correspondence optimization for nonrigid registration in radiotherapy. Medical Physics, 36(7), 2848-2859. Verhoef, C., Pool, A.E.M. van der, Nuyttens, J.J.M.E., Planting, A.S.T., Eggermont, A.M.M. & Wilt, J.H.W. de (2009). The "liverfirst approach" for patients with locally advanced rectal cancer and synchronous liver metastases. Diseases of the Colon & Rectum, 52(1), 23-30. Voort van Zyp, N.C.M.G. van der, Prevost, J.G.H.G., Hoogeman, M.S., Praag, J.O., Holt, B. van der, Levendag, P.C., Klaveren, R.J. van, Pattynama, P. & Nuyttens, J.J. (2009). Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: Clinical outcome. Radiotherapy and Oncology, 91(3), 296-300. Warmerdam, D.O., Freire, R., Kanaar, R. & Smits, V.A.J. (2009). Cell cycle-dependent processing of DNA lesions controls localization of Rad9 to sites of genotoxic stress. Cell Cycle, 8(11), 1765-1774. Wielen, G.J. van der, Vermeij, M., Jong, B.W.D. de, Schuit, M.R.H., Marijnissen, J.P.A., Kok, D.J., Weerden, W.M. van & Incrocci, L. (2009). Changes in the Penile Arteries of the Rat after Fractionated Irradiation of the Prostate: A Pilot Study. Journal of Sexual Medicine, 6(7), 1908-1913. Wolbers, J.G., Mendez Romero, A.M. & Nowak, P.J.C.M. (2009). Radiochirurgie of radiotherapie voor hersenmetastasen? De stand van zaken. Nederlands Tijdschrift voor Neurologie, 110, 191-199. Zijtveld, M. van, Dirkx, M.L.P., Breuers, M, Boer, H & Heijmen, B. (2009). Portal dose image prediction for in vivo treatment verification completely based on EPID measurements. Medical Physics, 36(3), 946-952. Part of book - abstract Levendag, P.C., Rooij, P.H.E. van, Teguh, D.N., Noever-Smit, I., Voet, P.W.J., Est, J.G.H. van der & Schmitz, PI (2009). Functional preservation and Quality of Life in Head and Neck Radiotherapy. Section Treatment Techniques with Potential Impact on Quality of Life. In PM Harari, NP Connor & C Grau (Eds.), Dysphagia Related Quality of Life of patients with cancer in the Oropharynx: An advantage for Brachytherapy? (pp. 135-144). --: --. Book editorship Levendag, P.C., Al-Mamgani, A. & Teguh, D.N. (Eds.). (2009). Contouring in Head & Neck Cancer. Munich: Elsevier. External report Visser, M de, Leer, J.W.H., Doorn, JAM van, Koppejan-Rensenbrink, AG, Langendijk, J.A., Leeuwen, F.E. van, Levendag, P.C., Ouderaa, MJM van der, Slot, A., Slotman, BJ, Vos, PH, Welleweerd, J & Bos, MA (2009). Protonenbestraling. Signalement. 2009/17. Den haag: Gezondheidsraad.

EMC MM-03-32-05 - Hyperthermia: a treatment for cancer Programme design in brief Hyperthermia (HT), i.e. heating tissue to 39-44 C for 60 to 90 minutes, results in a cascade of effects, which all can be exploited to improve tumor response to radiotherapy (RT) and chemotherapy (CT). Currently known effects are: inhibition of radiation-induced damage repair, changes in perfusion, re-oxygenation, effects on macromolecular and nanoparticle delivery, induction of the heat shock response and immunological stimulation. Generally, normal tissue tolerates a hyperthermic treatment of 1 hour up to 44 C without relevant clinical damage. This makes HT an ideal complementary treatment to both RT and CT. Consequently, HT is always implemented as part of a multimodal, oncological strategy. Its efficacy to improve clinical outcome of radiotherapy and chemotherapy has been demonstrated in multiple randomized phase III trials. At present, HT is part of standard therapy for several tumor pathologies in the Netherlands. The medical program is directed towards the development of the clinical application of HT as adjuvant to RT and CT. The group is internationally recognized for its coordination of the Dutch Deep Hyperthermia Trial, which was also of major importance for the recognition of hyperthermia as regular health care within the frame of the Dutch National Health Service. Currently, we coordinate a national phase III trial investigating RT+HT versus RT+CT in advanced cervical cancer. In close collaboration with the MD s of the departments of Radiation Oncology, Gynecology and Medical Oncology, we explore the feasibility of new clinical studies for tumor sites where treatment with regular RT or CT schedules does not result in a satisfactory probability of local control. The research in hyperthermia physics aims at improvement and assurance of the quality of the technical application of the hyperthermia treatment. The group has an international recognized guiding position in translating hyperthermia treatment planning towards clinical application. As strong focus of the research program is on the assessment of critical parameters for the application of 3-dimensional treatment planning on-line during loco-regional deep and superficial heating. In direct association to this objective we also invest in research aiming at (quantitative) validation of our treatment planning models for each individual applicator, including the development of new, accurate QA tools and procedures. Additionally, research is directed on the development of new hyperthermia systems to allow application of hyperthermia at tumor sites, which at this moment cannot be treated. The recent development of the HyperCollar for heating head and neck tumors is an compelling example of our work in this area. Finally, to enable prediction of treatment outcome it is important to perform extensive analysis of the relationship between thermal dose and tumor response. Eventually, this information will enable optimization of the treatment based on a probability of a successful treatment outcome. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot radiotherapy 2,25 0 2,1 0 4,35 Total 2,25 0 2,1 0 4,35 0 0 0 0 7 2 4 13 Article/Letter to the editor Bakker, J.F., Paulides, M.M., Obdeijn, A.I.M., Rhoon, G.C. van & Dongen, KWA van (2009). An ultrasound cylindrical phased array for deep heating in the breast: theoretical design using heterogeneous models. Physics in Medicine and Biology, 54(10), 3201-3215. Canters, R.A.M., Wust, P., Bakker, J.F. & Rhoon, G.C. van (2009). A literature survey on indicators for characterisation and optimisation of SAR distributions in deep hyperthermia, a plea for standardisation. International Journal of Hyperthermia, 25(7), 593-608. Canters, R.A.M., Franckena, M., Paulides, M.M. & Rhoon, G.C. van (2009). Patient positioning in deep hyperthermia: influences of inaccuracies, signal correction possibilities and optimization potential. Physics in Medicine and Biology, 54(12), 3923-3936. Fatehi, D., Zee, J. van der & Rhoon, G.C. van (2009). Hyperthermia: a new cancer treatment modality. Journal of Isfahan Medical School, 27, 94. Fatehi, D., Zee, J. van der & Rhoon, G.C. van (2009). Thermoradiotherapy for cancer: an effective approach. Australasian Medical Journal, 1, 224-234. Franckena, M., Fatehi, D., Bruijne, M. de, Canters, R.A.M., Norden, Y. van, Mens, J.W.M., Rhoon, G.C. van & Zee, J. van der (2009). Hyperthermia dose-effect relationship in 420 patients with cervical cancer treated with combined radiotherapy and hyperthermia. European Journal of Cancer, 45(11), 1969-1978. Franckena, M., Lutgens, LC, Koper, PC, Kleynen, C.E., Steen-Banasik, E.M. van de, Jobsen, J.J., Leer, J.W., Creutzberg, C.L., Dielwart, MF, Norden, Y. van, Canters, R.A.M., Rhoon, G.C. van & Zee, J. van der (2009). Radiotherapy and hyperthermia for treatment of primary locally advanced cervix cancer: results in 378 patients. International Journal of Radiation Oncology Biology Physics, 73(1), 242-250. Haas-Kock, DFM De, Buijsen, J, Pijls-Johannesma, M, Lutgens, L, Lammering, G, Mastrigt, GAPG van, Ruysscher, DKM De, Lambin, P & Zee, J. van der (2009). Concomitant hyperthermia and radiation therapy for treating locally advanced rectal cancer. Cochrane Database Systematics Review. Zee, J. van der & Overgaard, J (2009). Hyperthermia classic commentary: 'Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic Oncology' by J. Overgaard, D. Gonzalez Gonzalez, M. C. C. H. Hulshof, G. Arcangeli, O. Dahl, O. Mella & S. M. Bentzen, International Journal of Hyperthermia 1996; 12: 3-20. International Journal of Hyperthermia, 25(5), 335-337. Book editorship Dongen, KWA van, Bakker, J.F., Paulides, M.M., Obdeijn, A.I.M. & Rhoon, G.C. van (Eds.). (2009). Design of an ultrasound cylindrical phased-array for hyperthermia breast cancer treatment. NAG/DAGA: International Conference on Acoustics.

Paulides, M.M., Zee, J. v.d. & Rhoon, G.C. van (Eds.). (2009). Contouring in head and neck cancer, Contouring for targeted head and neck hyperthermia. Munich: Elsevier. External report Rhoon, G.C. van, Aernsbergen, L.M. van, Brussaard, G., Kelfkens, G., Kromhout, H., Leeuwen, F.E. van, Leonhard, H.K., Wadman, W.J., Weerdt, D.H.J. van de, Zwamborn, A.P.M. & Rongen, E. van (2009). Gezondheidsraad: Commissie Elektro magnetische velden. Jaarbericht 2008. 2009/02. Den Haag: Gezondheidsraad. Other output Neufeld, E, Paulides, M.M., Capstick, M, Rhoon, G.C. van & Kuster, N (2009). Latest Advances in EM Hyperthermia cancer treatments. Proceeding of the International Conference on Electromagnetics in Advanced Applications: Torino (2009, september 14-2009, september 18).

EMC MM-03-32-09 - Photodynamic therapy Programme design in brief Main objective of the research programme is to study the interaction between light and living tissue with the purpose of understanding, optimising and further developing applications of light for diagnosis and treatment of disease. In contrast to other physical modalities used for diagnostic or therapeutic purposes, such as ionising radiation, light has only shallow penetration in living tissue. This apparent limitation renders it excellently suitable for diagnosis and treatment of superficial disease. Fueled by rapid developments in optoelectronics, lasers and fiber optic technology, these techniques can be applied in vivo, in a noninvasive or minimally invasive manner. Research activities comprise ex vivo and animal experiments, as well as clinical studies. Current research activities are centered around two strongly interrelated research lines: photodynamic therapy (PDT) and optical dignostics (OD). PDT:Photodynamic therapy is a therapeutic technique that is based on the interaction of a light sensitive drug with light. PDT has been under study for several decades and is now an emerging treatment modality for a range of primarily malignant conditions. It is under clinical investigation for the treatment of cancers of head and neck, bladder, lung, prostate, oesophagus, brain, and skin and several non-malignant indications. For age-related macula degeneration (AMD) and non-melanoma skin cancer PDT is now the gold standard therapy. In the last decade PDT research in my group has focussed on the mechanisms of action of different photosensitisers, light dosimetry, light fractionation and the development of clinical applications. Research activities comprised preclinical work on animal models, phantom studies, theory development, clinical experimentation and clinical pilot studies. Greatest achievements of the reseach group is the improvement of ALA-PDT for basal cell carcinoma to a level at which it outperforms surgery using light fractionation and the development of a very successful approach for PDT of nasopharyngeal cancer. OD: Early attemps to use optical techniques for detecting cancer date from more than a century ago and were partly inspired by the fluorescent emission from the drugs used in early photodynamic therapy. The dramatic technological developments in optics and optoelectronics that have started a decade ago have enabled the use of a large number of new non invasive non destructive optical sampling techniques to probe inside the body. Sofar, my research group has a history in fluorescence imaging and spectroscopy as well as diffuse reflection spectroscopy. These techniques have been investigated for the diagnosis of cancer and are currently being used routinely in monitorring photodynamic therapy. Over the last few years Differential Pathlength Spectroscopy has been developed in my group, which is a special form of reflection spectroscopy. This technique has been used sucesfully in the bronchoscopic classification of early cancers, and is currently iunder investigation for diagnosis of cancer in the esophagus, the oral cavity, the brain and breast. A spin off company has been set up to enable further commercialisation of this technology. In collaboration with Utrecht University we are developing a new in vivo microscopic technique: Non-linear Spectral Imaging. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot radiotherapy 2,73 2,6 0 0 5,33 Total 2,73 2,6 0 0 5,33 0 0 0 0 6 5 1 12 Article/Letter to the editor Amelink, A., Christiaanse, T. & Sterenborg, H.J.C.M. (2009). Effect of hemoglobin extinction spectra on optical spectroscopic measurements of blood oxygen saturation. Optics Letters, 34(10), 1525-1527. Amelink, A., Haringsma, J. & Sterenborg, H.J.C.M. (2009). Noninvasive measurement of oxygen saturation of the microvascular blood in Barrett's dysplasia by use of optical spectroscopy. Gastrointestinal Endoscopy, 70(1), 1-6. Kanick, S.C., Sterenborg, H.J.C.M. & Amelink, A. (2009). Empirical model of the photon path length for a single fiber reflectance spectroscopy device. Optics Express, 17(2), 860-871. Kanick, S.C., Robinson, D.J., Sterenborg, H.J.C.M. & Amelink, A. (2009). Monte Carlo analysis of single fiber reflectance spectroscopy: photon path length and sampling depth. Physics in Medicine and Biology, 54(22), 6991-7008. Kascakova, S., Vischer, S. de, Kruijt, B., Bruijn, H.S. de, Ploeg- van den Heuvel, A., Sterenborg, H.J.C.M., Witjes, M.J.H., Amelink, A. & Robinson, D.J. (2009). In vivo quantification of m THPC fluorescence in skinfold obervation chamber using excitation and detection towards the near infrared region. SPIE. Kruijt, B., Kascakova, S., Bruijn, H.S. de, Heuvel, A. van den, Sterenborg, H.J.C.M., Robinson, D.J. & Amelink, A. (2009). In vivo quantification of chromophore concentration using fluorescence differential path length spectroscopy. Journal of Biomedical Optics, 14(3). Kruijt, B., Ploeg- van den Heuvel, A., Bruijn, H.S. de, Sterenborg, H.J.C.M., Amelink, A. & Robinson, D.J. (2009). Monitoring Interstitial m-thpc-pdt In Vivo Using Fluorescence and Reflectance Spectroscopy. Lasers in Surgery and Medicine, 41(9), 653-664. Ungureanu, C, Amelink, A., Sterenborg, H.J.C.M., Manohar, S & Leeuwen, T.G. van (2009). Discriminating between absorption and scattering coefficients in optical characterisation measurements on gold nanoparticle based photoacoustic contrast agents. SPIE, 717718. Upile, T., Jerjes, W, Sterenborg, H.J.C.M., El-Naggar, A.K., Sandison, A, Witjes, M.J.H., Biel, MA, Bigio, I.J., Wong, BJ, Gillenwater, A, Macrobert, AJ, Robinson, D.J., Betz, CS, Stepp, H, Bolotine, L, McKenzie, G, Mosse, CA, Barr, H., Chen, Z, Berg, K, D"Cruz, AK, Stone, N., Kendall, C., Fisher, S, Leunig, A, Olivo, M., Richards-Kortum, R, Soo, KC, Bagnato, V, Choo- Smith, LP, Svanberg, K., Tan, I.B., Wilson, B.C., Wolfsen, H, Yodh, A.G. & Hopper, C (2009). Head & Neck optical diagnostics: vision of the future of surgery. Head & Neck Oncology, 13(1), 25-25.

Vijlder, H.C. de, Middelburg, T.A., Bruijn, H.S. de, Neumann, H.A.M., Sterenborg, H.J.C.M., Robinson, D.J. & Haas, E.R.M. de (2009). Optimizing ALA-PDT in the management of non-melanoma skin cancer by fractionated illumination. Giornale Italiano Dermatologi Venereologia, 144(4), 433-439. Zaane, F. van, Middelburg, T.A., Bruijn, H.S. de, Ploeg- van den Heuvel, A., Haas, E.R.M. de, Sterenborg, H.J.C.M., Neumann, H.A.M. & Robinson, D.J. (2009). Correction of fluorescence for depth-specific optical and vascular properties using reflectance and differential path-length spectroscopy during PDT. SPIE, 7380. Part of book - abstract Sterenborg, H.J.C.M., Leest, C. van der, Canick, SC, Aerts, J.G.J.V. & Amelink, A. (2009). Differential Pathlength Spectroscopy. In Biomedical applications of Light Scattering (Biophotoncs series). --: Mc Graw-Hill.

EMC MM-03-44-06 - Neuro-oncology and pain Programme design in brief The overall aim of this scientific program is to study various aspects of cancer involving the nervous system, in close collaboration with many departments, including the departments of Pathology, Immunology, Medical Oncology and Radiotherapy. The program focuses on the following three main topics: 1. Primary Brain Tumors. 1.1 Identify molecular markers predicting treatment response in glial tumors using large scale analysis (genomics, transcriptomics, methylomics, metabolomics) and high-end mass spectrometry. 1.2 Develop experimental gene therapy modality for treatment of primary brain tumors. 1.3 Establish an effective treatment for patients with primary brain tumors. The department participates in phase I trials and is coordinator/initiator of several large international phase II-III trials. 2. Paraneoplastic disorders. 2.1 Identify the association between paraneoplastic autoantibodies, antigen specific T lymphocytes, clinical neurological syndrome and associated tumor. 2.2 Clone the target antigen of newly identified paraneoplastic autoantibodies. 2.3 Study the role of the paraneoplastic autoimmune response in anti-tumor immunity and neurological dysfunction. 3. Pain. 3.1 Study the role of neurotrophic factors in pain transmission in the superficial dorsal horn in animal models. 3.2 Establish an effective treatment for patients with cancer pain, focusing on neuropathic cancer pain and breakthrough pain. The department has initiated several clinical pain studies and coordinates an international randomized study to evaluate a new treatment modality for breakthrough pain. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot bioinformatics 0 0,75 0 0 0,75 neurology 5,69 2,45 1,13 3,66 12,93 neurosurgery 1,61 0 0 0 1,61 pathology 1,3 0,83 0 0 2,13 Total 8,6 4,03 1,13 3,66 17,42 2 0 0 2 38 1 3 44 Thesis Kampen, J.J.A. van (2009, oktober 21). Mass spectrometry to determine intracellular concentrations of antiretroviral drugs. EUR (216 pag.) (Rotterdam: Optima Grafische Communicatie). Prom./coprom.: Prof.Dr. P.A.E. Sillevis Smitt, Prof.Dr. R. de Groot & Dr. T.M. Luider. Mustafa, D.A.M. (2009, november 10). Identifying proteins involved in glioma angiogenesis: a proteomics approach. EUR. Prom./coprom.: Prof.Dr. J.M. Kros & Dr. T.M. Luider. Article/Letter to the editor Bent, M.J. van den, Vogelbaum, MA, Wen, PY, Macdonald, DR & Chang, SM (2009). End Point Assessment in Gliomas: Novel Treatments Limit Usefulness of Classical Macdonald's Criteria. Journal of Clinical Oncology, 27(18), 2905-2908. Bent, M.J. van den, Dubbink, H.J., Sanson, M, Lee-Haarloo, CR van der, Hegi, M, Jeuken, J.W.M., Ibdaih, A, Brandes, A.A., Taphoorn, M.J.B., Frenay, M., Lacombe, D., Gorlia, T., Dinjens, W.N.M. & Kros, J.M. (2009). MGMT Promoter Methylation Is Prognostic but Not Predictive for Outcome to Adjuvant PCV Chemotherapy in Anaplastic Oligodendroglial Tumors: A Report From EORTC Brain Tumor Group Study 26951. Journal of Clinical Oncology, 27(35), 5881-5886. Bent, M.J. van den, Brandes, A.A., Rampling, R., Kouwenhoven, M.C.M., Kros, J.M., Carpentier, A.F., Clement, PM, Frenay, M., Campone, M., Baurain, JF, Armand, JP, Taphoorn, M.J.B., Tosoni, A., Kletzl, H, Klughammer, B, Lacombe, D. & Gorlia, T. (2009). Randomized Phase II Trial of Erlotinib Versus Temozolomide or Carmustine in Recurrent Glioblastoma: EORTC Brain Tumor Group Study 26034. Journal of Clinical Oncology, 27(8), 1268-1274. Beukelaar, J.W. de, Milikan, J.C., Verjans, G.M., Graaf, M.T. de, Norden, Y. van, Lamers, C.H., Bent, M.J. van den, Bromberg, J.E., Hulsenboom, E., Sintnicolaas, K., Gratama, J.W. & Smitt, P.A.S. (2009). No evidence for the presence of HuD-specific T cells in the cerebrospinal fluid of patients with Huassociated paraneoplastic neurological syndromes. Journal of Neurology, 256(2), 279-282. Bromberg, J.E.C. & Bent, M.J. van den (2009). Oligodendrogliomas: Molecular Biology and Treatment. Oncologist, 14(2), 155-163. Carvalho Oliveira, I.M.D. de, Charro, N, Aarbiou, J., Offerman, R.M.G.B., Wilke, M., Schettgen, T, Kraus, T, Titulaer, M.K., Burgers, P., Luider, T.M., Penque, D. & Scholte, B.J. (2009). Proteomic Analysis of Naphthalene-Induced Airway Epithelial Injury and Repair in a Cystic Fibrosis Mouse Model. Journal of Proteome Research, 8(7), 3606-3616. Dekker, L.J.M., Kampen, J.J.A. van, Reedijk, M.L., Burgers, P.C., Gruters, R.A., Osterhaus, A.D.M.E. & Luider, T.M. (2009). A mass spectrometry based imaging method developed for the intracellular detection of HIV protease inhibitors. Rapid Communications in Mass Spectrometry, 23(8), 1183-1188. Dubbink, H.J., Taal, W., Marion, R. van, Kros, J.M., Heuvel, I. van, Bromberg, J.E., Zonnenberg, B.A., Zonnenberg, CBL, Postma, T.J., Gijtenbeek, J.M.M., Boogerd, W., Groenendijk, F.H., Sillevis Smitt, P.A.E., Dinjens, W.N.M. & Bent, M.J. van den (2009). IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Neurology, 73(21), 1792-1795.

Ervasti, HK, Jobst, KJ, Gerbaux, P, Burgers, P.C., Ruttink, PJA & Terlouw, JK (2009). The reaction of the acrylonitrile ion CH2=CH-C N center dot+ with HCN: Proton-transport catalysis vs formation of ionized pyrimidine. Chemical Physics Letters, 482(4-6), 211-216. Gehring, K, Sitskoorn, M.M., Gundy, CM, Sikkes, SAM, Klein, M., Postma, T.J., Bent, M.J. van den, Beute, GN, Enting, R.H., Kappelle, A.C., Boogerd, W., Veninga, T., Twijnstra, A., Boerman, DH, Taphoorn, M.J.B. & Aaronson, N.K. (2009). Cognitive Rehabilitation in Patients With Gliomas: A Randomized, Controlled Trial. Journal of Clinical Oncology, 27(22), 3712-3722. Goede, A.L. de, Boers, P.H.M., Dekker, L.J.M., Osterhaus, A.D.M.E., Gruters, R.A. & Rimmelzwaan, G.F. (2009). Characterization of recombinant influenza A virus as a vector for HIV-1 p17(gag). Vaccine, 27(42), 5735-5739. Gravendeel, A.M., Kouwenhoven, M.C.M., Gevaert, O, Rooi, J.J. de, Stubbs, A.P., Duijm, J.E., Daemen, A, Bleeker, FE, Bralten, L.B.C., Kloosterhof, N.K., Moor, B De, Eilers, P.H.C., Spek, P.J. van der, Kros, J.M., Sillevis Smitt, P.A.E., Bent, M.J. van den & French, P.J. (2009). Intrinsic Gene Expression Profiles of Gliomas Are a Better Predictor of Survival than Histology. Cancer Research, 69(23), 9065-9072. Hulleman, E, Quarto, M, Vernell, R, Masserdotti, G, Colli, E, Kros, J.M., Levi, D, Gaetani, P, Tunici, P, Finocchiaro, G, Baena, RRY, Capra, M & Helin, K (2009). A role for the transcription factor HEY1 in glioblastoma. Journal of Cellular and Molecular Medicine, 13(1), 136-146. Jansen, F.H., Krijgsveld, J., Rijswijk, A. van, Bemd, G.J.C.M. van den, Berg, M.S. van den, Weerden, W.M. van, Willemsen, R., Dekker, L.J.M., Luider, T.M. & Jenster, G.W. (2009). Exosomal Secretion of Cytoplasmic Prostate Cancer Xenograft-derived Proteins. Molecular & Cellular Proteomics, 8(6), 1192-1205. Kaletas, BK, Wiel, IM van der, Stauber, J, Dekker, L.J.M., Guzel, C., Kros, J.M., Luider, T.M. & Heeren, RMA (2009). Sample preparation issues for tissue imaging by imaging MS. Proteomics, 9(10), 2622-2633. Kampen, J.J.A. van, Luider, T.M., Ruttink, PJA & Burgers, P.C. (2009). Metal ion attachment to the matrix mesotetrakis(pentafluorophenyl)porphyrin, related matrices and analytes: an experimental and theoretical study. Journal of Mass Spectrometry, 44(11), 1556-1564. Kouwenhoven, M.C.M., Gorlia, T., Kros, J.M., Ibdaih, A, Brandes, A.A., Bromberg, J.E.C., Mokhtari, K, Duinen, S.G. van, Teepen, JL, Wesseling, P., Vandenbos, F, Grisold, W., Sipos, L, Mirimanoff, R, Vecht, C.J., Allgeier, A., Lacombe, D. & Bent, M.J. van den (2009). Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951. Neuro-Oncology, 11(6), 737-746. Lamfers, M., Idema, S, Milligen, F van, Schouten, T, Valk, P., Vandertop, P, Dirven, C.M.F. & Noske, D (2009). Homing properties of adipose-derived stem cells to intracerebral glioma and the effects of adenovirus infection. Cancer Letters, 274(1), 78-87. Lau, L.M.L. de, Vries, J.M. de, Woude, C.J. van der, Kuipers, E.J., Siepman, D.A.M., Sillevis Smitt, P.A.E. & Hintzen, R.Q. (2009). Acute CNS White Matter Lesions in Patients with Inflammatory Bowel Disease. Inflammatory Bowel Diseases, 15(4), 576-580. Luider, T.M. (2009). Detectie in een druppel. Chemisch2Weekblad, 1-3. Oldenmenger, W.H., Sillevis Smitt, P.A.E., Dooren, S. van, Stoter, G. & Rijt, C.C.D. van der (2009). A systematic review on barriers hindering adequate cancer pain management and interventions to reduce them: A critical appraisal. European Journal of Cancer, 45(8), 1370-1380. Reardon, D.A., Dresemann, G, Taillibert, S, Campone, M., Bent, M.J. van den, Clement, P, Blomquist, E, Gordower, L, Schultz, H, Raizer, J, Hau, P, Easaw, J, Gil, M, Tonn, J, Gijtenbeek, AA, Schlegel, U, Bergstrom, P, Green, S, Weir, A & Nikolova, Z (2009). Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma. British Journal of Cancer, 101(12), 1995-2004. Rosenling, T, Slim, CL, Christin, C, Coulier, L, Shi, S, Stoop, M.P., Bosman, J, Suits, F, Horvatovich, PL, Stockhofe-Zurwieden, N, Vreeken, R, Hankemeier, T, Gool, A.J. van, Luider, T.M. & Bischoff, R. (2009). The Effect of Preanalytical Factors on Stability of the Proteome and Selected Metabolites in Cerebrospinal Fluid (CSF). Journal of Proteome Research, 8(12), 5511-5522. Scheithauer, B.W., Erdogan, S, Rodriguez, FJ, Burger, P.C., Woodruff, JM, Kros, J.M., Gokden, M & Spinner, RJ (2009). Malignant Peripheral Nerve Sheath Tumors of Cranial Nerves and Intracranial Contents A Clinicopathologic Study of 17 Cases. American Journal of Surgical Pathology, 33(3), 325-338. Schiff, D, Wen, PY & Bent, M.J. van den (2009). Neurological adverse effects caused by cytotoxic and targeted therapies. Nature Reviews Clinical Oncology, 6(10), 596-603. Shams'ili, S., Leeuw, B.M.F. van der, Hulsenboom, E.S.P., Jaarsma, D. & Sillevis Smitt, P.A.E. (2009). A new paraneoplastic encephalomyelitis autoantibody reactive with the axon initial segment. Neuroscience Letters, 467(2), 169-172. Sigmond, J, Honeywell, RJ, Postma, T.J., Dirven, C.M.F., Lange, SM de, Born, K van der, Laan, A.C., Baayen, JCA, Groeningen, C.J. van, Bergman, AM, Giaccone, G. & Peters, G.J. (2009). Gemcitabine uptake in glioblastoma multiforme: potential as a radiosensitizer. Annals of Oncology, 20(1), 182-187. Stoop, M.P., Dekker, L.J.M., Titulaer, M.K., Lamers, RJAN, Burgers, P.C., Sillevis Smitt, P.A.E., Gool, A.J. van, Luider, T.M. & Hintzen, R.Q. (2009). Quantitative Matrix-Assisted Laser Desorption Ionization-Fourier Transform Ion Cyclotron Resonance

(MALDI-FT-ICR) Peptide Profiling and Identification of Multiple-Sclerosis-Related Proteins. Journal of Proteome Research, 8(3), 1404-1414. Stupp, R., Hegi, ME, Mason, WP, Bent, M.J. van den, Taphoorn, M.J.B., Janzer, RC, Ludwin, SK, Allgeier, A., Fisher, B, Belanger, K, Hau, P, Brandes, A.A., Gijtenbeek, J, Marosi, C, Vecht, C.J., Mokhtari, K, Wesseling, P., Villa, S, Eisenhauer, E, Gorlia, T., Weller, M, Lacombe, D., Cairncross, J.G. & Mirimanoff, RO (2009). Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncology, 10(5), 459-466. Titulaer, MJ, Klooster, R, Potman, M, Sabater, L, Graus, F., Hegeman, IM, Thijssen, PE, Wirtz, P.W., Twijnstra, A., Sillevis Smitt, P.A.E., Maarel, SM van der & Verschuuren, J.J.G.M. (2009). SOX Antibodies in Small-Cell Lung Cancer and Lambert- Eaton Myasthenic Syndrome: Frequency and Relation With Survival. Journal of Clinical Oncology, 27(26), 4260-4267. Umar, A., Kang, H., Timmermans, A.M., Look, M.P., Meijer-Gelder, M.E. van, Bakker, M.A. den, Jaitly, N, Martens, J.W.M., Luider, T.M., Foekens, J.A. & Pasa-Tolic, L (2009). Identification of a Putative Protein Profile Associated with Tamoxifen Therapy Resistance in Breast Cancer. Molecular & Cellular Proteomics, 8(6), 1278-1294. Verkerk, A.J.M.H., Schot, R., Dumee, B.C., Schellekens, K.P.C., Swagemakers, S.M.A., Bertoli Avella, A.M., Lequin, M.H., Dudink, J., Govaert, P., Zwol, A.L. van, Hirst, J., Wessels, M.W., Catsman-Berrevoets, C.E., Verheijen, F.W., Graaff, E. de, Coo, I.F.M. de, Kros, J.M., Willemsen, R., Spek, P.J. van der & Mancini, G.M.S. (2009). Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. American Journal of Human Genetics, 85, 40-52. Wit, M.C.Y. de, Kros, J.M., Halley, D.J.J., Coo, I.F.M. de, Verdijk, R.M., Jacobs, B.C. & Mancini, G.M.S. (2009). Filamin A mutation, a common cause for periventricular heterotopia, aneurysms and cardiac defects. Journal of Neurology Neurosurgery and Psychiatry, 80(4), 426-428. Zheng, P., Severijnen, E.A.W.F.M., Weiden, M.M. van der, Willemsen, R. & Kros, J.M. (2009). A crucial role of caldesmon in vascular development in vivo. Cardiovascular Research, 81(2), 362-369. Zheng, P., Severijnen, E.A.W.F.M., Willemsen, R. & Kros, J.M. (2009). Caldesmon is essential for cardiac morphogenesis and function: In vivo study using a zebrafish model. Biochemical & Biophysical Research Communications, 378(1), 37-40. Zheng, P., Severijnen, E.A.W.F.M., Weiden, MD van der, Willemsen, R. & Kros, J.M. (2009). Cell proliferation and migration are mutually exclusive cellular phenomena in vivo Implications for cancer therapeutic strategies. Cell Cycle, 8(6), 950-951. Zheng, P., Severijnen, E.A.W.F.M., Willemsen, R. & Kros, J.M. (2009). Circulation status of subintestinal vessels is a sensitive parameter for monitoring suboptimal systemic circulation in experimental zebrafish embryos. Cell Cycle, 8(22), 3782-3783. Zheng, P., Severijnen, E.A.W.F.M., Willemsen, R. & Kros, J.M. (2009). Functional Cardiac Phenotypes in Zebrafish Caldesmon Morphants A Digital Motion Analysis. Circulation, 120(17), E145-E146. Zheng, P., Severijnen, E.A.W.F.M., Willemsen, R. & Kros, J.M. (2009). Haemoglobin staining for in vivo portraying of functional vasculature in experimental zebrafish embryos. Biochemical & Biophysical Research Communications, 380(4), 823-824. Zheng, P., Severijnen, E.A.W.F.M., Willemsen, R. & Kros, J.M. (2009). Reduction of caldesmon expression induces apoptosis and causes disassembly of the sarcomeric protein complex in cardiomyocytes in vivo. Cell Cycle, 8(2), 325-326. Part of book - abstract Mustafa, D.A.M., Kros, J.M. & Luider, T.M. (2009). Biomarker discovery in glioma by combined approach of laser micordissection and advanced mass spectrometry. In O. Golubnitschaja (Ed.), Predictive diagnostics and personalized treatment (pp. XXIV). New York: Nova Science Publishers. Stoop, M.P., Hintzen, R.Q. & Luider, T.M. (2009). Multiple sclerosis related biomarkers. In O Golubnitschaja (Ed.), Predictive diagnostics and personalized treatment (pp. XVIII). New York: Nove Science publishers.

EMC MM-03-47-02-A - Pathophysiological aspects and treatment of gastro-intestinal diseases Programme design in brief A major objective of this project is to investigate the impact of recently developed modalities for the diagnosis and treatment of gastro-intestinal diseases. The etiology of functional disorders such as constipation, disordered defecation and fecal incontinence will be evaluated using new diagnostic tools such as conventional anorectal manometry, 24-hours ambulant anorectal manometry, electromyography, barostat-measurements and laser Doppler flowmetry. New immuno-histochemical techniques using monoclonal antibodies will be used to investigate the histopathological characteristics of slow transit constipation. The efficacy of new therapeutic options such as anterior rectopexy, enterocele repair and sacral neuromodulation will be evaluated in clinical trials. Treatment of fecal incontinence and obstructed defecation by means of neuromodulation with pacemakers is a major topic for the next years. Medical treatment of anal fissures by local application of drugs, such as exogenous NO-donors and botulin-toxin, will also be evaluated. New surgical procedures, such as the Iwadare-technique, will be implemented in the treatment of complex, high transsphincteric fistulas. Pathofysiological aspects of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis will be studied. Another objective of this project is to evaluate the functional results following ileo-anal anastomosis in patients with IBD and FAP and following colo-anal anastomosis in patients with rectal cancer. New radiological tools such as endorectal ultrasound and magnetic resonance imaging of the anal sphincters and pelvic floor using an endo-anal coil, will be used for the preoperative localisation and classification of perianal fistulas, sphincter defects and rectal cancer. The role of laparoscopic techniques will be evaluated in patiens with acute peritonitis and colorectal cancer. The potential benefit of endoscopic intersection of the splanchnic nerves for patients with severe abdominal pain due to chronic pancreatitis will be studied. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot immunology 1 0 0 0 1 surgery 3,9 0 0 0 3,9 Total 4,9 0 0 0 4,9 2 0 0 2 39 1 1 43 Thesis Mitalas, E. (2009, november 11). Identification of factors affecting the outcome of transanal advancement flap repair for high transsphincteric fistulas. EUR. Prom./coprom.: Prof.Dr. R. Benner, Prof.Dr. H.W. Tilanus & Dr. W.R. Schouten. Oom, D.M.J. (2009, november 19). Diagnosis and treatment of disorder of the posterior pelvic compartment. EUR. Prom./coprom.: Prof.Dr. J.J.B. van Lanschot. Article/Letter to the editor Bonjer, H.J., Cuesta, M.A., Lacy, A.M., Haglind, E., Furst, A, Lange, J.F., Hop, W.C.J., Buunen, M., D'Hoore, A, Inglis, K, Jess, P, Bulut, O, Rosenberg, J, Peiman,., Christensen, MM, Isalnieks, I, Jager, C., Kreis, M, Jeekel, J., Harst, E. van der, Coenen, PPLO, Gerhards, MF, Bemelman, W, Jakimowicz, JJ, Riet, YEA van, Hansson, BME, Rosman, C., Neijenhuis, PA, Outer, AJ den, Targarona, EM, Balague, C, Delgado, S, Lujan, J, Molina, FJG, Skullman, S, Kurlberg, G, Lackberg, Z, Pahlman, L., Kressner, U, Matthiessen, P & Kim, S.H. (2009). COLOR II - A randomized clinical trial comparing laparoscopic and open surgery for rectal cancer. Danish Medical Bulletin, 56(2), 89-91. Boonstra, J.J., Koppert, L.B., Wijnhoven, B.P.L., Tilanus, H.W., Dekken, H. van, Tran, T.C.K. & Gaast, A. van der (2009). Chemotherapy Followed by Surgery in Patients With Carcinoma of the Distal Esophagus and Celiac Lymph Node Involvement. Journal of Surgical Oncology, 100(5), 407-413. Buise, M, Bommel, J. van, Genderen, M van, Tilanus, H.W., Zundert, A van & Gommers, D. (2009). Two-Lung High-Frequency Jet Ventilation as an Alternative Ventilation Technique During Transthoracic Esophagectomy. Journal of Cardiothoracic and Vascular Anesthesia, 23(4), 509-512. Buunen, M., Lange, MM, Ditzel, M., Kleinrensink, G.J., Velde, C.J van de & Lange, J.F. (2009). Level of arterial ligation in total mesorectal excision (TME): an anatomical. International Journal of Colorectal Disease, 24(11), 1317-1320. Cheung, YM, Lange, MM, Buunen, M. & Lange, J.F. (2009). Current technique of laparoscopic total mesorectal excision (TME): an international questionnaire among 368 surgeons. Surgical Endoscopy-Ultrasound and Interventional Techniques, 23(12), 2796-2801. colon cancer laparoscopic group, -, Buunen, M., Veldkamp, R., Hop, W.C.J., Kuhry, E., Jeekel, J., Haglind, E., Pahlman, L., Cuesta, M.A., Msika, S., Morino, M., Lacy, A. & Bonjer, H.J. (2009). Survival after laparoscopic surgery versus open surgery for colon cancer: long-term outcome of a randomised clinical trial. Lancet Oncology, 10, 44-52. Dekken, H. van, Tilanus, H.W., Hop, W.C.J., Dinjens, W.N.M., Wink, JC, Vissers, K. & Marion, R. van (2009). Array comparative genomic hybridization, expression array, and protein analysis of critical regions on chromosome arms 1q, 7q, and 8p in adenocarcinomas of the gastroesophageal junction. Cancer Genetics & Cytogenetics, 189(1), 37-42. Demirkiran, A., Sewgobind, V.D.K.D., Weijde, J van der, Kok, A., Baan, C.C., Kwekkeboom, J., Tilanus, H.W., Metselaar, H.J. & Laan, L.J.W. van der (2009). Conversion From Calcineurin Inhibitor to Mycophenolate Mofetil-Based Immunosuppression Changes the Frequency and Phenotype of CD4(+)FOXP3(+) Regulatory T Cells. Transplantation, 87(7), 1062-1068.

Dols, L.F.C., Verhoef, C., Eskens, F.A.L.M., Schouten, O., Nonner, J., Hop, W.C.J., Mendez Romero, A.M., Man, R.A. de, Linden, E. van der, Dwarkasing, R.S. & Ijzermans, J.N.M. (2009). Improvement of 5 year survival rate after liver resection for colorectal metastases between 1984-2006. Nederlands Tijdschrift voor Geneeskunde, 153, 490-495. Ferenschild, F.T.J., Vermaas, M., Verhoef, C., Ansink, A.C., Kirkels, W.J., Eggermont, A.M.M. & Wilt, J.H.W. de (2009). Total Pelvic Exenteration for Primary and Recurrent Malignancies. World Journal of Surgery, 33(7), 1502-1508. Franssen, SJ, Lagarde, SM, Werven, JR van, Smets, E.M.A., Tran, KTC, Plukker, JTM, Lanschot, J.J.B. van & Haes, H.C.J.M. (2009). Psychological factors and preferences for communicating prognosis in esophageal cancer patients. Psycho-Oncology, 18(11), 1199-1207. Gosselink, M.P., Oom, D.M.J., Zimmerman, D.D. & Schouten, W.R. (2009). Martius flap: an adjunct for repair of complex, low rectovaginal fistula. American Journal of Surgery, 197(6), 833-834. Grotenhuis, B.A., Wijnhoven, B.P.L., Marion, R. van, Dekken, H. van, Hop, W.C., Tilanus, H.W., Lanschot, J.J.B. van & Eijck, C.H.J. van (2009). The sentinel node concept in adenocarcinomas of the distal esophagus and gastroesophageal junction. Journal of Thoracic and Cardiovascular Surgery, 138(3), 608-612. Harlaar, J.J., Ramshorst, G.H. van, Nieuwenhuizen, J., Brinke, J.G. ten, Hop, W.C.J., Kleinrensink, G.J., Jeekel, J. & Lange, J.F. (2009). Small stitches with small suture distances increase laparotomy closure strength. American Journal of Surgery, 198(3), 392-395. Heijl, M. van, Omloo, JMT, Henegouwen, MIV, Smits, NJ, Phoa, SSKS, Bergman, JJGHM, Sloof, G.W., Lanschot, J.J.B. van & Bossuyt, P.M.M. (2009). Diagnostic Strategies for Pre-Treatment Staging of Patients with Oesophageal Cancer. Digestive Surgery, 26(2), 149-155. Komen, N.A.P., Dijk, JW, Lalmahomed, Z, Klop, K, Hop, W., Kleinrensink, G.J., Jeekel, J., Schouten, W.R. & Lange, J.F. (2009). After-hours colorectal surgery: a risk factor for anastomotic leakage. International Journal of Colorectal Disease, 24(7), 789-795. Komen, N.A.P., Wal, HC van der, Ditzel, M., Kleinrensink, G.J., Jeekel, J. & Lange, J.F. (2009). Colorectal Anastomotic Leakage: A New Experimental Model. Journal of Surgical Research, 155(1), 7-12. Komen, N.A.P., Morsink, MC, Beiboer, S, Miggelbrink, A, Willemsen, P, Harst, E. van der, Lange, J.F. & Leeuwen, W.B. van (2009). Detection of colon flora in peritoneal drain fluid after colorectal surgery: Can RT-PCR play a role in diagnosing anastomotic leakage? Journal of Microbiological Methods, 79(1), 67-70. Lans, T.E., Ramshorst, G.H. van, Hermans, J.J., Bakker, M.A. den, Tran, T.C.K. & Kazemier, G. (2009). Perivascular Epithelioid Cell Tumor of the Retroperitoneum in a Young Woman Resulting in an Abdominal Chyloma. Journal of Gastrointestinal Surgery, 13(2), 389-392. Meerten, E. van, Gaast, A. van der, Tilanus, H.W., Poley, J.W., Muller, K. & Dekken, H. van (2009). Pathological Analysis After Neoadjuvant Chemoradiotherapy for Esophageal Carcinoma: The Rotterdam Experience. Journal of Surgical Oncology, 100(1), 32-37. Meijer, V.E. de, Verhoef, C. & Ijzermans, J.N.M. (2009). Radiofrequency Ablation in the Treatment of Hepatocellular Carcinoma: The Need for Centralization. Annals of Surgery, 250(3), 497-498. Mendez Romero, A.M., Zinkstok, R.T., Wunderink, W., Os, RM van, Joosten, P.J., Seppenwoolde, Y., Nowak, P.J.C.M., Brandwijk, R.P., Verhoef, C., Ijzermans, J.N.M., Levendag, P.C. & Heijmen, B.J.M. (2009). Stereotactic body radiation therapy for liver tumors: impact of daily setup corrections and day- to day anatomic anatomic variations on dose in target and organs at risk. International Journal of Radiation Oncology Biology Physics, 75(4), 1201-1208. Mitalas, LE, Schouten, SB, Gosselink, M.P., Oom, D.M.J., Zimmerman, D.D.E. & Schouten, W.R. (2009). Does Rectal Mucosal Blood Flow Affect the Outcome of Transanal Advancement Flap Repair? Diseases of the Colon & Rectum, 52(8), 1395-1399. Mitalas, LE, Gosselink, M.P., Oom, D.M.J., Zimmerman, D.D.E. & Schouten, W.R. (2009). Required length of follow-up after transanal advancement flap repair of high transsphincteric fistulas. Colorectal Disease, 11(7), 726-728. Omloo, JMT, Heijl, M. van, Smits, NJ, Phoa, SSKS, Henegouwen, MIV, Sloof, G.W. & Lanschot, J.J.B. van (2009). Additional Value of External Ultrasonography of the Neck after CT and PET Scanning in the Preoperative Assessment of Patients with Esophageal Cancer. Digestive Surgery, 26(1), 43-49. Omloo, JMT, Law, SYK, Launois, B, Prise, E Le, Wong, J, Henegouwen, MIV & Lanschot, J.J.B. van (2009). Short and longterm advantages of transhiatal and transthoracic oesophageal cancer resection. European Journal of Surgical Oncology, 35(8), 793-797. Oom, D.M.J., Gosselink, M.P. & Schouten, W.R. (2009). Anterior Sphincteroplasty for Fecal Incontinence: A Single Center Experience in the Era of Sacral Neuromodulation. Diseases of the Colon & Rectum, 52(10), 1681-1687. Oom, D.M.J., Gosselink, M.P. & Schouten, W.R. (2009). Enterocele - Diagnosis and treatment. Gastroenterologie Clinique et Biologique, 33(2), 135-137. Pan, Q., Henry, S.D., Metselaar, H.J., Scholte, B., Kwekkeboom, J., Tilanus, H.W., Janssen, H.L.A. & Laan, L.J.W. van der (2009). Combined antiviral activity of interferon-alpha and RNA interference directed against hepatitis C without affecting vector delivery and gene silencing. Journal of Molecular Medicine-Jmm, 87(7), 713-722.

Pan, Q., Tilanus, H.W., Janssen, H. & Laan, L.J.W. van der (2009). Prospects of RNAi and microrna-based therapies for hepatitis C. Expert Opinion on Biological Therapy, 9(6), 713-724. Poley, J.W., Kluijt, I., Gouma, D.J., Harinck, F., Wagner, A., Aalfs, C.M., Eijck, C.H.J. van, Cats, A., Kuipers, E.J., Nio, YC, Fockens, P. & Bruno, M.J. (2009). The yield of first-time endoscopic ultrasonography in screening individuals at a high-risk of developing pancreatic cancer. American Journal of Gastroenterology, 104, 2175-2181. Pool, A.E.M. van der, Lalmahomed, Z.S., Wilt, J.H.W. de, Eggermont, A.M.M., Ijzermans, J.N.M. & Verhoef, C. (2009). Local Treatment for Recurrent Colorectal Hepatic Metastases after Partial Hepatectomy. Journal of Gastrointestinal Surgery, 13(5), 890-895. Santvoort, H.C. van, Besselink, M.G., Vries, A.C. de, Boermeester, M.A., Fischer, K., Bollen, T.L., Cirkel, GA, Schaapherder, AF, Nieuwenhuijs, V.B., Goor, H. van, DeJong, C.H., Eijck, C.H. van, Witteman, B.J., Weusten, BL, Laarhoven, C.J. van, Wahab, P.J., Tan, AC, Schwartz, MP, Harst, E. van der, Cuesta, M.A., Siersema, P.D., Gooszen, H.G. & Erpecum, K.J. van (2009). Early Endoscopic Retrograde Cholangiopancreatography in Predicted Severe Acute Biliary Pancreatitis A Prospective Multicenter Study. Annals of Surgery, 250(1), 68-75. Sewgobind, V.D.K.D., Kho, M.M.L., Laan, L.J.W. van der, Hendrikx, T.K., Dam, T. van, Tilanus, H.W., Ijzermans, J.N.M., Weimar, W. & Baan, C.C. (2009). The effect of rabbit anti-thymocyte globulin induction therapy on regulatory T cells in kidney transplant patients. Nephrology Dialysis Transplantation, 24(5), 1635-1644. Verhoef, C., Pool, A.E.M. van der, Nuyttens, J.J.M.E., Planting, A.S.T., Eggermont, A.M.M. & Wilt, J.H.W. de (2009). The "liverfirst approach" for patients with locally advanced rectal cancer and synchronous liver metastases. Diseases of the Colon & Rectum, 52(1), 23-30. Vermeulen, J., Coene, PPLO, Hout, M.A. van der, Harst, E. van der, Gosselink, M.P., Mannaerts, G.H.H., Weidema, W.F. & Lange, J.F. (2009). Restoration of bowel continuity after surgery for acute perforated diverticulitis: should Hartmann's procedure be considered a one-stage procedure? Colorectal Disease, 11(6), 619-624. Verschuur, E.M.L., Steyerberg, E.W., Tilanus, H.W., Polinder, S., Essink-Bot, M.L., Tran, KTC, Gaast, A. van der, Stassen, L.P.S., Kuipers, E.J. & Siersema, P.D. (2009). Nurse-led follow-up of patients after oesophageal or gastric cardia cancer surgery: a randomised trial. British Journal of Cancer, 100(1), 70-76. Witjes, C.D.M., Verhoef, C., Verheul, HMW & Eskens, F.A.L.M. (2009). Systemic treatment in hepatocellular carcinoma; 'A small step for man...'. Netherlands Journal of Medicine, 67(3), 86-90. Wouters, MWJM, Karim-Kos, H.E., Cessie, S. le, Wijnhoven, B.P.L., Stassen, L.P.S., Steup, W.H., Tilanus, H.W. & Tollenaar, R.A.E.M. (2009). Centralization of Esophageal Cancer Surgery: Does It Improve Clinical Outcome? Annals of Surgical Oncology, 16(7), 1789-1798. Zingg, U, Langton, C, Addison, B, Wijnhoven, B.P.L., Forberger, J, Thompson, SK, Esterman, AJ & Watson, DI (2009). Risk Prediction Scores for Postoperative Mortality After Esophagectomy: Validation of Different Models. Journal of Gastrointestinal Surgery, 13(4), 611-618. Part of book - abstract Lanschot, J.J.B. van, Tran, T.C.K., Wijnhoven, B.P.L. & Tilanus, H.W. (2009). Transhiatal esphagectomy. In RA Audisio (Ed.), Atlas of procedures in surgical oncology with critical evidence-based commentary notes (pp. 103-108). New Yersey: World Scientific.

EMC MM-03-47-11 - Innovative tumor model development/tumor vasculature/tumor targeting/locoregional control Programme design in brief The Problem: Surgical treatment of primary tumors, recurrences or metastases may be technically impossible or insufficient to achieve local tumor control. Combination of surgery with infusion or perfusions techniques of organs or extremities, or a combination with peroperative insertion of catheters for peroperative radiotherapy or afterloading can improve the surgical results. The possibility to translate the success of isolated limb perfusions with TNFa + cytostatic drugs in patients with irresectable extremity tumors into its application in new regional perfusion settings (pelvis, liver) is under investigation. Moreover a genetherapy program using various vectors has been developed investigating the efficacy of isolated perfusion and regional infusion techniques for these new treatment modalities. The development of treating metastatic disease with tumortargeting devices such as liposomal encapsulation of TNF + cytostatic or other antiangiogenic drugs is another arm in the overall program. Optimalisation of pre- and peroperative diagnostic procedures as well as induction chemo- / radiation therapy may improve the resectability of tumors and improve the quality of life. These aspects are investigated in preclinical animal models and in clinical trial protocols. An important development is the intravital microscopy models and new in vitro tumor cell mobility assays and innovative invivo tumor models developed in our laboratory as well as the structural participation in the OIC Optical Imaging Center of the ErasmusMC. Regional isolated perfusion or infusion of cytokines, in particular TNFa or other "antistromal agents" in combination with cytostatic drugs are the central research item in this approach of biochemotherapy targeting both structural elements of neoplasms Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot nuclear medicine 0 0 0 1 1 surgery 1,6 2,5 2,05 5,09 11,24 Total 1,6 2,5 2,05 6,09 12,24 1 0 0 1 51 8 0 60 Thesis Ferenschild, F.T.J. (2009, december 09). Multidisciplinairy treatment of rectal cancer and other pelvic tumours. EUR (200 pag.). Prom./coprom.: Prof.Dr. A.M.M. Eggermont & Dr. J.H.W. de Wilt. Article/Letter to the editor Agarwala, SS, Keilholz, U., Gilles, E, Bedikian, AY, Wu, J., Kay, R, Stein, CA, Itri, LM, Suciu, S. & Eggermont, A.M.M. (2009). LDH correlation with survival in advanced melanoma from two large, randomised trials (Oblimersen GM301 and EORTC 18951). European Journal of Cancer, 45(10), 1807-1814. Agarwala, SS, Becker, JC, Eggermont, A.M.M., Flaherty, KT, Garbe, C, Goldstein, AM, Halpern, A, Kashani-Sabet, M, Hauschild, A, Kirkwood, J.M., Leachman, S, Lorigan, P, McMahon, M, Messina, J, Ribas, A, Samlowski, WE, Schadendorf, D. & Sondak, VK (2009). Meeting report: consensus from the first and second Global Workshops in Melanoma November 19-20, 2008. Pigment Cell & Melanoma Research, 22(5), 532-543. Akkooi, A.C.J. van, Spatz, A., Eggermont, A.M.M., Mihm, M. & Cook, M.G. (2009). Expert opinion in melanoma: The sentinel node; EORTC Melanoma Group recommendations on practical methodology of the measurement of the microanatomic location of metastases and metastatic tumour burden. European Journal of Cancer, 45(16), 2736-2742. Balch, CM, Gershenwald, JE, Soong, SJ, Thompson, J.F., Atkins, MB, Byrd, DR, Buzaid, AC, Cochran, A.J., Coit, DG, Ding, SL, Eggermont, A.M.M., Flaherty, KT, Gimotty, PA, Kirkwood, J.M., McMasters, KM, Mihm, MC, Morton, DL, Ross, MI, Sober, AJ & Sondak, VK (2009). Final Version of 2009 AJCC Melanoma Staging and Classification. Journal of Clinical Oncology, 27(36), 6199-6206. Besselink, M.G., Santvoort, H.C. van, Boermeester, M.A., Fischer, K., Renooij, W., Smet, MB de, Ali, UA, Cirkel, GA, Bollen, T.L., Ramshorst, B. van, Weusten, BL, Schaapherder, AF, Witteman, B.J., Ploeg, R.J., Goor, H. van, Laarhoven, C.J. van, Tan, AC, Brink, MA, Harst, E. van der, Wahab, P.J., Eijck, C.H.J. van, DeJong, C.H., Erpecum, K.J. van, Akkermans, L.M. & Gooszen, H.G. (2009). Intestinal barrier dysfunction in a randomised placebo-controlled trial of probiotic prophylaxis in acute pancreatitis. European Journal of Gastroenterology & Hepatology, 21(3), A2-A2. Besselink, M.G., Santvoort, H.C. van, Boermeester, M.A., Nieuwenhuijs, V.B., Goor, H. van, Dejong, CHC, Schaapherder, AF & Gooszen, H.G. (2009). Timing and impact of infections in acute pancreatitis. British Journal of Surgery, 96(3), 267-273. Boer, M. de, Deurzen, C.H.M. van, Dijck, J.A.A.M. van, Borm, GF, Diest, P.J. van, Adang, E.M.M., Nortier, J.W.R., Rutgers, EJT, Seynaeve, C., Menke-Pluymers, M.B.E., Bult, P. & Tjan-Heijnen, V.C.G. (2009). Micrometastases or Isolated Tumor Cells and the Outcome of Breast Cancer. New England Journal of Medicine, 361(7), 653-663. Bottomley, A., Coens, C., Suciu, S., Santinami, M., Kruit, W.H.J., Testori, A., Marsden, J., Punt, C., Sales, F., Gore, M., MacKie, R, Kusic, Z, Dummer, R., Patel, P, Schadendorf, D., Spatz, A., Keilholz, U. & Eggermont, A.M.M. (2009). Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation in Resected Stage III Melanoma: A Phase III Randomized Controlled Trial of Health-Related Quality of Life and Symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group. Journal of Clinical Oncology, 27(18), 2916-2923. Bouwhuis, M.G., Suciu, S., Collette, S, Aamdal, S., Kruit, W.H.J., Bastholt, L, Stierner, U, Sales, F., Patel, P, Punt, C.J.A., Hernberg, M, Spatz, A., Hagen, T.L.M. ten, Hansson, J. & Eggermont, A.M.M. (2009). Autoimmune Antibodies and Recurrence- Free Interval in Melanoma Patients Treated With Adjuvant Interferon. Journal of the National Cancer Institute, 101(12), 869-877. Chakera, AH, Hesse, B, Burak, Z, Ballinger, JR, Britten, A, Caraco, C, Cochran, A.J., Cook, M.G., Drzewiecki, KT, Essner, R, Even-Sapir, E, Eggermont, A.M.M., Stopar, TG, Ingvar, C, Mihm, MC, McCarthy, SW, Mozzillo, N, Nieweg, O.E., Scolyer, R.A.,

Starz, H, Thompson, J.F., Trifiro, G., Viale, G, Vidal-Sicart, S, Uren, R, Waddington, W, Chiti, A, Spatz, A. & Testori, A. (2009). EANM-EORTC general recommendations for sentinel node diagnostics in melanoma. European Journal of Nuclear Medicine and Molecular Imaging, 36(10), 1713-1742. Dols, L.F.C., Verhoef, C., Eskens, F.A.L.M., Schouten, O., Nonner, J., Hop, W.C.J., Mendez Romero, A.M., Man, R.A. de, Linden, E. van der, Dwarkasing, R.S. & Ijzermans, J.N.M. (2009). Improvement of 5 year survival rate after liver resection for colorectal metastases between 1984-2006. Nederlands Tijdschrift voor Geneeskunde, 153, 490-495. Eggermont, A.M.M. (2009). Immunostimulation Versus Immunosuppression after Multiple Vaccinations: the Woes of Therapeutic Vaccine Development. Clinical Cancer Research, 15(22), 6745-6747. Eggermont, A.M.M. & Schadendorf, D. (2009). Melanoma and Immunotherapy. Hematology-Oncology Clinics of North America, 23(3), 547-+. Eggermont, A.M.M. (2009). Therapeutic vaccines in solid tumours: canthey be harmful? European Journal of Cancer, 45(12), 2087-2090. Eggermont, A.M.M., Testori, A., Marsden, J., Hersey, P., Quirt, I, Petrella, T, Gogas, H, MacKie, RM & Hauschild, A (2009). Utility of adjuvant systemic therapy in melanoma. Annals of Oncology, 20, 30-34. Eggermont, A.M.M. (2009). Vaccine trials in melanoma-time for reflection. Nature Reviews Clinical Oncology, 6(5), 256-258. Etten, B. van, Wilt, J.H.W. de, Brunstein, F., Eggermont, A.M.M. & Verhoef, C. (2009). Isolated hypoxic hepatic perfusion with melphalan in patients with irresectable ocular melanoma metastases. European Journal of Surgical Oncology, 35(5), 539-545. Fekkes, D., Gool, A.R. van, Bannink, M., Sleijfer, S., Kruit, W.H.J., Holt, B. van der, Eggermont, A.M.M., Hengeveld, M.W. & Stoter, G. (2009). Nitric oxide production and monoamine oxidase activity in cancer patients during interferon-alpha therapy. Amino Acids, 37(4), 703-708. Ferenschild, F.T.J., Vermaas, M., Verhoef, C., Dwarkasing, R.S., Eggermont, A.M.M. & Wilt, J.H.W. de (2009). Abdominosacral resection for locally advanced and recurrent rectal cancer. British Journal of Surgery, 96(11), 1341-1347. Ferenschild, F.T.J., Dawson, I., Graaf, EJR de, Wilt, J.H.W. de & Tetteroo, GWM (2009). Preoperative Radiotherapy Has No Value for Patients with T2-3, N0 Adenocarcinomas of the Rectum. Digestive Surgery, 26(4), 291-296. Ferenschild, F.T.J., Dawson, I., Wilt, J.H.W. de, Graaf, EJR de, Groenendijk, RPR & Tetteroo, GWM (2009). Total mesorectal excision for rectal cancer in an unselected population: quality assessment in a low volume center. International Journal of Colorectal Disease, 24(8), 923-929. Ferenschild, F.T.J., Vermaas, M., Verhoef, C., Ansink, A.C., Kirkels, W.J., Eggermont, A.M.M. & Wilt, J.H.W. de (2009). Total Pelvic Exenteration for Primary and Recurrent Malignancies. World Journal of Surgery, 33(7), 1502-1508. Fusi, A, Collette, S, Busse, A, Suciu, S., Rietz, A, Santinami, M., Kruit, W.H.J., Testori, A., Punt, C.J.A., Dalgleish, AG, Spatz, A., Eggermont, A.M.M. & Keilholz, U. (2009). Circulating melanoma cells and distant metastasis-free survival in stage III melanoma patients with or without adjuvant interferon treatment (EORTC 18991 side study). European Journal of Cancer, 45(18), 3189-3197. Geel, A.N. van, Wouters, MW, Pol, C van der, Schmitz, P.I.M. & Lans, T. (2009). Chest wall resection for internal mammary lymph node metastases of breast cancer. Breast, 18(2), 94-99. Gogas, H, Eggermont, A.M.M., Hauschild, A, Hersey, P., Mohr, P, Schadendorf, D., Spatz, A. & Dummer, R. (2009). Biomarkers in melanoma. Annals of Oncology, 20, 8-13. Grotenhuis, B.A., Wijnhoven, B.P.L., Marion, R. van, Dekken, H. van, Hop, W.C., Tilanus, H.W., Lanschot, J.J.B. van & Eijck, C.H.J. van (2009). The sentinel node concept in adenocarcinomas of the distal esophagus and gastroesophageal junction. Journal of Thoracic and Cardiovascular Surgery, 138(3), 608-612. Grunhagen, D.J., Wilt, J.H.W. de, Geel, A.N. van, Verhoef, C. & Eggermont, A.M.M. (2009). Isolated lumb perfusion with TNFalpha and melphalan in locally advanced soft tissue sarcomas of the extremities. Recent Results in Cancer Research, 179, 257-270. Hauschild, A, Agarwala, SS, Trefzer, U, Hogg, D., Robert, C, Hersey, P., Eggermont, A.M.M., Grabbe, S, Gonzalez, R., Gille, J, Peschel, C, Schadendorf, D., Garbe, C, O'Day, S, Daud, A, White, JM, Xia, CH, Patel, K, Kirkwood, J.M. & Keilholz, U. (2009). Results of a Phase III, Randomized, Placebo-Controlled Study of Sorafenib in Combination With Carboplatin and Paclitaxel As Second-Line Treatment in Patients With Unresectable Stage III or Stage IV Melanoma. Journal of Clinical Oncology, 27(17), 2823-2830. Hersey, P., Bastholt, L, Chiarion-Sileni, V, Cinat, G, Dummer, R., Eggermont, A.M.M., Espinosa, E, Hauschild, A, Quirt, I, Robert, C & Schadendorf, D. (2009). Small molecules and targeted therapies in distant metastatic disease. Annals of Oncology, 20, 35-40. Horssen, R. van, Janssen, E., Peters, W, Pasch, L Van de, Lindert, MMT, Dommelen, MMT van, Linssen, PC, Hagen, T.L.M. ten, Fransen, J.A.M. & Wieringa, B. (2009). Modulation of Cell Motility by Spatial Repositioning of Enzymatic ATP/ADP Exchange Capacity. Journal of Biological Chemistry, 284(3), 1620-1627.

Kirkwood, J.M. & Eggermont, A.M.M. (2009). Highlights from the perspectives in melanoma XII conference. Pigment Cell & Melanoma Research, 22(2), 156-165. Kragten, A.T., Wilt, J.H.W. de, Schmitz, P.I.M., Bontenbal, M. & Levendag, P.C. (2009). Multimodality treatment for anaplastic thyroid carcinoma - Treatment outcome in 75 patients. Radiotherapy and Oncology, 92(1), 100-104. Kruit, A., Tilanus-Linthorst, M.M., Boonstra, J.G., Schaik, R.H.N. van, Grutters, J.C., Bosch, J.M.M. van den & Ruven, HJT (2009). MUC1 568 A/G genotype-dependent Cancer Antigen 15-3 levels in breast cancer patients. Clinical Biochemistry, 42(7-8), 662-665. Kuiper, JWP, Horssen, R. van, Oerlemans, F., Peters, W, Dommelen, MMT van, Lindert, MMT, Hagen, T.L.M. ten, Janssen, E., Fransen, J.A.M. & Wieringa, B. (2009). Local ATP Generation by Brain-Type Creatine Kinase (CK-B) Facilitates Cell Motility. PLoS One, 4(3). Kuipers, IM, Oostenbroek, RJ, Storm, R.K., Menke-Pluymers, M.B.E., Westenend, P.J. & Plaisier, P.W. (2009). Suppose a mammary carcinoma is absent from the surgical specimen. Nederlands Tijdschrift voor Geneeskunde, 153. Lans, T.E., Pol, C van der, Wouters, MW, Schmitz, P.I.M. & Geel, A.N. van (2009). Complications in Wound Healing after Chest Wall Resection in Cancer Patients; a Multivariate Analysis of 220 Patients. Journal of Thoracic Oncology, 4(5), 639-643. Lier, M.G.F. van, Wilt, J.H.W. de, Wagemakers, JJMF, Dinjens, W.N.M., Damhuis, RAM, Wagner, A., Kuipers, E.J. & Leerdam, M.E. van (2009). Underutilization of microsatellite instability analysis in colorectal cancer patients at high risk for Lynch syndrome. Scandinavian Journal of Gastroenterology, 44(5), 600-604. MacKie, RM, Hauschild, A & Eggermont, A.M.M. (2009). Epidemiology of invasive cutaneous melanoma. Annals of Oncology, 20, 1-7. Mast, J.J., Morak, M.J.M., Brett, BT & Eijck, C.H.J. van (2009). Ischemic acute necrotizing pancreatitis in a marathon runner. International Journal of Operations and Production Management, 8(10), 53-54. Meijer, V.E. de, Verhoef, C. & Ijzermans, J.N.M. (2009). Radiofrequency Ablation in the Treatment of Hepatocellular Carcinoma: The Need for Centralization. Annals of Surgery, 250(3), 497-498. Mendez Romero, A.M., Zinkstok, R.T., Wunderink, W., Os, RM van, Joosten, P.J., Seppenwoolde, Y., Nowak, P.J.C.M., Brandwijk, R.P., Verhoef, C., Ijzermans, J.N.M., Levendag, P.C. & Heijmen, B.J.M. (2009). Stereotactic body radiation therapy for liver tumors: impact of daily setup corrections and day- to day anatomic anatomic variations on dose in target and organs at risk. International Journal of Radiation Oncology Biology Physics, 75(4), 1201-1208. Mohr, P, Eggermont, A.M.M., Hauschild, A & Buzaid, A (2009). Staging of cutaneous melanoma. Annals of Oncology, 20, 14-21. Morak, M.J.M., Hermans, J.J., Smeenk, H.G., Renders, W.M., Nuyttens, J.J.M.E., Kazemier, G. & Eijck, C.H.J. van (2009). Staging for locally advanced pancreatic cancer. European Journal of Surgical Oncology, 35(9), 963-968. Petri, B.J., Eijck, C.H.J. van, Herder, W.W. de, Wagner, A. & Krijger, R.R. de (2009). Phaeochromocytomas and sympathetic paragangliomas. British Journal of Surgery, 96(12), 1381-1392. Poley, J.W., Kluijt, I., Gouma, D.J., Harinck, F., Wagner, A., Aalfs, C.M., Eijck, C.H.J. van, Cats, A., Kuipers, E.J., Nio, YC, Fockens, P. & Bruno, M.J. (2009). The yield of first-time endoscopic ultrasonography in screening individuals at a high-risk of developing pancreatic cancer. American Journal of Gastroenterology, 104, 2175-2181. Pool, A.E.M. van der, Lalmahomed, Z.S., Wilt, J.H.W. de, Eggermont, A.M.M., Ijzermans, J.N.M. & Verhoef, C. (2009). Local Treatment for Recurrent Colorectal Hepatic Metastases after Partial Hepatectomy. Journal of Gastrointestinal Surgery, 13(5), 890-895. Pool, S.E., Breeman, W.A.P., Eggermont, A.M.M., Eijck, C.H.J. van, Krenning, E.P., Hagen, T.L.M. ten, Koning, G.A. & Jong, M. de (2009). Multimodality imaging of somatostatin receptor positive tumours with nuclear and bioluminescence imaging. Daniel den Hoed Cancer News. Rickelt, J, Hoekstra, H, Coevorden, F. van, Vreeze, R de, Verhoef, C. & Geel, A.N. van (2009). Forequarter amputation for malignancy. British Journal of Surgery, 96(7), 792-798. Santvoort, H.C. van, Besselink, M.G., Vries, A.C. de, Boermeester, M.A., Fischer, K., Bollen, T.L., Cirkel, GA, Schaapherder, AF, Nieuwenhuijs, V.B., Goor, H. van, DeJong, C.H., Eijck, C.H. van, Witteman, B.J., Weusten, BL, Laarhoven, C.J. van, Wahab, P.J., Tan, AC, Schwartz, MP, Harst, E. van der, Cuesta, M.A., Siersema, P.D., Gooszen, H.G. & Erpecum, K.J. van (2009). Early Endoscopic Retrograde Cholangiopancreatography in Predicted Severe Acute Biliary Pancreatitis A Prospective Multicenter Study. Annals of Surgery, 250(1), 68-75. Schadendorf, D., Algarra, SM, Bastholt, L, Cinat, G, Dreno, B, Eggermont, A.M.M., Espinosa, E, Guo, J, Hauschild, A, Petrella, T, Schachter, J. & Hersey, P. (2009). Immunotherapy of distant metastatic disease. Annals of Oncology, 20, 41-50. Seynhaeve, A.L.B., Wiel-Ambagtsheer, G. aan de, Bruijn, E.A., Ruegg, C., Meyring, M, Grell, M, Goodman, SL, Eggermont, A.M.M. & Hagen, T.L.M. ten (2009). Inhibition of alphav integrins in combination with chemotherapy improves tumor response. Daniel den Hoed Cancer News.

Strijbos, M.H., Verhoef, C., Gratama, J.W. & Sleijfer, S. (2009). On the origin of (CD105+) circulating endothelial cells. Thrombosis and Haemostasis, 102(2), 347-351. Tan, M.B.M., Bleiker, EMA, Menke-Pluymers, M.B.E., Gool, A.R. van, Dooren, S. van, Geel, A.N. van, Tilanus-Linthorst, M.M.A., Bartels, C.C.M., Klijn, J.G.M., Brekelmans, C.T.M. & Seynaeve, C. (2009). Standard psychological consultations and follow up for women at increased risk of hereditary breast cancer considering prophylactic mastectomy. Hereditary Cancer in Clinical Practice, 7, 6-6. Testori, A., Rutkowski, P, Marsden, J., Bastholt, L, Chiarion-Sileni, V, Hauschild, A & Eggermont, A.M.M. (2009). Surgery and radiotherapy in the treatment of cutaneous melanoma. Annals of Oncology, 20, 22-29. Verhoef, C., Pool, A.E.M. van der, Nuyttens, J.J.M.E., Planting, A.S.T., Eggermont, A.M.M. & Wilt, J.H.W. de (2009). The "liverfirst approach" for patients with locally advanced rectal cancer and synchronous liver metastases. Diseases of the Colon & Rectum, 52(1), 23-30. Verseijden, F., Jahr, H., Sluijs, S.J. van, Hagen, T.L. ten, Hovius, S.E.R., Seynhaeve, A.L.B., Neck, J.W. van, Osch, G.J.V.M. van & Hofer, S.O.P. (2009). Angiogenic Capacity of Human Adipose-Derived Stromal Cells During Adipogenic Differentiation: An In Vitro Study. Tissue Engineering Part A, 15(2), 445-452. Voit, CA, Akkooi, A.C.J. van, Schafer-Hesterberg, G, Schoengen, A, Schmitz, P.I.M., Sterry, W & Eggermont, A.M.M. (2009). Rotterdam Criteria for Sentinel Node (SN) Tumor Burden and the Accuracy of Ultrasound (US) -Guided Fine-Needle Aspiration Cytology (FNAC): Can US-Guided FNAC Replace SN Staging in Patients With Melanoma? Journal of Clinical Oncology, 27(30), 4994-5000. Wilschut, KJ, Aa, MAEM van der, Oosting, RS, Hennink, WE, Koning, G.A., Crommelin, D.J.A. & Mastrobattista, E (2009). Fluorescence in situ hybridization to monitor the intracellular location and accessibility of plasmid DNA delivered by cationic polymer-based gene carriers. European Journal of Pharmaceutics and Biopharmaceutics, 72(2), 391-396. Witjes, C.D.M., Verhoef, C., Verheul, HMW & Eskens, F.A.L.M. (2009). Systemic treatment in hepatocellular carcinoma; 'A small step for man...'. Netherlands Journal of Medicine, 67(3), 86-90.

EMC MM-03-49-01 - Clinical and experimental aspects of urological tumors Programme design in brief The clinical and experimental aspects of urological malignancies are a central issue within the research programme of the Department of Urology, Erasmus MC. The research is concentrated towards identification and characterization of molecular mechanisms that are responsible for cancer development and progression, improvement of the (molecular) diagnostic procedures, aspects of epidemiology and prevention, the development of prognostic factors and the development of innovative approaches to treatment, especially with respect to cancer derived from the prostate, kidney and urinary bladder. Research related to prostate cancer is most developed at this time. The clinical research programme shows much interaction with the more basically oriented research efforts and offers an opportunity to introduce recent developments in the laboratory directly into early clinical research. The research programme benefits from a large database of prostate cancer patients and of their clinical course, which was set up 20 years ago together with a tissue and serum bank. Some international projects fall within this programme: The European Randomized Study of Screening for Prostate Cancer (KWF/EUR 98-1657, EMCR 2002-2722; Quality of Life: KWF-EUR-2000-2329, Preventiefonds 0028-22820, ZONMw 2200-0106; ERSPC) is co-ordinated nationally and internationally by the Department of Urology. The programme includes participation and co-ordination of multiple clinical trials (EORTC, etc.). Furthermore, an international project on the Development of Prostate Cancer Gene Therapy is incorporated in the 6th Framework Programme (FP6) project GIANT. Funding of this research topic was recently expanded by a grant from the ZonMw Translationeel Gentherapeutisch Onderzoek programme. In collaboration with the ERSPC, the value of PCA3 as first line screening test is analysed and a PRIAS project on active surveillance initiated. Elucidation of the mechanisms of androgen-regulated growth and loss of hormonal responsiveness of prostate cancer cells is a major goal of this project. A panel of xenografts and in vitro cell lines, comprising sublines that are different with respect to their hormone responsiveness, are analyzed for differential gene expression in order to identify the various genes involved in these processes. The study also includes the investigation of the possible role of intercellular interactions, epithelial-stromal as well as epithelial-epithelial. A further aspect is the investigation of the role of the androgen receptor in prostate development and prostate cancer. Within these fields of basic and translational research, we coordinate and manage two Marie Curie ITN projects which were merged into one PRO-NEST programme (coordinator G. Jenster and manager E. Schenk-Braat). Within PRO- NEST, the 17 partners will train 20 PhD students and 4 postdocs for a career in prostate cancer research. Translational research within the fields of prostate cancer biomarker and imaging has been initiated by a CTMM funded project called `Prostate Cancer Molecular Medicine: (PCMM) (coordinator C.H. Bangma and manager E. Schenk-Braat). Besides translational research, a tissue bank and clinical database will be build up for marker and imaging validation and for development of clinical decision support systems. The prostate cancer xenografts and human serum bank are also being utilized for our search for novel diagnostic and prognostic markers. Using Fourier Transform mass spectrometry, we have identified serum proteins associated with presence of prostate cancer and serum proteins derived from xenografts. As far as carcinoma of the kidney and bladder is concerned, the activities are concentrating on clinical studies. Regarding bladder cancer, molecular diagnostics and non-invasive spectrometry are a focus. Together with the department of Pathology Erasmus MC, marker research is performed in the context of KWF and FP7 programs. BLadder Cancer Urine marker Project (BLUP) is a bladder cancer screening feasibility study of our department (www.blu-project.org). These and other studies should lead to new diagnostic and therapeutic clinical applications. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot nuclear medicine 0 0 0,75 0 0,75 urology 6,25 4,41 1 0,5 12,16 Total 6,25 4,41 1,75 0,5 12,91 5 1 0 6 49 4 6 65 Thesis Barbosa Marques, R. (2009, september 02). The role of the androgen receptor pathway in prostate cancer progression. EUR (189 pag.). Prom./coprom.: Prof.Dr. C.H. Bangma. Bergh, R.C.N. van den (2009, december 09). Active surveillance for low rick prostate cancer. EUR (225 pag.). Prom./coprom.: Prof.Dr. C.H. Bangma, Prof.Dr. E.W. Steyerberg, Dr. M.J. Roobol-Bouts & dr M.L. Essink-Bot. Heul-Nieuwenhuijsen, L. (2009, februari 11). Cancer related gene expression of the human prostate zones. EUR (103 pag.). Prom./coprom.: Prof.Dr. C.H. Bangma. Raaijmakers, PFJ (2009, mei 20). Prostate cancer screening. EUR. Prom./coprom.: Prof.Dr. F.H. Schroder & Prof.Dr. C.H. Bangma. Vries, S.H. de (2009, december 02). Active surveillance and prostate cancer screening. EUR (149 pag.). Prom./coprom.: Prof.Dr. F.H. Schroder & Prof.Dr. C.H. Bangma. Wijngaart, D.J. van de (2009, april 01). Peptides and proteins interacting with the androgen receptor. EUR (170 pag.). Prom./coprom.: Prof.Dr. J. Trapman. Article/Letter to the editor Aa, M.N.M. van der, Zwarthoff, E.C., Steyerberg, E.W., Boogaard, M.W., Nijsen, Y., Keur, K.A. van der, Exsel, A.J.A. van, Kirkels, W.J., Bangma, C. & Kwast, T.H. van der (2009). Microsatellite Analysis of Voided-Urine Samples for Surveillance of Low-Grade Non-Muscle-Invasive Urothelial Carcinoma: Feasibility and Clinical Utility in a Prospective Multicenter Study (Cost- Effectiveness of Follow-Up of Urinary Bladder Cancer Trial [CEFUB]). European Urology, 55(3), 659-668. Alcaraz, A, Hammerer, P, Tubaro, A, Schroder, F.H. & Castro, R (2009). Is There Evidence of a Relationship between Benign Prostatic Hyperplasia and Prostate Cancer? Findings of a Literature Review. European Urology, 55(4), 864-875.

Auvinen, A., Raitanen, J, Moss, S., Koning, H.J. de, Hugosson, J., Tammela, T., Roobol-Bouts, M.J., Lilja, H. & Hakama, M. (2009). Test Sensitivity in the European Prostate Cancer Screening Trial: Results from Finland, Sweden, and the Netherlands. Cancer Epidemiology Biomarkers & Prevention, 18(7), 2000-2005. Bakker, M.A. den, Goemaere, N.N.T., Severin, J.A., Nouwen, J.L. & Verhagen, P.C.M.S. (2009). Histoplasma-associated inflammatory pseudotumour of the kidney mimicking renal carcinoma. Virchows Archiv. An International Journal of Pathology, 454(2), 229-232. Bangma, C.H., Roobol-Bouts, M.J. & Steyerberg, E.W. (2009). Predictive Models in Diagnosing Indolent Cancer. Cancer, 115(13), 3100-3106. Bangma, C.H., Roobol-Bouts, M.J., Koning, H.J. de, Denis, L. & Schroder, F.H. (2009). Screening vermindert sterfte aan prostaatkanker. Huisarts en Wetenschap, 52(7), 352-357. Bergh, R.C.N. van den, Essink-Bot, M.L., Roobol-Bouts, M.J., Wolters, T., Schroder, F.H., Bangma, C.H. & Steyerberg, E.W. (2009). Anxiety and Distress During Active Surveillance for Early Prostate Cancer. Cancer, 115(17), 3868-3878. Bergh, R.C.N. van den, Roemeling, S., Roobol-Bouts, M.J., Aus, G, Hugosson, J., Rannikko, AS, Tammela, TL, Bangma, C.H. & Schroder, F.H. (2009). Gleason score 7 screen-detected prostate cancers initially managed expectantly: outcomes in 50 men. Bju International, 103(11), 1472-1477. Bergh, R.C.N. van den, Wolters, T., Spaander, V.M.C.W., Schroder, F.H. & Leenders, G.J.L.H. van (2009). Non-prostatic pathology on prostate needle-biopsy-colorectal carcinoid: a case report. Cases Journal, 2, 75. Bergh, R.C.N. van den, Roemeling, S., Roobol-Bouts, M.J., Aus, G, Hugosson, J., Rannikko, AS, Tammela, TL, Bangma, C.H. & Schroder, F.H. (2009). Outcomes of Men with Screen-Detected Prostate Cancer Eligible for Active Surveillance Who Were Managed Expectantly. European Urology, 55(1), 1-8. Bergh, R.C.N. van den, Roobol-Bouts, M.J. & Bangma, C.H. (2009). De PRIAS studie protocol voor afwachtend beleid in de praktijk. Best Practices Zorg, 4. Blom, J.H.M., Poppel, H. van, Marechal, J.M., Jacqmin, D., Schroder, F.H., Prijck, L. de & Sylvester, R. (2009). Radical Nephrectomy with and without Lymph-Node Dissection: Final Results of European Organization for Research and Treatment of Cancer (EORTC) Randomized Phase 3 Trial 30881. European Urology, 55(1), 28-34. Chi, K.N., Bjartell, A, Dearnaley, D, Saad, F, Schroder, F.H., Sternberg, C, Tombal, B & Visakorpi, T. (2009). Castrationresistant Prostate Cancer: From New Pathophysiology to New Treatment Targets. European Urology, 56(4), 594-605. Ferenschild, F.T.J., Vermaas, M., Verhoef, C., Ansink, A.C., Kirkels, W.J., Eggermont, A.M.M. & Wilt, J.H.W. de (2009). Total Pelvic Exenteration for Primary and Recurrent Malignancies. World Journal of Surgery, 33(7), 1502-1508. Fitzpatrick, J.M., Schulman, C, Zlotta, A.R. & Schroder, F.H. (2009). Prostate cancer: a serious disease suitable for prevention. Bju International, 103(7), 864-870. Gosselaar, C., Roobol-Bouts, M.J., Bergh, R.C.N. van den, Wolters, T. & Schroder, F.H. (2009). Digital Rectal Examination and the Diagnosis of Prostate Cancer-a Study Based on 8 Years and Three Screenings within the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam. European Urology, 55(1), 139-147. Heijnsdijk, E.A.M., Kinderen, A.J. der, Wever, E.M., Draisma, G., Roobol, M.J. & Koning, H.J. de (2009). Overdetection, overtreatment and costs in prostate-specific antigen screening for prostate cancer. British Journal of Cancer, 101(11), 1833-1838. Hermans, K.G.L., Boormans, J.L., Gasi, D., Leenders, G.J.L.H. van, Jenster, G.W., Verhagen, P.C.M.S. & Trapman, J. (2009). Overexpression of Prostate-Specific TMPRSS2(exon 0)-ERG Fusion Transcripts Corresponds with Favorable Prognosis of Prostate Cancer. Clinical Cancer Research, 15(20), 6398-6403. Jansen, F.H., Krijgsveld, J., Rijswijk, A. van, Bemd, G.J.C.M. van den, Berg, M.S. van den, Weerden, W.M. van, Willemsen, R., Dekker, L.J.M., Luider, T.M. & Jenster, G.W. (2009). Exosomal Secretion of Cytoplasmic Prostate Cancer Xenograft-derived Proteins. Molecular & Cellular Proteomics, 8(6), 1192-1205. Jansen, F.H., Roobol-Bouts, M.J., Jenster, G., Schroder, F.H. & Bangma, C.H. (2009). Screening for Prostate Cancer in 2008 II: The Importance of Molecular Subforms of Prostate-Specific Antigen and Tissue Kallikreins. European Urology, 55(3), 563-574. Jurhill, R.R., Veen, H. de, Leenders, G.J.L.H. van & Verhagen, P.C.M.S. (2009). Reduction of Serum Prostate-Specific Antigen Levels following Varicella-Zoster Infection and Valaciclovir Treatment in Prostate Cancer. European Urology, 56(2), 392-394. Kompier, L.C., Aa, M.N.M. van der, Lurkin, I., Vermeij, M., Kirkels, W.J., Bangma, C.H., Kwast, T.H. van der & Zwarthoff, E.C. (2009). The development of multiple bladder tumour recurrences in relation to the FGFR3 mutation status of the primary tumour. Journal of Pathology, 218(1), 104-112. Korfage, I.J., Pluijm, S., Roobol-Bouts, M.J., Dohle, G.R., Schroder, F.H. & Essink-Bot, M.L. (2009). Erectile Dysfunction and Mental Health in a General Population of Older Men. Journal of Sexual Medicine, 6(2), 505-512. Leeuwen, P. van, Bergh, R. van den, Wolters, T., Schroder, F.H. & Roobol, M (2009). Screening: should more biopsies be taken in larger prostates? Bju International, 104(7), 919-924.

Ma, QP, Fu, W, Li, PF, Nicosia, S.V., Jenster, G.W., Zhang, XH & Bai, WL (2009). FoxO1 Mediates PTEN Suppression of Androgen Receptor N- and C-Terminal Interactions and Coactivator Recruitment. Molecular Endocrinology, 23(2), 213-225. Nieuwenhuijsen, L., Dits, N.F. & Jenster, G.W. (2009). Gene expression of forkhead transcription factors in the normal and diseased human prostate. Bju International, 103(11), 1574-1580. Nieuwenhuijsen, L., Dits, N., Ijcken, W.F.J. van, Lange, D. de & Jenster, G.W. (2009). The FOXF2 Pathway in the Human Prostate Stroma. Prostate, 69(14), 1538-1547. Roermund, JGH van, Kok, DEG, Wildhagen, M.F., Kiemeney, LA, Struik, F, Sloot, S, Oort, IM van, Kaa, CA Hulsbergen-van, Leenders, G.J.L.H. van, Bangma, C.H. & Witjes, JA (2009). Body mass index as a prognostic marker for biochemical recurrence in Dutch men treated with radical prostatectomy. Bju International, 104(3), 321-325. Roobol, M.J., Schroder, F.H., Crawford, ED, Freedland, SJ, Sartor, AO, Fleshner, N & Andriole, GL (2009). A Framework for the Identification of Men at Increased Risk for Prostate Cancer. Journal of Urology, 182(5), 2112-2120. Roobol, M.J., Kerkhof, M., Schroder, F.H., Cuzick, J., Sasieni, P., Hakama, M., Stenman, UH, Ciatto, S., Nelen, V., Kwiatkowski, M, Lujan, M, Lilja, H., Zappa, M., Denis, L., Recker, F, Berenguer, A., Ruutu, M, Kujala, P, Bangma, C.H., Aus, G, Tammela, T.L.J., Villers, A., Rebillard, X, Moss, S.M., Koning, H.J. de, Hugosson, J. & Auvinen, A. (2009). Prostate Cancer Mortality Reduction by Prostate-Specific Antigen-Based Screening Adjusted for Nonattendance and Contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC). European Urology, 56(4), 584-591. Roobol, M.J. (2009). Words of Wisdom. European Urology, 55(6), 1481-1482. Roobol-Bouts, M.J. (2009). Higher PSA threshold did not lead to more incurable prostate cancer. HemOnc Today. Roobol-Bouts, M.J. (2009). De keerzijde van schreening op kanker. Medisch Contact, 35. Roobol-Bouts, M.J. (2009). Slim screenen heet de toekomst. Diagned. Schenk, E. & Jenster, G.W. (2009). Training of young scientists in prostate cancer research: the PRO-NEST project. European Urology Today, 21, 13. Schroder, F.H. & Roobol, M.J. (2009). A comment on prostate cancer screening in the prostate, lung, colorectal and ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomized trial. Bju International, 103(2), 143-144. Schroder, F.H., Bangma, C.H., Wolff, JM, Alcaraz, A, Montorsi, F, Mongiat-Artus, P., Abrahamsson, PA, McNicholas, TA, Castro, RS & Nandy, IM (2009). Can dutasteride delay or prevent the progression of prostate cancer in patients with biochemical failure after radical therapy? Rationale and design of the Avodart after Radical Therapy for Prostate Cancer Study. Bju International, 103(5), 590-596. Schroder, F.H., Roobol, M.J., Andriole, GL & Fleshner, N (2009). Defining Increased Future Risk for Prostate Cancer: Evidence From a Population Based Screening Cohort. Journal of Urology, 181(1), 69-74. Schroder, F.H. & Roobol, M.J. (2009). Defining the optimal prostate-specific antigen threshold for the diagnosis of prostate cancer. Current Opinion in Urology, 19(3), 227-231. Schroder, F.H., Kurth, K.H., Fossa, S.D., Hoekstra, W., Karthaus, P.P., Prijck, L. de & Collette, L. (2009). Early Versus Delayed Endocrine Treatment of T2-T3 pn1-3 M0 Prostate Cancer Without Local Treatment of the Primary Tumour: Final Results of European Organisation for the Research and Treatment of Cancer Protocol 30846 After 13 Years of Follow-up (A Randomised Controlled Trial). European Urology, 55(1), 14-22. Schroder, F.H. & Weerden, W.M. van (2009). Prostate cancer -- chemoprevention. European Journal of Cancer, 45, 355-359. Schroder, F.H. (2009). PSA screening - a review of recent studies. European Journal of Cancer, 45, 402-404. Schroder, F.H. (2009). Review of Diagnostic Markers for Prostate Cancer. Recent Results in Cancer Research, 181, 173-182. Schroder, F.H., Hugosson, J., Roobol-Bouts, M.J., Tammela, T.L.J., Ciatto, S., Nelen, V., Kwiatkowski, M, Lujan, M, Lilja, H., Zappa, M., Denis, L.J., Recker, F, Berenguer, A., Maattanen, L, Bangma, C.H., Aus, G, Villers, A., Rebillard, X, Kwast, T.H. van der, Blijenberg, B.G., Moss, S.M., Koning, H.J. de & Auvinen, A. (2009). Screening and Prostate-Cancer Mortality in a Randomized European Study. New England Journal of Medicine, 360(13), 1320-1328. Schroeder, R.P.J., Weerden, W.M. van, Bangma, C., Krenning, E.P. & Jong, M. de (2009). Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues. Methods-A Companion to Methods in Enzymology, 48(2), 200-204. Schroten-Loef, C., Ridder, C.M.A. de, Reneman, S., Crezee, M., Dalgleish, A, Todryk, SM, Bangma, C.H. & Kraaij, R. (2009). A prostate cancer vaccine comprising whole cells secreting IL-7, effective against subcutaneous challenge, requires local GM- CSF for intra-prostatic efficacy. Cancer Immunology Immunotherapy, 58(3), 373-381. Smedts, H.P.M., Vries, J.H. de, Rakhshandehroo, M, Wildhagen, M.F., Verkleij-Hagoort, A.C., Steegers, E.A. & Steegers- Theunissen, R.P.M. (2009). High maternal vitamin E intake by diet or supplements is associated with congenital heart defects in the offspring. Bjog-An International Journal of Obstetrics and Gynaecology, 116(3), 416-423.

Tilborg, AAG van, Bangma, C.H. & Zwarthoff, E.C. (2009). Bladder cancer biomarkers and their role in surveillance and screening. International Journal of Urology, 16(1), 23-30. Tomlins, SA, Bjartell, A, Chinnaiyan, A.M., Jenster, G.W., Nam, RK, Rubin, M.A. & Schalken, JA (2009). ETS Gene Fusions in Prostate Cancer: From Discovery to Daily Clinical Practice. European Urology, 56(2), 275-286. Verhagen, P.C.M.S. (2009). Re: Endocrine Treatment, with or without Radiotherapy, in Locally Advanced Prostate Cancer (SPCG-7/SFUO-3): An Open Randomised Phase III Trial. European Urology, 55(5), 1239-1240. Vickers, AJ, Wolters, T., Savage, CJ, Cronin, AM, O'Brien, MF, Pettersson, K., Roobol, M.J., Aus, G, Scardino, P.T., Hugosson, J., Schroder, F.H. & Lilja, H. (2009). Prostate-Specific Antigen Velocity for Early Detection of Prostate Cancer: Result from a Large, Representative, Population-based Cohort. European Urology, 56(5), 753-760. Vis, A.N. & Schroder, F.H. (2009). Key targets of hormonal treatment of prostate cancer. Part 1: the androgen receptor and steroidogenic pathways. Bju International, 104(4), 438-448. Vis, A.N. & Schroder, F.H. (2009). Key targets of hormonal treatment of prostate cancer. Part 2: the androgen receptor and 5 alpha-reductase. Bju International, 104(9), 1191-1197. Weerden, W.M. van, Bangma, C. & Wit, R. de (2009). Human xenograft models as useful tools to assess the potential of novel therapeutics in prostate cancer. British Journal of Cancer, 100(1), 13-18. Wielen, G.J. van der, Vermeij, M., Jong, B.W.D. de, Schuit, M.R.H., Marijnissen, J.P.A., Kok, D.J., Weerden, W.M. van & Incrocci, L. (2009). Changes in the Penile Arteries of the Rat after Fractionated Irradiation of the Prostate: A Pilot Study. Journal of Sexual Medicine, 6(7), 1908-1913. Wijngaart, D.J. van de, Dubbink, H.J., Molier, M., Vos, C. de, Trapman, J. & Jenster, G.W. (2009). Functional Screening of FxxLF-Like Peptide Motifs Identifies SMARCD1/BAF60a as an Androgen Receptor Cofactor that Modulates TMPRSS2 Expression. Molecular Endocrinology, 23(11), 1776-1786. Wolters, T., Roobol-Bouts, M.J., Bangma, C.H. & Schroder, F.H. (2009). Is Prostate-Specific Antigen Velocity Selective for Clinically Significant Prostate Cancer in Screening? European Randomized Study of Screening for Prostate Cancer (Rotterdam). European Urology, 55(2), 385-393. Part of book - abstract Schenk-Braat, E.A.M. & Bangma, C.H. (2009). Aanvullend onderzoek: nieuwe markers. In R Bosch, H van Poppel, F Witjes & T Boon (Eds.), Handboek Prostaataandoeningen. Utrecht: De Tijdstroom. Schenk-Braat, E.A.M. & Bangma, C.H. (2009). Gentherapie voor porstaatkanker. In R Bosch, H van Poppel, F Witjes & T Boon (Eds.), Handboek prostaataandoeningen. Utrecht: De Tijdstroom.

EMC MM-03-52-02-A - Gynaecological oncology; basics, epidemiology and clinical aspects Programme design in brief Elevated levels of steroid hormones like estradiol and progesterone are important factors in the development of endometrial, breast and probably also ovariancancer. nevertheless, some medical interventions like hormone treatment for In Vitro Fertilization (IVF), Hormone replacement Therapy (HRT) after menopause, and tamoxifen-treatment of breast cancer casue significant increases in steroid signaling. Questions we are trying to answer are: Is temporarily administration of gonadotropins significantly correlated with an increased risk of ovarian, endometrial, breast and thyroid cancer in women treated with In Vitro Fertilization? Furthermore, are women who have a poor response to IVF more prone for gynaecological and breast cancer?furthermore, in our laboratory we are investigating the molecular mechanism behind the question why steroids are sometimes causing cancer development (increases estrogen signaling can cause endometrial cancer), while in other cases steroids seem to protect against cancer growth (progesterone inhibits estrogen induced carcinogenesis in the endometrium). In these investigations Wnt signaling plays an important role. The life-time risk for infection with HPV is around 80%. Fortunately most women are able to clear this infection, and less than 10% of women infected with a high-risk HPV develop a persistent infection, which is one of the leading causes of preneoplastic and neoplastic lesions in the female genital tract, including cervical and vulvar intraepithelial neoplasia( CIN and VIN). Acquisition and clearing of HPV infection, viral load and persistence, T-cell response, cytokine expression, changes in cellular genome, viral oncogene proteins E6 and E7, role of human tumor suppressor genes p53 and Rb, loss of heterozygosity and telomerase activation are all factors that are studied to understand HPV-induced carcinogenesis. In addition to these molecular studies we are also investigating clinical aspects like the consequences of a national based primary screening program for cervical cancer and the role of HPV testing in the management of women with premalignant cervical lesions. Furthermore, in a number a randomized clinical trials alternative treatments,to otherwise mutilating surgery for VIN, are evaluated. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot gynaecology/obstetrics 2 0,2 0 0 2,2 reproduction and development 0,9 0 0 0 0,9 Total 2,9 0,2 0 0 3,1 2 0 0 2 21 1 1 25 Thesis Hove, M.C.P. ten (2009, september 23). Pelvic organ prolapse and pelvic floor muscle function. EUR. Prom./coprom.: Prof.Dr. C.W. Burger. Steensma, A.B. (2009, juni 23). Ultrasound imaging of the pelvic floor. EUR. Prom./coprom.: Prof.Dr. C.W. Burger. Article/Letter to the editor Ansink, A.C. (2009). Symptomen ovariumcarcinoom minder aspecifiek dan gedacht. Nederlands Tijdschrift voor Geneeskunde, 153, 8-9. Bais, A.G., Eijkemans, M.J.C., Rebolj, M., Snijders, P.J.F., Verheijen, R.H.M., Ballegooijen, M. van, Meijer, C.J.L.M. & Helmerhorst, T.J.M. (2009). Post-treatment CIN: Randomised clinical trial using hrhpv testing for prediction of residual/recurrent disease. International Journal of Cancer, 124(4), 889-895. Doorn, H.C. van, Opmeer, B.C., Kooi, G.S., Ewing-Graham, P.C., Kruitwagen, RFPM & Mol, B.W.J. (2009). Value of Cervical Cytology in Diagnosing Endometrial Carcinoma in Women with Postmenopausal Bleeding. Acta Cytologica, 53(3), 277-282. Dykgraaf, R.H.M., Jong, D. de, Veen, MMS van, Ewing-Graham, P.C., Helmerhorst, T.J.M. & Burg, M.E.L. van der (2009). Clinical Management of Ovarian Small-Cell Carcinoma of the Hypercalcemic Type A Proposal for Conservative Surgery in an Advanced Stage of Disease. International Journal of Gynecological Cancer, 19(3), 348-353. Ferenschild, F.T.J., Vermaas, M., Verhoef, C., Ansink, A.C., Kirkels, W.J., Eggermont, A.M.M. & Wilt, J.H.W. de (2009). Total Pelvic Exenteration for Primary and Recurrent Malignancies. World Journal of Surgery, 33(7), 1502-1508. Fons, G., Groenen, S.M.A., Oonk, MHM, Ansink, A.C., Zee, A.GJ van der, Burger, M.P.M., Stalpers, L.J.A. & Velden, J. van der (2009). Adjuvant radiotherapy in patients with vulvar cancer and one intra capsular lymph node metastasis is not beneficial. Gynecologic Oncology, 114(2), 343-345. Gaast, M.H. van der, Macklon, N.S., Beier-Hellwig, K., Krusche, CA, Fauser, B.C.J.M., Beier, H.M. & Classen-Linke, I (2009). The feasibility of a less invasive method to assess endometrial maturation-comparison of simultaneously obtained uterine secretion and tissue biopsy. Bjog-An International Journal of Obstetrics and Gynaecology, 116(2), 304-312. Gerestein, C.G., Damhuis, R.A.M., Burger, C.W. & Kooi, G.S. (2009). Postoperative mortality after primary cytoreductive surgery for advanced stage epithelial ovarian cancer: A systematic review. Gynecologic Oncology, 114(3), 523-527. Gerestein, C.G., Spek, D.W. van der, Eijkemans, M.J., Bakker, J., Kooi, G.S. & Burger, C.W. (2009). Prediction of Residual Disease After Primary Cytoreductive Surgery for Advanced-Stage Ovarian Cancer Accuracy of Clinical Judgment. International Journal of Gynecological Cancer, 19(9), 1511-1515. Gerestein, C.G., Eijkemans, M.J.C., Jong, D. de, Burg, M.E.L. van der, Dykgraaf, R.H.M., Kooi, G.S., Baalbergen, A., Burger, C.W. & Ansink, A.C. (2009). The prediction of progression-free and overall survival in women with an advanced stage of epithelial ovarian carcinoma. Bjog-An International Journal of Obstetrics and Gynaecology, 116(3), 372-380.

Heijkoop, S.T., Wijk, F.H. van, Kan, R. de & Doorn, H.C. van (2009). Hersenmetastasen als eerste presentatie van endometriumcarcinoom. Nederlands Tijdschrift voor Oncologie, 6, 255-260. Hove, M.C.P. ten, Pool-Goudzwaard, A., Eijkemans, M.J.C., Steegers-Theunissen, R.P.M., Burger, C.W. & Vierhout, M.E. (2009). Face validity and reliability of the first digital assessment scheme of pelvic floor muscle function conform the new standardized terminology of the International Continence Society. Neurourology and Urodynamics, 28, 295-300. Hove, M.C.P. ten, Pool-Goudzwaard, A.L., Eijkemans, M.J.C., Steegers-Theunissen, R.P.M., Burger, C.W. & Vierhout, M.E. (2009). Prediction model and prognostic index to estimate clinically relevant pelvic organ prolapse in a general female population. International Urogynecology Journal and Pelvic Floor Dysfunction, 20(9), 1013-1021. Hove, M.C.P. ten, Pool-Goudzwaard, A.L., Eijkemans, M.J.C., Steegers-Theunissen, R.P.M., Burger, C.W. & Vierhout, M.E. (2009). Symptomatic pelvic organ prolapse and possible risk factors in a general population. American Journal of Obstetrics and Gynecology, 184, 1-7. Hove, M.C.P. ten, Pool-Goudzwaard, A.L., Eijkemans, M.J.C., Steegers-Theunissen, R.P.M., Burger, C.W. & Vierhout, M.E. (2009). The prevalence of pelvic organ prolapse symptoms and signs and their relation with bladder and bowel disorders in a general female population. International Urogynecology Journal and Pelvic Floor Dysfunction, 20(9), 1037-1045. Hove, M.C.P. ten, Pool-Goudzwaard, A.L., Eijkemans, M.J.C., Steegers-Theunissen, R.P.M., Burger, C.W. & Vierhout, M.E. (2009). Vaginal noise: prevalence, bother and risk factors in a general female population aged 45-85 years. International Urogynecology Journal and Pelvic Floor Dysfunction, 20(8), 905-911. Martens, J.E., Smedts, F.M.M., Ploeger, D, Helmerhorst, T.J.M., Ramaekers, F.C.S., Arends, JW & Hopman, AHN (2009). Distribution Pattern and Marker Profile Show Two Subpopulations of Reserve Cells in the Endocervical Canal. International Journal of Gynecological Pathology, 28(4), 381-388. Oonk, MHM, Os, MA van, Bock, G.H. de, Hullu, J.A. de, Ansink, A.C. & Zee, A.GJ van der (2009). A comparison of quality of life between vulvar cancer patients after sentinel lymph node procedure only and inguinofemoral lymphadenectomy. Gynecologic Oncology, 113(3), 301-305. Timmers, P.J., Zwinderman, A.H., Teodorovic, I., Vergote, I. & Trimbos, J.B. (2009). Clear Cell Carcinoma Compared to Serous Carcinoma in Early Ovarian Cancer Some Prognosis in a Large Randomized Trial. International Journal of Gynecological Cancer, 19(1), 88-93. Wang, YY, Hanifi Moghaddam, P., Hanekamp, E.E., Kloosterboer, H.J., Franken, P., Veldscholte, J., Doorn, H.C. van, Ewing, PC, Kim, JJ, Grootegoed, J.A., Burger, C.W., Fodde, R. & Blok, L.J. (2009). Progesterone Inhibition of Wnt/beta-Catenin Signaling in Normal Endometrium and Endometrial Cancer. Clinical Cancer Research, 15(18), 5784-5793. Wijk, F.H. van, Burg, M.E.L. van der, Burger, C.W., Vergote, I. & Doorn, H.C. van (2009). Management of Recurrent Endometrioid Endometrial Carcinoma An overview. International Journal of Gynecological Cancer, 19(3), 314-320. Wijk, F.H. van, Burg, M.E.L. van der, Burger, C.W., Vergote, I. & Doorn, H.C. van (2009). Management of Surgical Stage III and IV Endometrioid Endometrial Carcinoma An Overview. International Journal of Gynecological Cancer, 19(3), 431-446. Wilting, S.M., Steenbergen, R.D.M., Tijssen, M, Wieringen, WN Van, Helmerhorst, T.J.M., Kemenade, F.J. van, Bleeker, MCG, Wiel, M.A. van de, Carvalho, B, Meijer, G.A., Ylstra, B., Meijer, C.J.L.M. & Snijders, P.J.F. (2009). Chromosomal Signatures of a Subset of High-Grade Premalignant Cervical Lesions Closely Resemble Invasive Carcinomas. Cancer Research, 69(2), 647-655.

EMC MM-03-54-04-A - Developmental biology; pathophysiology of the newborn Programme design in brief Growth and development of the fetus, the transition of the fetus to the newbom and growth and development of the newbom infant are among the most critical periods in human lire. Pertubations of the normal development in these critical periods can cause temporary or persistent effects. Knowledge of the normal development is essential fot the evaluation of an abnormal pattem of development. Abnormal growth and development is mainly gene in groups of infants like preterm infants. Our research therefore focusses on these infants, but also on normal and sick term infants and infants with inherited metabolic disease. 1. Substrate utilization, metabolism, nutrition and body composition of the preterm and term newbom. 2. Intestinal development in rodents, mammals and preterm infants 3. Neonatal neuroimaging, neurology and long term-development 4. Neonatal lung development and surfactant metabolism. 5. Neonatal pharmacology; developmental and neonatal pharmacology. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot pediatrics 2,44 0 2,58 4,61 9,63 Total 2,44 0 2,58 4,61 9,63 1 0 0 1 53 12 2 68 Thesis Schierbeek, H. (2009, december 10). You are what you eat. EUR. Prom./coprom.: Prof.Dr. J.B. van Goudoever. Article/Letter to the editor Aarnoudse-Moens, C, Smidts, D.P., Oosterlaan, J., Duivenvoorden, H.J. & Weisglas-Kuperus, N. (2009). Executive function in very preterm children at early school age. Journal of Abnormal Child Psychology, 37, 981-993. Aarnoudse-Moens, C, Weisglas-Kuperus, N., Goudoever, J.B. van & Oosterlaan, J. (2009). Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children. Pediatrics, 124, 717-728. Agostoni, C., Braegger, C., Decsi, T, Kolacek, S, Koletzko, B., Fleischer Michaelsen, K., Mihatsch, W., Moreno, L.A., Puntis, J., Shamir, R., Szajewska, H., Turck, D. & Goudoever, J.B. van (2009). Breast-feeding: a commentary by the ESPGHAN Committee on Nurtrition. Journal of Pediatric Gastroenterology and Nutrition, 49, 112-125. Akker, C.H.P. van den, Schierbeek, H., Dorst, KY, Schoonderwaldt, E.M., Vermes, A., Duvekot, J.J., Steegers, E.A.P. & Goudoever, J.B. van (2009). Human fetal amino acid metabolism at term gestation. American Journal of Clinical Nutrition, 89(1), 153-160. Argent, A., Kissoon, N., Devictor, D., Madden, M.A., Singhi, S., Voort, E. van der & Latour, J.M. (2009). Response to: Twentythree thousand unnecessary deaths every day: What are you doing about it. Pediatric Critical Care Medicine, 10(5), 610-612. Bax, L., Woittiez, A.J.J., Kouwenberg, HJ, Mali, W.P.T.M., Buskens, E., Beek, F.J.A., Braam, B., Huysmans, FTM, Kool, LJS, Rutten, MJCM, Doorenbos, CJ, Aarts, JCNM, Rabelink, T.J., Plouin, P.F., Raynaud, A., Montfrans, GA van, Reekers, J.A., Meiracker, A.H. van den, Pattynama, P.M.T., Ven, PJG van de, Vroegindeweij, D., Kroon, A.A., Haan, M.W. de, Postma, C.T. & Beutler, JJ (2009). Stent Placement in Patients With Atherosclerotic Renal Artery Stenosis and Impaired Renal Function A Randomized Trial. Annals of Internal Medicine, 150(12), 840-U41. Been, J.V., Kornelisse, R.F., Rours, G.I.J.G., Lima Passos, V., Krijger, R.R. de & Zimmermann, L.J.I. (2009). Early postnatal blood pressure in preterm infants: effects of chorioamnionitis and timing of antenatal steriods. Pediatric Research, 66(5), 571-576. Been, J.V., Rours, G.I.J.G., Kornelisse, R.F., Lima Passos, V., Kramer, B.W., Schneider, T.A.J., Krijger, R.R. de & Zimmermann, L.J.I. (2009). Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants. American Journal of Obstetrics and Gynecology, 201, 587.e1-587.e8. Boer, J. de & Smit, B.J. (2009). Nasogastric tube position and intragastric air collection in a neonatal intensiver care population. Advances in Neonatal Care, 9(6), 293-298. Braake, F.W.J. te, Schierbeek, H., Vermes, A., Huijmans, J.G.M. & Goudoever, J.B. van (2009). High-dose cysteine administration does not increase synthesis of the antioxidant glutathione preterm infants. Pediatrics, 124, e978-e984. Brakel, A.J.M. van, Bogers, B.H.E.M. & Helder, O.K. (2009). The efficacy of facilitated tucking of the neonate: a systematic review. Pediatric Intensive Care Nursing, 10(1-2), 4-12. Cherian, P.J., Swarte, R.M.C. & Visser, G.H. (2009). Technical standards for recording and interpretation of neonatal electroencephalogram in clinical practice. Annals of Indian Academy of Neurology, 12(1), 58-70. Cornette, L., deveber, G. & Govaert, P. (2009). Editorial. Seminars in Fetal & Neonatal Medicine, 14, 243-244. Deburchgraeve, W, Cherian, P.J., De Vos, M., Swarte, R.M.C., Blok, J.H., Visser, G.H., Govaert, P. & Huffel, S Van (2009). Neonatal seizure localization using PARAFAC decomposition. Clinical Neurophysiology, 120, 1787-1796.

Dijk, M. van, Roofthooft, D.W.E., Anand, K.J.S., Guldemond, F, Graaf, J. de, Simons, S, Jager, Y de, Goudoever, J.B. van & Tibboel, D. (2009). Taking Up the Challenge of Measuring Prolonged Pain in (Premature) Neonates The COMFORTneo Scale Seems Promising. Clinical Journal of Pain, 25(7), 607-616. Dongen, J.C.A. van, Dalinghaus, M., Kroon, A.A., Vries, A.C.H. de & Heuvel-Eibrink, M.M. van den (2009). Succesful treatment of congenital acute myeloid leukemia (AML-M6) in a premature infant. Journal of Pediatric Hematology Oncology, 31(11), 853-854. Dudink, J., Mercuri, E., Al-Nakib, L., Govaert, P., Counsell, S.J., Rutherford, M.A. & Cowan, F.M. (2009). Evolution of unilateral perinatal arterial ischemic stroke on conventional an diffusion-weighted MR Imaging. American Journal of Neuroradiology, 30, 998-1004. Duijsters, C.E.P.M., Halbertsma, F.J.J., Kornelisse, R.F., Arents, N.L.A. & Andriessen, P (2009). Recurring staphylococcal scalded skin syndrome in a very low birth weight infant: a case report. Journal of Medical Case Reports, 3, 7313. Govaert, P., Ramenghi, LA, Taal, R., Vries, L. de & deveber, G. (2009). Diagnosis of perinatal stroke I: definitions, differental diagnosis and registration. Acta Paediatrica, 98, 1556-1567. Govaert, P., Ramenghi, LA, Taal, R., Dudink, J. & Lequin, M.H. (2009). Diagnosis of perinatal stroke II: mechanisms and clinical phenotypes. Acta Paediatrica, 98, 1720-1726. Govaert, P., Smith, L. & Dudink, J. (2009). Diagnostic management of neonatal stroke. Seminars in Fetal & Neonatal Medicine, 14, 323-328. Govaert, P. (2009). Prenatal stroke. Seminars in Fetal & Neonatal Medicine, 14, 250-266. Govaert, P. (2009). Sonographic stroke templates. Seminars in Fetal & Neonatal Medicine, 14, 284-298. Govaert, P., Dudink, J., Visser, G.H., Breukhoven, P.E., Vanhatalo, S. & Lequin, M.H. (2009). Top of the basilar artery embolic stroke and neonatal myoclonus. Developmental Medicine & Child Neurology, 51, 324-327. Greisen, G., Mirante, N., Haumont, D., Pierrat, V., Pallas-Alonso, C.R., Warren, I., Smit, B.J., Westrup, B., Sizun, J., Maraschini, A. & Cuttini, M. (2009). Parents, siblings and grandparents in the Neonatal Intensive Care Unit. A survey of policies in eight European countries. Acta Paediatrica, 98, 1744-1750. Hack, K.E.A., Esseboom, C., Derks, J.B., Elias, S.G., Kleine, MJK de, Baerts, W., Go, A.T.J.I., Schaap, A.H.P., Hoeven, M.A.H.B.M van der, Eggink, A.J., Sollie, KM, Weisglas-Kuperus, N. & Visser, G.H.A. (2009). Long-term neurodevelopmental outcome of monochorionic and matched dichorionic twins. PLoS One, 4(8), e6815. Helder, O.K. & Latour, J.M. (2009). Endotracheal suctioning: There's more to is than just technical care. Pediatric Critical Care Medicine, 9(5), 539-540. Helder, O.K. & Latour, J.M. (2009). Reduction of catheter related bloodstreaum infections in intensive care: one for all, all for one? Nursing in Critical Care, 14(3), 107-108. Helder, O.K., Hoogen, A. van den, Mansvelt, P., Cranendonk, A. & Wielenga, J. (2009). Kan schedelvervorming bij premature pasgeborenen voorkomen worden? Verpleegkunde, 1, 12-17. Hoeks, S.E., Scholte op Reimer, W.J.M., Gestel, Y.R.B.M. van, Schouten, O., Lenzen, M.J., Flu, W.J.P., Kuijk, J.P. van, Latour, J.M., Bax, J.J., Urk, H. van & Poldermans, D. (2009). Medication underuse during long-term follow-up in patients with peripheral arterial disease. Circulation: Cardiovascular Quality and Outcomes, 2(4), 338-343. Hoffen, E., Ruiter, B., Faber, J, M'Rabet, L, Knol, E.F., Stahl, B., Arslanoglu, S., Moro, G., Boehm, G. & Garssen, J. (2009). A specific mixture of short-chain galacto-oligosaccharides and long-chain fructo-olisaccharides induces a beneficial immunoglobulin profile in infants at high risk for allergy. Allergy, 64, 484-487. Holzhauer, S., Zwijsen, R.M.L., Jaddoe, V.W.V.K., Boehm, G., Moll, H.A., Mulder, P.G.H., Kleyburg-Linkers, V.E., Hofman, A. & Witteman, J.C.M. (2009). Sonographic assessment of abdominal fat distribution in infancy. European Journal of Epidemiology, 24, 521-529. Hoogstraate, S.R., Lequin, M.H., Huysman, W.A., Ahmed, S. & Govaert, P. (2009). Apnoe in relation to neonatal temporal lobe haemorrhage. European Journal of Paediatric Neurology, 13, 356-361. Horsch, S., Bengtsson, J., Nordell, A., Lagercrantz, H., Aden, U. & Blennow, M. (2009). Lateral ventricular size in extremely premature infants: 3D MRI confirms 2D ultrasound measurements. Ultrasound in Medicine and Biology, 35(3), 360-366. Huis, M. van, Kempen, A.A.M.W. van, Peelen, M., Timmers, M, Boer, K., Smit, B.J. & Rijn, R..R. van (2009). Brain ultrasonography findings in neonates with exposure to cocaine during pregnancy. Pediatric Radiology, 39, 232-238. Imhoff, D.E. van, Dijk, P.H., Hulzebos, C.V. & Govaert, P. (2009). Uniforme bilirubinegrenzen voor de behandeling van icterische premature neonaten. Nederlands Tijdschrift voor Geneeskunde, 153, A94. Indrio, F., Riezzo, G., Raimondi, F., Francavilla, R., Montagna, O., Valenzano, M.L., Cavallo, L. & Boehm, G. (2009). Prebiotics improve gastric motility and gastric electrical activity in preterm newborns. Journal of Pediatric Gastroenterology and Nutrition, 49, 258-261.

Kievit, J.F. de, Piek, J.P., Aarnoudse-Moens, C & Oosterlaan, J. (2009). Motor development in very preterm and very low-birthweight children form birth to adolescence. Jama - Journal of the American Medical Association, 302(20), 2235-2242. Kissoon, N., Argent, A., Devictor, D., Madden, M.A., Singhi, S., Voort, E. van der & Latour, J.M. (2009). World Federation of Pediatric Intensive and Critical Care Societies - Its global agenda. Pediatric Critical Care Medicine, 10(5), 597-600. Knibbe, C.A.J., Krekels, EHJ, Anker, J.N. van den, DeJongh, J, Santen, GWE, Dijk, M. van, Simons, S.H.P., Lingen, R.A. van, Jacqz-Aigrain, EM, Danhof, M & Tibboel, D. (2009). Morphine Glucuronidation in Preterm Neonates, Infants and Children Younger than 3 Years. Clinical Pharmacokinetics, 48(6), 371-385. Kutz, P., Horsch, S., Kuhn, L. & Roll, C. (2009). Single-centre vs. population-based outcome data of extremely preterm infants at the limits of viability. Acta Paediatrica, 98, 1451-1455. Latour, J.M., Hazelzet, J.A., Duivenvoorden, H.J. & Goudoever, J.B. van (2009). Construction of a parent satisfaction instrument: perceptions of pediatric intensive care nurses and physicians. Journal of Critical Care, 24, 255-266. Latour, J.M., Fulbrook, P & Albarran, J.W. (2009). EfCCNa surveay: European intensive care nurses' attitides and beliefs towards end-of-life care. Critical Care, 14(3), 110-121. Latour, J.M., Goudoever, J.B. van, Duivenvoorden, H.J., Dam, N.A.M. van, Dullaart, E., Albers, M.J.I.J., Verlaat, C.W.M., Vught, E.M. van, Heerde, M.J. van & Hazelzet, J.A. (2009). Perceptions of parents on satisfaction with care in the pediatric intensive care unit: the EMPATHIC study. Intensive Care Medicine, 35, 1082-1089. Lequin, M.H., Dudink, J., Tong, K.A. & Obenaus, A. (2009). Magnetic resonance imaging in neonatal stroke. Seminars in Fetal & Neonatal Medicine, 14, 299-310. Mook-Kanamori, D.O., Holzhauer, S., Hollestein, L.M., Durmus, B., Manniesing, R., Koek, M., Boehm, G., Beek, E.M. van der, Hofman, A., Witteman, J.C.M., Lequin, M.H. & Jaddoe, V.W.V.K. (2009). Abdominal fat in children measured by ultrasound in computed tomography. Ultrasound in Medicine and Biology, 35(12), 1938-1946. Nordell, A., Lundh, M., Horsch, S., Hallberg, B., Aden, U., Nordell, B. & Blennow, M. (2009). The acoustic hood: a petientindependent device improving acoustic noise protection during neonatal magnetic resonance imaging. Acta Paediatrica, 98, 1278-1283. Paassen, N. van, Vincent, A., Puiman, P.J., Sluis, M. van der, Bouma, J., Boehm, G., Goudoever, J.B. van, Seuningen, I. van & Renes, I.B. (2009). The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection. Biochemical Journal, 420, 211-219. Ramenghi, LA, Govaert, P., Fumagalli, M., Bassi, L. & Mosca, F. (2009). Neonatal cerebral sinovenous thrombosis. Seminars in Fetal & Neonatal Medicine, 14, 278-283. Schaart, M.W., Bruijn, A.C.J.M. de, Bouwman, D.M., Krijger, R.R. de, Goudoever, J.B. van, Tibboel, D. & Renes, I.B. (2009). Epithelial functions of the residual bowel after surgery for necrotising enterocolitis in human infants. Journal of Pediatric Gastroenterology and Nutrition, 49, 31-41. Schaart, M.W., Bruijn, A.C.J.M. de, Schierbeek, H., Tibboel, D., Renes, I.B. & Goudoever, J.B. van (2009). Small intestinal MUC2 synthesis in human preterm infants. American Journal of Physiology-Gastrointestinal and Liver Physiology, 296, G1085- G1090. Schierbeek, H., Moerdijk-Poortvliet, T.C.W., Akker, C.H.P. van den, Braake, F.W.J. te, Boschker, H.T. & Goudoever, J.B. van (2009). Analysis of [U-13C6]glucose in human plasma using liquid chromatography/isotope ratio mass spectrometry compared with two orther mass spectrometry techniques. Rapid Communications in Mass Spectrometry, 23, 3824-3830. Schierbeek, H., Rook, D., Braake, F.W.J. te, Dorst, KY, Minderman-Voortman, G.J., Godin, JP, Fay, LB & Goudoever, J.B. van (2009). Simultaneous analysis of 13C-glutathione as its dimeric form GSSG and its precursor [1-13C]glycine using liquid chromatography/isotope ratio mass spectrometry. Rapid Communications in Mass Spectrometry, 23, 2897-2902. Schierbeek, H., Rieken, R., Dorst, KY, Penning, C. & Goudoever, J.B. van (2009). Validation of deuterium and oxygen18 in urine and salica samples from children using on-line continuous-flow isotope ratio mass spectrometry. Rapid Communications in Mass Spectrometry, 23, 3549-3554. Sluis, M. van der, Schaart, M.W., Koning, B.A.E. de, Schierbeek, H., Velcich, A., Renes, I.B. & Goudoever, J.B. van (2009). Threonine metabolism in the intestine of mice: loss of mucin 2 induces the threonine catabolic pathway. Journal of Pediatric Gastroenterology and Nutrition, 49, 99-107. Starre, C. van der, Bos-Boon, A van, Tuyn, Y. van der, Maas, I., Molendijk, A., Offringa, M., Vreede, W.B. & Tibboel, D. (2009). Multidisciplinaire aanpak van patiëntveiligheid op de kinder-ic. Nederlands Tijdschrift voor Geneeskunde, 153, 60. Swarte, R.M.C., Lequin, M.H., Cherian, P.J., Zecic, A., Goudoever, J.B. van & Govaert, P. (2009). Imaging patterns of brain injury in term-birth asphyxia. Acta Paediatrica, 98, 586-592. Vansteenkiste, E., Govaert, P., Conneman, H.N.L., Lequin, M.H. & Philips, W. (2009). Segmentation of white matter flaring areas in ultrasound images of very-low-birth-weight preterm infants. Ultrasound in Medicine and Biology, 35(6), 991-1004. Verkerk, A.J.M.H., Schot, R., Dumee, B.C., Schellekens, K.P.C., Swagemakers, S.M.A., Bertoli Avella, A.M., Lequin, M.H., Dudink, J., Govaert, P., Zwol, A.L. van, Hirst, J., Wessels, M.W., Catsman-Berrevoets, C.E., Verheijen, F.W., Graaff, E. de, Coo,

I.F.M. de, Kros, J.M., Willemsen, R., Spek, P.J. van der & Mancini, G.M.S. (2009). Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. American Journal of Human Genetics, 85, 40-52. Vermeulen, M.J., Peeters, M.F., Moor, R.A., Roord, J.J. & Dijken, P.J. van (2009). No etiological role for Bartonella henselae infection in Henoch Schonlein Purpura. Pediatric Infectious Disease Journal, 28(12), 1142-1143. Vermeulen, M.J., Roord, J.J. & Peeters, M.F. (2009). Kattenkrabziekte: infectie door Bartonella henselae. Tijdschr Infectieziekten, 4(1), 18-23. Vlaardingerbroek, H., Goudoever, J.B. van & Akker, C.H.P. van den (2009). Initial nutritional management of the preterm infant. Early Human Development, 85, 691-695. Waardenburg, D.A. van, Betue, C.T. de, Goudoever, J.B. van, Zimmermann, L.J.I. & Joosten, K.F.M. (2009). Critically ill infants benefit from early administration of protein and energy-enriched formula: a randomized controlled trial. Clinical Nutrition, 28, 249-255. Weisglas-Kuperus, N., Hille, E.T.M., Duivenvoorden, H.J., Finken, MJJ, Wit, J.M., Buuren, S. van, Goudoever, J.B. van & Verloove-Vanhorick, S.P. (2009). Intelligence of very preterm of very low birthweight infants in young adulthood. Archives of Disease in Childhood. Fetal and Neonatal Edition, 94, F196-F200. Westra, A.E., Willems, D.L. & Smit, B.J. (2009). Communicatin with Muslum parents: "the four principles" are not as culturally neutral as suggested. European Journal of Pediatrics, 168, 1383-1387. Wielenga, J.M., Smit, B.J., Merkus, MP, Wolf, M.J. & Kok, J.H. (2009). Develpment and growth in very preterm infants in relation to NIDCAP in a Dutch NICU: two years of follow-up. Acta Paediatrica, 98, 291-297. Zwol, A.L. van, Lequin, M.H., Tesselaar, C.D., Eijk, A.A. van der, Driessen, G.J.A., Hoog, M. de & Govaert, P. (2009). Fatal neonatal parechovirus encephalitis. BMJ Case Reports, 2009(14-12).

EMC MM-03-61-05-A - Experimental therapeutical approaches in inflammatory dermatoses and cutaneous oncology Programme design in brief The Department of Dermatology will focus its scientific efforts on inflammatory dermatoses and cutaneous oncology. At present time we are exploring clinically related basic research possibilities. Our first step towards the research target consists mainly of in vivo, ex vivo and in vitro studies of psoriasis and non-melanoma skin cancer. With these studies we aim at gaining more insight in the molecular and immunopathological aspects of psoriasis and the protective immunological mechanisms during tumor growth of basal cell carcinoma. In addition various therapeutic approaches in psoriasis and in non-melanoma skin cancers will be investigated regarding to their mode of action and immunomodulatory potential. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot clinical chemistry 0 0 0 0,02 0,02 dermatology 1,7 0 0 3 4,7 immunology 0,4 0 0 1 1,4 Total 2,1 0 0 4,02 6,12 5 0 0 5 40 3 10 58 Thesis Devillers, A.C.A. (2009, februari 18). Diagnostic work-up and treatment of severe and/or refractory atopic dermatitis. EUR. Prom./coprom.: Prof.Dr. A.P. Oranje. Heide, R. (2009, januari 07). Clinical aspects of pediatric and adult onset mastocytosis in the skin. EUR. Prom./coprom.: Prof.Dr. A.P. Oranje. Leeuw, J. de (2009, november 04). Innovative use of pulsed dye laser and liposomes in dermatology. EUR. Prom./coprom.: Prof.Dr. H.A.M. Neumann. Racz, E. (2009, november 19). Molecular targets of narrow-band UVB phototherapy in psoriasis. EUR. Prom./coprom.: Prof.Dr. E.P. Prens, Prof.Dr. J.D. Laman & Drs. C.T.E. van der Fits. Wegen-Franken, C.P.M. van der (2009, oktober 22). Medical elastic compression stockings. EUR. Prom./coprom.: Prof.Dr. H.A.M. Neumann. Article/Letter to the editor Bos, R.R. van den, Neumann, H.A.M., Roos, K.P. & Nijsten, T.E.C. (2009). Endovenous Laser Ablation-Induced Complications: Review of the Literature and New Cases. Dermatologic Surgery, 35(8), 1206-1214. Bos, R.R. van den, Kockaert, M.A., Neumann, H.A.M., Bremmer, RH, Nijsten, T.E.C. & Gemert, M.J.C. (2009). Heat conduction from the exceedingly hot fiber tip contributes to the endovenous laser ablation of varicose veins. Lasers in Medical Science, 24(2), 247-251. Bos, R.R. van den, Wentel, T, Neumann, H.A.M. & Nijsten, T.E.C. (2009). Treatment of incompetent perforating veins using the radiofrequency ablation stylet: a pilot study. Phlebology, 24(5), 208-212. Bos, R.R. van den, Arends, L.R., Kockaert, M., Neumann, H.A.M. & Nijsten, T. (2009). Endovenous therapies of lower extremity varicosities: a meta-analysis. Journal of Vascular Surgery, 49(1), 230-239. Cornish, D, Holterhues, C., Poll-Franse, L.V. van de, Coebergh, J.W. & Nijsten, T. (2009). A systematic review of health-related quality of life in cutaneous melanoma. Annals of Oncology, 20, 51-58. Devillers, A.C.A., Spek, F.B. van der, Mulder, P.G.H. & Oranje, A.P. (2009). Delayed- and immediate-type reactions in the atopy patch test with food allergens in young children with atopic dermatitis. Pediatric Allergy and Immunology, 20(1), 53-58. Fits, C.T.E. van der, Mourits, S., Voerman, J.S.A., Kant, M., Laman, J.D., Boon, L., Cornelissen, F.H.J., Mus, A.M.C., Florencia, E.F.I.I.I., Prens, E.P. & Lubberts, E. (2009). Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL- 23/IL-17 axis. Journal of Immunology, 182, 5836-5845. Frew, JW, Martin, LK, Nijsten, T.E.C. & Murrell, DF (2009). Quality of life evaluation in epidermolysis bullosa (EB) through the development of the QOLEB questionnaire: an EB-specific quality of life instrument. British Journal of Dermatology, 161(6), 1323-1330. Geer-Rutten, S. van der & Krekels, G.A.M. (2009). Treatment of actinic keratoses on the dorsum of the hands: ALA-PDT versus diclofenac 3% gel followed by ALA-PDT. A placebo-controlled, double-blind, pilot study. Journal of Dermatological Treatment, 20(5), 259-265. Geer-Rutten, S. van der, Ostertag, J.U. & Krekels, G.A.M. (2009). Treatment of basal cell carcinomas in patients with nevoid basal cell carcinoma syndrome. Journal of the European Academy of Dermatology and Venereology, 23(3), 308-313. Geer-Rutten, S. van der, Krekels, G.A.M. & Verhaegh, ME (2009). Treatment of the Patient with Nevoid Basal Cell Carcinoma Syndrome in a Megasession. Dermatologic Surgery, 35(4), 709-713. Habbema, L. (2009). Breast Reduction Using Liposuction with Tumescent Local Anesthesia and Powered Cannulas. Dermatologic Surgery, 35(1), 41-52.

Habbema, L. (2009). Safety of Liposuction Using Exclusively Tumescent Local Anesthesia in 3,240 Consecutive Cases. Dermatologic Surgery, 35(11), 1728-1735. Hajdarbegovic, E., Leest, R.J.T. van der, Munte, K., Thio, H.B. & Neumann, H.A.M. (2009). Neoplasms of the Facial Skin. Clinics in Plastic Surgery, 36(3), 319-+. Hattem, S. van, Aarts, MJ, Louwman, W.J., Neumann, H.A.M., Coebergh, J.W.W., Looman, C.W.N., Koomen, ER, Joosse, A., Herings, R.M.C., Casparie, M.K., Guchelaar, HJ & Nijsten, T.E.C. (2009). Does use of estrogens decrease Breslow thickness of melanoma of the skin? Melanoma Research, 9, 327-332. Hattem, S. van, Aarts, MJ, Louwman, W.J., Neumann, H.A.M., Coebergh, J.W.W., Looman, C.W.N., Nijsten, T. & Vries, E. de (2009). Increase in basal cell carcinoma incidence steepest in individuals with high socioeconomic status: results of a cancer registry study in the Netherlands. British Journal of Dermatology, 161(4), 840-845. Holterhues, C., Vries, E. de & Nijsten, T.E.C. (2009). De epidemiologie van huidkanker: zorg om de zorg. Nederlands Tijdschrift voor Dermatologie & Venereologie, 19(8). Iversen, L., Gniadecki, R & Thio, H.B. (2009). Clinical Reviews. Expert commentary on recent key papers. Remedica, 1, 59-71. Joosse, A., Koomen, ER, Casparie, M.K., Herings, R.M.C., Guchelaar, HJ & Nijsten, T.E.C. (2009). Non-Steroidal Anti- Inflammatory Drugs and Melanoma Risk: Large Dutch Population-Based Case-Control Study. Journal of Investigative Dermatology, 129(11), 2620-2627. Koomen, ER, Joosse, A., Herings, R.M.C., Casparie, M.K., Guchelaar, HJ & Nijsten, T.E.C. (2009). Estrogens, oral contraceptives and hormonal replacement therapy increase the incidence of cutaneous melanoma: a population-based casecontrol study. Annals of Oncology, 20(2), 358-364. Langendoen, S.I. & Neumann, H.A.M. (2009). Classification of reflux. Phlebology Digest, 22, 9-11. Langendoen, S.I., Habbema, L., Nijsten, T.E.C. & Neumann, H.A.M. (2009). Lipoedema: from clinical presentation to therapy. A review of the literature. British Journal of Dermatology, 161(5), 980-986. Lanjouw, E., Daele, P.L.A. van, Raes, M.P.E. & Meijden, W.I. van der (2009). Consecutively Acquired Sexually Transmitted Infections Mimicking Crohn's Disease. American Journal of Gastroenterology, 104(2), 532-533. Lanjouw, E., Meijden, W.I. van der, Hollander, J.C. den & Neumann, H.A.M. (2009). Unusual late nodular presentation of secondary syphilis. International Journal of Std & Aids, 20(4), 271-273. Leeuw, J. de, Lingen, RG van, Both, H., Tank, B., Nijsten, T.E.C. & Neumann, H.A.M. (2009). A Comparative Study on the Efficacy of Treatment with 585 nm Pulsed Dye Laser and Ultraviolet B-TL01 in Plaque Type Psoriasis. Dermatologic Surgery, 35(1), 80-91. Leeuw, J. de, Beek, N. van der, Neugebauer, WD, Bjerring, P. & Neumann, H.A.M. (2009). Fluorescence Detection and Diagnosis of Non-Melanoma Skin Cancer at an Early Stage. Lasers in Surgery and Medicine, 41(2), 96-103. Leeuw, J. de, Vijlder, H.C. de, Bjerring, P. & Neumann, H.A.M. (2009). Liposomes in dermatology today. Journal of the European Academy of Dermatology and Venereology, 23(5), 505-516. Linden, MW van der, Beest, F.J.A. van, Nijsten, T.E.C. & Herings, P.J.J. (2009). Topical Corticosteroids and the Risk of Diabetes Mellitus A Nested Case-Control Study in the Netherlands. Drug Safety, 32(6), 527-537. Neer, P van, Kessels, FG, Estourgie, RJ, Haan, EF de, Neumann, H.A.M. & Veraart, JC (2009). Persistent reflux below the knee after stripping of the great saphenous vein. Journal of Vascular Surgery, 50(4), 831-834. Nijssen, A., Koljenovic, S., Bakker Schut, T.C., Caspers, P.J. & Puppels, G.J. (2009). Towards oncological application of Raman spectroscopy. Journal of Biophotonics, 2, 29-36. Nijsten, T.E.C., Sampogna, F & Abeni, D (2009). Categorization of Skindex-29 Scores Using Mixture Analysis. Dermatology, 218(2), 151-154. Nijsten, T.E.C. & Wakkee, M. (2009). Complexity of the Association Between Psoriasis and Comorbidities. Journal of Investigative Dermatology, 129(7), 1601-1603. Nijsten, T.E.C., Bos, R.R. van den, Goldman, MP, Kockaert, M.A., Proebstle, T.M., Rabe, E, Sadick, NS, Weiss, RA & Neumann, H.A.M. (2009). Minimally invasive techniques in the treatment of saphenous varicose veins. Journal of the American Academy of Dermatology, 60(1), 110-119. Nijsten, T.E.C., Spuls, P.I., Naldi, L & Stern, RS (2009). The Misperception That Clinical Trial Data Reflect Long-term Drug Safety Lessons Learned From Efalizumab's Withdrawal. Archives of Dermatology, 145(9), 1037-1039. Oranje, A.P., Verbeek, R., Verzaal, P, Haspels, I, Prens, E.P. & Nagelkerken, L. (2009). Wet-wrap treatment using dilutions of tacrolimus ointment and fluticasone propionate cream in human APOC1 (+/+) mice with atopic dermatitis. British Journal of Dermatology, 160(1), 54-61. Oranje, A.P. & Waard- van der Spek, F.B. de (2009). Atopisch eczeem. Patient Care (Brussel), 36, 29-33.

Pathirana, D, Ormerod, AD, Saiag, P, Smith, C., Spuls, P.I., Nast, A, Barker, J, Bos, J.D., Burmester, GR, Chimenti, S, Dubertret, L, Eberlein, B, Erdmann, R, Ferguson, J., Girolomoni, G, Gisondi, P, Giunta, A, Griffiths, C, Honigsmann, H, Hussain, M., Jobling, R, Karvonen, SL, Kemeny, L, Kopp, I, Leonardi, C, Maccarone, M, Menter, A, Mrowietz, U, Naldi, L, Nijsten, T.E.C., Ortonne, JP, Orzechowski, H.D., Rantanen, T, Reich, K, Reytan, N, Richards, H, Thio, H.B., Kerkhof, P van de & Rzany, B (2009). European S3-Guidelines on the systemic treatment of psoriasis vulgaris. Journal of the European Academy of Dermatology and Venereology, 23. Reeder, S.W.I., Middelburg, T.A. & Neumann, H.A.M. (2009). Een zeer pijnlijk ulcus op het onderbeen. Ulcus arterioloscleroticum van Martorell. Nederlands Tijdschrift voor Geneeskunde, 153, 421. Schelke, L.W., Elzen, H.J. van den, Canninga, M & Neumann, MHA (2009). Complications after Treatment with Polyalkylimide. Dermatologic Surgery, 35(2), 1625-1628. Snoek, E.M. van der, Amelink, A., Ende, M.E. van der, Hollander, J.C. den, Hollander, J.G. den, Kroon, F.P., Vriesendorp, R., Neumann, H.A.M. & Robinson, D.J. (2009). Photodynamic Therapy With Topical Metatetrahydroxychlorin (Fosgel) Is Ineffective for the Treatment of Anal Intraepithelial Neoplasia, Grade III. Jaids. Journal of Acquired Immune Deficiency Syndromes, 52(1), 141-143. Snoek, E.M. van der, Meijs, J., Waard- van der Spek, F.B. de & Meijden, W.I. van der (2009). Pruritus ani: onderzoek bij honderd Rotterdammers met anale jeuk. Nederlands Tijdschrift voor Dermatologie & Venereologie, 19, 518-521. Spek, F.B. van der & Oranje, A.P. (2009). Patch Tests in Children with Suspected Allergic Contact Dermatitis: A Prospective Study and Review of the Literature. Dermatology, 218(2), 119-125. Vijlder, H.C. de, Middelburg, T.A., Bruijn, H.S. de, Neumann, H.A.M., Sterenborg, H.J.C.M., Robinson, D.J. & Haas, E.R.M. de (2009). Optimizing ALA-PDT in the management of non-melanoma skin cancer by fractionated illumination. Giornale Italiano Dermatologi Venereologia, 144(4), 433-439. Waard- van der Spek, F.B. de (2009). Een kind met huiduitslag rond de mond. Ned. Tijdschrift voor Allergie, 9, 25-29. Wakkee, M. & Nijsten, T.E.C. (2009). Comorbidities in Dermatology. Dermatologic Clinics, 27(2), 137-+. Wakkee, M., Meijer, WJ, Neumann, H.A.M., Herings, R.M.C. & Nijsten, T.E.C. (2009). Psoriasis May Not Be an Independent Predictor for the Use of Cardiovascular and Anti-diabetic Drugs: A 5-year Prevalence Study. Acta Dermato-Venereologica, 89(5), 476-483. Wegen-Franken, C.P.M. van der, Tank, B., Nijsten, T.E.C. & Neumann, H.A.M. (2009). Changes in the pressure and the dynamic stiffness index of medical elastic compression stockings after having been worn for eight hours: a pilot study. Phlebology, 24(1), 31-37. Zee, H.H. van der, Boer, J. de, Prens, E.P. & Jemec, GBE (2009). The Effect of Combined Treatment with Oral Clindamycin and Oral Rifampicin in Patients with Hidradenitis Suppurativa. Dermatology, 219(2), 143-147. Part of book - abstract Reeder, S.W.I. & Neumann, H.A.M. (2009). Functional tests in venous disease. In Innovative treatments of venous disorders (pp. 87-97). Turijn: Edizioni Minerva Medica. Book editorship Leeuw, J. de, Boukes, F.S., Liem, T.B.Y. & Neumann, H.A.M. (Eds.). (2009). Diagnose en Therapie, Hoofdstuk Dermatologie. Houten: Bohn Stafleu van Loghum. Sillevis Smitt, J.H. & Neumann, H.A.M. (Eds.). (2009). Leerboek kindergeneeskunde, hoofdstuk dermatologie. Utrecht: De Tijdstroom. Thiery, L., Neumann, H.A.M. & Uytterhaegen, P. (Eds.). (2009). Insightful Phlebology. Overveen: Belvedere BV Publishing. Waal, R.I.F. van der & Neumann, H.A.M. (Eds.). (2009). Praktische dermatologie. Houten: Prelum uitgevers.

EMC MM-03-86-01 - Translational genomics and proteomics of cancer Programme design in brief The overall aim of the section of Translational Cancer Genomics & Proteomics is to investigate the cell biological and genetic factors involved in the development of sporadic and hereditary breast and ovarian cancer, to investigate the processes of tumor progression and treatment failure, and to come to tailored treatments (for subgroups of patients) that are based on risk factors and cell biological phenotypes of individual tumors and circulating tumor cells. To carry out our research programs involving clinical, translational and mechanistic genomics and proteomics studies on sporadic and hereditary cancer our laboratories have available a database on over 3,000 families with familial and hereditary breast cancer, breast and ovarian tissue (>15,000 samples stored in liquid nitrogen) and serum banks (>50,000 samples), 60 well-characterized breast and ovarian cancer cell lines, and various metastasizing and non-metastasizing rat and mouse tumor models. In our clinic, phase I, II and III trails with various (targeted) drugs are performed. The research is carried out in 3 different, but extensively collaborating, research groups: - Breast Cancer Genomics & Proteomics - Integrated Genomics of Breast and Ovarian Cancer - Hereditary Cancer Syndromes Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot medical oncology 8,82 3,16 3,63 0 15,61 Total 8,82 3,16 3,63 0 15,61 4 0 0 4 44 3 3 54 Thesis Bresser, P.J.C. (2009, mei 13). The psychosocial impact of prhphylactic mastectomy and salpingo-ooporectomy. EUR. Prom./coprom.: A. Tibben, Prof.Dr. M.F. Niermeijer & Dr. C.M. Seynaeve. Hollestelle, A. (2009, januari 07). A genetic basis for luminal and basal-type breast cancer. EUR (114 pag.). Prom./coprom.: Prof.Dr. J.G.M. Klijn & dr. M. Schutte. Strijbos, M.H. (2009, november 27). Quantification of circulating endothelial cells as surrogate marker for vascular damage. EUR (151 pag.). Prom./coprom.: Prof.Dr. J.A. Foekens, J.W. Gratama & Dr. S. Sleijfer. Wasielewski, M. (2009, september 24). CHEK2 1100delC and polygenic susceptibility to breast cancer and colorectal cancer. EUR (167 pag.). Prom./coprom.: Prof.Dr. J.G.M. Klijn & dr. M. Schutte. Patent Foekens, J.A., Martens, J.W.M., Kraan, J., Sleijfer, S., Mostert, B. & Sieuwerts, A.M. (26-06-2009). Identifying circulating tumor cells (CTCs) using CD146 in breast cancer patients. no NL2009/050378. Foekens, J.A., Martens, J.W.M., Eppenberger-Castori, S., Vuaroqueaux, V., Spyratos, F., Harbeck, N., Schmitt, M., Hoefler, H, Maier, S., Weiss, G., Lesche, R, Hildemann, Th. & Plum, A. (03-04-2009). Markers for the prediction of outcome of anthracycline treatment. no US2009111707. Lesche, R, Fassbender, A., Juenemann, K.P., Foekens, J.A. & Martens, J.W.M. (03-12-2009). Epigenetic methods and nucleic acids for the detection of breast cell proliferative disorders. no US2009111707. Article/Letter to the editor Agthoven, T. van, Sieuwerts, A.M., Veldscholte, J., Meijer-Gelder, M.E. van, Smid, M., Brinkman, A., Dekker, A.T. den, Leroy, I.M., Ijcken, W.F.J. van, Sleijfer, S., Foekens, J.A. & Dorssers, L.C.J. (2009). CITED2 and NCOR2 in anti-oestrogen resistance and progression of breast cancer. British Journal of Cancer, 101(11), 1824-1832. Agthoven, T. van, Sieuwerts, A.M., Meijer-Gelder, M.E. van, Look, M.P., Smid, M., Veldscholte, J., Sleijfer, S., Foekens, J.A. & Dorssers, L.C.J. (2009). Relevance of Breast Cancer Antiestrogen Resistance Genes in Human Breast Cancer Progression and Tamoxifen Resistance. Journal of Clinical Oncology, 27(4), 542-549. Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK, Platte R, Morrison J, Maranian M, Pooley KA, Luben R, Eccles D, Evans DG, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Stratton MR, Rahman N, Jacobs K, Prentice R, Anderson GL, Rajkovic A, Curb JD, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Diver WR, Bojesen S, Nordestgaard BG, Flyger H, Dörk T, Schürmann P, Hillemanns P, Karstens JH, Bogdanova NV, Antonenkova NN, Zalutsky IV, Bermisheva M, Fedorova S, Khusnutdinova E; SEARCH, Kang D, Yoo KY, Noh DY, Ahn SH, Devilee P, van Asperen CJ, Tollenaar RA, Seynaeve C, Garcia-Closas M, Lissowska J, Brinton L, Peplonska B, Nevanlinna H, Heikkinen T, Aittomäki K, Blomqvist C, Hopper JL, Southey MC, Smith L, Spurdle AB, Schmidt MK, Broeks A, van Hien RR, Cornelissen S, Milne RL, Ribas G, González-Neira A, Benitez J, Schmutzler RK, Burwinkel B, Bartram CR, Meindl A, Brauch H, Justenhoven C, Hamann U; GENICA Consortium, Chang-Claude J, Hein R, Wang-Gohrke S, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Kataja V, Olson JE, Wang X, Fredericksen Z, Giles GG, Severi G, Baglietto L, English DR, Hankinson SE, Cox DG, Kraft P, Vatten LJ, Hveem K, Kumle M, Sigurdson A, Doody M, Bhatti P, Alexander BH, Hooning MJ, van den Ouweland AM, Oldenburg RA, Schutte M, Hall P, Czene K, Liu J, Li Y, Cox A, Elliott G, Brock I, Reed MW, Shen CY, Yu JC, Hsu GC, Chen ST, Anton- Culver H, Ziogas A, Andrulis IL, Knight JA; kconfab; Australian Ovarian Cancer Study Group, Beesley J, Goode EL, Couch F, Chenevix-Trench G, Hoover RN, Ponder BA, Hunter DJ, Pharoah PD, Dunning AM, Chanock SJ, Easton DF. (2009). Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2. Nature Genetics, May 41(5), 585-90. Alles, MC, Gardiner-Garden, M, Nott, DJ, Wang, YX, Foekens, J.A., Sutherland, R.L., Musgrove, EA & Ormandy, CJ (2009). Meta-Analysis and Gene Set Enrichment Relative to ER Status Reveal Elevated Activity of MYC and E2F in the "Basal" Breast Cancer Subgroup. PLoS One, 4(3).

Boer, M. de, Deurzen, C.H.M. van, Dijck, J.A.A.M. van, Borm, GF, Diest, P.J. van, Adang, E.M.M., Nortier, J.W.R., Rutgers, EJT, Seynaeve, C., Menke-Pluymers, M.B.E., Bult, P. & Tjan-Heijnen, V.C.G. (2009). Micrometastases or Isolated Tumor Cells and the Outcome of Breast Cancer. New England Journal of Medicine, 361(7), 653-663. Bos, PD, Zhang, XHF, Nadal, C, Shu, WP, Gomis, RR, Nguyen, DX, Minn, AJ, Vijver, M.J. van de, Gerald, WL, Foekens, J.A. & Massague, J (2009). Genes that mediate breast cancer metastasis to the brain. Nature, 459(7249), 1005-U137. Creighton, CJ, Osborne, CK, Vijver, M.J. van de, Foekens, J.A., Klijn, J.G.M., Horlings, HM, Nuyten, D, Wang, Y., Zhang, Y., Chamness, GC, Hilsenbeck, SG, Lee, AV & Schiff, R (2009). Molecular profiles of progesterone receptor loss in human breast tumors. Breast Cancer Research and Treatment, 114(2), 287-299. Dooren, S. van, Duivenvoorden, H.J., Passchier, J., Bannink, M., Tan, M.B.M., Oldenmenger, W.H., Seynaeve, C. & Rijt, C.C.D. van der (2009). The Distress Thermometer assessed in women at risk of developing hereditary breast cancer. Psycho- Oncology, 18(10), 1080-1087. Duffy, M.J., Napieralski, R, Martens, J.W.M., Span, P.N., Spyratos, F., Sweep, F.C.G.J., Brunner, N., Foekens, J.A. & Schmitt, M. (2009). Methylated genes as new cancer biomarkers. European Journal of Cancer, 45(3), 335-346. Gaudet MM, Milne RL, Cox A, Camp NJ, Goode EL, Humphreys MK, Dunning AM, Morrison J, Giles GG, Severi G, Baglietto L, English DR, Couch FJ, Olson JE, Wang X, Chang-Claude J, Flesch-Janys D, Abbas S, Salazar R, Mannermaa A, Kataja V, Kosma VM, Lindblom A, Margolin S, Heikkinen T, Kämpjärvi K, Aaltonen K, Nevanlinna H, Bogdanova N, Coinac I, Schürmann P, Dörk T, Bartram CR, Schmutzler RK, Tchatchou S, Burwinkel B, Brauch H, Torres D, Hamann U, Justenhoven C, Ribas G, Arias JI, Benitez J, Bojesen SE, Nordestgaard BG, Flyger HL, Peto J, Fletcher O, Johnson N, Dos Santos Silva I, Fasching PA, Beckmann MW, Strick R, Ekici AB, Broeks A, Schmidt MK, van Leeuwen FE, Van't Veer LJ, Southey MC, Hopper JL, Apicella C, Haiman CA, Henderson BE, Le Marchand L, Kolonel LN, Kristensen V, Grenaker Alnaes G, Hunter DJ, Kraft P, Cox DG, Hankinson SE, Seynaeve C, Vreeswijk MP, Tollenaar RA, Devilee P, Chanock S, Lissowska J, Brinton L, Peplonska B, Czene K, Hall P, Li Y, Liu J, Balasubramanian S, Rafii S, Reed MW, Pooley KA, Conroy D, Baynes C, Kang D, Yoo KY, Noh DY, Ahn SH, Shen CY, Wang HC, Yu JC, Wu PE, Anton-Culver H, Ziogoas A, Egan K, Newcomb P, Titus-Ernstoff L, Trentham Dietz A, Sigurdson AJ, Alexander BH, Bhatti P, Allen-Brady K, Cannon-Albright LA, Wong J; Australian Ovarian Cancer Study Group, Chenevix-Trench G, Spurdle AB, Beesley J, Pharoah PD, Easton DF, Garcia-Closas M; Breast Cancer Association Consortium. 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Adjuvant chemotherapy in older patients with breast cancer. Nature Reviews Clinical Oncology, 6(10), 563-565. Jansen, M.P.H.M., Ritstier, K., Dorssers, L.C.J., Staveren, I.L. van, Look, M.P., Meijer-Gelder, M.E. van, Sieuwerts, A.M., Helleman, J., Sleijfer, S., Klijn, J.G.M., Foekens, J.A. & Berns, P.M.J.J. (2009). Downregulation of SIAH2, an ubiquitin E3 ligase, is associated with resistance to endocrine therapy in breast cancer. Breast Cancer Research and Treatment, 116(2), 263-271. 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Kok, M, Linn, SC, Laar, RK Van, Jansen, M.P.H.M., Berg, T.M. van den, Delahaye, LJMJ, Glas, AM, Peterse, J.L., Hauptmann, M., Foekens, J.A., Klijn, J.G.M., Wessels, L.F.A., Veer, L.J. van 't & Berns, P.M.J.J. (2009). Comparison of gene expression profiles predicting progression in breast cancer patients treated with tamoxifen. Breast Cancer Research and Treatment, 113(2), 275-283. Kreike, B, Halfwerk, H, Armstrong, N, Bult, P., Foekens, J.A., Veltkamp, SC, Nuyten, DSA, Bartelink, H. & Vijver, M.J. van de (2009). Local Recurrence after Breast-Conserving Therapy in Relation to Gene Expression Patterns in a Large Series of Patients. Clinical Cancer Research, 15(12), 4181-4190. Kriege, M., Seynaeve, C., Meijers-Heijboer, E.J., Collee, J.M., Menke-Pluymers, M.B.E., Bartels, C.C.M., Tilanus-Linthorst, M.M.A., Blom, J., Huijskens van Herpen, E.J. van, Jager, A., Ouweland, A.M.W. van den, Geel, A.N. van, Hooning, M.J., Brekelmans, C.T.M. & Klijn, J.G.M. (2009). Sensitivity to First-Line Chemotherapy for Metastatic Breast Cancer in BRCA1 and BRCA2 Mutation Carriers. Journal of Clinical Oncology, 27(23), 3764-3771.

Kuijper, A, Snijders, A.M., Berns, P.M.J.J., Kuenen-Boumeester, V., Wall, E van der, Albertson, D.G. & Diest, P.J. van (2009). Genomic profiling by array comparative genomic hybridization reveals novel DNA copy number changes in breast phyllodes tumours. Cellular Oncology, 31(1), 31-39. Kuijper, T.M., Ritstier, K., Verhoef-Post, M., Piersma, D., Bruysters, M.W.P., Berns, P.M.J.J. & Themmen, A.P.N. (2009). LH receptor gene expression is essentially absent in breast tumor tissue: Implications for treatment. Molecular and Cellular Endocrinology, 302(1), 58-64. Martens, J.W.M., Margossian, AL, Schmitt, M., Foekens, J.A. & Harbeck, N. (2009). DNA methylation as a biomarker in breast cancer. Future Oncology, 5(8), 1245-1256. Meijer, D., Jansen, M.P.H.M., Look, M.P., Ritstier, K., Staveren, I.L. van, Sieuwerts, A.M., Agthoven, T. van, Foekens, J.A., Dorssers, L.C.J. & Berns, P.M.J.J. (2009). TSC22D1 and PSAP predict clinical outcome of tamoxifen treatment in patients with recurrent breast cancer. Breast Cancer Research and Treatment, 113(2), 253-260. Milne, RL, Benitez, J., Nevanlinna, H., Heikkinen, T, Aittomaki, K, Blomqvist, C., Arias, J.I., Zamora, MP, Burwinkel, B, Bartram, C.R., Meindl, A, Schmutzler, RK, Cox, A., Brock, I, Elliott, G, Reed, MWR, Southey, MC, Smith, L., Spurdle, A.B., Hopper, J.L., Couch, F.J., Olson, JE, Wang, XS, Fredericksen, Z, Schurmann, P, Bremer, M., Hillemanns, P., Dork, T., Devilee, P., Asperen, C.J. van, Tollenaar, R.A.E.M., Seynaeve, C., Hall, P., Czene, K., Liu, JJ, Li, YQ, Ahmed, S., Dunning, A.M., Maranian, M, Pharoah, PDP, Chenevix-Trench, G., Beesley, J, Bogdanova, NV, Antonenkova, NN, Zalutsky, IV, Anton-Culver, H, Ziogas, A, Brauch, H, Justenhoven, C, Ko, YD, Haas, S, Fasching, PA, Strick, R, Ekici, AB, Beckmann, MW, Giles, G.G., Severi, G, Baglietto, L, English, DR, Fletcher, O, Johnson, N, Silva, ID, Peto, J., Turnbull, C, Hines, S, Renwick, A., Rahman, N., Nordestgaard, BG, Bojesen, SE, Flyger, H, Kang, D, Yoo, KY, Noh, DY, Mannermaa, A., Kataja, V., Kosma, VM, Garcia-Closas, M, Chanock, S, Lissowska, J, Brinton, LA, Chang-Claude, J., Wang-Gohrke, S., Shen, CY, Wang, HC, Yu, JC, Chen, ST, Bermisheva, M, Nikolaeva, T, Khusnutdinova, E, Humphreys, MK, Morrison, J, Platte, R & Easton, D.F. 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Anti-Epithelial Cell Adhesion Molecule Antibodies and the Detection of Circulating Normal- Like Breast Tumor Cells. Journal of the National Cancer Institute, 101(1), 61-66. Sieuwerts, A.M., Kraan, J., Vries, J. de, Spoel, P. van der, Mostert, B., Martens, J.W.M., Gratama, J.W., Sleijfer, S. & Foekens, J.A. (2009). Molecular characterization of circulating tumor cells in large quantities of contaminating leukocytes by a multiplex real-time PCR. Breast Cancer Research and Treatment, 118(3), 455-468. Sleijfer, S. & Verweij, J. (2009). The Price of Success: Cost-Effectiveness of Molecularly Targeted Agents. Clinical Pharmacology & Therapeutics, 85(2), 136-138. Span, P.N., Sieuwerts, A.M., Heuvel, J.J.T.M., Spyratos, F., Duffy, M.J., Eppenberger-Castori, S., Vacher, S, O'Brien, K, McKiernan, E, Pierce, A., Vuaroqueaux, V., Foekens, J.A., Sweep, F.C.G.J. & Martens, J.W.M. (2009). 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Circulating endothelial cells: A potential parameter of organ damage in sickle cell anemia? Blood Cells Molecules & Diseases, 43(1), 63-67.

Strijbos, M.H., Verhoef, C., Gratama, J.W. & Sleijfer, S. (2009). On the origin of (CD105+) circulating endothelial cells. Thrombosis and Haemostasis, 102(2), 347-351. Strijbos, M.H., Kraan, J., Lamers, C.H.J., Sleijfer, S. & Gratama, J.W. (2009). Quantification of Circulating Endothelial Cells by Flow Cytometry. Clinical Cancer Research, 15(10), 3640-3640. Tan, M.B.M., Bleiker, EMA, Menke-Pluymers, M.B.E., Gool, A.R. van, Dooren, S. van, Geel, A.N. van, Tilanus-Linthorst, M.M.A., Bartels, C.C.M., Klijn, J.G.M., Brekelmans, C.T.M. & Seynaeve, C. (2009). Standard psychological consultations and follow up for women at increased risk of hereditary breast cancer considering prophylactic mastectomy. Hereditary Cancer in Clinical Practice, 7, 6-6. Toussaint, J, Sieuwerts, A.M., Haibe-Kains, B, Desmedt, C, Rouas, G, Harris, A.L., Larsimont, D, Piccart, M., Foekens, J.A., Durbecq, V & Sotiriou, C (2009). Improvement of the clinical applicability of the Genomic Grade Index through a qrt-pcr test performed on frozen and formalin-fixed paraffin-embedded tissues. Bmc Genomics, 10. Trinh, XB, Tjalma, WAA, Vermeulen, PB, Eynden, G Van den, Auwera, I Van der, Laere, SJ Van, Helleman, J., Berns, P.M.J.J., Dirix, LY & Dam, PA van (2009). The VEGF pathway and the AKT/mTOR/p70S6K1 signalling pathway in human epithelial ovarian cancer. British Journal of Cancer, 100(6), 971-978. Umar, A., Kang, H., Timmermans, A.M., Look, M.P., Meijer-Gelder, M.E. van, Bakker, M.A. den, Jaitly, N, Martens, J.W.M., Luider, T.M., Foekens, J.A. & Pasa-Tolic, L (2009). Identification of a Putative Protein Profile Associated with Tamoxifen Therapy Resistance in Breast Cancer. Molecular & Cellular Proteomics, 8(6), 1278-1294. Wasielewski, M., Bakker, M.A. den, Ouweland, A.M.W. van den, Meijer-Gelder, M.E. van, Portengen, H., Klijn, J.G.M., Meijers- Heijboer, E.J., Foekens, J.A. & Schutte, M. (2009). CHEK2 1100delC and male breast cancer in the Netherlands. Breast Cancer Research and Treatment, 116(2), 397-400. Wasielewski, M., Hanifi Moghaddam, P., Hollestelle, A., Merajver, SD, Ouweland, A. van den, Klijn, J.G.M., Ethier, SP & Schutte, M. (2009). Deleterious CHEK2 1100delC and L303X mutants identified among 38 human breast cancer cell lines. Breast Cancer Research and Treatment, 113(2), 285-291. Zhang, XHF, Wang, QQ, Gerald, W, Hudis, CA, Norton, L, Smid, M., Foekens, J.A. & Massague, J (2009). Latent Bone Metastasis in Breast Cancer Tied to Src-Dependent Survival Signals. Cancer Cell, 16(1), 67-78. Zhang, Y., Martens, J.W.M., Yu, JX, Jiang, J., Sieuwerts, A.M., Smid, M., Klijn, J.G.M., Wang, YX & Foekens, J.A. (2009). Copy Number Alterations that Predict Metastatic Capability of Human Breast Cancer. Cancer Research, 69(9), 3795-3801. Zhang, Y., Sieuwerts, A.M., McGreevy, M, Casey, G, Cufer, T., Paradiso, A, Harbeck, N., Span, P.N., Hicks, DG, Crowe, J, Tubbs, RR, Budd, GT, Lyons, J, Sweep, F.C.G.J., Schmitt, M., Schittulli, F, Golouh, R, Talantov, D, Wang, YX & Foekens, J.A. (2009). The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy. Breast Cancer Research and Treatment, 116(2), 303-309.

EMC MM-03-86-08 - Translational pharmacology Programme design in brief The programme Translational Pharmacology covers a broad range of topics with clinical trials involving patients on one hand and pharmacological and biological approaches using preclinical models on the other hand. In the clinic cancer patients are treated with new classes of anticancer agents e.g. receptor tyrosine kinase inhibitors, angiogenesis inhibitors and cell cycle inhibitors, in early (phase I and II) and late (phase III) clinical trials. Linked to these studies is an extensive translational research program addressing the pharmacokinetics and pharmacodynamics of the investigational drugs as well as the pharmacogenetics that influences these pharmacological parameters. Special attention is given to identify pre-treatment patient characteristics that influence the distribution - and hence the efficacy and/or toxicity - of anticancer agents in order to develop genotype and/or phenotype based dosing approaches to correct for interpatient variation. In addition research is carried out to elucidate the molecular mechanisms of carcinogenesis and the ways (cancer) cells respond to various kinds of stress notably exposure to chemotherapeutic agents and/or DNA damaging conditions. The overall aim is to improve chemotherapy of cancer either through the use of novel anticancer agents and/or novel combinations of chemotherapeutic compounds, the tailoring of existing treatments for specific patient populations and the discovery of novel drug targets. The research program is carried out by five closely interacting research groups: - Molecular Pharmacodynamics - Personalized Medicine - Early Clinical Trials - Experimental Systemic Therapy of Urogenital Tumours Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot medical oncology 4,2 1 1 2,2 8,4 Total 4,2 1 1 2,2 8,4 0 0 0 0 35 2 2 39 Article/Letter to the editor Alphen, R.J. van, Wiemer, E.A.C., Burger, H. & Eskens, F.A.L.M. (2009). The spliceosome as target for anticancer treatment. British Journal of Cancer, 100(2), 228-232. Baird, RD, Kitzen, J.J.E.M., Clarke, PA, Planting, A.S.T., Reade, S., Reid, A., Welsh, L, Lazaro, LL, Heras, BDL, Judson, I.R., Kaye, S.B., Eskens, F.A.L.M., Workman, P., debono, JS & Verweij, J. (2009). Phase I safety, pharmacokinetic, and pharmacogenomic trail of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors. Molecular Cancer Therapeutics, 8(6), 1430-1437. Belt-Dusebout, A.W. van den, Aleman, B.M.P., Besseling, G, Bruin, M.L. de, Hauptmann, M., Veer, M.B. van t, Wit, R. de, Ribot, J.G., Noordijk, E.M., Kerst, JM, Gietema, J.A. & Leeuwen, F.E. van (2009). Roles of radiation dose and chemotherapy in the etiology of stomach cancer as a second malignancy. International Journal of Radiation Oncology Biology Physics, 75(5), 1420-1429. Bogaerts, J, Ford, R, Sargent, D, Schwartz, LH, Rubinstein, L., Lacombe, D., Eisenhauer, E, Verweij, J. & Therasse, P. (2009). Individual patient data analysis to assess modifications to the RECIST criteria. European Journal of Cancer, 45(2), 248-260. Boonstra, J.J., Koppert, L.B., Wijnhoven, B.P.L., Tilanus, H.W., Dekken, H. van, Tran, T.C.K. & Gaast, A. van der (2009). Chemotherapy Followed by Surgery in Patients With Carcinoma of the Distal Esophagus and Celiac Lymph Node Involvement. Journal of Surgical Oncology, 100(5), 407-413. Bruijn, P. de, Ghobadi Moghaddam-Helmantel, I., Jonge, M.J.A. de, Meyer, T, Lam, M.H., Verweij, J., Wiemer, E.A.C. & Loos, W.J. (2009). Validated bioanalytical method for the quantification of RGB-286638, a novel multi-targeted protein kinase inhibitor, in human plasma and urine by liquid chromatography/tandem triple-quadrupole mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis, 50(5), 977-982. Cesne, A. le, Glabbeke, M. van, Verweij, J., Casali, P.G., Findlay, M., Reichardt, P., Issels, R., Judson, I., Schoffski, P, Leyvraz, S., Bui, B, Hogendoorn, P.C.W., Sciot, R. & Blay, J.Y. (2009). Absence of Progression As Assessed by Response Evaluation Criteria in Solid Tumors Predicts Survival in Advanced GI Stromal Tumors Treated With Imatinib Mesylate: The Intergroup EORTC-ISG-AGITG Phase III Trial. Journal of Clinical Oncology, 27(24), 3969-3974. DePrimo, SE, Huang, X, Blackstein, ME, Garrett, CR, Harmon, CS, Schoffski, P, Shah, MH, Verweij, J., Baum, CM & Demetri, G.D. (2009). Circulating Levels of Soluble KIT Serve as a Biomarker for Clinical Outcome in Gastrointestinal Stromal Tumor Patients Receiving Sunitinib following Imatinib Failure. Clinical Cancer Research, 15(18), 5869-5877. Eisenhauer, E.A., Therasse, P., Bogaerts, J, Schwartz, LH, Sargent, D, Ford, R, Dancey, J, Arbuck, S, Gwyther, S., Mooney, M, Rubinstein, L., Shankar, L, Dodd, L, Kaplan, R, Lacombe, D. & Verweij, J. (2009). New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer, 45(2), 228-247. Erp, NP van, Eechoute, K., Veldt, AA van der, Haanen, JB, Reyners, AKL, Mathijssen, R.H.J., Boven, E., Straaten, T van der, Baak-Pablo, RF, Wessels, J.A.M., Guchelaar, HJ & Gelderblom, H. (2009). Pharmacogenetic Pathway Analysis for Determination of Sunitinib-Induced Toxicity. Journal of Clinical Oncology, 27(26), 4406-4412. Eskens, F.A.L.M., Steeghs, N., Verweij, J., Bloem, J.L., Christensen, O, Doorn, L. van, Ouwerkerk, J, Jonge, M.J.A. de, Nortier, J.W.R., Kraetzschmar, J, Rajagopalan, P & Gelderblom, H. (2009). Phase I Dose Escalation Study of Telatinib, a Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor 2 and 3, Platelet-Derived Growth Factor Receptor beta, and c- Kit, in Patients With Advanced or Metastatic Solid Tumors. Journal of Clinical Oncology, 27(25), 4169-4176.

Filipski, KK, Mathijssen, R.H.J., Mikkelsen, TS, Schinkel, A.H. & Sparreboom, A. (2009). Contribution of Organic Cation Transporter 2 (OCT2) to Cisplatin-Induced Nephrotoxicity. Clinical Pharmacology & Therapeutics, 86(4), 396-402. Fitzpatrick, J.M., Sternberg, C.N., Saad, F, Extermann, M, Caffo, O, Halabi, S, Kramer, G, Oudard, S. & Wit, R. de (2009). Treatment Decisions for Advanced Genitourinary Cancers: From Symptoms to Risk Assessment. European Urology Supplements, 8(9), 738-746. Ford, R, Schwartz, L, Dancey, J, Dodd, LE, Eisenhauer, E.A., Gwyther, S., Rubinstein, L., Sargent, D, Shankar, L, Therasse, P. & Verweij, J. (2009). Lessons learned from independent central renew. European Journal of Cancer, 45(2), 268-274. Ghodgaonkar, MM, Shah, RG, Kandan-Kulangara, F, Affar, EB, Qi, HH, Wiemer, E.A.C. & Shah, GM (2009). Abrogation of DNA vector-based RNAi during apoptosis in mammalian cells due to caspase-mediated cleavage and inactivation of Dicer-1. Cell Death & Differentiation, 16(6), 858-868. Hamberg, A.P. & Verweij, J. (2009). Phase I Drug Combination Trial Design: Walking the Tightrope. Journal of Clinical Oncology, 27(27), 4441-4443. Jager, A., Verweij, J. & Sleijfer, S. (2009). Adjuvant chemotherapy in older patients with breast cancer. Nature Reviews Clinical Oncology, 6(10), 563-565. Kitzen, J.J.E.M., Jonge, M.J.A. de, Lamers, C.H.J., Eskens, F.A.L.M., Biessen, A.J. van der, Doorn, L. van, Steeg, J.D. ter, Brandely, M, Puozzo, C & Verweij, J. (2009). Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours. European Journal of Cancer, 45(10), 1764-1772. Konings, I.R.H.M., Engels, F.K., Sleijfer, S., Verweij, J., Wiemer, E.A.C. & Loos, W.J. (2009). Application of prolonged microdialysis sampling in carboplatin-treated cancer patients. Cancer Chemotherapy & Pharmacology, 64(3), 509-516. Konings, I.R.H.M., Verweij, J., Wiemer, E.A.C. & Sleijfer, S. (2009). The Applicability of mtor Inhibition in Solid Tumors. Current Cancer Drug Targets, 9(3), 439-450. Mathijssen, R.H.J. & Gurney, H (2009). Irinogenetics: How Many Stars Are There in the Sky? Journal of Clinical Oncology, 27(16), 2578-2579. Meerten, E. van, Gaast, A. van der, Tilanus, H.W., Poley, J.W., Muller, K. & Dekken, H. van (2009). Pathological Analysis After Neoadjuvant Chemoradiotherapy for Esophageal Carcinoma: The Rotterdam Experience. Journal of Surgical Oncology, 100(1), 32-37. Meulenbeld, H.J., Hamberg, A.P. & Wit, R. de (2009). Chemotherapy in patients with castration-resistant prostate cancer. European Journal of Cancer, 45(1), 161-171. Mom, CH, Verweij, J., Oldenhuis, CNAM, Gietema, J.A., Fox, NL, Miceli, R, Eskens, F.A.L.M., Loos, W.J., Vries, E.G.E. de & Sleijfer, S. (2009). Mapatumumab, a Fully Human Agonistic Monoclonal Antibody That Targets TRAIL-R1, in Combination with Gemcitabine and Cisplatin: a Phase I Study. Clinical Cancer Research, 15(17), 5584-5590. Oosten, A.W., Seynaeve, C.M., Schmitz, P.I.M., Bakker, M.A. den, Verweij, J. & Sleijfer, S. (2009). Outcomes of first-line chemotherapy in patients with advanced leiomyosarcoma of uterine and non-uterine origin to first-line chemotherapy. Sarcoma, 348910. Pothof, J., Verkaik, N.S., Ijcken, W. van, Wiemer, E.A.C., Ta, T.B.V., Horst, G.T.J. van der, Jaspers, N.G.J., Gent, D.C. van, Hoeijmakers, J.H.J. & Persengiev, S.P. (2009). MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response. Embo Journal, 28(14), 2090-2099. Ray-Coquard, I, Cropet, C, Glabbeke, M. van, Sebban, C., Cesne, A. le, Judson, I., Tredan, O, Verweij, J., Biron, P, Labidi, I, Guastalla, J.P., Bachelot, T, Perol, D, Chabaud, S, Hogendoorn, P.C.W., Cassier, P, Dufresne, A & Blays, JY (2009). Lymphopenia as a Prognostic Factor for Overall Survival in Advanced Carcinomas, Sarcomas, and Lymphomas. Cancer Research, 69(13), 5383-5391. Romeo, S, Debiec-Rychter, M., Glabbeke, M. van, Paassen, H Van, Comite, P, Eijk, R. van, Oosting, J., Verweij, J., Terrier, P, Schneider, U, Sciot, R., Blay, J.Y. & Hogendoorn, P.C.W. (2009). Cell Cycle/Apoptosis Molecule Expression Correlates with Imatinib Response in Patients with Advanced Gastrointestinal Stromal Tumors. Clinical Cancer Research, 15(12), 4191-4198. Santis, M De, Bellmunt, J., Mead, G, Kerst, JM, Leahy, M, Maroto, P, Skoneczna, I, Marreaud, S, Wit, R. de & Sylvester, R. (2009). Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer "Unfit" for Cisplatin-Based Chemotherapy: Phase II-Results of EORTC Study 30986. Journal of Clinical Oncology, 27(33), 5634-5639. Sleijfer, S., Ray-Coquard, I, Papai, Z, Cesne, A. le, Scurr, M., Schoffski, P, Collin, F, Pandite, L, Marreaud, S, Brauwer, A De, Glabbeke, M. van, Verweij, J. & Blay, J.Y. (2009). Pazopanib, a Multikinase Angiogenesis Inhibitor, in Patients With Relapsed or Refractory Advanced Soft Tissue Sarcoma: A Phase II Study From the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC Study 62043). Journal of Clinical Oncology, 27(19), 3126-3132. Sleijfer, S. & Verweij, J. (2009). The Price of Success: Cost-Effectiveness of Molecularly Targeted Agents. Clinical Pharmacology & Therapeutics, 85(2), 136-138. Sparreboom, A. & Verweij, J. (2009). Advances in Cancer Therapeutics. Clinical Pharmacology & Therapeutics, 85(2), 113-117.

Steeghs, N., Eskens, F.A.L.M., Gelderblom, H., Verweij, J., Nortier, J.W.R., Ouwerkerk, J, Noort, C.H.C. van, Mariani, M, Spinelli, R., Carpinelli, P, Laffranchi, B & Jonge, M.J.A. de (2009). Phase I Pharmacokinetic and Pharmacodynamic Study of the Aurora Kinase Inhibitor Danusertib in Patients With Advanced or Metastatic Solid Tumors. Journal of Clinical Oncology, 27(30), 5094-5101. Troost, M.M., Sternberg, C.N. & Wit, R. de (2009). Management of good risk germ-cell tumours. Bju International, 104(9B), 1387-1391. Verweij, J., Therasse, P. & Eisenhauer, E (2009). Cancer clinical trial outcomes: Any progress in tumour-size assessment? European Journal of Cancer, 45(2), 225-227. Verweij, J. (2009). Soft Tissue Sarcoma Trials: One Size No Longer Fits All. Journal of Clinical Oncology, 27(19), 3085-3087. Weerden, W.M. van, Bangma, C. & Wit, R. de (2009). Human xenograft models as useful tools to assess the potential of novel therapeutics in prostate cancer. British Journal of Cancer, 100(1), 13-18. Part of book - abstract Eskens, F.A.L.M. & Verweij, J. (2009). Principles and examples of cancer (cell) specific therapies. In F Cavalli, SB Kaye, HH Hansen, JO Armitage & MJ Piccart-Gebhart (Eds.), Textbook of Medical Oncology (pp. 41-55). London: Informa. Kitzen, J.J.E.M., Jonge, M.J.A. de & Verweij, J. (2009). How to define treatment success or failure if tumors do not shrink. In H.L. Kaufman, S. Wadler & K Antman (Eds.), Cancer drug discovery and development: molecular targeting in oncology (pp. 657). Totowa NJ: Humana Press.

EMC MM-03-86-12 - Translational tumor immunology Programme design in brief MAIN OBJECTIVE: Immuno(gene) therapy of cancer in general, and the therapeutic use of T lymphocytes genetically endowed with cancerspecificity in particular. MAIN RESULT: Succesful generation of tumor-specific T lymphocytes following genetic introduction of genes encoding tumor-specific receptors, design and testing of strategies to improve efficacy and safety of TCR gene therapy, and the current continuation of a phase I study to treat metastat ic renal cancer with gene-modified T lymphocytes, the first clinical study of its kind in Europe. MAIN FOCUS: 1. CLINICAL TUMOR IMMUNOLOGY a. GMP T cell processing and conduct of clinical immuno(gene) therapy - A more than 20-year track record in clinical trials of immunotherapy of solid tumors. - Gene transduction and T cell expansion procedures at clinical scale that meet criteria of good clinical practice (GCP). - A phase I immunogene therapy trial to treat metasta tic renal cell cancer with autologous gene modified T cells (P00.0040C/DDHK 97-29). b. Immunological monitoring of therapeutic interventions - Laboratory activities have been accredited by CCKL, the Dutch foundation for quality improvement of laboratory studies and accreditation of laboratories active in health care. - Experimental and clinical custom-tailored (immune) monitoring packages are set up and validated, and are offered to external parties (i.e., `contract research ). - Reference center at the national (Stichting Kwaliteitsbewaking Medische Laboratorium Diagnostiek) and European levels. - Routine services to immune phenotype leukemia and lymphoma or quantify minimal residual disease (see also under c). - Immune monitoring techniques: up to 6-color flow cytometry and real-time PCR to assess absolute numbers, phenotype and function of patient T lymphocyte subsets (including assessment of the phosphorylation state of key molecules in T cell signalling), and in vitro technologies to measure general and antigen-specific T cell functions. c. Monitoring circulating tumor and endothelial cells (CTC and CEC) - CTCs are enriched by immunomagnetic cell selection using a CellSearch instrument, followed by counting using a CellTracks Analyzer (in collaboration with the Laboratory for Translational Genomics and Proteomics). - CECs are enriched and enumerated using the same instrumentation as CTCs, but using different reagents. CEC counts are under study as markers for vascular damage and tumor progression. 2. EXPERIMENTAL TUMOR IMMUNOLOGY a. TCR gene therapy directed against MAGE antigens - Molecular engineering of TCR to enhance efficacy and safety of TCR gene therapy. - Genetic and non-genetic strategies that enable T lymphocytes to counteract the immunosuppressive milieu of tumors. - Mouse models include: (a) transplantation of tumors onto mice transgenic for Human Leucocyte Antigens (HLA molecules) and (b) spontaneous melanoma. - Real-time non-invasive in vivo monitoring of gene-modified T lymphocytes via advanced intravital fluorescence microscopy (in collaboration with Laboratory of Experimental and Surgical Oncology, Erasmus MC). b. Selection and validation of antibodies from phage-display library We generated a non-immune phage Fab display library allowing selections of antibodies directed against any antigen (including pmhc) of interest (repertoire about 1010). Isolated antibodies are characterized for binding and can be molecularly modified to genetically direct T cells. c. Anti-tumor effect of novel molecules and their receptors Develop and test strategies to direct potential anti-tumor activities of native molecules (i.e. members of the IL-1 and IL-10 family) as well as synthetic molecules with known pro-apoptotic and/or anti-angiogenic activities to the site of the tumor cell. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot medical oncology 5,93 2 0 1 8,93 neurology 0 0 0 1 1 surgery 0,01 0 0 0 0,01 Total 5,94 2 0 2 9,94 1 0 0 1 20 0 0 21 Thesis Strijbos, M.H. (2009, november 27). Quantification of circulating endothelial cells as surrogate marker for vascular damage. EUR (151 pag.). Prom./coprom.: Prof.Dr. J.A. Foekens, J.W. Gratama & Dr. S. Sleijfer. Article/Letter to the editor Beukelaar, J.W. de, Milikan, J.C., Verjans, G.M., Graaf, M.T. de, Norden, Y. van, Lamers, C.H., Bent, M.J. van den, Bromberg, J.E., Hulsenboom, E., Sintnicolaas, K., Gratama, J.W. & Smitt, P.A.S. (2009). No evidence for the presence of HuD-specific T cells in the cerebrospinal fluid of patients with Huassociated paraneoplastic neurological syndromes. Journal of Neurology, 256(2), 279-282. Bobisse, S, Rondina, M, Merlo, A, Tisato, V, Mandruzzato, S, Amendola, M, Naldini, L, Willemsen, R.A., Debets, J.E.M.A., Zanovello, P & Rosato, A (2009). Reprogramming T Lymphocytes for Melanoma Adoptive Immunotherapy by T-Cell Receptor Gene Transfer with Lentiviral Vectors. Cancer Research, 69(24), 9385-9394. Bottomley, A., Coens, C., Suciu, S., Santinami, M., Kruit, W.H.J., Testori, A., Marsden, J., Punt, C., Sales, F., Gore, M., MacKie, R, Kusic, Z, Dummer, R., Patel, P, Schadendorf, D., Spatz, A., Keilholz, U. & Eggermont, A.M.M. (2009). Adjuvant Therapy With Pegylated Interferon Alfa-2b Versus Observation in Resected Stage III Melanoma: A Phase III Randomized Controlled Trial of

Health-Related Quality of Life and Symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group. Journal of Clinical Oncology, 27(18), 2916-2923. Bouwhuis, M.G., Suciu, S., Collette, S, Aamdal, S., Kruit, W.H.J., Bastholt, L, Stierner, U, Sales, F., Patel, P, Punt, C.J.A., Hernberg, M, Spatz, A., Hagen, T.L.M. ten, Hansson, J. & Eggermont, A.M.M. (2009). Autoimmune Antibodies and Recurrence- Free Interval in Melanoma Patients Treated With Adjuvant Interferon. Journal of the National Cancer Institute, 101(12), 869-877. Brooimans, R.A., Kraan, J., Putten, W.L.J. v., Cornelissen, J.J., Lowenberg, B. & Gratama, J.W. (2009). Flow Cytometric Differential of Leukocyte Populations in Normal Bone Marrow: Influence of Peripheral Blood Contamination. Cytometry Part B- Clinical Cytometry, 76B(1), 18-26. Fekkes, D., Gool, A.R. van, Bannink, M., Sleijfer, S., Kruit, W.H.J., Holt, B. van der, Eggermont, A.M.M., Hengeveld, M.W. & Stoter, G. (2009). Nitric oxide production and monoamine oxidase activity in cancer patients during interferon-alpha therapy. Amino Acids, 37(4), 703-708. Fusi, A, Collette, S, Busse, A, Suciu, S., Rietz, A, Santinami, M., Kruit, W.H.J., Testori, A., Punt, C.J.A., Dalgleish, AG, Spatz, A., Eggermont, A.M.M. & Keilholz, U. (2009). Circulating melanoma cells and distant metastasis-free survival in stage III melanoma patients with or without adjuvant interferon treatment (EORTC 18991 side study). European Journal of Cancer, 45(18), 3189-3197. Hulspas, R., O'Gorman, MRG, Wood, B.L., Gratama, J.W. & Sutherland, D.R. (2009). Considerations for the Control of Background Fluorescence in Clinical Flow Cytometry. Cytometry Part B-Clinical Cytometry, 76B(6), 355-364. Kitzen, J.J.E.M., Jonge, M.J.A. de, Lamers, C.H.J., Eskens, F.A.L.M., Biessen, A.J. van der, Doorn, L. van, Steeg, J.D. ter, Brandely, M, Puozzo, C & Verweij, J. (2009). Phase I dose-escalation study of F60008, a novel apoptosis inducer, in patients with advanced solid tumours. European Journal of Cancer, 45(10), 1764-1772. Lambert, C, Arroz, M., Campos, L, Bene, M.C., Chatelain, B, Janos, K, Papa, S. & Gratama, J.W. (2009). Clinical Cytometry in Europe, 2009 Preface. Cytometry Part B-Clinical Cytometry, 76B(6), 408-409. Lamers, C.H.J., Willemsen, R.A., Elzakker, P.M.M.L. van, Gratama, J.W. & Debets, J.E.M.A. (2009). Gibbon Ape Leukemia Virus Poorly Replicates in Primary Human T Lymphocytes Implications for Safety Testing of Primary Human T Lymphocytes Transduced With GALV-pseudotyped Vectors. Journal of Immunotherapy, 32(3), 272-279. mandy, F. & Gratama, J.W. (2009). Flow Cytometry: A Biomedical Platform Offering Diagnostic Diversity. Cytometry Part B- Clinical Cytometry, 76B(6), 365-366. Mom, CH, Verweij, J., Oldenhuis, CNAM, Gietema, J.A., Fox, NL, Miceli, R, Eskens, F.A.L.M., Loos, W.J., Vries, E.G.E. de & Sleijfer, S. (2009). Mapatumumab, a Fully Human Agonistic Monoclonal Antibody That Targets TRAIL-R1, in Combination with Gemcitabine and Cisplatin: a Phase I Study. Clinical Cancer Research, 15(17), 5584-5590. Mostert, B., Sleijfer, S., Foekens, J.A. & Gratama, J.W. (2009). Circulating tumor cells (CTCs): Detection methods and their clinical relevance in breast cancer. Cancer Treatment Reviews, 35(5), 463-474. Sieuwerts, A.M., Kraan, J., Bolt- de Vries, J., Spoel, P. van der, Elstrodt, F., Schutte, M., Martens, J.W.M., Gratama, J.W., Sleijfer, S. & Foekens, J.A. (2009). Anti-Epithelial Cell Adhesion Molecule Antibodies and the Detection of Circulating Normal- Like Breast Tumor Cells. Journal of the National Cancer Institute, 101(1), 61-66. Sieuwerts, A.M., Kraan, J., Vries, J. de, Spoel, P. van der, Mostert, B., Martens, J.W.M., Gratama, J.W., Sleijfer, S. & Foekens, J.A. (2009). Molecular characterization of circulating tumor cells in large quantities of contaminating leukocytes by a multiplex real-time PCR. Breast Cancer Research and Treatment, 118(3), 455-468. Sieuwerts, A.M., Kraan, J., Vries, J. de, Spoel, P. van der, Elstrodt, F., Smid, M., Timmermans, M, Mostert, B., Schutte, M., Martens, J.W.M., Gratama, J.W., Sleijfer, S. & Foekens, J.A. (2009). Response: Re: Anti-Epithelial Cell Adhesion Molecule Antibodies and the Detection of Circulating Normal-Like Breast Tumor Cells. Journal of the National Cancer Institute, 101(12), 896-897. Strijbos, M.H., Landburg, PP, Nur, E, Teerlink, T., Leebeek, F.W.G., Rijneveld, A.W., Biemond, BJ, Sleijfer, S., Gratama, J.W., Duits, AJ & Schnog, JJB (2009). Circulating endothelial cells: A potential parameter of organ damage in sickle cell anemia? Blood Cells Molecules & Diseases, 43(1), 63-67. Strijbos, M.H., Verhoef, C., Gratama, J.W. & Sleijfer, S. (2009). On the origin of (CD105+) circulating endothelial cells. Thrombosis and Haemostasis, 102(2), 347-351. Strijbos, M.H., Kraan, J., Lamers, C.H.J., Sleijfer, S. & Gratama, J.W. (2009). Quantification of Circulating Endothelial Cells by Flow Cytometry. Clinical Cancer Research, 15(10), 3640-3640.

EMC MM-04-20-01 - Neoplastic lesions and chronic inflammatation of the gastrointestinal tract Programme design in brief The research of the Department of Gastroenterology & Hepatology is centered around the themes premalignant lesions and chronic inflammatory processes of the gastrointestinal epithelium. The main focus is on molecular, immunological and optical detection of the development, the diagnosis, and treatment of chronic inflammatory and neoplastic diseases of 1) esophagus, 2) stomach, and 3) colon. Ad 1)Esophagus: Reflux induced chronic inflammation is thought to be the main initiating factor for the development of Barrett's esophagus, a precursor lesion for adenocarcinoma of the esophagus. Concerning Barrett's esophagus, the investigations aim at: a) the understanding of the inflammatory inducing factors in reflux esophagitis and Barrett s esophagus; b) the determination of prognostic parameters in Barrett's epithelium, that predict development of malignancy, c) uncovering of optical and molecular techniques for detection of dysplasia in Barrett s, and d) development of minimal invasive treatment strategies for early malignancy. Ad 2) Stomach: endoscopic surveillance of patients with pre-malignant gastric lesions may provide a basis for gastric cancer prevention. current surveillance in routine practice often relies on histological assessment of random biopsies obtained during conventional endoscopy. however, the appropriate biopsy strategy is unclear. Research aims to: a) improve detection of precursor lesions that precede development of early gastric cancer; b) to assess the predictive value of clinical, histological and serological parameters c) to develop guidelines for clinical management of patients at increased risk for gastric cancer Ad 3) Colon: Colon research concerns effective screening, and intervention strategies in sporadic colorectal cancer (CRC), familial and hereditary cancer syndromes. The investigations aim at: a) to develop and compare resection techniques for neoplasms of the colon b) uncovering of optical and molecular techniques for detection of dysplasia in members of familial and hereditary coloncancer families c) to develop strategies for population based screening for colorectal cancer Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot gastroenterology & hepatology 16,68 0 1 8 25,68 Total 16,68 0 1 8 25,68 2 0 0 2 60 5 2 69 Thesis Jeurnink, S.M. (2009, januari 30). Clinical issues in endoscopic interventions for pancreatico-biliary disorders. EUR. Prom./coprom.: Prof.Dr. E.J. Kuipers & Dr. P.D. Siersema. Jonge, P.J.F. de (2009, mei 20). Barrett's esophagus revisited: epidemiology risk stratification and cancer prevention. EUR. Prom./coprom.: Prof.Dr. E.J. Kuipers & Dr. P.D. Siersema. Article/Letter to the editor Aktas, H., Mensink, P.B.F., Haringsma, J. & Kuipers, E.J. (2009). Low incidence of hyperamylasemia after proximal doubleballoon enteroscopy: has the insertion technique improved? Endoscopy, 41(8), 670-673. Amelink, A., Haringsma, J. & Sterenborg, H.J.C.M. (2009). Noninvasive measurement of oxygen saturation of the microvascular blood in Barrett's dysplasia by use of optical spectroscopy. Gastrointestinal Endoscopy, 70(1), 1-6. Baars, J.E., Zelinkova, Z, Mensink, P.B.F., Markus, T, Looman, C.W.N., Kuipers, E.J. & Woude, C.J. van der (2009). High therapy adherence but substantial limitations to daily activities amongst members of the Dutch inflammatory bowel disease patients' organization: a patient empowerment study. Alimentary Pharmacology & Therapeutics, 30(8), 864-872. Baars, J.E., Siegel, CA, Kuipers, E.J. & Woude, C.J. van der (2009). Patient's Perspectives Important for Early Anti-Tumor Necrosis Factor Treatment in Inflammatory Bowel Disease. Digestion. International Journal of Gastroenterology, 79(1), 30-35. Barkun, AN, Kuipers, E.J. & Sung, JJY (2009). It Is Premature to Recommend Low-Dose Intravenous Proton Pump Inhibition After Endoscopic Hemostasis in Patients With Bleeding Ulcers. American Journal of Gastroenterology, 104(8), 2120-2121. Belzer, C., Stoof, J., Breijer, S., Kusters, J.G., Kuipers, E.J. & Vliet, A.H.M. van (2009). The Helicobacter hepaticus hefa Gene is Involved in Resistance to Amoxicillin. Helicobacter, 14(1), 72-79. Bergh, R.C.N. van den, Wolters, T., Spaander, V.M.C.W., Schroder, F.H. & Leenders, G.J.L.H. van (2009). Non-prostatic pathology on prostate needle-biopsy-colorectal carcinoid: a case report. Cases Journal, 2, 75. Besselink, M.G., Santvoort, H.C. van, Boermeester, M.A., Fischer, K., Renooij, W., Smet, MB de, Ali, UA, Cirkel, GA, Bollen, T.L., Ramshorst, B. van, Weusten, BL, Schaapherder, AF, Witteman, B.J., Ploeg, R.J., Goor, H. van, Laarhoven, C.J. van, Tan, AC, Brink, MA, Harst, E. van der, Wahab, P.J., Eijck, C.H.J. van, DeJong, C.H., Erpecum, K.J. van, Akkermans, L.M. & Gooszen, H.G. (2009). Intestinal barrier dysfunction in a randomised placebo-controlled trial of probiotic prophylaxis in acute pancreatitis. European Journal of Gastroenterology & Hepatology, 21(3), A2-A2. Besselink, M.G., Santvoort, H.C. van, Boermeester, M.A., Nieuwenhuijs, V.B., Goor, H. van, Dejong, CHC, Schaapherder, AF & Gooszen, H.G. (2009). Timing and impact of infections in acute pancreatitis. British Journal of Surgery, 96(3), 267-273. Broek, FJ van den, Graaf, E.J. de, Dijkgraaf, MGW, Reitsma, JB, Haringsma, J., Timmer, R., Weusten, BL, Gerhards, MF, Consten, E.C., Schwartz, MP, Boom, MJ, Derksen, EJ, Bijnen, A.B., Davids, P.H., Hoff, C. van t, Dullemen, HM van, Heine,

GDN, Linde, K. v.d., Jansen, J.M., Mallant-Hent, RC, Beumelhof, R, Geldof, H., Hardwick, JC, Doornebosch, P.G., Depla, A.C.T.M., Ernst, M.F., Munster, IP van, Hingh, I.H. de, Schoon, EJ, Bemelman, W.A., Fockens, P. & Dekker, E (2009). Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study). BMC Surgery, 13(9), 4. Bruno, M.J. (2009). Diagnosing and staging bile duct cancer: cholangiographically guided biopsies or cholangioscopy? Endoscopy, 41(11), 991-992. Capelle, L.G., Vries, A.C. de, Haringsma, J., Steyerberg, E.W., Looman, C.W.N., Nagtzaam, N.M.A., Dekken, H. van, Borg, F. ter, Vries, R.A. de & Kuipers, E.J. (2009). Serum Levels of Leptin As Marker For Patients At High Risk of Gastric Cancer. Helicobacter, 14(6), 596-604. Claessen, M.M.H., Lutgens, MWMD, Buuren, H.R. van, Oldenburg, B, Stokkers, P.C.F., Woude, C.J. van der, Hommes, DW, Jong, DJ de, Dijkstra, G., Bodegraven, A.A. van, Siersema, P.D. & Vleggaar, F.P. (2009). More Right-sided IBD-associated Colorectal Cancer in Patients with Primary Sclerosing Cholangitis. Inflammatory Bowel Diseases, 15(9), 1331-1336. Dekker, E, Boparai, KS, Poley, J.W., Mathus-Vliegen, EMH, Offerhaus, G.J.A., Kuipers, E.J., Fockens, P. & Dees, J. (2009). High resolution endoscopy and the additional value of chromoendoscopy in the evaluation of duodenal adenomatosis in patients with familial adenomatous polyposis. Endoscopy, 41(8), 666-669. Demirkiran, A., Sewgobind, V.D.K.D., Weijde, J van der, Kok, A., Baan, C.C., Kwekkeboom, J., Tilanus, H.W., Metselaar, H.J. & Laan, L.J.W. van der (2009). Conversion From Calcineurin Inhibitor to Mycophenolate Mofetil-Based Immunosuppression Changes the Frequency and Phenotype of CD4(+)FOXP3(+) Regulatory T Cells. Transplantation, 87(7), 1062-1068. Dieren, J.M. van, Bodegraven, A.A. van, Kuipers, E.J., Bakker, E.N., Poen, A.C., Dekken, H. van, Nieuwenhuis, E.E.S. & Woude, C.J. van der (2009). Local application of tacrolimus in distal colitis: feasible and safe. Inflammatory Bowel Diseases, 15(2), 193-198. Gaag, N.A. van der, Boermeester, M.A., Cahen, D.L., Busch, O.R.C., Rauws, E.A.J., Gulik, T.M., Bruno, M.J. & Gouma, D.J. (2009). Treatment of chronic pancreatitis. Recent cases. Nederlands Tijdschrift voor Geneeskunde, 153, 232-239. Geenen, EJM van, Peet, D.L. van der, Mulder, C.J.J., Cuesta, M.A. & Bruno, M.J. (2009). Recurrent acute biliary pancreatitis: the protective role of cholecystectomy and endoscopic sphincterotomy. Surgical Endoscopy-Ultrasound and Interventional Techniques, 23(5), 950-956. Groenen, M.J.M., Ajodhia, S., Wynstra, J.Y.F., Lesterhuis, W., Weijgert, EJH Mvan De, Kuipers, E.J. & Ouwendijk, RJT (2009). A cost-benefit analysis of endoscopy reporting methods: handwritten, dictated and computerized. Endoscopy, 41(7), 603-607. Groenen, M.J.M., Kuipers, E.J., Hansen, B.E. & Ouwendijk, RJT (2009). Incidence of duodenal ulcers and gastric ulcers in a Western population: Back to where it started. Canadian Journal of Gastroenterology, 23(9), 604-608. Groeneweg, M., Poley, J.W., Dansen, M.J., Brinkman, J.G., Escher, J.C. & Nieuwenhuis, E.E.S. (2009). Chronic hereditary pancretatitis in a girl with a serine protease inhibitor Kazal type I (SPINK-1) gene mutation an a Coxsackie type B5 infection. Pediatric Infectious Disease Journal, 28(2), 169-170. Harinck, F. & Bruno, M.J. (2009). Endosonography in the management of biliopancreatic orders. Best Practice & Research in Clinical Gastroenterology, 23, 703-710. Hofman, A., Breteler, M.M.B., Duijn, C.M. van, Janssen, H.L.A., Krestin, G.P., Kuipers, E.J., Stricker, B.H.C., Tiemeier, H.W., Uitterlinden, A.G., Vingerling, J.R. & Witteman, J.C.M. (2009). The Rotterdam Study: 2010 objectives and design update. European Journal of Epidemiology, 24, 553-572. Hol, L., Wilschut, J.A., Ballegooijen, M. van, Vuuren, A.J. van, Valk, H. van der, Reijerink, JCIY, Togt, A van der, Kuipers, E.J., Habbema, J.D.F. & Leerdam, M. van (2009). Screening for colorectal cancer: random comparison of guaiac and immunochemical faecal occult blood testing at different cut-off levels. British Journal of Cancer, 100(7), 1103-1110. Hooft, JE van, Uitdehaag, M.J., Bruno, M.J., Timmer, R, Siersema, P.D., Dijkgraaf, MGW & Fockens, P. (2009). Efficacy and safety of the new WallFlex enteral stent in palliative treatment of malignant gastric outlet obstruction (DUOFLEX study): a prospective multicenter study. Gastrointestinal Endoscopy, 69(6), 1059-1066. Hordijk, M.L., Hooft, JE van, Hansen, B.E., Fockens, P. & Kuipers, E.J. (2009). A randomized comparison of electrocautery incision with Savary bougienage for relief of anastomotic gastroesophageal strictures. Gastrointestinal Endoscopy, 70(5), 849-855. Jeurnink, S.M., Repici, A, Luigiano, C, Pagano, N, Kuipers, E.J. & Siersema, P.D. (2009). Use of a colonoscope for distal duodenal stent placement in patients with malignant obstruction. Surgical Endoscopy-Ultrasound and Interventional Techniques, 23(3), 562-567. Kluijt, I., Cats, A., Fockens, P., Nio, Y, Gouma, D.J. & Bruno, M.J. (2009). Atypical Familial Presentation of FAMMM Syndrome With a High Incidence of Pancreatic Cancer Case Finding of Asymptomatic Individuals by EUS Surveillance. Journal of Clinical Gastroenterology, 43(9), 853-857. Kuipers, E.J. (2009). Emerging Diseases of the Gastrointestinal Tract Preface. Best Practice & Research in Clinical Gastroenterology, 23(1), 1-2.

Lansdorp - Vogelaar, I., Ballegooijen, M. van, Zauber, A.G., Habbema, J.D.F. & Kuipers, E.J. (2009). Effect of Rising Chemotherapy Costs on the Cost Savings of Colorectal Cancer Screening. Journal of the National Cancer Institute, 101(20), 1412-1422. Lau, L.M.L. de, Vries, J.M. de, Woude, C.J. van der, Kuipers, E.J., Siepman, D.A.M., Sillevis Smitt, P.A.E. & Hintzen, R.Q. (2009). Acute CNS White Matter Lesions in Patients with Inflammatory Bowel Disease. Inflammatory Bowel Diseases, 15(4), 576-580. Leest, HTJI De, Steen, KS, Bloemena, E., Lems, W.F., Kuipers, E.J., Laar, MAFJV, Bijlsma, J.W.J., Janssen, M., Houben, HHML, Kostense, P.J., Boers, M. & Dijkmans, B.A.C. (2009). Helicobacter pylori Eradication in Patients on Long-term Treatment With NSAIDs Reduces the Severity of Gastritis A Randomized Controlled Trial. Journal of Clinical Gastroenterology, 43(2), 140-146. Lier, M.G.F. van, Wilt, J.H.W. de, Wagemakers, JJMF, Dinjens, W.N.M., Damhuis, RAM, Wagner, A., Kuipers, E.J. & Leerdam, M.E. van (2009). Underutilization of microsatellite instability analysis in colorectal cancer patients at high risk for Lynch syndrome. Scandinavian Journal of Gastroenterology, 44(5), 600-604. Linden, M.W. van der, Gaugris, S, Kuipers, E.J., Bemt, BJF van den, Herk-Sukel, MPP van & Herings, R.M.C. (2009). Gastroprotection among new chronic users of non-steroidal anti-inflammatory drugs: a study of utilization and adherence in the Netherlands. Current Medical Research & Opinion, 25(1), 195-204. Linden, MW van der, Gaugris, S, Kuipers, E.J., Herk-Sukel, MPP van, Bemt, BJF van den, Sen, SS & Herings, R.M.C. (2009). COX-2 inhibitors: complex association with lower risk of hospitalization for gastrointestinal events compared to traditional NSAIDs plus proton pump inhibitors. Pharmacoepidemiology and Drug Safety, 18(10), 880-890. Lutgens, MWMD, Oldenburg, B, Siersema, P.D., Bodegraven, A.A. van, Dijkstra, G., Hommes, DW, Jong, DJ de, Stokkers, P.C.F., Woude, C.J. van der & Vleggaar, F.P. (2009). Colonoscopic surveillance improves survival after colorectal cancer diagnosis in inflammatory bowel disease. British Journal of Cancer, 101(10), 1671-1675. Meerten, E. van, Gaast, A. van der, Tilanus, H.W., Poley, J.W., Muller, K. & Dekken, H. van (2009). Pathological Analysis After Neoadjuvant Chemoradiotherapy for Esophageal Carcinoma: The Rotterdam Experience. Journal of Surgical Oncology, 100(1), 32-37. Mensink, P.B.F., Groenen, M.J., Buuren, H.R. van, Kuipers, E.J. & Woude, C.J. van der (2009). Double-balloon enteroscopy in Crohn's disease patients suspected of small bowel activity: findings and clinical impact. Journal of Gastroenterology, 44(4), 271-276. Mensink, P.B.F., Hol, L., Borghuis-Koertshuis, N, Geelkerken, RH, Huisman, AB, Doelman, CJA, Vuuren, A.J. van, Kuipers, E.J. & Kolkman, J.J. (2009). Transient postprandial ischemia is associated with increased intestinal fatty acid binding protein in patients with chronic gastrointestinal ischemia. European Journal of Gastroenterology & Hepatology, 21(3), 278-282. Mulder, S.A., Ouwendijk, RJT, Giard, RW, Leerdam, M.E. van & Kuipers, E.J. (2009). Risk analyses for screening sigmoidoscopy based on a colorectal cancer (CRC) population. Scandinavian Journal of Gastroenterology, 44(2), 205-210. Noord, D. van, Kuipers, E.J. & Mensink, P.B.F. (2009). Single vessel abdominal arterial disease. Best Practice & Research in Clinical Gastroenterology, 23(1), 49-60. Panteris, V., Haringsma, J. & Kuipers, E.J. (2009). Colonoscopy perforation rate, mechanisms and outcome: from diagnostic to therapeutic colonoscopy. Endoscopy, 41(11), 941-951. Poley, J.W. (2009). Endoscopic ultrasound. Endoscopy, 41(10), 885-889. Poley, J.W., Kluijt, I., Gouma, D.J., Harinck, F., Wagner, A., Aalfs, C.M., Eijck, C.H.J. van, Cats, A., Kuipers, E.J., Nio, YC, Fockens, P. & Bruno, M.J. (2009). The yield of first-time endoscopic ultrasonography in screening individuals at a high-risk of developing pancreatic cancer. American Journal of Gastroenterology, 104, 2175-2181. Polinder, S., Verschuur, E.M.L., Siersema, P.D., Kuipers, E.J. & Steyerberg, E.W. (2009). Cost comparison study of two different follow-up protocols after surgery for oesophageal cancer. European Journal of Cancer, 45(12), 2110-2115. Putten, P.G. van, Leerdam, M.E. van & Kuipers, E.J. (2009). The views of gastroenterologists about the role of nurse endoscopists, especially in colorectal cancer screening. Alimentary Pharmacology & Therapeutics, 29(8), 892-897. Ramsoekh, D., Wagner, A., Leerdam, M.E. van, Dooijes, D., Tops, CMJ, Steyerberg, E.W. & Kuipers, E.J. (2009). Cancer risk in MLH1, MSH2 and MSH6 mutation carriers; different risk profiles may influence clinical management. Hereditary Cancer in Clinical Practice, 7. Ramsoekh, D., Leerdam, M.E. van, Wagner, A., Kuipers, E.J. & Steyerberg, E.W. (2009). Mutation prediction models in Lynch syndrome: evaluation in a clinical genetic setting. Journal of Medical Genetics, 46(11), 745-751. Roth, S, Franken, P., Veelen, W. van, Blonden, L, Raghoebir, L, Beverloo, H.B., Drunen, E. van, Kuipers, E.J., Rottier, R., Fodde, R. & Smits, R. (2009). Generation of a Tightly Regulated Doxycycline-Inducible Model for Studying Mouse Intestinal Biology. Genesis, 47(1), 7-13. Santvoort, H.C. van, Besselink, M.G., Vries, A.C. de, Boermeester, M.A., Fischer, K., Bollen, T.L., Cirkel, GA, Schaapherder, AF, Nieuwenhuijs, V.B., Goor, H. van, DeJong, C.H., Eijck, C.H. van, Witteman, B.J., Weusten, BL, Laarhoven, C.J. van, Wahab, P.J., Tan, AC, Schwartz, MP, Harst, E. van der, Cuesta, M.A., Siersema, P.D., Gooszen, H.G. & Erpecum, K.J. van

(2009). Early Endoscopic Retrograde Cholangiopancreatography in Predicted Severe Acute Biliary Pancreatitis A Prospective Multicenter Study. Annals of Surgery, 250(1), 68-75. Sewgobind, V.D.K.D., Kho, M.M.L., Laan, L.J.W. van der, Hendrikx, T.K., Dam, T. van, Tilanus, H.W., Ijzermans, J.N.M., Weimar, W. & Baan, C.C. (2009). The effect of rabbit anti-thymocyte globulin induction therapy on regulatory T cells in kidney transplant patients. Nephrology Dialysis Transplantation, 24(5), 1635-1644. Sikkema, M., Kerkhof, M., Steyerberg, E.W., Kusters, J.G., Strien, P.M.H. van, Looman, C.W.N., Dekken, H. van, Siersema, P.D. & Kuipers, E.J. (2009). Aneuploidy and Overexpression of Ki67 and p53 as Markers for Neoplastic Progression in Barrett's Esophagus: A Case-Control Study. American Journal of Gastroenterology, 104(11), 2673-2680. Sprenger, RA, Arends, JW, Poley, J.W., Kuipers, E.J. & Borg, F. ter (2009). Eosinophilic oesophagitis: an enigmatic, emerging disease. Netherlands Journal of Medicine, 67(1), 8-12. Sung, JJY, Barkun, A, Kuipers, E.J., Mossner, J, Jensen, DM, Stuart, R, Lau, JY, Ahlbom, H, Kilhamn, J & Lind, T (2009). Intravenous Esomeprazole for Prevention of Recurrent Peptic Ulcer Bleeding A Randomized Trial. Annals of Internal Medicine, 150(7), 455-+. Sung, JJY, Kuipers, E.J. & El-Serag, HB (2009). Systematic review: the global incidence and prevalence of peptic ulcer disease. Alimentary Pharmacology & Therapeutics, 29(9), 938-946. Uiterwaal, MT, Overbosch, EH, Bruno, M.J. & Hulst, R.W.M. van der (2009). Spontaneous Drainage of a Pancreatic Pseudocyst After Embolization of a Bleeding Pseudoaneurysm. Cardiovascular & Interventional Radiology, 32(1), 192-194. Verschuur, E.M.L., Steyerberg, E.W., Tilanus, H.W., Polinder, S., Essink-Bot, M.L., Tran, KTC, Gaast, A. van der, Stassen, L.P.S., Kuipers, E.J. & Siersema, P.D. (2009). Nurse-led follow-up of patients after oesophageal or gastric cardia cancer surgery: a randomised trial. British Journal of Cancer, 100(1), 70-76. Vliet, E.P.M. van, Steyerberg, E.W., Otten, H.J.A.M., Rudolphus, A, Knoester, P.D., Hoogsteden, H.C., Gelder, T. van, Kuipers, E.J. & Siersema, P.D. (2009). The effects of guideline implementation for proton pump inhibitor prescription on two pulmonary medicine wards. Alimentary Pharmacology & Therapeutics, 29(2), 213-221. Vogelaar, L., Spijker, A. van t & Woude, C.J. van der (2009). The impact of biologics on health related quality of life in patients with inflammatory bowel disease. Clinical and Experimental Gastroenterology, 2, 101-109. Vries, A.C. de, Kuipers, E.J. & Rauws, E.A.J. (2009). Helicobacter pylori eradication and gastric cancer: when is the horse out of the barn? American Journal of Gastroenterology, 104, 1342-1345. Vries, A.C. de, Capelle, L.G., Looman, C.W.N., Blankenstein, M. van, Grieken, N.C.T. van, Casparie, M.K., Meijer, G.A. & Kuipers, E.J. (2009). Increased risk of esophageal squamous cell carcinoma in patients with gastric atrophy: Independent of the severity of atrophic changes. International Journal of Cancer, 124(9), 2135-2138. Vries, A.C. de, Haringsma, J., Vries, R.A. de, Borg, F. ter, Nagtzaam, NM, Steyerberg, E.W., Dekken, H. van & Kuipers, E.J. (2009). The use of clinical, histologic, and serologic parameters to predict the intragastric extent of intestinal metaplasia: a recommendation for routine practice. Gastrointestinal Endoscopy, 70(1), 18-25. Weersma, RK, Stokkers, P.C.F., Bodegraven, A.A. van, Hogezand, R.A. van, Verspaget, H.W., Jong, DJ de, Woude, C.J. van der, Oldenburg, B, Linskens, RK, Festen, EAM, Steege, G van der, Hommes, DW, Crusius, JBA, Wijmenga, C., Nolte, I.M. & Dijkstra, G. (2009). Molecular prediction of disease risk and severity in a large Dutch Crohn's disease cohort. Gut, 58(3), 388-395. Wiarda, BM, Horsthuis, K, Dobben, AC, Geenen, R.W.F., Heitbrink, MA, Moolenaar, W, Kuipers, E.J. & Stoker, J. (2009). Magnetic resonance imaging of the small bowel with the true FISP sequence: intra- and interobserver agreement of enteroclysis and imaging without contrast material. Clinical Imaging, 33(4), 267-273. Zelinkova, Z, Boer, IP De, Dijke, MJ Van, Kuipers, E.J. & Woude, C.J. van der (2009). Azathioprine treatment during lactation. Alimentary Pharmacology & Therapeutics, 30(1), 90-91. Part of book - abstract Cahen, D.L. & Bruno, M.J. (2009). Endoscopic therapy for chronic pancreatitis. In K. Monkemuller, CM Wilcox & M Munoz- Navas (Eds.), International Therapeutic Endoscopy (pp. 459-476). Basel: Karger Publishing. Kooten, C. van, Stax, AM, Klaveren-Woltman, A.M. van & Gelderman, KA (2009). The use of dexamethasone in the induction of tolerogenic dendritic cells. In Dendritic Cells Handb Exp Pharmacol (pp. 233-249). Berlin: Springer Verlag.

EMC MM-04-20-02-A - Liverspecific immunopathology; mechanism and therapeutic modulation Programme design in brief The mission of the research program is to unravel the mechanisms underlying inadequate immunological reactions which lead to liver damage, and the development of effective diagnosis and treatment of these disorders. On the one hand, an insufficient immune response to hepatitis viruses causes persistence of the viruses leading to chronic hepatitis and hepatocellular carcinoma, on the other hand over-reactivity of the host immune system to antigens presented in the liver is the primary cause of hepatobiliary auto-immune diseases and of rejection after liver transplantation. The program is performed by integrated preclinical and clinical research. The pre-clinical research is focused on intra-hepatic immunological reactions between Antigen- Presenting Cells and T-cells in the liver of patients. The clinical research is focused on medicinal modulation of these interactions by cytokines, anti-viral-, and immunosuppressive drugs. Cohorts of patients with chronic hepatitis B, chronic hepatitis C, primary biliary cirrosis, primary sclerosing cholangitis and vascular liver disease are the basis from which investigator-initiated randomised controlled trials are organised. Numerous global multicenter studies on antiviral therapy in chronic viral hepatitis have been coordinated by the liver group. The effects of these treatments on the intrahepatic immune reactivity are studied by sophisticated methods developed in the laboratory, such as the fine needle liver aspiration biopsy Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot gastroenterology & hepatology 13,4 0,86 0 12,51 26,77 Total 13,4 0,86 0 12,51 26,77 3 0 0 3 32 4 14 53 Thesis Buster, E.H.C.J. (2009, oktober 23). Immune modifying treatment in chronic HBV infection. EUR (218 pag.). Prom./coprom.: Prof.Dr. H.L.A. Janssen. Tha-In, T.H. (2009, november 21). Intravenous immunoglobulins after liver transplantation. EUR. Prom./coprom.: Prof.Dr. H.J. Metselaar & Dr. J. Kwekkeboom. Veldhuijzen, I.K. (2009, september 04). Epidemiology of hepatitis B among immigrants in the Netherlands. EUR (175 pag.). Prom./coprom.: Prof.Dr. H.L.A. Janssen. Article/Letter to the editor Boonstra, P.A., Laan, L.J.W. van der, Vanwolleghem, T. & Janssen, H.L.A. (2009). Experimental Models for Hepatitis C Viral Infection. Hepatology, 50(5), 1646-1655. Brouw, M.L. op den, Binda, R.S., Roosmalen, M.H. van, Protzer, U, Janssen, H.L.A., Molen, R.G. van der & Woltman, A.M. (2009). Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus. Immunology, 126(2), 280-289. Brouw, M.L. op den, Binda, R.S., Geijtenbeek, T.B.H., Janssen, H.L.A. & Woltman, A.M. (2009). The mannose receptor acts as hepatitis B virus surface antigen receptor mediating interaction with intrahepatic dendritic cells. Virology, 393(1), 84-90. Buster, E.H.C.J., Flink, H.J., Simsek, H, Heathcote, E.J., Sharmila, S, Kitis, GE, Gerken, G., Buti, M, Vries, R.A. de, Verhey, E, Hansen, B.E. & Janssen, H.L.A. (2009). Early HBeAg Loss During Peginterferon alpha-2b Therapy Predicts HBsAg Loss: Results of a Long-Term Follow-Up Study in Chronic Hepatitis B Patients. American Journal of Gastroenterology, 104(10), 2449-2457. Buster, E.H.C.J., Hansen, B.E., Lau, GKK, Piratvisuth, T, Zeuzem, S., Steyerberg, E.W. & Janssen, H.L.A. (2009). Factors That Predict Response of Patients With Hepatitis B e Antigen-Positive Chronic Hepatitis B to Peginterferon-Alfa. Gastroenterology, 137(6), 2002-2009. Claessen, M.M.H., Vleggaar, F.P., Tytgat, K.M.A.J., Siersema, P.D. & Buuren, H.R. van (2009). High lifetime risk of cancer in primary sclerosing cholangitis. Journal of Hepatology, 50(1), 158-164. Claessen, M.M.H., Lutgens, MWMD, Buuren, H.R. van, Oldenburg, B, Stokkers, P.C.F., Woude, C.J. van der, Hommes, DW, Jong, DJ de, Dijkstra, G., Bodegraven, A.A. van, Siersema, P.D. & Vleggaar, F.P. (2009). More Right-sided IBD-associated Colorectal Cancer in Patients with Primary Sclerosing Cholangitis. Inflammatory Bowel Diseases, 15(9), 1331-1336. Daha, TJ, Bilkert-Mooiman, M.A.J., Ballemans, C, Frijstein, G, Keeman, JN, Man, R.A. de, Steenbergen, J.E. van, Weers- Pothoff, G & Zaaijer, H.L (2009). Hepatitis B virus infected health care workers in the Netherlands, 2000-2008. European Journal of Clinical Microbiology & Infectious Diseases, 28(9), 1041-1044. Darwish Murad, S., Plessier, A, Hernandez-Guerra, M, Fabris, F., Eapen, CE, Bahr, MJ, Trebicka, J, Morard, I, Lasser, L, Heller, J, Hadengue, A., Langlet, P, Miranda, H, Primignani, M., Elias, E., Leebeek, F.W., Rosendaal, F.R., Garcia-Pagan, JC, Valla, DC & Janssen, H.L.A. (2009). Etiology, Management, and Outcome of the Budd-Chiari Syndrome. Annals of Internal Medicine, 151(3), 167-W40. Dietvorst, MHP, Wijngaarden, P. van & Man, R.A. de (2009). Autoimmune haemolytic anaemia due to chronic hepatitis C virus infection treated with prednisone, pegylated interferon and ribavirin. Netherlands Journal of Medicine, 67(3), 109-110. Dols, L.F.C., Verhoef, C., Eskens, F.A.L.M., Schouten, O., Nonner, J., Hop, W.C.J., Mendez Romero, A.M., Man, R.A. de, Linden, E. van der, Dwarkasing, R.S. & Ijzermans, J.N.M. (2009). Improvement of 5 year survival rate after liver resection for colorectal metastases between 1984-2006. Nederlands Tijdschrift voor Geneeskunde, 153, 490-495.

Hoekstra, J., Leebeek, F.W.G., Plessier, A, Raffa, S, Darwish Murad, S., Heller, J, Hadengue, A., Chagneau, C, Elias, E., Primignani, M., Garcia-Pagan, J-C., Valla, DC & Janssen, H.L.A. (2009). Paroxysmal Nocturnal Hemoglobinuria in Budd-Chiari Syndrome: Findings from a Cohort Study. Journal of Hepatology, 51, 696-706. Hofman, A., Breteler, M.M.B., Duijn, C.M. van, Janssen, H.L.A., Krestin, G.P., Kuipers, E.J., Stricker, B.H.C., Tiemeier, H.W., Uitterlinden, A.G., Vingerling, J.R. & Witteman, J.C.M. (2009). The Rotterdam Study: 2010 objectives and design update. European Journal of Epidemiology, 24, 553-572. Houdt, R van, Koedijk, FDH, Bruisten, S.M., Coul, ELMO de, Heijnen, M.L.A., Waldhober, Q, Veldhuijzen, I.K., Richardus, J.H., Schutten, M., Doornum, G.J.J. van, Man, R.A. de, Hahne, SJ, Coutinho, R.A. & Boot, HJ (2009). Hepatitis B vaccination targeted at behavioural risk groups in the Netherlands: Does it work? Vaccine, 27(27), 3530-3535. Janssen, H.L.A. & Buster, E.H.C.J. (2009). Comments on the EASL practice guidelines for the management of chronic hepatitis B: Controversies in interferon-based therapy. Journal of Hepatology, 51(1), 224-226. Janssen, H.L.A. & Reijnders, J.G.P. (2009). Treatment with nucleos(t)ide analogues in chronic hepatitis B: Where does the road map lead us? Journal of Hepatology, 51(1), 1-3. Keimpema, L van, Nevens, F., Vanslembrouck, R, Oijen, MGH van, Hoffmann, A.L., Dekker, H.M., Man, R.A. de & Drenth, J.P.H. (2009). Lanreotide reduces the volume of polycystic liver: A randomized, double-blind, placebo-controlled trial. Gastroenterology, 137(5), 1661-1668. Kuiper, E.M.M., Hansen, B.E., Vries, R.A. de, Ouden-Muller, J.W. den, Ditzhuijsen, TJM van, Haagsma, E.B., Houben, M.H.M.G., Witteman, BJM, Erpecum, K.J. van & Buuren, H.R. van (2009). Improved Prognosis of Patients With Primary Biliary Cirrhosis That Have a Biochemical Response to Ursodeoxycholic Acid. Gastroenterology, 136(4), 1281-1287. Kuiper, E.M.M., Ouden-Muller, J.W. den & Buuren, H.R. van (2009). Primary biliary cirrhosis. Nederlands Tijdschrift voor Geneeskunde, 153, 483. Liu, BS, Woltman, A.M., Janssen, H.L.A. & Boonstra, P.A. (2009). Modulation of dendritic cell function by persistent viruses. Journal of Leukocyte Biology, 85(2), 205-214. Meer, A.J.P. van der & Knegt, R.J. de (2009). Telaprevir for Chronic HCV Infection. New England Journal of Medicine, 361(5), 533-534. Mensink, P.B.F., Groenen, M.J., Buuren, H.R. van, Kuipers, E.J. & Woude, C.J. van der (2009). Double-balloon enteroscopy in Crohn's disease patients suspected of small bowel activity: findings and clinical impact. Journal of Gastroenterology, 44(4), 271-276. Moons, LGM, Wolfhagen, F.H.J., Beukers, R., Man, R.A. de, Leenders, G.J.L.H. van & Buuren, H.R. van (2009). A Rare Cause of Large Liver Cysts. American Journal of Gastroenterology, 104(4), 1056-1058. Pan, Q., Henry, S.D., Metselaar, H.J., Scholte, B., Kwekkeboom, J., Tilanus, H.W., Janssen, H.L.A. & Laan, L.J.W. van der (2009). Combined antiviral activity of interferon-alpha and RNA interference directed against hepatitis C without affecting vector delivery and gene silencing. Journal of Molecular Medicine-Jmm, 87(7), 713-722. Pan, Q., Tilanus, H.W., Janssen, H. & Laan, L.J.W. van der (2009). Prospects of RNAi and microrna-based therapies for hepatitis C. Expert Opinion on Biological Therapy, 9(6), 713-724. Reijnders, J.G.P., Pas, S.D., Schutten, M., Man, R.A. de & Janssen, H.L.A. (2009). Entecavir shows limited efficacy in HBeAgpositive hepatitis B patients with a partial virologic response to adefovir therapy. Journal of Hepatology, 50(4), 674-683. Reijnders, J.G.P. & Janssen, H.L.A. (2009). New approaches in the management of chronic hepatitis B; role of tenofovir. Infection and drug resistance, 2, 13-26. Reijnders, J.G.P., Leemans, W.F., Hansen, B.E., Pas, S.D., Man, R.A. de, Schutten, M. & Janssen, H.L.A. (2009). On-treatment monitoring of adefovir therapy in chronic hepatitis B: virologic response can be assessed at 24 weeks. Journal of Viral Hepatitis, 16(2), 113-120. Roon, A.H.C. van, Borg, P.C.J. ter, Zondervan, P.E., Stoop, H. & Man, R.A. de (2009). A patient with an alpha-foetoprotein producing tumour. Nederlands Tijdschrift voor Geneeskunde, 153, 364. Slavenburg, S, Lamers, MH, Roomer, R., Knegt, R.J. de, Oijen, MGH van & Drenth, J.P.H. (2009). Current clinical care compared with new Dutch guidelines for hepatitis C treatment. Netherlands Journal of Medicine, 67(5), 177-181. Sluis, F.J. van der, Bosch, J.L., Terkivatan, T., Man, R.A. de, Ijzermans, J.N.M. & Hunink, M.G.M. (2009). Hepatocellular adenoma: cost-effectiveness of different treatment strategies. Radiology, 252(3), 737-746. Swinkels, D.W., Jorna, A.T.M., Bokhoven, M.A. van, Castel, A, Deursen, C.T.B.M. van, Giltay, J.C., Man, R.A. de, Marx, J.J.M., Vries, R.A. de, Macfarlane, J.D., Krieken, J.H.J.M. van, Sterke, P. de, Pijl, M.E.J. & Raymakers, R.A.P. (2009). Samenvatting van de richtlijn Diagnostiek en behandeling van hereditaire hemochromatose. Nederlands Tijdschrift voor Hematologie, 6, 143-149. Toy, M., Veldhuijzen, I.K., Man, R.A. de, Richardus, J.H. & Schalm, S.W. (2009). Potential Impact of Long-Term Nucleoside Therapy on the Mortality and Morbidity of Active Chronic Hepatitis B. Hepatology, 50(3), 743-751.

Veldhuijzen, I.K., Mes, T.H.M., Mostert, M.C., Niesters, H.G.M., Pas, S.D., Voermans, J., Man, R.A. de, Gotz, H.M., Doornum, G.J.J. van & Richardus, J.H. (2009). An Improved Approach to Identify Epidemiological and Phylogenetic Transmission Pairs of Source and Contact Tracing of Hepatitis B. Journal of Medical Virology, 81(3), 425-434. Veldhuijzen, I.K., Driel, HF Van, Vos, D., Zwart, O. de, Doornum, G.J.J. van, Man, R.A. de & Richardus, J.H. (2009). Viral hepatitis in a multi-ethnic neighborhood in the Netherlands: results of a community-based study in a low prevalence country. International Journal of Infectious Diseases, 13(1), 9-13. Veldt, B.J., Poterucha, J.J., Watt, KDS, Wiesner, R.H., Hay, JE, Rosen, CB, Heimbach, JK, Janssen, H.L.A. & Charlton, MR (2009). Insulin Resistance, Serum Adipokines and Risk of Fibrosis Progression in Patients Transplanted for Hepatitis C. American Journal of Transplantation, 9(6), 1406-1413. Woltman, A.M., Borg, M.J. ter, Binda, R.S., Sprengers, D., Blomberg, B.M.E. von, Scheper, R.J., Hayashi, K, Nishi, N, Boonstra, P.A., Molen, R.G. van der & Janssen, H.L.A. (2009). alpha-galactosylceramide in chronic hepatitis B infection: results from a randomized placebo-controlled Phase I/II trial. Antiviral Therapy, 14(6), 809-818. Part of book - abstract Beuers, U, Rauws, E.A.J., Borg, P.C.J. ter, Buuren, H.R. van & Koek, G (2009). Cholestatische leverziekten. In HLA Janssen, JPH Drenth & B van Hoek (Eds.), Leverziekten (pp. 100-107). Houten: Bohn Stafleu van Loghum. Buuren, H.R. van (2009). PBC. In Cursus klinische hepatology (pp. 27-31). Haarlem: --. Buuren, H.R. van, Coenraad, MJ & Scherptong, RWS (2009). Portale hypertensie. In HLA Janssen, JPH Drenth & B van Hoek (Eds.), Leverziekten (pp. 48-63). Houten: Bohn Stafleu van Loghum. Buuren, H.R. van (2009). Preventie en behandeling van varicesbloedingen. In Cursus klinische hepatologie (pp. 51-54). Haarlem: --. Hoekstra, J. & Janssen, H.L.A. (2009). Vasculaire Leverziekten. In HLA Janssen, JPH Drenth & B van Hoek (Eds.), Leverziekten (pp. 194-200). Houten: Bohn Stafleu van Loghum. Man, R.A. de (2009). Preventie en behandeling van ascites en spontaan bacteriële peritonitis. In Cursus klinische hepatologie (pp. 55-58). haarlem: --. Metselaar, H.J. & Hoek, B. van (2009). Leverfalen. In HLA Janssen, JPH Drenth & B van Hoek (Eds.), Leverziekten. Houten: Bohn Stafleu van Loghum. Reijnders, J.G.P. & Janssen, H.L.A. (2009). Virale hepatitis. In HLA Janssen, JPH Drenth & B van Hoek (Eds.), Leverziekten (pp. 83-99). houten: Bohn Stafleu van Loghum. Rijckborst, V. & Janssen, H.L.A. (2009). Hepatitis B, present standard of care. In Cursus klinische hepatologie (pp. 93-100). Haarlem: --. Roomer, R. & Knegt, R.J. de (2009). Hepatitis C present standard of care. In Cursus klinische hepatologie (pp. 85-92). Haarlem: --. Schouten, J.N.L. & Janssen, H.L.A. (2009). Onderzoeksmethoden in de hepatologie. In HLA Janssen, JPH Drenth & B van Hoek (Eds.), Leverziekten. Houten: Bohn Stafleu van Loghem. Terkivatan, T., Verhoef, C., Ijzermans, J.N.M. & Man, R.A. de (2009). Levertumoren. In HLA Janssen, JPH Drenth & B van Hoek (Eds.), Leverziekten (pp. 160-171). Houten: Bohn Stafleu van Loghum. Book editorship Janssen, H.L.A., Drenth, J.P.H. & Hoek, B. van (Eds.). (2009). Leverziekten. Houten: Bohn Stafleu van Loghum.

EMC MM-04-27-01 - Human virus infections: immunity, therapy and epidemiology Programme design in brief The role of virus specific immune responses in the (immune) pathogenesis of, and protection against virus infections is studied in humans and in animal models for human virus infections. Special attention is paid to infections with morbilli-, lenti-, herpes-, influenza- and hepatitis viruses. The role of virus specific antibodies in neutralization and/or enhancement of virus infectivity and the kinetics of the emergence of these antibodies, is subject of study in different systems. Similarly, also the evaluation of the role of virus specific T helper- and cytotoxic T cells is carried out. The knowledge generated in this way is used to design novel strategies of intervention in viral spreading and pathogenesis, like e.g. vaccination, diagnosis and post-exposure treatment. In this framework novel antiviral therapeutic strategies, based on immunological and non-immunological principles, are also developed. Finally, epidemilogical research questions, related to infections with the aforemeentioned viruses and "exotic" viruses, are adressed. Besides the continuation of the above mentioned activities, studies concerning the epidemiology and epizootiology of influenza viruses of man and animals will be extended in the next year, with a special emphasis on possibly emerging influenza pandemics. Research concerning the possible development of an HIV vaccine based on the use of Rev and Tat will be intensified. This will also be the case for research concerning the immunopathogenesis of chronic infections with HBV, HCV, EBV, CMV and HIV, with special attention for problems with multiple infections and infections in immunocompromised and transplantation patients. Finally, a focus will be on virus infections if wild and threatened animal species as well as exotic and zoonotic virus infections. Morbillivirus, lentivirus, herpesvirus, hepatitis virus, pathogenesis, immunopathogenesis, neutralizing antibody, enhancement, cytotoxic T cell, T cell phenotype, antiviral, epidemiology, zoonosis Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 0,75 0 0 0 0,75 pharmacy 0,5 0 0 0 0,5 virology 15,62 20,33 1 3,74 40,69 Total 16,87 20,33 1 3,74 41,94 4 0 0 4 62 4 0 70 Thesis Duan, R. (2009, juni 30). Herpetic Keratitis in Humans: Interaction between virus and host. EUR. Prom./coprom.: Prof.Dr. A.D.M.E. Osterhaus. Geurts van Kessel, C.H. (2009, juni 05). Division of Labor between dendritic cell subsets. EUR. Prom./coprom.: Prof.Dr. A.D.M.E. Osterhaus & Prof.Dr. B.N.M. Lambrecht. Graaf, M. de (2009, januari 15). Metapneumovirus: determinants of host range and replication. EUR. Prom./coprom.: Prof.dr. R.A.M. Fouchier & Prof.Dr. A.D.M.E. Osterhaus. Kreijtz, J.H.C.M. (2009, september 03). Protection against influenza A(H5N1) induced by influenza A(H3N2) infection and MVAbased vaccines. EUR. Prom./coprom.: Prof.Dr. A.D.M.E. Osterhaus & Prof.Dr. T. Kuiken. Article/Letter to the editor Artois, M, Bicout, D, Doctrinal, D, Fouchier, R., Gavier-Widen, D, Globig, A, Hagemeijer, W, Mundkur, T, Munster, V. & Olsen, B. (2009). Outbreaks of highly pathogenic avian influenza in Europe: the risks associated with wild birds. Revue Scientifique et Technique de l'office International des Epizooties, 28(1), 69-92. Asten, L van, Lubben, M van der, Wijngaard, C van den, Pelt, W. van, Verheij, R.A., Jacobi, A, Overduin, P, Meijer, A., Luijt, D, Claas, E, Hermans, M, Melchers, W, Rossen, J, Schuurman, R., Wolffs, P, Bouchier, C, Schirm, J., Kroes, L, Leenders, S, Galama, J, Peeters, M., Loon, A van, Stobberingh, E, Schutten, M. & Koopmans, DVMM (2009). Strengthening the diagnostic capacity to detect Bio Safety Level 3 organisms in unusual respiratory viral outbreaks. Journal of Clinical Virology, 45(3), 185-190. Beersma, M.F.C., Schutten, M., Vennema, H., Hartwig, N.G., Mes, T.H.M., Osterhaus, A.D.M.E., Doornum, G.J.J. van & Koopmans, M.P.G. (2009). Norovirus in a Dutch tertiary care hospital (2002-2007): frequent nosocomial transmission and dominance of GIIb strains in young children. Journal of Hospital Infection, 71, 199-205. Bennett, DE, Camacho, RJ, Otelea, D, Kuritzkes, DR, Fleury, H, Kiuchi, M, Heneine, W, Kantor, R, Jordan, MR, Schapiro, JM, Vandamme, AM, Sandstrom, P, Boucher, C.A.B., Vijver, D. van de, Rhee, SY, Liu, TF, Pilay, D & Shafer, RW (2009). Drug Resistance Mutations for Surveillance of Transmitted HIV-1 Drug-Resistance: 2009 Update. PLoS One, 4(3). Beukelaar, J.W. de, Milikan, J.C., Verjans, G.M., Graaf, M.T. de, Norden, Y. van, Lamers, C.H., Bent, M.J. van den, Bromberg, J.E., Hulsenboom, E., Sintnicolaas, K., Gratama, J.W. & Smitt, P.A.S. (2009). No evidence for the presence of HuD-specific T cells in the cerebrospinal fluid of patients with Huassociated paraneoplastic neurological syndromes. Journal of Neurology, 256(2), 279-282. Bierman, WFW, Agtmael, M.A. van, Nijhuis, M, Danner, S.A. & Boucher, C.A.B. (2009). HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. Aids, 23(3), 279-291. Bij, A van der, Betjes, M., Weening, J.J., Cornelissen, J., Mes, T., Osterhaus, A. & Beersma, M. (2009). BK virus nephropathy in an immunodeficient patient with chronic lymphocytic leukemia. Journal of Clinical Virology, 45(4), 341-344.

Bodewes, R., Geelhoed-Mieras, M.M., Heldens, JGM, Glover, J, Lambrecht, B.N., Fouchier, R.A.M., Osterhaus, A.D.M.E. & Rimmelzwaan, G.F. (2009). The novel adjuvant CoVaccineHT (TM) increases the immunogenicity of cell-culture derived influenza A/H5N1 vaccine and induces the maturation of murine and human dendritic cells in vitro. Vaccine, 27(49), 6833-6839. Bodewes, R., Kreijtz, J.H.C.M., Baas, C., Geelhoed-Mieras, M.M., Mutsert, G. de, Amerongen, G. van, Brand, J.M.A. van den, Fouchier, R.A.M., Osterhaus, A.D.M.E. & Rimmelzwaan, G.F. (2009). Vaccination against Human Influenza A/H3N2 Virus Prevents the Induction of Heterosubtypic Immunity against Lethal Infection with Avian Influenza A/H5N1 Virus. PLoS One, 4(5). Bodewes, R., Kreijtz, J.H.C.M. & Rimmelzwaan, G.F. (2009). Yearly influenza vaccinations: a double-edged sword? Lancet Infectious Diseases, 9(12), 784-788. Carotenuto, P., Artsen, A.A., Niesters, H.G., Osterhaus, A.D. & Pontesilli, O. (2009). In Vitro Use of Autologous Dendritic Cells Improves Detection of T Cell Responses to Hepatitis B Virus (HBV) Antigens. Journal of Medical Virology, 81(2), 332-339. Daoust, P.Y., McBurney, SR, Godson, DL, Bildt, M.W.G. van de & Osterhaus, A.D.M.E. (2009). Canine distemper virusassociated encephalitis in free-living lynx (lynx canadensis) and bobcats (lynx rufus) of eastern Canada. Journal of Wildlife Diseases, 45(3), 611-624. Dekker, L.J.M., Kampen, J.J.A. van, Reedijk, M.L., Burgers, P.C., Gruters, R.A., Osterhaus, A.D.M.E. & Luider, T.M. (2009). A mass spectrometry based imaging method developed for the intracellular detection of HIV protease inhibitors. Rapid Communications in Mass Spectrometry, 23(8), 1183-1188. Duan, R., Vries, R.D. de, Dun, J.M. van, Loenen, F.B. van, Osterhaus, A.D.M.E., Remeijer, L. & Verjans, G.M.G.M. (2009). Acyclovir Susceptibility and Genetic Characteristics of Sequential Herpes Simplex Virus Type 1 Corneal Isolates from Patients with Recurrent Herpetic Keratitis. Journal of Infectuous Diseases, 200(9), 1402-1414. Fouchier, R.A.M. & Munster, V.J. (2009). Epidemiology of low pathogenic avian influenza viruses in wild birds. Revue Scientifique et Technique de l'office International des Epizooties, 28(1), 49-58. Garten, RJ, Davis, CT, Russell, C.A., Shu, B, Lindstrom, S, Balish, A, Sessions, WM, Xu, XY, Skepner, E, Deyde, V, Okomo- Adhiambo, M, Gubareva, L, Barnes, J, Smith, CB, Emery, SL, Hillman, MJ, Rivailler, P, Smagala, J, Graaf, M. de, Burke, DF, Fouchier, R.A.M., Pappas, C, Alpuche-Aranda, CM, Lopez-Gatell, H, Olivera, H, Lopez, I, Myers, CA, Faix, D, Blair, PJ, Yu, C, Keene, KM, Dotson, PD, Boxrud, D, Sambol, AR, Abid, SH, George, KS, Bannerman, T, Moore, A.L., Stringer, DJ, Blevins, P, Demmler-Harrison, GJ, Ginsberg, M, Kriner, P, Waterman, S, Smole, S, Guevara, HF, Belongia, EA, Clark, PA, Beatrice, ST, Donis, R, Katz, J, Finelli, L, Bridges, CB, Shaw, M, Jernigan, DB, Uyeki, TM, Smith, D.J., Klimov, AI & Cox, NJ (2009). Antigenic and Genetic Characteristics of Swine-Origin 2009 A(H1N1) Influenza Viruses Circulating in Humans. Science, 325(5937), 197-201. Gelinck, L.B.S., Bemt, BJF van den, Marijt, WAF, Bijl, AE van der, Visser, L.G., Cats, H.A., Rimmelzwaan, G.F. & Kroon, F.P. (2009). Intradermal influenza vaccination in immunocompromized patients is immunogenic and feasible. Vaccine, 27(18), 2469-2474. Geurts van Kessel, C.H., Bergen, I.M., Muskens, A.M., Boon, L., Hoogsteden, H.C., Osterhaus, A.D.M.E., Rimmelzwaan, G.F. & Lambrecht, B.N. (2009). Both Conventional and Interferon Killer Dendritic Cells Have Antigen-Presenting Capacity during Influenza Virus Infection. PLoS One, 4(9). Geurts van Kessel, C.H., Willart, M.A.M., Bergen, I.M., Rijt, L.S. van, Muskens, A.M., Elewaut, D, Osterhaus, A.D.M.E., Hendriks, R., Rimmelzwaan, G.F. & Lambrecht, B.N. (2009). Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. Journal of Experimental Medicine, 206(11), 2339-2349. Goede, A.L. de, Boers, P.H.M., Dekker, L.J.M., Osterhaus, A.D.M.E., Gruters, R.A. & Rimmelzwaan, G.F. (2009). Characterization of recombinant influenza A virus as a vector for HIV-1 p17(gag). Vaccine, 27(42), 5735-5739. Graaf, M. de, Schrauwen, E.J.A., Herfst, S., Amerongen, G. van, Osterhaus, A.D.M.E. & Fouchier, R.A.M. (2009). Fusion protein is the main determinant of metapneumovirus host tropism. Journal of General Virology, 90, 1408-1416. Haagmans, B.L., Andeweg, A.C. & Osterhaus, A.D.M.E. (2009). The Application of Genomics to Emerging Zoonotic Viral Diseases. PLoS Pathogens, 5(10). Huisman, W., Martina, B.E.E., Rimmelzwaan, G.F., Gruters, R.A. & Osterhaus, A.D.M.E. (2009). Vaccine-induced enhancement of viral infections. Vaccine, 27(4), 505-512. Klepac, P, Pomeroy, LW, Bjornstad, ON, Kuiken, T., Osterhaus, A.D.M.E. & Rijks, J.M. (2009). Stage-structured transmission of phocine distemper virus in the Dutch 2002 outbreak. Proceedings of the Royal Society of London Series B-Biological Sciences, 276(1666), 2469-2476. Koopmans, M., Meijer, A, Lubben, M van der, Boucher, C.A.B., Fouchier, R.A.M., Osterhaus, A.D.M.E., Timen, A, Jong, M.D. de & Steenbergen, J.E. van (2009). Overview of the relevant virological aspects. Nederlands Tijdschrift voor Geneeskunde, 153, 770. Koraka, P., Williams, M.M., Djamiatun, K., Setiati, T.E., Batenburg, FHD van, Stittelaar, K.J., Osterhaus, A.D.M.E. & Martina, B.E.E. (2009). RNA secondary structures in the proximal 3 ' UTR of Indonesian Dengue 1 virus strains. Virus Research, 142(1-2), 213-216.

Kousiappa, I, Vijver, D.A.M.C. van de, Demetriades, I & Kostrikis, LG (2009). Genetic Analysis of HIV Type 1 Strains from Newly Infected Untreated Patients in Cyprus: High Genetic Diversity and Low Prevalence of Drug Resistance. Aids Research & Human Retroviruses, 25(1), 23-35. Kousiappa, I, Vijver, D.A.M.C. van de & Kostrikis, LG (2009). Near Full-Length Genetic Analysis of HIV Sequences Derived from Cyprus: Evidence of a Highly Polyphyletic and Evolving Infection. Aids Research & Human Retroviruses, 25(8), 727-740. Kreijtz, J.H.C.M., Bodewes, R., Brand, J.M.A. van den, Mutsert, G. de, Baas, C., Amerongen, G. van, Fouchier, R.A.M., Osterhaus, A.D.M.E. & Rimmelzwaan, G.F. (2009). Infection of mice with a human influenza A/H3N2 virus induces protective immunity against lethal infection with influenza A/H5N1 virus. Vaccine, 27(36), 4983-4989. Kreijtz, J.H.C.M., Suezer, Y, Mutsert, G. de, Brand, J.M.A. van den, Amerongen, G. van, Schnierle, BS, Kuiken, T., Fouchier, R.A.M., Lower, J, Osterhaus, A.D.M.E., Sutter, G. & Rimmelzwaan, G.F. (2009). Preclinical evaluation of a modified vaccinia virus Ankara (MVA)-based vaccine against influenza A/H5N1 viruses. Vaccine, 27(45), 6296-6299. Kreijtz, J.H.C.M., Suezer, Y, Mutsert, G. de, Brand, J.M.A. van den, Amerongen, G. van, Schnierle, BS, Kuiken, T., Fouchier, R.A.M., Lower, J, Osterhaus, A.D.M.E., Sutter, G. & Rimmelzwaan, G.F. (2009). Recombinant Modified Vaccinia Virus Ankara Expressing the Hemagglutinin Gene Confers Protection against Homologous and Heterologous H5N1 Influenza Virus Infections in Macaques. Journal of Infectuous Diseases, 199(3), 405-413. Kreijtz, J.H.C.M., Osterhaus, A.D.M.E. & Rimmelzwaan, G.F. (2009). Vaccination strategies and vaccine formulations for epidemic and pandemic influenza control. Human Vaccines, 5(3), 126-135. Lang, A. de, Baas, T, Smits, S.L., Katze, MG, Osterhaus, A.D.M.E. & Haagmans, B.L. (2009). Unraveling the complexities of the interferon response during SARS-CoV infection. Future Virology, 4(1), 71-78. Latorre-Margalef, N, Gunnarsson, G, Munster, V.J., Fouchier, R.A.M., Osterhaus, A.D.M.E., Elmberg, J, Olsen, B., Wallensten, A, Haemig, PD, Fransson, T, Brudin, L & Waldenstrom, J (2009). Effects of influenza A virus infection on migrating mallard ducks. Proceedings of the Royal Society of London Series B-Biological Sciences, 276(1659), 1029-1036. Loizidou, EZ, Kousiappa, I, Zeinalipour-Yazdi, CD, Vijver, D.A.M.C. van de & Kostrikis, LG (2009). Implications of HIV-1 M Group Polymorphisms on Integrase Inhibitor Efficacy and Resistance: Genetic and Structural in Silico Analyses. Biochemistry, 48(1), 4-6. Martina, B.E.E., Koraka, P. & Osterhaus, A.D.M.E. (2009). Dengue Virus Pathogenesis: an Integrated View. Clinical Microbiology Reviews, 22(4), 564-+. Meijer, A., Beerens, A, Claas, E, Hermans, M, Jong, A. de, Molenkamp, R, Niesters, H., Overduin, P, Rossen, J, Schuurman, R., Wolffs, P, Fouchier, R., Osterhaus, A., Schutten, M. & Koopmans, M. (2009). Preparing the outbreak assistance laboratory network in the Netherlands for the detection of the influenza virus A(H1N1) variant. Journal of Clinical Virology, 45(3), 179-184. Milikan, J.C.M., Baarsma, G.S., Kuijpers, R.W.A.M., Osterhaus, A.D.M.E. & Verjans, G.M.G.M. (2009). Human Ocular-Derived Virus-Specific CD4(+) T Cells Control Varicella Zoster Virus Replication in Human Retinal Pigment Epithelial Cells. Investigative Ophthalmology & Visual Science, 50(2), 743-751. Munster, V.J. & Fouchier, R.A.M. (2009). Avian influenza virus: Of virus and bird ecology. Vaccine, 27(45), 6340-6344. Munster, V.J., Wit, E. de, Brand, J.M.A. van den, Herfst, S., Schrauwen, E.J.A., Bestebroer, T.M., Vijver, D. van de, Boucher, C.A., Koopmans, M., Rimmelzwaan, G.F., Kuiken, T., Osterhaus, A.D.M.E. & Fouchier, R.A.M. (2009). Pathogenesis and Transmission of Swine-Origin 2009 A(H1N1) Influenza Virus in Ferrets. Science, 325(5939), 481-483. Munster, V.J., Baas, C., Lexmond, P., Bestebroer, T.M., Guldemeester, J., Beyer, W.E.P., Wit, E. de, Schutten, M., Rimmelzwaan, G.F., Osterhaus, A.D.M.E. & Fouchier, R.A.M. (2009). Practical Considerations for High-Throughput Influenza A Virus Surveillance Studies of Wild Birds by Use of Molecular Diagnostic Tests. Journal of Clinical Microbiology, 47(3), 666-673. Nauta, JJP, Beyer, W.E.P. & Osterhaus, A.D.M.E. (2009). On the relationship between mean antibody level, seroprotection and clinical protection from influenza. Biologicals, 37(4), 216-221. Nijhuis, M, Wensing, AMJ, Bierman, WFW, Jong, D. de, Kagan, R, Fun, A, Jaspers, CAJJ, Schurink, KAM, Agtmael, M.A. van & Boucher, C.A.B. (2009). Failure of Treatment with First-Line Lopinavir Boosted with Ritonavir Can Be Explained by Novel Resistance Pathways with Protease Mutation 76V. Journal of Infectuous Diseases, 200(5), 698-709. Opstelten, W., Rimmelzwaan, G.F., Essen, G.A. van & Bijlsma, J.W.J. (2009). Influenzavaccinatie van patienten met verminderde afweer. Nederlands Tijdschrift voor Geneeskunde, 153, 902. Osterhaus, A.D.M.E. & Vanlangendonck, C (2009). Stakeholder dialogue, broadening of support and use of communication: An integrated and integral part of influenza preparedness. Vaccine, 27(45), 6390-6391. Pagter, APJ de, Haveman, LM, Schuurman, R., Schutten, M., Bierings, M. & Boelens, J.J. (2009). Adenovirus DNA Positivity in Nasopharyngeal Aspirate Preceding Hematopoietic Stem Cell Transplantation: A Very Strong Risk Factor for Adenovirus DNAemia in Pediatric Patients. Clinical Infectious Diseases, 49(10), 1536-1539. Paraskevis, D, Pybus, O, Magiorkinis, G, Hatzakis, A, Wensing, AMJ, Vijver, DAV de, Albert, J, Angarano, G, Asjo, B, Balotta, C, Boeri, E, Camacho, R, Chaix, ML, Coughlan, S, Costagliola, D, Luca, A, Mendoza, C de, Derdelinckx, I, Grossman, Z, Hamouda, O, Hoepelman, I.M., Horban, A, Korn, K, Kucherer, C, Leitner, T, Loveday, C, MacRae, E, Maljkovic-Berry, I, Meyer, L, Nielsen, C, Coul, ELMO de, Ormaasen, V, Perrin, L, Puchhammer-Stockl, E, Ruiz, L, Salminen, MO, Schmit, JC, Schuurman,

R., Soriano, V, Stanczak, J, Stanojevic, M, Struck, D, Laethem, K Van, Violin, M, Yerly, S, Zazzi, M, Boucher, C.A. & Vandamme, AM (2009). Tracing the HIV-1 subtype B mobility in Europe: a phylogeographic approach. Retrovirology, 6. Philippa, J.D.W., Bildt, M.W.G. van de, Hart, P. & Osterhaus, A.D.M.E. (2009). Neurological signs in juvenile harbour seals (Phoca vitulina) with fatal phocine distemper. Veterinary Record, 164(11), 327-331. Rappuoli, R, Giudice, G Del, Nabel, GJ, Osterhaus, A.D.M.E., Robinson, R, Salisbury, D, Stohr, K. & Treanor, J.J. (2009). Rethinking Influenza. Science, 326(5949), 50-50. Reijnders, J.G.P., Pas, S.D., Schutten, M., Man, R.A. de & Janssen, H.L.A. (2009). Entecavir shows limited efficacy in HBeAgpositive hepatitis B patients with a partial virologic response to adefovir therapy. Journal of Hepatology, 50(4), 674-683. Remeijer, L., Duan, R., Dun, J.M. van, Bettink, MAW, Osterhaus, A.D.M.E. & Verjans, G.M.G.M. (2009). Prevalence and Clinical Consequences of Herpes Simplex Virus Type 1 DNA in Human Cornea Tissues. Journal of Infectuous Diseases, 200(1), 11-19. Riel, D. van, Brand, J.M.A. van den, Munster, V.J., Besteboer, TM, Fouchier, R.A.M., Osterhaus, A.D.M.E. & Kuiken, T. (2009). Pathology and Virus Distribution in Chickens Naturally Infected with Highly Pathogenic Avian Influenza A Virus (H7N7) During the 2003 Outbreak in The Netherlands. Veterinary Pathology, 46(5), 971-976. Rimmelzwaan, G.F. & Sutter, G. (2009). Candidate influenza vaccines based on recombinant modified vaccinia virus Ankara. Expert Review of Vaccines, 8(4), 447-454. Rimmelzwaan, G.F., Kreijtz, J.H.C.M., Bodewes, R., Fouchier, R.A.M. & Osterhaus, A.D.M.E. (2009). Influenza virus CTL epitopes, remarkably conserved and remarkably variable. Vaccine, 27(45), 6363-6365. Rockx, B, Baas, T, Zornetzer, GA, Haagmans, B., Sheahan, T, Frieman, M, Dyer, MD, Teal, TH, Proll, S., Brand, J.M.A. van den, Baric, R & Katze, MG (2009). Early Upregulation of Acute Respiratory Distress Syndrome-Associated Cytokines Promotes Lethal Disease in an Aged-Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Infection (vol 83, pg 7062, 2009). Journal of Virology, 83(17), 9022-9022. Rygiel, TP, Rijkers, ESK, Ruiter, T. de, Stolte, EH, Valk, M. van der, Rimmelzwaan, G.F., Boon, L., Loon, A.M. van, Coenjaerts, FE, Hoek, RM van, Tesselaar, K & Meyaard, L (2009). Lack of CD200 Enhances Pathological T Cell Responses during Influenza Infection. Journal of Immunology, 183(3), 1990-1996. Scharpe, J, Peetermans, W.E., Vanwalleghem, J, Maes, B, Bammens, B, Claes, K, Osterhaus, A.D., Vanrenterghem, Y. & Evenepoel, P (2009). Immunogenicity of a Standard Trivalent Influenza Vaccine in Patients on Long-term Hemodialysis: An Open-Label Trial. American Journal of Kidney Diseases, 54(1), 77-85. Sloot, PMA, Coveney, PV, Ertaylan, G, Muller, V, Boucher, C.A. & Bubak, M (2009). HIV decision support: from molecule to man. Philosophical Transactions of the Royal Society A-Mathematical Physical and Engineering Sciences, 367(1898), 2691-2703. Swart, R.L. de, Yuksel, S., Langerijs, C.N., Muller, C.P. & Osterhaus, A.D.M.E. (2009). Depletion of measles virus glycoprotelnspecific antibodies from human sera reveals genotype-specific neutralizing antibodies. Journal of General Virology, 90, 2982-2989. Swart, R.L. de (2009). Measles studies in the macaque model. Current Topics in Microbiology and Immunology, 330, 55-72. Thiel, PPAM van, Bie, RMA de, Eftimov, F., Tepaske, R., Zaaijer, H.L, Doornum, G.J.J. van, Schutten, M., Osterhaus, A.D.M.E., Majoie, C.B.L.M., Aronica, E, Fehlner-Gardiner, C, Wandeler, AI & Kager, P.A. (2009). Fatal Human Rabies due to Duvenhage Virus from a Bat in Kenya: Failure of Treatment with Coma-Induction, Ketamine, and Antiviral Drugs. PLoS Neglected Tropical Diseases, 3(7). Timen, A, Koopmans, M.P.G., Vossen, A.C.T.M., Doornum, G.J.J. van, Gunther, S, Berkmortel, F van den, Verduin, KM, Dittrich, S, Emmerich, P, Osterhaus, A.D.M.E., Dissel, J.T. van & Coutinho, R.A. (2009). Response to Imported Case of Marburg Hemorrhagic Fever, the Netherlands. Emerging Infectious Diseases, 15(8), 1171-1175. Velzen, M. van, Laman, J.D., Kleinjan, A., Poot, A.M., Osterhaus, A.D.M.E. & Verjans, G.M.G.M. (2009). Neuron-Interacting Satellite Glial Cells in Human Trigeminal Ganglia Have an APC Phenotype. Journal of Immunology, 183(4), 2456-2461. Vercauteren, J., Wensing, AMJ, Vijver, D.A.M.C. van de, Albert, J, Balotta, C, Hamouda, O, Kucherer, C, Struck, D, Schmit, JC, Asjo, B, Bruckova, M, Camacho, RJ, Clotet, B., Coughlan, S, Grossman, Z, Horban, A, Korn, K, Kostrikis, L, Nielsen, C, Paraskevis, D, Poljak, M, Puchhammer-Stockl, E, Riva, C, Ruiz, L, Salminen, M, Schuurman, R., Sonnerborg, A, Stanekova, D, Stanojevic, M, Vandamme, AM & Boucher, C.A.B. (2009). 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EMC MM-04-28-01 - Infections due to bacteria, fungi and parasites: diagnosis, molecular mechanisms, epidemiology, therapy and prevention Programme design in brief The project is focused on the infectious complications caused by bacteria, fungi and parasites related to recent developments in clinical medicine, such as new therapeutic modalities or resistance, an increased use of medical devices, frequent diagnostic and therapeutic intervention, and an increasing number of immunocompromised patients. As a consequence, a growing number of patients are prone to severe (nosocomial) infections that are often difficult to treat. These infections are a major cause of morbidity and mortality in these patients, which is partially enforced by failure of antibiotic treatment despite the availability of potent antibiotics. The focus of this programme is on the molecular mechanism of infection, the epidemiology, the early diagnosis using molecular techniques, the preven tion of infections, as well as treatment using alternative methods. The approach is partly fundamental/animal-experimental and partly clinical/epidemiological. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot clinical microbiology 7,24 2,3 0 0,84 10,38 Total 7,24 2,3 0 0,84 10,38 3 2 0 5 43 1 9 58 Thesis Kerremans, J.J. (2009, december 09). Rapid bacterial diagnostics and their effect on patient treatment and outcome. EUR (136 pag.). Prom./coprom.: Prof.Dr. H.A. Verbrugh & dr. M.C. Vos. Kooistra-Smid, AMD (2009, januari 29). Molecular epidemiology of Stapylococcus aureus nasal carriage and wound colonization in a burn centre. EUR (167 pag.). Prom./coprom.: Prof.Dr. H.A. Verbrugh & M.K. Nieuwenhuis. Lestari, ES (2009, december 15). Antimicrobial resistance in Indonesia, prevalence, determinants and genetic basis. EUR (310 pag.). Prom./coprom.: Prof.Dr. H.A. Verbrugh, K Kuntaman, Dr. W.H.F. Goessens & M. Keuter. Mollema, F.P.N. (2009, november 18). Clinical epidemiological studies on methicillin resistant and susceptible staphylococci. EUR (136 pag.). Prom./coprom.: Prof.Dr. H.A. Verbrugh, dr. M.C. Vos & Dr. J.L. Nouwen. Severin, J.A. (2009, december 15). Antimicrobial resistance in Indonesia, prevalence, determinants and genetic basis.. EUR (310 pag.). Prom./coprom.: Prof.Dr. H.A. Verbrugh, K Kuntaman, Dr. W.H.F. Goessens & M. Keuter. Article/Letter to the editor Acton, DS, Plat-Sinnige, MJT, Wamel, W van, Groot, N. de & Belkum, A. van (2009). Intestinal carriage of Staphylococcus aureus: how does its frequency compare with that of nasal carriage and what is its clinical impact? European Journal of Clinical Microbiology & Infectious Diseases, 28(2), 115-127. Ammerlaan, H.S.M., Kluytmans, J.A.J.W., Wertheim, H.F.L., Nouwen, J.L. & Bonten, M.J.M. (2009). Eradication of Methicillin- Resistant Staphylococcus aureus Carriage: A Systematic Review. Clinical Infectious Diseases, 48(7), 922-930. Bakker, M.A. den, Goemaere, N.N.T., Severin, J.A., Nouwen, J.L. & Verhagen, P.C.M.S. (2009). Histoplasma-associated inflammatory pseudotumour of the kidney mimicking renal carcinoma. Virchows Archiv. An International Journal of Pathology, 454(2), 229-232. Belkum, A. van (2009). A new year, new challenges, a renewed journal? European Journal of Clinical Microbiology & Infectious Diseases, 28(2), 113-113. Belkum, A. van, Jacobs, B.C., Beek, E. van, Louwen, R., Rijs, W. van, Debruyne, L, Gilbert, M., Li, J., Jansz, A, Megraud, F & Endtz, H.P. (2009). Can Campylobacter coli induce Guillain-Barre syndrome? European Journal of Clinical Microbiology & Infectious Diseases, 28(5), 557-560. Belkum, A. van, Melles, D.C., Nouwen, J.L., Leeuwen, W.B. van, Wamel, W van, Vos, M., Wertheim, H.F.L. & Verbrugh, H.A. (2009). Co-evolutionary aspects of human colonisation and infection by Staphylococcus aureus. Infection, Genetics and Evolution, 9(1), 32-47. Belkum, A. van, Verkaik, N.J., Vogel, C.P. de, Boelens, H.A., Verveer, J, Nouwen, J.L., Verbrugh, H.A. & Wertheim, H.F.L. (2009). Reclassification of Staphylococcus aureus Nasal Carriage Types. Journal of Infectuous Diseases, 199(12), 1820-1826. Bij, A van der, Betjes, M., Weening, J.J., Cornelissen, J., Mes, T., Osterhaus, A. & Beersma, M. (2009). BK virus nephropathy in an immunodeficient patient with chronic lymphocytic leukemia. Journal of Clinical Virology, 45(4), 341-344. Bruins, M, Bos, A., Petit, P.L.C., Eadie, K., Rog, A, Bos, R. van den, Ramshorst, G.H. van & Belkum, A. van (2009). Deviceindependent, real-time identification of bacterial pathogens with a metal oxide-based olfactory sensor. European Journal of Clinical Microbiology & Infectious Diseases, 28(7), 775-780. Buijtels, P.C.A.M., Sande, MAB van der, Graaff, CS de, Parkinson, S, Verbrugh, H.A., Petit, P.L.C. & Soollingen, D van (2009). Nontuberculous; Mycobacteria, Zambia. Emerging Infectious Diseases, 15(2), 242-249. Chai, LYA, Netea, MG, Vonk, A.G. & Kullberg, B.J. (2009). Fungal strategies for overcoming host innate immune response. Medical Mycology, 47(3), 227-236.

Chai, LYA, Kullberg, B.J., Vonk, A.G., Warris, A., Cambi, A, Latge, JP, Joosten, LAB, Meer, J.W.M. van der & Netea, MG (2009). Modulation of Toll-Like Receptor 2 (TLR2) and TLR4 Responses by Aspergillus fumigatus. Infection & Immunity, 77(5), 2184-2192. Elzakker, E van, Yahiaoui, R, Visser, C, Oostvogel, P, Muller, A., Ho, YR, Wu, JJ & Belkum, A. van (2009). Epidemiology of and prenatal molecular distinction between invasive and colonizing group B streptococci in The Netherlands and Taiwan. European Journal of Clinical Microbiology & Infectious Diseases, 28(8), 921-928. Erasmus, V., Brouwer, W., Beeck, E.F. van, Oenema, A., Daha, TJ, Richardus, J.H., Vos, M.C. & Brug, J. (2009). A Qualitative Exploration of Reasons for Poor Hand Hygiene Among Hospital Workers: Lack of Positive Role Models and of Convincing Evidence That Hand Hygiene Prevents Cross-Infection. Infection Control & Hospital Epidemiology, 30(5), 415-419. Fanoy, E, Helmhout, LC, Vaart, WL van der, Weijdema, K, Santen-Verheuvel, M.G. van, Thijsen, S.F.T., Neeling, A.J. de, Wamel, W.J.B. van, Manaskova, S. & Kingma-Thijssen, JL (2009). An outbreak of non-typeable MRSA within a residential care facility. Eurosurveillance weekly, 14, 1-5. Habib, I, Louwen, R., Uyttendaele, M, Houf, K, Vandenberg, O, Miller, WG, Belkum, A. van, Zutter, L De & Nieuwenhuis, EES (2009). Correlation between Genotypic Diversity, Lipooligosaccharide Gene Locus Class Variation, and Caco-2 Cell Invasion Potential of Campylobacter jejuni Isolates from Chicken Meat and Humans: Contribution to Virulotyping. Applied Environmental Microbiology, 75(13), 4277-4288. Haringhuizen, G & Vos, M.C.P.J. de (2009). De verantwoordelijkheid voor contactonderzoek rondom een patiënt met tuberculose in het ziekenhuis. Infectieziekten-Bulletin, 3, 92-94. Hays, J.P. (2009). Moraxella catarrhalis: A mini review. Journal of Pediatric Infectious Diseases, 4, 211-220. Hays, J.P. (2009). The evaluation of putative endogenous control housekeeping genes for real-time polymerase chain reaction expression studies in Moraxella catarrhalis. Diagnostic Microbiology & Infectious Disease, 65(3), 323-326. Holtfreter, S, Thi, THN, Wertheim, H.F.L., Steil, L, Kusch, H, Quoc, PT, Engelmann, S, Hecker, M, Volker, U, Belkum, A. van & Broker, BM (2009). Human Immune Proteome in Experimental Colonization with Staphylococcus aureus. Clinical and Vaccine Immunology, 16(11), 1607-1614. Islam, Z., Belkum, A. van, Wagenaar, J.A., Cody, AJ, Boer, A.G. de, Tabor, H, Jacobs, B.C., Talukder, KA & Endtz, H.P. (2009). Comparative Genotyping of Campylobacter jejuni Strains from Patients with Guillain-Barre Syndrome in Bangladesh. PLoS One, 4(9). Islam, Z., Belkum, A. van, Cody, AJ, Tabor, H, Jacobs, B.C., Talukder, KA & Endtz, H.P. (2009). Pigs as Source for Toxigenic Corynebactedum ulcerans. Emerging Infectious Diseases, 15(8), 1316-1317. Kerremans, J.J., Bij, A.K. van der, Goessens, W.H.F., Verbrugh, H.A. & Vos, M. (2009). Immediate Incubation of Blood Cultures Outside Routine Laboratory Hours of Operation Accelerates Antibiotic Switching. Journal of Clinical Microbiology, 47(11), 3520-3523. Kerremans, J.J., Bij, A.K. van der, Goessens, W.H.F., Verbrugh, H.A. & Vos, M. (2009). Needle-to-Incubator Transport Time: Logistic Factors Influencing Transport Time for Blood Culture Specimens. Journal of Clinical Microbiology, 47(3), 819-822. Khan, M.A., Lemmens, N., Riera, E, Blonk, T, Goedhart, J, Belkum, A. van, Goessens, W.H.F., Hays, J.P. & Westreenen, M. van (2009). Dominance of CTX-M-2 and CTX-M-56 among extended-spectrum beta-lactamases produced by Klebsiella pneumoniae and Escherichia coli isolated in hospitals in Paraguay. Journal of Antimicrobial Chemotherapy, 64(6), 1330-1332. Komen, N.A.P., Morsink, MC, Beiboer, S, Miggelbrink, A, Willemsen, P, Harst, E. van der, Lange, J.F. & Leeuwen, W.B. van (2009). Detection of colon flora in peritoneal drain fluid after colorectal surgery: Can RT-PCR play a role in diagnosing anastomotic leakage? Journal of Microbiological Methods, 79(1), 67-70. Kooistra-Smid, M., Nieuwenhuis, M.K., Belkum, A. van & Verbrugh, H.A. (2009). The role of nasal carriage in Staphylococcus aureus burn wound colonization. Fems Immunology & Medical Microbiology, 57(1), 1-13. Lebon, A., Labout, J.A.M., Verbrugh, H.A., Jaddoe, V.W.V.K., Hofman, A., Wamel, W.J.B. van, Belkum, A. van & Moll, H.A. (2009). Role of Staphylococcus aureus nasal colonization in atopic dermatitis in infants. Archives of Pediatrics & Adolescent Medicine, 163(8), 745-749. Melles, D.C., Schouls, L, Francois, P, Herzig, S, Verbrugh, H.A., Belkum, A. van & Schrenzel, J (2009). High-throughput typing of Staphylococcus aureus by amplified fragment length polymorphism (AFLP) or multi-locus variable number of tandem repeat analysis (MLVA) reveals consistent strain relatedness. European Journal of Clinical Microbiology & Infectious Diseases, 28(1), 39-45. Mohamed, R., Hanafiah, A, Rose, IM, Manaf, MRA, Abdullah, SA, Sagap, I, Belkum, A. van & Yaacob, JA (2009). Helicobacter pylori caga gene variants in Malaysians of different ethnicity. European Journal of Clinical Microbiology & Infectious Diseases, 28(7), 865-869. Mortensen, NP, Kuijf, M.L., Ang, C.W., Schiellerup, P, Krogfelt, KA, Jacobs, B.C., Belkum, A. van, Endtz, H.P. & Bergman, M.P. (2009). Sialylation of Campylobacter jejuni lipo-oligosaccharides is associated with severe gastro-enteritis and reactive arthritis. Microbes and Infection, 11(12), 988-994.

Nahar, S, Kibria, KMK, Hossain, ME, Sultana, J, Sarker, SA, Engstrand, L, Bardhan, PK, Rahman, M & Endtz, H.P. (2009). Evidence of intra-familial transmission of Helicobacter pylori by PCR-based RAPD fingerprinting in Bangladesh. European Journal of Clinical Microbiology & Infectious Diseases, 28(7), 767-773. Neela, V, Zafrul, AM, Mariana, NS, Belkum, A. van, Liew, YK & Rad, EG (2009). Prevalence of ST9 Methicillin-Resistant Staphylococcus aureus among Pigs and Pig Handlers in Malaysia. Journal of Clinical Microbiology, 47(12), 4138-4140. Neela, V, Ehsanollah, GR, Zamberi, S, Belkum, A. van & Mariana, NS (2009). Prevalence of ST9 methicillin-resistant Staphylococcus aureus among pigs and pig handlers in Malaysia. International Journal of Infectious Diseases, 13, 131-132. Plat-Sinnige, MJT, Verkaik, N.J., Wamel, W.J.B. van, Groot, N. de, Acton, DS & Belkum, A. van (2009). Induction of Staphylococcus aureus-specific IgA and agglutination potency in milk of cows by mucosal immunization. Vaccine, 27(30), 4001-4009. Rours, G.I.J.G., Hammerschlag, M., Doornum, G.J.J. van, Hop, W.C.J., Groot, R. de, Willemse-Erix, H.F.M., Verbrugh, H.A. & Verkooijen, R.P.A.J. (2009). Chlamydia trachomatis respiratory infection in Dutch infants. Archives of Disease in Childhood, 94, 705-707. Sande, W.W.J. van de, Mathot, R.A.A., Kate, M.T. ten, Vianen, W. van, Tavakol, M., Rijnders, B.J.A. & Bakker-Woudenberg, I.A.J.M. (2009). Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin. Antimicrobial Agents & Chemotherapy, 53(5), 2005-2013. Scholtes-Timmerman, M, Willemse-Erix, H, Schut, TB, Belkum, A. van, Puppels, G.J. & Maquelin, K. (2009). A novel approach to correct variations in Raman spectra due to photo-bleachable cellular components. Analyst, 134(2), 387-393. Steenwinkel, J.E.M. de, Knegt, G.J. de, Kate, M.T. ten, Belkum, A. van, Verbrugh, H.A., Hernandez-Pando, R., Soolingen, D. van & Bakker-Woudenberg, I.A.J.M. (2009). Immunological parameters to define infection progression and therapy response in a well-defined tuberculosis model in mice. International Journal of Immunopathology and Pharmacology, 22(3), 723-734. VasanthaKumari, N, Alshrari, ASD, Rad, EG, Moghaddam, HG, Belkum, A. van, Alreshidi, MA, Selamat, N & Shamsudin, MN (2009). Highly dynamic transient colonization by Staphylococcus aureus in healthy Malaysian students. Journal of Medical Microbiology, 58(11), 1531-1532. Verkaik, N.J., Vogel, C.P. de, Boelens, H.A.M., Grumann, D., Hoogenboezem, T., Vink, C., Hooijkaas, H., Foster, T.J., Verbrugh, H.A., Belkum, A. van & Wamel, W.J.B. van (2009). Anti-staphylococcal humoral immune response in persistent nasal carriers and noncarriers of Staphylococcus aureus. Journal of Infectuous Diseases, 199, 625-632. Vos, M., Behrendt, M.D., Melles, D.C., Mollema, F.P.N., Groot, W. de, Parlevliet, G, Ott, A., Horst-Kreft, D., Belkum, A. van & Verbrugh, H.A. (2009). 5 Years of Experience Implementing a Methicillin-Resistant Staphylococcus aureus Search and Destroy Policy at the Largest University Medical Center in the Netherlands. Infection Control & Hospital Epidemiology, 30(10), 977-984. Vries, SPW de, Bootsma, H, Hays, J.P. & Hermans, PWM (2009). Molecular Aspects of Moraxella catarrhalis Pathogenesis. Microbiology and Molecular Biology Reviews, 73(3), 389-406. Willemse-Erix, DFM, Scholtes-Timmerman, MJ, Jachtenberg, J.W., Leeuwen, W.B. van, Horst-Kreft, D., Bakker Schut, T.C., Deurenberg, RH, Puppels, G.J., Belkum, A. van, Vos, M. & Maquelin, K. (2009). Optical Fingerprinting in Bacterial Epidemiology: Raman Spectroscopy as a Real-Time Typing Method. Journal of Clinical Microbiology, 47(3), 652-659. Witt, R. te, Kanhai, V & Leeuwen, W.B. van (2009). Comparison of the DiversiLab (TM) system, Pulsed-Field Gel Electrophoresis and Multi-Locus Sequence Typing for the characterization of epidemic reference MRSA strains. Journal of Microbiological Methods, 77(1), 130-133. Part of book - abstract Belkum, A. van, Pelt-Verkuil, E. van & Hays, J.P. (2009). The application of randomly amplified DNA analysis in the molecular epidemiology of microorganisms. In DA Caugant (Ed.), Molecular Epidemiology of Microorganisms (pp. 37-47). Heidelberg: Humana Press. Leeuwen, W.B. van (2009). Molecular diagnostics in clinical microbiology. In WB van Leeuwen & C Vink (Eds.), Molecular Diagnostics. Rotterdam: IVA group. Pelt-Verkuil, E. van & Leeuwen, W.B. van (2009). Ensuring PCR quality - laboratory organization, PCR optimization and controls. In WB van Leeuwen & C Vink (Eds.), Molecular Diagnostics. Rotterdam: IVA group. Pelt-Verkuil, E. van & Leeuwen, W.B. van (2009). Ensuring PCR quality, quality criteria and quality assurance. In WB van Leeuwen & C Vink (Eds.), Molecular Diagnostics. Rotterdam: IVA group. Verbrugh, H.A. (2009). Colonization with Staphylococcus aureus and the role of colonization in causing infection. In K.B. Crossley, K.K. Jefferson, G.L. Archer & V.G. Fowler (Eds.), Staphylococci in human disease. England: Wiley Blackwell. Book editorship Belkum, A. van, Boekhout, T., Driel, J.W. van, Duim, B., Kampert, E, Maquelin, K., Rottier, P.J.M. & Schellekens, H. (Eds.). (2009). Veilig werken met micro-organismen, parasieten en cellen in laboratoria en andere werkruimten. Delft: Nederlandse Vereniging voor Microbiologie. Vink, C. (Ed.). (2009). Molecular diagnostics. Rotterdam: IVA Groep.

Book review Belkum, A. van (2009). Book review [Bespreking van het boek Real Time PCR]. J Microbiol Meth, 77, 330.

EMC MM-04-28-04 - Clinical research in infectious diseases in adults Programme design in brief The programme focuses on problems of diagnosis, prevention and therapy of infections in immunocompromised adult patients including HIV, and co-infections such as hepatitis B. Inpatients are mainly studied in the department of haematology and in the intensive care setting. Catheter-related infections, infections in neutropenic patients and HIV-infected patients are topics of specific interest. The programme explores the value of novel tools like vibrational spectroscopy in the diagnosis of infections by bacteria and fungi. In these infections that are often difficult-to-treat, new management strategies of antimicrobial drugs or inflammation modulators are expected to result in a better outcome. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot clinical microbiology 0,75 0 0 0 0,75 internal medicine 0,8 0 0 0 0,8 virology 0,35 0 0 0 0,35 Total 1,9 0 0 0 1,9 0 0 0 0 20 1 2 23 Article/Letter to the editor Ammerlaan, H.S.M., Kluytmans, J.A.J.W., Wertheim, H.F.L., Nouwen, J.L. & Bonten, M.J.M. (2009). Eradication of Methicillin- Resistant Staphylococcus aureus Carriage: A Systematic Review. Clinical Infectious Diseases, 48(7), 922-930. Arends, J.E., Stuart, JC, Baak, LC, Ende, M.E. van der, Erpecum, K.J. van, Simons, C.P.M., Boland, G.J., Baarle, D. van & Hoepelman, A.I.M. (2009). Plasma HCV-RNA decline in the first 48 h identifies hepatitis C virus mono-infected but not HCV/HIVcoinfected patients with an undetectable HCV viral load at week 4 of peginterferon-alfa-2a/ribavirin therapy. Journal of Viral Hepatitis, 16(12), 867-875. Bakker, M.A. den, Goemaere, N.N.T., Severin, J.A., Nouwen, J.L. & Verhagen, P.C.M.S. (2009). Histoplasma-associated inflammatory pseudotumour of the kidney mimicking renal carcinoma. Virchows Archiv. An International Journal of Pathology, 454(2), 229-232. Belkum, A. van, Melles, D.C., Nouwen, J.L., Leeuwen, W.B. van, Wamel, W van, Vos, M., Wertheim, H.F.L. & Verbrugh, H.A. (2009). Co-evolutionary aspects of human colonisation and infection by Staphylococcus aureus. Infection, Genetics and Evolution, 9(1), 32-47. Belkum, A. van, Verkaik, N.J., Vogel, C.P. de, Boelens, H.A., Verveer, J, Nouwen, J.L., Verbrugh, H.A. & Wertheim, H.F.L. (2009). Reclassification of Staphylococcus aureus Nasal Carriage Types. Journal of Infectuous Diseases, 199(12), 1820-1826. Gelinck, LB & Ende, M.E. van der (2009). Early versus Deferred Antiretroviral Therapy for HIV. New England Journal of Medicine, 361(8), 823-823. Katlama, C., Haubrich, R., Lalezari, J, Lazzarin, A., Madruga, JV, Molina, JM, Schechter, M, Peeters, M., Picchio, G, Vingerhoets, J, Woodfall, B & Smedt, G De (2009). Efficacy and safety of etravirine in treatment-experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials. Aids, 23(17), 2289-2300. Kesselring, AM, Wit, FW, Sabin, C.A., Lundgren, J.D., Gill, MJ, Gatell, JM, Rauch, A, Montaner, JS, Wolf, F. de, Reiss, P. & Mocroft, A. (2009). Risk factors for treatment-limiting toxicities in patients starting nevirapine-containing antiretroviral therapy. Aids, 23(13), 1689-1699. Lug, J van der, Colbers, A, Molto, J, Hawkins, D, Ende, M. van der, Vogel, M., Wyen, C, Schutz, M, Koopmans, P, Ruxrungtham, K, Richter, C. & Burger, D (2009). The pharmacokinetics, safety and efficacy of boosted saquinavir tablets in HIV type-1-infected pregnant women. Antiviral Therapy, 14(3), 443-450. Luin, M van, Gras, L., Richter, C., Ende, M.E. van der, Prins, J.M., Wolf, F. de, Burger, D.M. & Wit, FW (2009). Efavirenz Dose Reduction Is Safe in Patients With High Plasma Concentrations and May Prevent Efavirenz Discontinuations. Jaids. Journal of Acquired Immune Deficiency Syndromes, 52(2), 240-245. Mermel, LA, Allon, M, Bouza, E., Craven, DE, Flynn, P, O'Grady, NP, Raad, II, Rijnders, B.J.A., Sherertz, RJ & Warren, DK (2009). Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection: 2009 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases, 49(1), 1-45. Mocroft, A. (2009). Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal. Antiretroviral Therapy Cohort Collaboration (ART-CC). Clinical Infectious Diseases, 48, 1138-1151. Rijnders, B.J.A. (2009). Evaluation of 30-day mortality of levosimendan versus enoximone. Critical Care Medicine, 37(3), 1181-1182. Roefs, A.M.J., Ende, M.E. van der, Ijzermans, J.N.M., Weimar, W. & Gelder, T. van (2009). Long-term survival after kidney transplantation in an HIV-positive patient. Clinical Transplantation, 23(2), 278-281. Sande, W.W.J. van de, Mathot, R.A.A., Kate, M.T. ten, Vianen, W. van, Tavakol, M., Rijnders, B.J.A. & Bakker-Woudenberg, I.A.J.M. (2009). Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin. Antimicrobial Agents & Chemotherapy, 53(5), 2005-2013.

Slobbe, L., Barzouhi, A el, Boersma, E. & Rijnders, B.J.A. (2009). Comparison of the Roll Plate Method to the Sonication Method To Diagnose Catheter Colonization and Bacteremia in Patients with Long-Term Tunnelled Catheters: a Randomized Prospective Study. Journal of Clinical Microbiology, 47(4), 885-888. Slobbe, L., Waal, L. de, Jongman, L.R., Lugtenburg, P.J. & Rijnders, B.J.A. (2009). Three-day treatment with imipenem for unexplained fever during prolonged neutropaenia in haematology patients receiving fluoroquinolone and fluconazole prophylaxis: A prospective observational safety study. European Journal of Cancer, 45(16), 2810-2817. Snoek, E.M. van der, Amelink, A., Ende, M.E. van der, Hollander, J.C. den, Hollander, J.G. den, Kroon, F.P., Vriesendorp, R., Neumann, H.A.M. & Robinson, D.J. (2009). Photodynamic Therapy With Topical Metatetrahydroxychlorin (Fosgel) Is Ineffective for the Treatment of Anal Intraepithelial Neoplasia, Grade III. Jaids. Journal of Acquired Immune Deficiency Syndromes, 52(1), 141-143. Snoek, E.M. van der & Ende, M.E. van der (2009). Voorstadia van anus kanker. Derma Novum, 9, 3. Steketee, W.H. & Zijlstra, E.E. (2009). An HIV positive man with skin ulcers in the face. Cryptococcus. Nederlands Tijdschrift voor Geneeskunde, 153, 677. Visscher, S, Lucas, PJF, Schurink, C.A.M. & Bonten, M.J.M. (2009). Modelling treatment effects in a clinical Bayesian network using Boolean threshold functions. Artificial Intelligence in Medicine, 46(3), 251-266. Vonderen, M.G.A. van, Gras, L., Wit, F. de, Brinkman, K., Ende, M.E. van der, Hoepelman, A.I.M., Wolf, F. de & Reiss, P. (2009). Baseline Lipid Levels Rather Than the Presence of Reported Body Shape Changes Determine the Degree of Improvement in Lipid Levels After Switching to Atazanavir. HIV Clinical Trials, 10(3), 168-180. Part of book - abstract Ende, M.E. van der (2009). Oud wordende vrouwen met HIV. In Oud worden met HIV. Gezondheid en ziekte van oudere HIV patienten: een inventarisatie (pp. 112-119). Amsterdam: AIDS fonds.

EMC MM-04-39-05 - Renal insufficiency and organ transplantation Programme design in brief This program concerns various methods of renal replacement: Therapy: haemodialysis, peritoneal dialysis and transplantation. In the clinical setting we try to find optimal treatment modalities for acute renal failure i.e. continuous dialysis techniques (CAVHD,CVVH) and for haemodynamic instability during intermittent dialysis. In CAPD patients we study the effect of dialysis fluids on nutrition, while in patient on hemodialysis we characterize their inherent immuno deficiency. The main topic of the program is immunological monitoring of kidney- and heart transplant recipients. We study the cascades of immunological factors that lead to acute and chronic rejection. In attempt to find strategies to prevent and treat these processes Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot internal medicine 9,57 0 1,44 0,3 11,31 Total 9,57 0 1,44 0,3 11,31 2 0 0 2 49 3 1 55 Thesis Dijke, I.E. (2009, januari 14). Immune regulation after heart transplantation. EUR (171 pag.). Prom./coprom.: Prof.Dr. W. Weimar. Hendrikx, T.K. (2009, december 17). The role of regulatory T cells in kidney transplantation. EUR (144 pag.). Prom./coprom.: Prof.Dr. W. Weimar. Article/Letter to the editor Aalten, J, Bemelman, FJ, Berg-Loonen, EM van den, Claas, FH, Christiaans, MH, Fijter, J.W. de, Hepkema, B.G., Hene, R.J., Heide, JJH van der, Hooff, J.P. van, Lardy, NM, Lems, SP, Otten, H.G., Weimar, W., Allebes, WA & Hoitsma, A.J. (2009). Prekidney-transplant blood transfusions do not improve transplantation outcome: a Dutch national study. Nephrology Dialysis Transplantation, 24(8), 2559-2566. Athanassopoulos, P., Balk, A.H.M.M., Vaessen, L.M.B., Caliskan, K., Takkenberg, J.J.M., Weimar, W. & Bogers, A.J.J.C. (2009). Blood dendritic cell levels and phenotypic characteristics in relation to etiology of end-stage heart failure: Implications for dilated cardiomyopathy. International Journal of Cardiology, 131(2), 246-256. Baan, C.C., Dijke, I.E. & Weimar, W. (2009). Regulatory T cells in alloreactivity after clinical heart transplantation. Current Opinion in Organ Transplantation, 14(5), 577-582. Besouw, N.M. van, Kuiper, R., Mast, B.J. van der, Wetering, J. van de, Baan, C.C. & Weimar, W. (2009). Deficient TNF-alpha and IFN-gamma Production Correlates With Nondetectable Donor-Specific Cytotoxicity After Clinical Kidney Transplantation. Transplantation, 87(10), 1451-1454. Betjes, M.G.H., Weimar, W. & Litjens, N.H.R. (2009). CMV Seropositivity Determines Epoetin Dose and Hemoglobin Levels in Patients with CKD. Journal of the American Society of Nephrology, 20(12), 2661-2666. Betjes, M.G.H. & Roodnat, J.I. (2009). Resolution of IgM Nephropathy After Rituximab Treatment. American Journal of Kidney Diseases, 53(6), 1059-1062. Crop, M., Baan, C.C., Weimar, W. & Hoogduijn, M. (2009). Potential of mesenchymal stem cells as immune therapy in solidorgan transplantation. Transplant International, 22(4), 365-376. Crop, M.J., Baan, C.C., Korevaar, S.S., Ijzermans, J.N.M., Alwayn, I.P.J., Weimar, W. & Hoogduijn, M.J. (2009). Donor-Derived Mesenchymal Stem Cells Suppress Alloreactivity of Kidney Transplant Patients. Transplantation, 87(6), 896-906. Dahlke, MH, Hoogduijn, M., Eggenhofer, E, Popp, FC, Renner, P, Slowik, P, Rosenauer, A, Piso, P, Geissler, EK, Lange, C. de, Chabannes, D, Mazzanti, B, Bigenzahn, S, Bertolino, P, Kunter, U, Introna, M, Rambaldi, A., Capelli, C, Perico, N, Casiraghi, F, Noris, M, Gotti, E, Seifert, M, Saccardi, R, Verspaget, H.W., Hoek, B. van, Bartholomew, A, Wekerle, T, Volk, HD, Remuzzi, G, Deans, R, Lazarus, H, Schlitt, HJ & Baan, C.C. (2009). Toward MSC in Solid Organ Transplantation: 2008 Position Paper of the MISOT Study Group. Transplantation, 88(5), 614-619. Demirkiran, A., Sewgobind, V.D.K.D., Weijde, J van der, Kok, A., Baan, C.C., Kwekkeboom, J., Tilanus, H.W., Metselaar, H.J. & Laan, L.J.W. van der (2009). Conversion From Calcineurin Inhibitor to Mycophenolate Mofetil-Based Immunosuppression Changes the Frequency and Phenotype of CD4(+)FOXP3(+) Regulatory T Cells. Transplantation, 87(7), 1062-1068. Dijke, I.E., Caliskan, K., Klepper, M., Kuiper, R., Balk, A.H.M.M., Maat, A.P.W.M., Weimar, W. & Baan, C.C. (2009). Donorspecific Immune Regulation by CD8(+) Lymphocytes Expanded from Rejecting Human Cardiac Allografts. American Journal of Transplantation, 9(2), 397-403. Dijke, I.E., Korevaar, S.S., Caliskan, K., Balk, A.H.M.M., Maat, A.P.W.M., Weimar, W. & Baan, C.C. (2009). Inadequate Immune Regulatory Function of CD4(+)CD25(bright+)FoxP3(+) T Cells in Heart Transplant Patients who Experience Acute Cellular Rejection. Transplantation, 87(8), 1191-1200. Dols, L.F.C., Kok, N.F.M., Alwayn, I.P.J., Tran, T.C.K., Weimar, W. & Ijzermans, J.N.M. (2009). Laparoscopic Donor Nephrectomy: A Plea for the Right-Sided Approach. Transplantation, 87(5), 745-750.

Dols, L.F.C., Weimar, W. & Ijzermans, J.N.M. (2009). Long-Term Consequences of Kidney Donation. New England Journal of Medicine, 360(22), 2371-2372. Eckardt, KU & Kasiske, BL (2009). KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. American Journal of Transplantation, 9, S1-S155. Epker, J.L., Biezen, P. van, Daele, P.L.A. van, Gelder, T. van, Vossen, A.C.T.M. & Saase, J.L.C.M. van (2009). Progressive multifocal leukoencephalopathy, a review and an extended report of five patients with different immune compromised states. European Journal of Internal Medicine, 20(3), 261-267. Gelder, T. van, Domke, I, Engelmayer, J, Fijter, H. de, Kuypers, D, Budde, K, Koeger, R, Luthe, H & Oellerich, M (2009). Clinical Utility of a New Enzymatic Assay for Determination of Mycophenolic Acid in Comparison With an Optimized LC-MS/MS Method. Therapeutic Drug Monitoring, 31(2), 218-223. Gelder, T. van (2009). Mycophenolate Blood Level Monitoring: Recent Progress. American Journal of Transplantation, 9(7), 1495-1499. Gerrits, J.H., Wetering, J. van de, Beelen, E van, Claas, F.H.J., Weimar, W. & Besouw, N.M. van (2009). A Multiplex Bead Array Analysis to Monitor Donor-Specific Cytokine Responses After Withdrawal of Immunosuppression in HLA-Identical living Related Kidney Transplant Patients. Transplantation Proceedings, 41(5), 1577-1582. Gerrits, J.H., Wetering, J. van de, Drabbels, JJ, Ijzermans, J.N.M., Claas, F.H.J., Weimar, W. & Besouw, N.M. van (2009). Non- HLA T-cell reactivity during the first year after HLA-identical living-related kidney transplantation. Clinical Transplantation, 23(5), 740-747. Gerrits, J.H., Wetering, J. van de, Weimar, W. & Besouw, N.M. van (2009). T-Cell Reactivity During Tapering of Immunosuppression to Low-Dose Monotherapy Prednisolone in HLA-Identical Living-Related Renal Transplant Recipients. Transplantation, 87(6), 907-914. Glander, P, Sombogaard, F., Budde, K, Gelder, T. van, Hambach, P, Liefeldt, L, Lorkowski, C, Neaumayer, HH, Vulto, A.G., Mathot, R.A. & Mai, M (2009). Improved Assay for the Nonradioactive Determination of Inosine 5 '-Monophosphate Dehydrogenase Activity in Peripheral Blood Mononuclear Cells. Therapeutic Drug Monitoring, 31(3), 351-359. Gurp, E.A.F.J. van, Schoordijk- Verschoor, W., Klepper, M., Korevaar, S.S., Chan, G, Weimar, W. & Baan, C.C. (2009). The Effect of the JAK Inhibitor CR-690,550 on Peripheral Immune Parameters in Stable Kidney Allograft Patients. Transplantation, 87(1), 79-86. Heemskerk, MBA, Haase-Kromwijk, BJJM, Claas, F.H.J., Doxiadis, I.I.N., Haasnoot, GW, Heide, JJH van der, Weimar, W. & Hoitsma, A.J. (2009). Regional Kidney Allocation Based Only on Full HLA-DR Compatibility Is Not Feasible. Transplantation, 88(4), 600-601. Hendrikx, T.K., Klepper, M., Ijzermans, J., Weimar, W. & Baan, C.C. (2009). Clinical rejection and persistent immune regulation in kidney transplant patients. Transplant Immunology, 21(3), 129-135. Hendrikx, T.K., Gurp, E.A.F.J. van, Mol, W.M., Schoordijk- Verschoor, W., Sewgobind, V.D.K.D., Ijzermans, J.N.M., Weimar, W. & Baan, C.C. (2009). End-stage renal failure and regulatory activities of CD4(+)CD25(bright+)FoxP3(+) T-cells. Nephrology Dialysis Transplantation, 24(6), 1969-1978. Hendrikx, T.K., Gurp, E.A.F.J. van, Sewgobind, V.D.K.D., Mol, W.M., Schoordijk- Verschoor, W., Klepper, M., Velthuis, J.H.L., Geel, A.N. van, Ijzermans, J.N.M., Weimar, W. & Baan, C.C. (2009). Generation of Donor-Specific Regulatory T-Cell Function in Kidney Transplant Patients. Transplantation, 87(3), 376-383. Hendrikx, T.K., Velthuis, J.H.L., Klepper, M., Gurp, E.A.F.J. van, Geel, A.N. van, Schoordijk- Verschoor, W., Baan, C.C. & Weimar, W. (2009). Monotherapy rapamycin allows an increase of CD4(+) CD25(bright+) FoxP3(+) T cells in renal recipients. Transplant International, 22(9), 884-891. Hesselink, D.A., Burgerhart, J.S., Bosmans-Timmerarends, H, Petit, P & Genderen, P.J.J. van (2009). Procalcitonin as a biomarker for severe Plasmodium falciparum disease: a critical appraisal of a semi-quantitative point-of-care test in a cohort of travellers with imported malaria. Malaria Journal, 8. Hest, R.M. van, Gelder, T. van, Vulto, A.G., Shaw, LM & Mathot, R.A.A. (2009). Pharmacokinetic Modelling of the Plasma Protein Binding of Mycophenolic Acid in Renal Transplant Recipients. Clinical Pharmacokinetics, 48(7), 463-476. Hoek, J. van der, Hoorn, E.J., Jong, GMT de, Janssens, ENW & Herder, W.W. de (2009). Severe Hyponatremia with High Urine Sodium and Osmolality. Clinical Chemistry, 55(11), 1905-1908. Hoogduijn, M.J., Crop, M.J., Peeters, A.M.A., Korevaar, S.S., Eijken, M, Drabbels, JJ, Roelen, DL, Maat, A.P.W.M., Balk, A.H.M.M., Weimar, W. & Baan, C.C. (2009). Donor-Derived Mesenchymal Stem Cells Remain Present and Functional in the Transplanted Human Heart. American Journal of Transplantation, 9(1), 222-230. Jansen, N.E., Haase-Kromwijk, BJJM, Leiden, H.A. van, Weimar, W. & Hoitsma, A.J. (2009). A plea for uniform European definitions for organ donor potential and family refusal rates. Transplant International, 22(11), 1064-1072. Kranenburg, L.W., Richards, M, Zuidema, W.C., Weimar, W., Hilhorst, M.T., Ijzermans, J.N.M., Passchier, J. & Busschbach, J.J.V. van (2009). Avoiding the issue: Patients' (non)communication with potential living kidney donors. Patient Education and Counseling, 74(1), 39-44.

Kranenburg, L.W., Zuidema, W., Weimar, W., Hilhorst, M.T., Ijzermans, J., Passchier, J. & Busschbach, J.J. van (2009). Strategies to advance living kidney donation: a single center's experience. Progress in Transplantation, 19(1), 71-75. Liem, Y.S. & Weimar, W. (2009). Early Living-Donor Kidney Transplantation: A Review of the Associated Survival Benefit. Transplantation, 87(3), 317-318. Litjens, N.H.R., Wetering, J. van de, Besouw, N.M. van & Betjes, M.G.H. (2009). The human alloreactive CD4(+) T-cell repertoire is biased to a Th17 response and the frequency is inversely related to the number of HLA class II mismatches. Blood, 114(18), 3947-3955. Quaedackers, M.E., Baan, C.C., Weimar, W. & Hoogduijn, M.J. (2009). Cell contact interaction between adipose-derived stromal cells and allo-activated T lymphocytes. European Journal of Immunology, 39(12), 3436-3446. Quaedackers, M.E., Mol, W.M., Korevaar, S.S., Gurp, E.A.F.J. van, Ijcken, W.F.J. van, Chan, G, Weimar, W. & Baan, C.C. (2009). Monitoring of the Immunomodulatory Effect of CP-690,550 by Analysis of the JAK/STAT Pathway in Kidney Transplant Patients. Transplantation, 88(8), 1002-1009. Riekstina, U, Cakstina, I, Parfejevs, V, Hoogduijn, M., Jankovskis, G, Muiznieks, I, Muceniece, R & Ancans, J (2009). Embryonic Stem Cell Marker Expression Pattern in Human Mesenchymal Stem Cells Derived from Bone Marrow, Adipose Tissue, Heart and Dermis. Stem Cell Reviews, 5(4), 378-386. Roefs, A.M.J., Ende, M.E. van der, Ijzermans, J.N.M., Weimar, W. & Gelder, T. van (2009). Long-term survival after kidney transplantation in an HIV-positive patient. Clinical Transplantation, 23(2), 278-281. Roodnat, J.I., Kal-van Gestel, J.A., Zuidema, W., Noord, MAA van, Wetering, J. van de, Ijzermans, J.N.M. & Weimar, W. (2009). Successful Expansion of the Living Donor Pool by Alternative Living Donation Programs. American Journal of Transplantation, 9(9), 2150-2156. Schaik, R.H.N. van, Agteren, M. van, Fijter, J.W. de, Hartmann, A, Schmidt, J, Budde, K, Kuypers, D, Meur, Y. Le, Werf, M. van der, Mamelok, R & Gelder, T. van (2009). UGT1A9-275T > A/-2152C > T Polymorphisms Correlate With Low MPA Exposure and Acute Rejection in MMF/Tacrolimus-Treated Kidney Transplant Patients. Clinical Pharmacology & Therapeutics, 86(3), 319-327. Sewgobind, V.D.K.D., Kho, M.M.L., Laan, L.J.W. van der, Hendrikx, T.K., Dam, T. van, Tilanus, H.W., Ijzermans, J.N.M., Weimar, W. & Baan, C.C. (2009). The effect of rabbit anti-thymocyte globulin induction therapy on regulatory T cells in kidney transplant patients. Nephrology Dialysis Transplantation, 24(5), 1635-1644. Sijs, H. van der, Kowlesar, R., Klootwijk, A.P.J., Nelwan, S.P., Vulto, A.G. & Gelder, T. van (2009). Clinically relevant QTc prolongation due to overridden drug-drug interaction alerts: a retrospective cohort study. British Journal of Clinical Pharmacology, 67(3), 347-354. Sombogaard, F., Peeters, A.M.A., Baan, C.C., Mathot, R.A.A., Quaedackers, M.E., Vulto, A.G., Weimar, W. & Gelder, T. van (2009). Inosine Monophosphate Dehydrogenase Messenger RNA Expression Is Correlated to Clinical Outcomes in Mycophenolate Mofetil-Treated Kidney Transplant Patients, Whereas Inosine Monophosphate Dehydrogenase Activity Is Not. Therapeutic Drug Monitoring, 31(5), 549-556. Sombogaard, F., Schaik, R.H.N. van, Mathot, R.A., Budde, K, Werf, M. van der, Vulto, A.G., Weimar, W., Glander, P, Essioux, L. & Gelder, T. van (2009). Interpatient variability in IMPDH activity in MMF-treated renal transplant patients is correlated with IMPDH type II 3757T > C polymorphism. Pharmacogenetics Genomics, 19(8), 626-634. Tjiong, H.L., Swart, R.L. de, Berg, J.W.O. van den & Fieren, M.W.J.A. (2009). Amino acid-based peritoneal dialysis solutions for malnutrition: new perspectives Peritoneal Dialysis International, 29(4), 384-393. Wetering, J. van de, Gerrits, J.H., Besouw, N.M. van, Ijzermans, J.N.M. & Weimar, W. (2009). Successful Tapering of Immunosuppression to Low-Dose Monotherapy Steroids After Living-Related Human Leukocyte Antigen-Identical Renal Transplantation. Transplantation, 87(5), 740-744. Winter, B.C.M. de, Gelder, T. van, Mathot, R.A.A., Glander, P, Tedesco-Silva, H., Hilbrands, L, Budde, K & Hest, R.M. van (2009). Limited Sampling Strategies Drawn Within 3 Hours Postdose Poorly Predict Mycophenolic Acid Area-Under-the-Curve After Enteric-Coated Mycophenolate Sodium. Therapeutic Drug Monitoring, 31(5), 585-591. Winter, B.C.M. de, Gelder, T. van, Sombogaard, F., Shaw, LM, Hest, R.M. van & Mathot, R.A.A. (2009). Pharmacokinetic role of protein binding of mycophenolic acid and its glucuronide metabolite in renal transplant recipients. Journal of Pharmacokinetics and Pharmacodynamics, 36(6), 541-564. Zuidema, W.C., Roodnat, J.I., Kranenburg, L.W., Erdman, R.A.M., Hilhorst, M.T., Ijzermans, J.N.M. & Weimar, W. (2009). Program for Samaritan kidney donation at Erasmus University Medical Center, 2000- September 2008. Nederlands Tijdschrift voor Geneeskunde, 153(13), 595-599. Part of book - abstract Klerk, M. de, Witvliet, M.D., Haase-Kromwijk, B. & Weimar, W. (2009). A flexible national living kidney exchange program taking advantage of a central histocompatibility laboratory: The Dutch Model. In JM Cecka & PI Terasaki (Eds.), Clinical transplants (pp. 69-73). California: Terasaki foundation laboratory.

EMC MM-04-42-02 - Cell biological and pathophysiological investigations on pulmonary diseases Programme design in brief Investigations of immunological, cell biological processes in inflammation, infection, transplantation and malignancies in the lungs are performed to get insight into the contribution of inflammatory cells and mediators. Emphasis is on I) the antigen presenting cell as a major contributor to the inflammatory process in obstructive and interstitial pulmonary diseases and as target and tool for therapy II) the role of transcription factors and signal transduction pathways that are essential for development and function of lymphocytes. Pathophysiological investigations are performed to increase our understanding of structure function relationships in the lungs. In this programme investigations are done in animal models and in humans. The effects of therapeutic interventions on cell biological processes and structural and functional properties of the lungs are also under investigation. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot medical psychology & psychotherapy 0,4 0 0 0 0,4 pediatrics 0,03 0 0 0 0,03 pulmonology 5,71 1,23 2,01 0 8,95 virology 0 0,38 0 0 0,38 Total 6,14 1,61 2,01 0 9,76 0 0 0 0 38 4 4 46 Article/Letter to the editor Berge, B. ten, Muskens, A.M., Kleinjan, A., Hammad, H., Hoogsteden, H.C., Lambrecht, B.N.M. & Blink, B. van den (2009). A novel method for isolating dendritic cells from human bronchoalveolar lavage fluid. Journal of Immunological Methods, 351(1-2), 13-23. Bergh, K.A.M. van den, Essink-Bot, M.L., Klaveren, R.J. van & Koning, H.J. de (2009). Informed participation in a randomised controlled trial on CT screening for lung cancer. European Respiratory Journal, 34(3), 711-720. Bodewes, R., Geelhoed-Mieras, M.M., Heldens, JGM, Glover, J, Lambrecht, B.N., Fouchier, R.A.M., Osterhaus, A.D.M.E. & Rimmelzwaan, G.F. (2009). The novel adjuvant CoVaccineHT (TM) increases the immunogenicity of cell-culture derived influenza A/H5N1 vaccine and induces the maturation of murine and human dendritic cells in vitro. Vaccine, 27(49), 6833-6839. Boxmeer, J.C., Smit, M., Utomo, E., Romijn, J.C., Eijkemans, M.J.C., Lindemans, J., Laven, J.S.E., Macklon, N.S., Steegers, E.A.P. & Steegers-Theunissen, R.P.M. (2009). Low folate in seminal plasma is associated with increased sperm DNA damage. Fertility & Sterility, 92(2), 548-556. Broere, F., Pre, M.F. du, Berkel, L.A. van, Garssen, J., Schmid-Weber, CB, Lambrecht, B.N., Hendriks, R.W., Nieuwenhuis, E.E.S., Kraal, G. & Samsom, J.N. (2009). Cyclooxygenase-2 in mucosal DC mediates induction of regulatory T cells in the intestine through suppression of IL-4. Mucosal Immunology, 2(3), 254-264. Brugge, P.J. ter, Ta, T.B.V., Bruijn, J.W. de, Keijzers, G., Maas, A., Gent, D.C. van & Hendriks, R.W. (2009). A mouse model for chronic lymphocytic leukemia based on expression of the SV40 large T antigen. Blood, 114(1), 119-127. Gestel, Y.R.B.M. van, Chonchol, M, Hoeks, S.E., Welten, G.M.J.M., Stam, H., Mertens, F.W., Domburg, R.T. van & Poldermans, D. (2009). Association between chronic obstructive pulmonary disease and chronic kidney disease in vascular surgery patients. Nephrology Dialysis Transplantation, 24(9), 2763-2767. Gestel, Y.R.B.M. van, Hoeks, S.E., Sin, D.D., Stam, H., Mertens, F.W., Bax, J.J., Domburg, R.T. van & Poldermans, D. (2009). Beta-blockers and health-related quality of life in patients with peripheral arterial disease and COPD. International Journal of Chronic Obstructive Pulmonary Disease, 4, 177-183. Gestel, Y.R.B.M. van, Hoeks, S.E., Sin, D.D., Huzeir, V., Stam, H., Mertens, F.W., Domburg, R.T. van, Bax, J.J. & Poldermans, D. (2009). COPD and cancer mortality: the influence of statins. Thorax, 64(11), 963-967. Geurts van Kessel, C.H., Bergen, I.M., Muskens, A.M., Boon, L., Hoogsteden, H.C., Osterhaus, A.D.M.E., Rimmelzwaan, G.F. & Lambrecht, B.N. (2009). Both Conventional and Interferon Killer Dendritic Cells Have Antigen-Presenting Capacity during Influenza Virus Infection. PLoS One, 4(9). Geurts van Kessel, C.H., Willart, M.A.M., Bergen, I.M., Rijt, L.S. van, Muskens, A.M., Elewaut, D, Osterhaus, A.D.M.E., Hendriks, R., Rimmelzwaan, G.F. & Lambrecht, B.N. (2009). Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus-infected mice. Journal of Experimental Medicine, 206(11), 2339-2349. Giaccone, G., Zatloukal, P, Roubec, J., Floor, K., Musil, J., Kuta, M., Klaveren, R.J. van, Chauddhary, S., Gunther, A & Shamsili, S. (2009). Multicenter phase II trial of YM155, a small-molecule suppressor of survivin, in patients with advanced, refractory, non-small-cell lung cancer. Journal of Clinical Oncology, 27, 4481-4486. Hamburg, J.P. van, Mus, A.M., Bruijn, J.W. de, Vogel, L.L. de, Boon, L., Cornelissen, F., Asmawidjaja, P., Hendriks, R.W. & Lubberts, E. (2009). GATA-3 Protects Against Severe Joint Inflammation and Bone Erosion and Reduces Differentiation of Th17 Cells During Experimental Arthritis. Arthritis & Rheumatism, 60(3), 750-759.

Hamburg, J.P. van, Bruijn, J.W. de, Ribeiro de Almeida, C.A., Dingjan, G.M. & Hendriks, R.W. (2009). Gene expression profiling in mice with enforced Gata3 expression reveals putative targets of Gata3 in double positive thymocytes. Molecular Immunology, 46(16), 3251-3260. Hammad, H., Chieppa, M, Perros, F, Willart, M.A., Germain, RN & Lambrecht, B.N.M. (2009). House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nature Medicine, 15(4), 410-416. Hegmans, J.P.J.J., Veltman, J.D., Fung, E.T., Verch, T., Glover, C., Zhang, F., Allard, W.J., Tjampens, D., Hoogsteden, H.C., Lambrecht, B.N.M. & Aerts, J.G.J.V. (2009). Protein profiling of pleural effusions to identify malignant pleural mesothelioma using SELDI-TOF MS. Technology in Cancer Research & Treatment, 8(5), 323-332. Klaveren, R.J. van (2009). Lung cancer screening with low dose computed tomography: where do we stand today? European Journal of Cancer, 45, 375-376. Klaveren, R.J. van, Oudkerk, M., Prokop, M, Scholten, ET, Nackaerts, K, Vernhout, R, Iersel, C.A. van, Bergh, K.A.M. van den, Westeinde, S van't, Aalst, C. van der, Thunnissen, E, Xu, DM, Wang, Y., Zhao, YR, Gietema, HA, Hoop, BJ de, Groen, H.J.M., Bock, G.H. de, Ooijen, P van, Weenink, C., Verschakelen, J, Lammers, JWJ, Timens, W., Willebrand, D, Vink, A., Mali, W. & Koning, H.J. de (2009). Management of Lung Nodules Detected by Volume CT Scanning. New England Journal of Medicine, 361(23), 2221-2229. Klaveren, R.J. van, Westeinde, S.C. van t, Hoop, BJ de & Hoogsteden, H.C. (2009). Stem Cells and the Natural History of Lung Cancer: Implications for Lung Cancer Screening. Clinical Cancer Research, 15(7), 2215-2218. Kool, M., Nimwegen, M. van, Willart, M.A.M., Muskens, A.M., Boon, L., Smit, J.J., Coyle, A, Clausen, B.E., Hoogsteden, H.C., Lambrecht, B.N. & Hammad, H. (2009). An Anti-Inflammatory Role for Plasmacytoid Dendritic Cells in Allergic Airway Inflammation. Journal of Immunology, 183(2), 1074-1082. Kuipers, H., Soullie, T., Hammad, H., Willart, M., Kool, M., Hijdra, D., Hoogsteden, H.C. & Lambrecht, B.N. (2009). Sensitization by intratracheally injected dendritic cells is independent of antigen presentation by host antigen-presenting cells. Journal of Leukocyte Biology, 85(1), 64-70. Lambrecht, B.N., Kool, M., Willart, M.A.M. & Hammad, H. (2009). Mechanism of action of clinically approved adjuvants. Current Opinion in Immunology, 21(1), 23-29. Lee, I van der, Gietema, HA, Zanen, P, Klaveren, R.J. van, Prokop, M, Lammers, JWJ & Bosch, J.M.M. van den (2009). Nitric oxide diffusing capacity versus spirometry in the early diagnosis of emphysema in smokers. Respiratory Medicine, 103(12), 1892-1897. Levy, M.L., Quanjer, Ph.H., Booker, R., Cooper, B.G., Holmes, S. & Small, I.R. (2009). Diagnostic Spirometry in primary care. Proposed standards for general practice compliant with American Thoracic Society and European Respiratory Society recommendations. Primary Care Respiratory Journal, 18(3), 130-147. Loeve, M., Hal, P.T.W. van, Robinson, P., Jong, P.A. de, Lequin, M.H., Hop, W.C.J., Williams, T.J., Nossent, G.D. & Tiddens, H.A.W.M. (2009). The spectrum of structural abnormalities on CT scans from patients with CR with severe advanced lung disease. Thorax, 64, 876-882. Mortaz, E., Kraneveld, A.D., Smit, J.J., Kool, M., Lambrecht, B.N.M., Kunkel, S.L., Lukacs, N.W., Nijkamp, F.P. & Folkerts, G (2009). Effect of cigarette smoke extract on dendritic cells and their impact on proliferation. PLoS One, 4(3), 946-946. Peetsold, MG, Heij, HA, Nagelkerke, A.F., Meijers-IJsselstijn, H., Tibboel, D., Quanjer, P.H. & Gemke, R.J.B.J. (2009). Pulmonary function and exercise capacity in survivors of congenital diaphragmatic hernia. European Respiratory Journal, 34(5), 1140-1147. Perros, F, Hoogsteden, H.C., Coyle, A.J., Lambrecht, B.N. & Hammad, H. (2009). Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation. Allergy, 64(7), 995-1002. Poels, P.J., Schermer, T.R.J., Thoonen, BP, Jacobs, J.F., Akkermans, R.P., Vries-Robbe, PF de, Quanjer, P.H., Bottema, B.J.A.M. & Weel, C. van (2009). Spirometry expert support in family practice: a cluster-randomised trial. Primary Care Respiratory Journal, 18(3), 189-197. Pothof, J., Verkaik, N.S., Ijcken, W. van, Wiemer, E.A.C., Ta, T.B.V., Horst, G.T.J. van der, Jaspers, N.G.J., Gent, D.C. van, Hoeijmakers, J.H.J. & Persengiev, S.P. (2009). MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response. Embo Journal, 28(14), 2090-2099. Raymond, M, Rubio, M, Fortin, G, Shalaby, KH, Hammad, H., Lambrecht, B.N.M. & Sarfati, M (2009). Selective control of SIRPalpha-positive airway dendritic cell trafficking through CD47 is critical for the development of T(H)2-mediated allergic inflammation. Journal of Allergy and Clinical Immunology, 124(6), 1333-1342. Ribeiro de Almeida, C.A., Heath, H.E., Krpic, S., Dingjan, G.M., Hamburg, J.P. van, Bergen, I.M., Nobelen, S. van de, Sleutels, F., Grosveld, F., Galjart, N. & Hendriks, R.W. (2009). Critical Role for the Transcription Regulator CCCTC-Binding Factor in the Control of Th2 Cytokine Expression. Journal of Immunology, 182(2), 999-1010. Smits, H.H., Gloudemans, A.K., Nimwegen, M. van, Willart, M.A., Soullie, T., Muskens, A.M., Jong, E.C. de, Boon, L., Pilette, C, Johansen, FE, Hoogsteden, H.C., Hammad, H. & Lambrecht, B.N. (2009). Cholera toxin B suppresses allergic inflammation through induction of secretory IgA. Mucosal Immunology, 2(4), 331-339.

Surmont, V., Aerts, JG, Pouw, E.M., Tan, K.Y., Vernhout, R, Gras, J, Salome, J, Pronk, T.J.P., Schmitz, P.I.M., Hoogsteden, H.C. & Klaveren, R.J. van (2009). Oral UFT, etoposide and leucovorin in recurrent non-small cell lung cancer: A nonrandomized phase II study. Lung Cancer, 66(3), 333-337. Tilburg, P.M.B. van, Stam, H., Hoogsteden, H.C. & Klaveren, R.J. van (2009). Pre-operative pulmonary evaluation of lung cancer patients: a review of the literature. European Respiratory Journal, 33(5), 1206-1215. Velzen, M. van, Laman, J.D., Kleinjan, A., Poot, A.M., Osterhaus, A.D.M.E. & Verjans, G.M.G.M. (2009). Neuron-Interacting Satellite Glial Cells in Human Trigeminal Ganglia Have an APC Phenotype. Journal of Immunology, 183(4), 2456-2461. Vliet, E.P.M. van, Steyerberg, E.W., Otten, H.J.A.M., Rudolphus, A, Knoester, P.D., Hoogsteden, H.C., Gelder, T. van, Kuipers, E.J. & Siersema, P.D. (2009). The effects of guideline implementation for proton pump inhibitor prescription on two pulmonary medicine wards. Alimentary Pharmacology & Therapeutics, 29(2), 213-221. Vonk, MC, Broers, B, Heijdra, YF, Ton, E, Snijder, R, Dijk, APJ van, Laar, J.A.M. van, Bootsma, H, Hal, P.T.W. van, Hoogen, F.H.J van den & Daele, P.L.A. van (2009). Systemic sclerosis and its pulmonary complications in The Netherlands: an epidemiological study. Annals of the Rheumatic Diseases, 68(6), 961-965. Voort van Zyp, N.C.M.G. van der, Prevost, J.G.H.G., Hoogeman, M.S., Praag, J.O., Holt, B. van der, Levendag, P.C., Klaveren, R.J. van, Pattynama, P. & Nuyttens, J.J. (2009). Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: Clinical outcome. Radiotherapy and Oncology, 91(3), 296-300. Willart, M.A.M., Heer, H.J. de, Hammad, H., Soullie, T., Deswarte, K, Clausen, B.E., Boon, L., Hoogsteden, H.C. & Lambrecht, B.N.M. (2009). The lung vascular filter as a site of immune induction for T cell responses to large embolic antigen. Journal of Experimental Medicine, 206(12), 2823-2835. Xu, DM, Zaag-Loonen, H.J. van der, Oudkerk, M., Wang, Y., Vliegenthart, R., Scholten, ET, Verschakelen, J, Prokop, M, Koning, H.J. de & Klaveren, R.J. van (2009). Smooth or Attached Solid Indeterminate Nodules Detected at Baseline CT Screening in the NELSON Study: Cancer Risk during 1 Year Follow-up. Radiology, 250(1), 264-272. Zorn, CN, Keck, S, Hendriks, R.W., Leitges, M., Freudenberg, MA & Huber, M. (2009). Bruton's tyrosine kinase is dispensable for the Toll-like receptor-mediated activation of mast cells. Cellular Signalling, 21(1), 79-86. Part of book - abstract Kleinjan, A. & Lambrecht, B.N.M. (2009). Lung dendritic cells: targets for therapy in allergic disease. In G Lombardi & Y Riffo- Vasquez (Eds.), Handbook of Experimental Pharmacology (pp. 115-136). Berlin: Springer Verlag. Lambrecht, B.N.M. & Hammad, H. (2009). Lung dendritic cells: targets for therapy in allergic disease. In G Lombardi & Y Riffo- Vasquez (Eds.), Handbook of experimental pharmacology (pp. 99-114). Berlin: Springer Verlag. Sterenborg, H.J.C.M., Leest, C. van der, Canick, SC, Aerts, J.G.J.V. & Amelink, A. (2009). Differential Pathlength Spectroscopy. In Biomedical applications of Light Scattering (Biophotoncs series). --: Mc Graw-Hill. Patent Hou, J., Aerts, J.G.J.V., Grosveld, F.G. & Philipsen, J.N.J. (23-03-2009). Tumour gene profile. no GB 904957.9.

EMC MM-04-44-02 - Neuromuscular and Neuroinflammatory Disorders Programme design in brief This research programme aims to study various aspects of immune-mediated of the central (multiple sclerosis, encephalitis, epilepsy) and peripheral (Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, mitochondrial myopathy, Pompe s disease) nervous system. Studies are conducted in close collaboration in particular with the Departments of Immunology, Medical Microbiology and Infectious diseases, Virology, Genetics, Epidemiology, Rehabilitation of the Erasmus MC, as well as with neurological, neuroimmunological and genetic centers around the world. Clinical neurophysiological research focuses on the development and application of non-invasive EMG techniques to assess motor unit function in neuromuscular disorders. The Rotterdam MS center ErasMS-or MS and CNS inflammation integrates research and care. The Paediatric Neurology Department coordinates the long-term follow-up of the Dutch Study of Epilepsy in Childhood and participates in the `Generation R project, and in national and international collaborative groups for the identification of genes and genotype-phenotype correlations in mitochondrial disorders, malformations of cortical development (MCD) and epilepsy.. The programme is focused on the following topics: Neuromuscular disorders / neuroimmunology - peripheral nervous system. 1. Immunological, microbiological and genetic determinants leading to Guillain-Barré syndrome (GBS) and Miller Fisher syndrome. 2. Prognostic modelling of the Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP). 3. Clinical trials and laboratory studies with intravenous immunoglobulin (IVIg) and other immunomodulatory drugs in GBS and the chronic inflammatory demyelinating polyneuropathy (CIDP). 4. Clinimetric evaluation of assessment scales in immune-mediated neuropathies (Perinoms study) 5. Non-invasive EMG techniques to monitor changes in motor unit function. 6. Electrophysiological studies in immune-mediated neuropathies. 7. Enzyme replacement therapy, assessment of longterm-outcome in Pompe disease. 8. Mitochondrial disorders leading to neuromuscular disorders, visual system disorders and encephalopathies. 9. Gene discovery in families with mitochondrial encephalomyopathies 10.Protein profiles in PBMC in Leber s Hereditary Optic Neuropathy patients Multiple sclerosis/ neuroimmunology - central nervous system. 1. Immunological, genetic and infectious determinants on the disease course in Multiple Sclerosis (MS) and Acute Disseminated Encephalomyelitis (ADEM). 2. Determinants of ADEM and MS in childhood. 3. Gene discovery in MS families. 4. Immunomodulatory treatment of central nervous system (CNS) inflammatory disease. 5. The Rotterdam `ErasMS multiple sclerosis center, including research in animal models. 6. Retinal measurements as a tool to monitor CNS inflammation. Epilepsy and other neurological disorders in childhood 1. Incidence and determinants of epilepsy and other paroxysmal disorders in childhood ( Generation R study). 2. Course of childhood epilepsy in cohort studies with prospective long-term follow-up, developing prognostic models and evaluating modified treatment strategies. 3. Initiating and conducting therapeutic trials in childhood epilepsy (anti-epileptic drugs, ketogenic diet). 4. Genes and genetic mechanisms in childhood epilepsy and in families with epilepsy. 5. Monitoring techniques, diagnosis and treatment modalities in neonatal seizures. 6. Genes causing cortical migration disorders and their relation with seizures. 7. Molecular genetics and cognitive aspects of cerebellar dysfunction in Williams syndrome. 8. Treatment of migraine and other headaches in childhood. 9. Hereditary causes of mental retardation, epilepsy and neurological syndromes. 10 Continuous EEG monitoring in neonatal asphyxia. 11 Cognitive functioning and its treatment in children with neurofibromatosis type 1. 12.Cognitive functioning and epilepsy in children with tuberous sclerosis. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot immunology 0 0 0,5 0 0,5 neurology 6,53 2 6,25 3,45 18,23 pediatrics 0,15 0 0 0 0,15 Total 6,68 2 6,75 3,45 18,88 1 0 0 1 51 4 5 61 Thesis Kuijf, M.L. (2009, november 05). Host-pathogen interactions in Guillain-Barre syndrome. EUR. Prom./coprom.: Prof.Dr. P.A. van Doorn & Dr. B.C. Jacobs. Article/Letter to the editor Aarsen, F.K., Paquier, P.F., Arts, W.F.M., Veelen, M.L.C. van, Michiels, E.M.C., Lequin, M.H. & Catsman-Berrevoets, C.E. (2009). Cognitive deficits and predictors 3 years after diagnosis of a pilocytic astrocytoma in childhood. Journal of Clinical Oncology, 27, 3526-3532. Arts, W.F.M., Aarsen, F.K., Boer, M. de & Catsman-Berrevoets, C.E. (2009). Landau-Kleffner syndrome and CSWS syndrome: Treatment with intravenous immunoglobulins. Epilepsia, 50, 55-58. Arts, W.F.M. & Geerts, A.T. (2009). When to start drug treatment for childhood epilepsy: The clinical-epidemiological evidence. European Journal of Paediatric Neurology, 13(2), 93-101.

Bakkers, M., Merkies, I.S.J., Lauria, G, Devigili, G, Penza, P, Lombardi, R, Hermans, MCE, Nes, S.I. van, Baets, M De & Faber, C.G. (2009). Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology, 73(14), 1142-1148. Beek, N.A.M.E. van der, Hagemans, M.L.C., Reuser, A.J.J., Hop, W.C.J., Ploeg, A.T. van der, Doorn, P.A. van & Wokke, J.H.J. (2009). Rate of disease progression during long-term follow-up of patients with late-nset Pompe disease. Neuromuscular Disorders, 19, 113-117. Belkum, A. van, Jacobs, B.C., Beek, E. van, Louwen, R., Rijs, W. van, Debruyne, L, Gilbert, M., Li, J., Jansz, A, Megraud, F & Endtz, H.P. (2009). Can Campylobacter coli induce Guillain-Barre syndrome? European Journal of Clinical Microbiology & Infectious Diseases, 28(5), 557-560. Bril, V, Katzberg, H, Donofrio, P, Banach, M, Dalakas, MC, Deng, CQ, Hanna, K, Hartung, H.P., Hughes, R.A.C., Latov, N, Merkies, I.S.J. & Doorn, P.A. van (2009). Electrophysiology in chronic inflammatory demyelinating polyneuropathy with IGIV. Muscle & Nerve, 39(4), 448-455. Brugman, F, Veldink, J.H., Franssen, H., Visser, M., Jong, JMBV de, Faber, C.G., Kremer, BHP, Schelhaas, HJ, Doorn, P.A. van, Verschuuren, J.J.G.M., Bruyn, RPM, Kuks, JBM, Robberecht, W, Wokke, J.H.J. & Berg, L.H. van den (2009). Differentiation of Hereditary Spastic Paraparesis From Primary Lateral Sclerosis in Sporadic Adult-Onset Upper Motor Neuron Syndromes. Archives of Neurology, 66(4), 509-514. Bruijn, J.J. de, Arts, W.F., Duivenvoorden, H., Dijkstra, N., Raat, H. & Passchier, J. (2009). Quality of life in children with primary headache in a general hospital. Cephalalgia, 29(6), 624-630. Brusse, E., Majoor-Krakauer, D.F., Graaf, B.M. de, Visser, G.H., Swagemakers, S.M.A., Boon, A.J.W., Oostra, B.A. & Bertoli Avella, A.M. (2009). A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier? Neurogenetics, 10(4), 289-297. Callenbach, P.M.C., Bouma, PAD, Geerts, A.T., Arts, W.F.M., Stroink, H., Peeters, E.A.J., Donselaar, C.A. v, Peters, A.C.B. & Brouwer, O.F. (2009). Long-term outcome of childhood absence epilepsy: Dutch Study of Epilepsy in Childhood. Epilepsy Research, 83(2-3), 249-256. Catsman-Berrevoets, C.E., Aarsen, F.K., Hemsbergen, M.L.C. van, Noesel, M.M. van, Hakvoort-Cammel, F.G.A.J. & Heuvel- Eibrink, M.M. van den (2009). Improvement of neurological status and quality of life in children with opsoclonus myoclonus syndrome at long-term follow-up. Pediatric Blood & Cancer, 53, 1048-1053. Dekker, M.J.H.J., Akker, E.L.T. van den, Koper, F.J.W., Manenschijn, L., Geleijns, K, Ruts, L., Rijs, W. van, Tio-Gillen, A.P., Doorn, P.A. van, Lamberts, S.W.J. & Jacobs, B.C. (2009). Effect of glucocorticoid receptor gene polymorphisms in Guillain- Barre syndrome. Journal of the Peripheral Nervous System, 14(2), 75-83. Diggelen, O.P. van, Oemardien, L.F., Beek, N.A.M.E. van der, Kroos, M.A., Wind, H.K., Voznyi, Y.V., Burke, D, Jackson, M, Winchester, BG & Reuser, A.J.J. (2009). Enzyme analysis for Pompe disease in leukocytes; superior results with natural substrate compared with artificial substrates. Journal of Inherited Metabolic Disease, 32(3), 416-423. Doorn, P.A. van (2009). What's new in Guillain-Barre syndrome in 2007-2008?(*). Journal of the Peripheral Nervous System, 14(2), 72-74. Driessche, A Van, Velde, ALR Van de, Nijs, G, Braeckman, T, Stein, B, Vries, J.M. de, Berneman, ZN & Tendeloo, VFI Van (2009). Clinical-grade manufacturing of autologous mature mrna-electroporated dendritic cells and safety testing in acute myeloid leukemia patients in a phase I dose-escalation clinical trial. Cytotherapy, 11(5), 653-668. Faber, C.G., Molenaar, P.C., Vles, J.S.H., Bonifati, DM, Verschuuren, J.J.G.M., Doorn, P.A. van, Kuks, JBM, Wokke, J.H.J., Beeson, D & Baets, M De (2009). AChR deficiency due to epsilon-subunit mutations: two common mutations in the Netherlands. Journal of Neurology, 256(10), 1719-1723. Groot, V de, Beckerman, H., Uitdehaag, BM, Hintzen, R.Q., Minneboo, A, Heymans, M.W., Lankhorst, G.J., Polman, C.H. & Bouter, L.M. (2009). Physical and Cognitive Functioning After 3 Years Can Be Predicted Using Information From the Diagnostic Process in Recently Diagnosed Multiple Sclerosis. Archives of Physical Medicine and Rehabilitation, 90(9), 1478-1488. Hart, B.A. 't, Hintzen, R.Q. & Laman, J.D. (2009). Multiple sclerosis - a response-to-damage model. Trends in Molecular Medicine, 15(6), 235-244. Hoppenbrouwers, I.A., Aulchenko, Y.S., Janssens, A.C., Ramagopalan, SV, Broer, L., Kayser, M., Ebers, GC, Oostra, B.A., Duijn, C.M. van & Hintzen, R.Q. (2009). Replication of CD58 and CLEC16A as genome-wide significant risk genes for multiple sclerosis. Journal of Human Genetics, 54(11), 676-680. Houliston, RS, Jacobs, B.C., Tio-Gillen, A.P., Verschuuren, J.J., Khieu, NH, Gilbert, M. & Jarrell, HC (2009). STD-NMR Used To Elucidate the Fine Binding Specificity of Pathogenic Anti-Ganglioside Antibodies Directly in Patient Serum. Biochemistry, 48(2), 220-222. Huizinga, H.G., Hintzen, R.Q., Assink, K., Meurs, M. van & Amor, S. (2009). T-cell responses to neurofilament light protein are part of the normal immune repertoire. International Immunology, 21(4), 433-441. Islam, Z., Belkum, A. van, Wagenaar, J.A., Cody, AJ, Boer, A.G. de, Tabor, H, Jacobs, B.C., Talukder, KA & Endtz, H.P. (2009). Comparative Genotyping of Campylobacter jejuni Strains from Patients with Guillain-Barre Syndrome in Bangladesh. PLoS One, 4(9).

Jacobs, B.C., Wijnans, E.G., Sturkenboom, M.C.J.M. & Maas, N.A.T. van der (2009). Guillain-barré-syndroom en het nieuwe influenza A(H1N1)-virus. Nederlands Tijdschrift voor Geneeskunde, 153, 1490. Jacobs, B.C. & Willison, H.J. (2009). Peripheral neuropathies Biomarkers for axonal damage in immune-mediated neuropathy. Nature Reviews Neurology, 5(11), 584-585. Jafari, N., Kreft, K.L., Flach, H.Z., Janssens, A.C.J.W. & Hintzen, R.Q. (2009). Callosal lesion predicts future attacks after clinically isolated syndrome. Neurology, 73(22), 1837-1841. Jafari, N., Hoppenbrouwers, I.A., Hop, W.C.J., Breteler, M.M.B. & Hintzen, R.Q. (2009). Cigarette smoking and risk of MS in multiplex families. Multiple Sclerosis, 15(11), 1363-1367. Kreft, K.L., Mellema, SJ & Hintzen, R.Q. (2009). Spinal cord involvement in Balo's concentric sclerosis. Journal of the Neurological Sciences, 279(1-2), 114-117. Kuijf, M.L., Eurelings, M., Tio-Gillen, A.P., Doorn, P.A. van, Berg, L.H. van den, Hooijkaas, H., Stork, J, Notermans, N.C. & Jacobs, B.C. (2009). Detection of anti-mag antibodies in polyneuropathy associated with IgM monoclonal gammopathy. Neurology, 73(9), 688-695. Kuitwaard, K., Ruts, L., Doorn, P.A. van & Pol, WL van der (2009). Individual patients who experienced both Guillain-BarrE syndrome and CIDP. Journal of the Peripheral Nervous System, 14(1), 66-68. Kuitwaard, K. & Doorn, P.A. van (2009). Newer Therapeutic Options for Chronic Inflammatory Demyelinating Polyradiculoneuropathy. Drugs, 69(8), 987-1001. Kuitwaard, K., Gelder, J. van, Tio-Gillen, A.P., Hop, W.C.J., Gelder, T. van, Toorenenbergen, A.W. van, Doorn, P.A. van & Jacobs, B.C. (2009). Pharmacokinetics of Intravenous Immunoglobulin and Outcome in Guillain-Barre Syndrome. Annals of Neurology, 66(5), 597-603. Kuitwaard, K., Bos-Eyssen, ME, Blomkwist-Markens, PH & Doorn, P.A. van (2009). Recurrences, vaccinations and long-term symptoms in GBS and CIDP. Journal of the Peripheral Nervous System, 14(4), 310-315. Kuitwaard, K., Koningsveld, R. van, Ruts, L., Jacobs, B.C. & Doorn, P.A. van (2009). Recurrent Guillain-Barre syndrome. Journal of Neurology Neurosurgery and Psychiatry, 80(1), 56-59. Lau, L.M.L. de, Vries, J.M. de, Woude, C.J. van der, Kuipers, E.J., Siepman, D.A.M., Sillevis Smitt, P.A.E. & Hintzen, R.Q. (2009). Acute CNS White Matter Lesions in Patients with Inflammatory Bowel Disease. Inflammatory Bowel Diseases, 15(4), 576-580. Maessen, M., Veldink, J.H., Onwuteaka-Philipsen, B.D., Vries, J.M. de, Wokke, J.H.J., Wal, G. van der & Berg, L.H. van den (2009). Trends and determinants of end-of-life practices in ALS in the Netherlands. Neurology, 73(12), 954-961. Mensink, H.W., Doorn, P.A. van & Paridaens, A.D.A. (2009). Concurrent myopathy in patients with Graves' orbitopathy. Orbit, 28, 66-70. Merkies, I.S.J., Bril, V, Dalakas, MC, Deng, C, Donofrio, P, Hanna, K, Hartung, H.P., Hughes, R.A.C., Latov, N & Doorn, P.A. van (2009). Health-related quality-of-life improvements in CIDP with immune globulin IV 10% The ICE Study. Neurology, 72(15), 1337-1344. Merkies, I.S.J. & Faber, C.G. (2009). Outcome measures in Duchenne muscular dystrophy: Are we ready for the new therapeutic era? Neuromuscular Disorders, 19(6), 447-447. Meulen, B.C. ter, Tavy, D & Jacobs, B.C. (2009). From Stroboscope to Dream Machine: A History of Flicker-Induced Hallucinations. European Neurology, 62(5), 316-320. Mortensen, NP, Kuijf, M.L., Ang, C.W., Schiellerup, P, Krogfelt, KA, Jacobs, B.C., Belkum, A. van, Endtz, H.P. & Bergman, M.P. (2009). Sialylation of Campylobacter jejuni lipo-oligosaccharides is associated with severe gastro-enteritis and reactive arthritis. Microbes and Infection, 11(12), 988-994. Neck, J.W. van, Kool, B.S. de, Hekking-Weijma, J.M., Walbeehm, E.T., Visser, G.H. & Blok, J.H. (2009). Histological validation of ultrasound-guided neurography in early nerve regeneration. Muscle & Nerve, 40(6), 967-975. Nemes, A., Geleijnse, M.L., Sluiteir, W, Vydt, TCG, Soliman, OLI, Dalen, B.M. van, Vletter, W.B., Cate, F.J. ten, Smeets, HFM & Coo, I.F.M. de (2009). Aortic distensibility alterations in adults with m.3243a > G MELAS gene mutation. Swiss Medical Weekly, 139(7-8), 117-120. Nes, S.I. van, Vanhoutte, EK, Faber, C.G., Garssen, M.P.J., Doorn, P.A. van & Merkies, I.S.J. (2009). Improving fatigue assessment in immune-mediated neuropathies: the modified Rasch-built fatigue severity scale. Journal of the Peripheral Nervous System, 14(4), 268-278. Neuteboom, R.F., Verbraak, E., Voerman, J.S.A., Meurs, M. van, Steegers, E.A.P., Groot, C.J.M. de, Laman, J.D. & Hintzen, R.Q. (2009). First trimester interleukin 8 levels are associated with postpartum relapse in multiple sclerosis. Multiple Sclerosis, 15(11), 1356-1358. Neuteboom, R.F., Verbraak, E., Voerman, J.S.A., Meurs, M. van, Steegers, E.A.P., Groot, C.J.M. de, Laman, J.D. & Hintzen, R.Q. (2009). Serum leptin levels during pregnancy in multiple sclerosis. Multiple Sclerosis, 15(8), 907-912.

Sas, A.M.G., Niks, E.H., Lequin, M.H., Catsman-Berrevoets, C.E. & Wit, M.C.Y. de (2009). Herpes Simplex Virus Type-1 Encephalitis and Occipital Ischemic Stroke. Pediatric Neurology, 41(4), 294-296. Spijker, RC van, Monasch, E, Compier-Mahboob, N. & Merkies, I.S.J. (2009). Neurological symptoms following lightening strike. Nederlands Tijdschrift voor Geneeskunde, 153, 774. Stoop, M.P., Dekker, L.J.M., Titulaer, M.K., Lamers, RJAN, Burgers, P.C., Sillevis Smitt, P.A.E., Gool, A.J. van, Luider, T.M. & Hintzen, R.Q. (2009). Quantitative Matrix-Assisted Laser Desorption Ionization-Fourier Transform Ion Cyclotron Resonance (MALDI-FT-ICR) Peptide Profiling and Identification of Multiple-Sclerosis-Related Proteins. Journal of Proteome Research, 8(3), 1404-1414. Verkerk, A.J.M.H., Schot, R., Dumee, B.C., Schellekens, K.P.C., Swagemakers, S.M.A., Bertoli Avella, A.M., Lequin, M.H., Dudink, J., Govaert, P., Zwol, A.L. van, Hirst, J., Wessels, M.W., Catsman-Berrevoets, C.E., Verheijen, F.W., Graaff, E. de, Coo, I.F.M. de, Kros, J.M., Willemsen, R., Spek, P.J. van der & Mancini, G.M.S. (2009). Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. American Journal of Human Genetics, 85, 40-52. Vermunt, L.C.A.C., Buysse, C.M.P., Aarsen, F.K., Catsman-Berrevoets, C.E., Duivenvoorden, H.J., Joosten, K.F.M., Hazelzet, J.A., Verhulst, F.C. & Utens, E.M.W.J. (2009). Long-term cognitive functioning in children and adolescents who survived septic shock caused by Neisseria meningitidis. British Journal of Clinical Psychology, 48, 195-208. Wit, M.C.Y. de, Kros, J.M., Halley, D.J.J., Coo, I.F.M. de, Verdijk, R.M., Jacobs, B.C. & Mancini, G.M.S. (2009). Filamin A mutation, a common cause for periventricular heterotopia, aneurysms and cardiac defects. Journal of Neurology Neurosurgery and Psychiatry, 80(4), 426-428. Wit, M.C.Y. de, Coo, I.F.M. de, Halley, D.J.J., Lequin, M.H. & Mancini, G.M.S. (2009). Movement disorder and neuronal migration disorder due to ARFGEF2 mutation. Neurogenetics, 10(4), 333-336. Zwam, M. van, Huizinga, H.G., Melief, J.A.M., Wierenga-Wolf, A.F., Meurs, M. van, Voerman, J.S.A., Biber, KPH, Boddeke, H.W.G.M., Hopken, UE, Meisel, C, Meisel, A, Bechmann, I, Hintzen, R.Q., Hart, B.A. 't, Amor, S., Laman, J.D. & Boven, L.A. (2009). Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE. Journal of Molecular Medicine-Jmm, 87(3), 273-286. Zwam, M. van, Huizinga, H.G., Heijmans, N, Meurs, M. van, Wierenga-Wolf, A.F., Melief, J.A.M., Hintzen, R.Q., Hart, B.A. 't, Amor, S., Boven, L.A. & Laman, J.D. (2009). Surgical excision of CNS-draining lymph nodes reduces relapse severity in chronic-relapsing experimental autoimmune encephalomyelitis. Journal of Pathology, 217(4), 543-551. Part of book - abstract Dijk, J.P. van, Stegeman, D.F., Zwarts, M.J. & Blok, J.H. (2009). Motor unit number estimation with high-density surface EMG: principles and implications. In MB Bromberg (Ed.), Motor unit number estimation (MUNE) and Quantitative EMG. Supplements to Clinical Neurophysiology (pp. 65-78). Amsterdam: Elsevier. Doorn, P.A. van (2009). Spierpijn of krampen. In Probleemgeoriënteerd denken in de neurologie (pp. 265-274). Utrecht: De Tijdstroom. Jacobs, B.C., Belkum, A. van & Endtz, H.P. (2009). Campylobacter. In I Nachamkin, CM Szymanski & MJ Blaser (Eds.), Guillain-Barré syndrome and Campylobacter infection. --: ASM Press. Stoop, M.P., Hintzen, R.Q. & Luider, T.M. (2009). Multiple sclerosis related biomarkers. In O Golubnitschaja (Ed.), Predictive diagnostics and personalized treatment (pp. XVIII). New York: Nove Science publishers. Visser, G.H. & Blok, J.H. (2009). The CMAP scan. In MB Bromberg (Ed.), Motor unit number estimation (MUNE) and Quantitative EMG. Supplements to clinical neurophysiology (pp. 65-78). Amsterdam: Elsevier.

EMC MM-04-47-07 - Organ transplantation Programme design in brief Ischemia reperfusion injury, chronic transplant dysfunction after transplantation, and hepatic steatosis are the main focus of the experimental studies on liver surgery and allotransplantation. Effects of ischemia reperfusion injury are studied in small animal models, including well defined renal, lung and hepatic models. Current experimental research focuses on the molecular mechanisms by which ischemia reperfusion injury leads to organ failure and, in the kidney allotransplantation model, to chronic transplant dysfunction. In addition, the contribution of ageing to this process is being studied. Accumulation of oxidative damage to DNA is thought to play a major role in organismal aging by compromising cellular function, triggering cell death and limiting the proliferative capacity of regenerative tissues. Clinical observations suggest an inverse relationship between ischemia time and long-term transplant success, leading to the hypothesis that this injury leads to processes also activated during premature aging of organs. Use of knockout mice that are defective in DNA repair pathways are used to study the effects of ischemia reperfusion injury after liver resection and organ transplantation. Transcriptional profiling will be used to understand the molecular basis of the injury process. These studies are being conducted in close collaboration with the Department of Cell Biology (Prof. Dr. J. Hoeijmakers) and the Department of Immunology (Prof. Dr. R. Benner). The role of the angiotensin system in renal ischemic damage is studied in collaboration with Dr. T. Walther of the Department of Pharmacology, University Hospital Charité, Berlin, Germany. Ischemia reperfusion injury in the lung is used to study therapeutic options to ameliorate reperfusion injury with the aim to decrease the incidence of acute respiratory distress syndrome and chronic deterioration of lung function following lung transplantation. This is done in collaboration with Prof. Dr. B. Lachmann, Department of Experimental Anaesthesiology, and Prof. Dr. B. Lambrecht, Department of Pulmonary Diseases. Additional studies on hepatic steatosis in relation to resection and transplantation are being studied in close collaboration with Prof. Dr. J. Folkman. Department of Surgery, Childrens Hospital, Harvard Medical School, Boston, USA. Specifically, the roles of matrixmetalloproteinases in the process of hepatic lipid metabolism are being evaluated in rodent models of dietary-induced hepatic steatosis. Research on xenotransplantation has been hampered by potential risks of viral transmission from the animal donor to the human recipient. Progress has been made on genetic modification of donor animals, including elimination of Gal-epitopes and introduction of complement-regulating factors. Using larger animal models the effects of these modifications are being studied in collaboration with Prof. Dr. D. Cooper at the Thomas Starzl Transplantation Institute, Pittsburgh, USA. Studies involving the induction of immunological tolerance are conducted in close collaboration with Prof. Dr. D. Sachs, Transplantation Biology Research Center, Harvard Medical School, Boston, USA. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot gastroenterology & hepatology 0,5 0 0 0 0,5 internal medicine 0,5 0 0 0 0,5 surgery 5,7 0 2,1 2 9,8 Total 6,7 0 2,1 2 10,8 0 0 0 0 22 4 0 26 Article/Letter to the editor Boonstra, P.A., Laan, L.J.W. van der, Vanwolleghem, T. & Janssen, H.L.A. (2009). Experimental Models for Hepatitis C Viral Infection. Hepatology, 50(5), 1646-1655. Crop, M.J., Baan, C.C., Korevaar, S.S., Ijzermans, J.N.M., Alwayn, I.P.J., Weimar, W. & Hoogduijn, M.J. (2009). Donor-Derived Mesenchymal Stem Cells Suppress Alloreactivity of Kidney Transplant Patients. Transplantation, 87(6), 896-906. Demirkiran, A., Sewgobind, V.D.K.D., Weijde, J van der, Kok, A., Baan, C.C., Kwekkeboom, J., Tilanus, H.W., Metselaar, H.J. & Laan, L.J.W. van der (2009). Conversion From Calcineurin Inhibitor to Mycophenolate Mofetil-Based Immunosuppression Changes the Frequency and Phenotype of CD4(+)FOXP3(+) Regulatory T Cells. Transplantation, 87(7), 1062-1068. Dols, L.F.C., Verhoef, C., Eskens, F.A.L.M., Schouten, O., Nonner, J., Hop, W.C.J., Mendez Romero, A.M., Man, R.A. de, Linden, E. van der, Dwarkasing, R.S. & Ijzermans, J.N.M. (2009). Improvement of 5 year survival rate after liver resection for colorectal metastases between 1984-2006. Nederlands Tijdschrift voor Geneeskunde, 153, 490-495. Dols, L.F.C., Kok, N.F.M., Alwayn, I.P.J., Tran, T.C.K., Weimar, W. & Ijzermans, J.N.M. (2009). Laparoscopic Donor Nephrectomy: A Plea for the Right-Sided Approach. Transplantation, 87(5), 745-750. Dols, L.F.C., Weimar, W. & Ijzermans, J.N.M. (2009). Long-Term Consequences of Kidney Donation. New England Journal of Medicine, 360(22), 2371-2372. Dols, L.F.C., Kok, N.F.M. & Ijzermans, J.N.M. (2009). Surgical aspects of live kidney donation. Frontiers in Bioscience, 14, 4746-4757. Gerrits, J.H., Wetering, J. van de, Drabbels, JJ, Ijzermans, J.N.M., Claas, F.H.J., Weimar, W. & Besouw, N.M. van (2009). Non- HLA T-cell reactivity during the first year after HLA-identical living-related kidney transplantation. Clinical Transplantation, 23(5), 740-747. Hendrikx, T.K., Klepper, M., Ijzermans, J., Weimar, W. & Baan, C.C. (2009). Clinical rejection and persistent immune regulation in kidney transplant patients. Transplant Immunology, 21(3), 129-135. Hendrikx, T.K., Gurp, E.A.F.J. van, Mol, W.M., Schoordijk- Verschoor, W., Sewgobind, V.D.K.D., Ijzermans, J.N.M., Weimar, W. & Baan, C.C. (2009). End-stage renal failure and regulatory activities of CD4(+)CD25(bright+)FoxP3(+) T-cells. Nephrology Dialysis Transplantation, 24(6), 1969-1978.

Hendrikx, T.K., Gurp, E.A.F.J. van, Sewgobind, V.D.K.D., Mol, W.M., Schoordijk- Verschoor, W., Klepper, M., Velthuis, J.H.L., Geel, A.N. van, Ijzermans, J.N.M., Weimar, W. & Baan, C.C. (2009). Generation of Donor-Specific Regulatory T-Cell Function in Kidney Transplant Patients. Transplantation, 87(3), 376-383. Khan, N.A., Susa, D., Berg, J.W. van den, Huisman, M., Ameling, M.H., Engel, S. van den, Roest, H.P., Ijzermans, J.N.M., Dik, W.A., Benner, R. & Bruin, R.W.F. de (2009). Amelioration of renal ischaemia-reperfusion injury by synthetic oligopeptides related to human chorionic gonadotropin. Nephrology Dialysis Transplantation, 24(9), 2701-2708. Kranenburg, L.W., Richards, M, Zuidema, W.C., Weimar, W., Hilhorst, M.T., Ijzermans, J.N.M., Passchier, J. & Busschbach, J.J.V. van (2009). Avoiding the issue: Patients' (non)communication with potential living kidney donors. Patient Education and Counseling, 74(1), 39-44. Kranenburg, L.W., Zuidema, W., Weimar, W., Hilhorst, M.T., Ijzermans, J., Passchier, J. & Busschbach, J.J. van (2009). Strategies to advance living kidney donation: a single center's experience. Progress in Transplantation, 19(1), 71-75. Meijer, V.E. de, Verhoef, C. & Ijzermans, J.N.M. (2009). Radiofrequency Ablation in the Treatment of Hepatocellular Carcinoma: The Need for Centralization. Annals of Surgery, 250(3), 497-498. Mendez Romero, A.M., Zinkstok, R.T., Wunderink, W., Os, RM van, Joosten, P.J., Seppenwoolde, Y., Nowak, P.J.C.M., Brandwijk, R.P., Verhoef, C., Ijzermans, J.N.M., Levendag, P.C. & Heijmen, B.J.M. (2009). Stereotactic body radiation therapy for liver tumors: impact of daily setup corrections and day- to day anatomic anatomic variations on dose in target and organs at risk. International Journal of Radiation Oncology Biology Physics, 75(4), 1201-1208. Pan, Q., Henry, S.D., Metselaar, H.J., Scholte, B., Kwekkeboom, J., Tilanus, H.W., Janssen, H.L.A. & Laan, L.J.W. van der (2009). Combined antiviral activity of interferon-alpha and RNA interference directed against hepatitis C without affecting vector delivery and gene silencing. Journal of Molecular Medicine-Jmm, 87(7), 713-722. Pan, Q., Tilanus, H.W., Janssen, H. & Laan, L.J.W. van der (2009). Prospects of RNAi and microrna-based therapies for hepatitis C. Expert Opinion on Biological Therapy, 9(6), 713-724. Pool, A.E.M. van der, Lalmahomed, Z.S., Wilt, J.H.W. de, Eggermont, A.M.M., Ijzermans, J.N.M. & Verhoef, C. (2009). Local Treatment for Recurrent Colorectal Hepatic Metastases after Partial Hepatectomy. Journal of Gastrointestinal Surgery, 13(5), 890-895. Roefs, A.M.J., Ende, M.E. van der, Ijzermans, J.N.M., Weimar, W. & Gelder, T. van (2009). Long-term survival after kidney transplantation in an HIV-positive patient. Clinical Transplantation, 23(2), 278-281. Roodnat, J.I., Kal-van Gestel, J.A., Zuidema, W., Noord, MAA van, Wetering, J. van de, Ijzermans, J.N.M. & Weimar, W. (2009). Successful Expansion of the Living Donor Pool by Alternative Living Donation Programs. American Journal of Transplantation, 9(9), 2150-2156. Sewgobind, V.D.K.D., Kho, M.M.L., Laan, L.J.W. van der, Hendrikx, T.K., Dam, T. van, Tilanus, H.W., Ijzermans, J.N.M., Weimar, W. & Baan, C.C. (2009). The effect of rabbit anti-thymocyte globulin induction therapy on regulatory T cells in kidney transplant patients. Nephrology Dialysis Transplantation, 24(5), 1635-1644. Sluis, F.J. van der, Bosch, J.L., Terkivatan, T., Man, R.A. de, Ijzermans, J.N.M. & Hunink, M.G.M. (2009). Hepatocellular adenoma: cost-effectiveness of different treatment strategies. Radiology, 252(3), 737-746. Terkivatan, T. & Ijzermans, J.N.M. (2009). Hepatocellular adenoma Should phenotypic classification direct management? Nature reviews gastroenterology & Hepatology, 6(12), 697-698. Wetering, J. van de, Gerrits, J.H., Besouw, N.M. van, Ijzermans, J.N.M. & Weimar, W. (2009). Successful Tapering of Immunosuppression to Low-Dose Monotherapy Steroids After Living-Related Human Leukocyte Antigen-Identical Renal Transplantation. Transplantation, 87(5), 740-744. Zuidema, W.C., Roodnat, J.I., Kranenburg, L.W., Erdman, R.A.M., Hilhorst, M.T., Ijzermans, J.N.M. & Weimar, W. (2009). Program for Samaritan kidney donation at Erasmus University Medical Center, 2000- September 2008. Nederlands Tijdschrift voor Geneeskunde, 153(13), 595-599.

EMC MM-04-49-03-A - Genitourinary tract disorders in children Programme design in brief Experimental and clinical investigation of normal and pathological function and recovery of the urinary tract and reproductive tract. Antenatal diagnostics, detection of congenital disorders before birth and the resulting postnatal evaluation and treatment. Bladder dysfunction, neurogenic and structural. The mechanisms that connect loss of bladder and renal function to changes in bladder structure plus new treatments are investigated in an animal model for infravesical obstruction. Raman spectroscopy is applied for in vitro and in vivo analysis of the bladder wall-structure (also in bladder cancer). In co-operation with the centre for optical diagnostics and therapy, Dr. G.J. Puppels. Gonadal dysgenesis. The chromosal changes occuring in gonadal tissue of patients with gonadal dysgenesis are studied to improve its diagnosis, to gain insight into its development and to discover early markers of testicular cancer. Joint KWF project with the laboratory of experimental pathology and oncology, Dr. L.H.J. Looijenga. Hypospadia, possible causes of hypospadias like androgen receptor and the effect of hypospadias correction on urodynamics are investigated. Inborn errors predisposing to stone formation. The role of inborn errors in renal metabolite handling for urinary stone formation is studied. Obstruction and reflux, of the pyelo-ureteric junction, ureter with (functional) obstructions, vesicoureteric reflux and infravesical obstruction in prospective studies. In co-operation with the department of Nuclear Medicine, Prof. Dr. H.Y. Oei. Urinary tract infection. Proteomics and bacterial DNA analysis are used to study bacterial populations in the urinary tract and to improve diagnosis of UTI. Specific complications like bladder stone formation are analysed. New bladder rinsing fluids are developed. In co-operation with departments of medical microbiology and infectious diseases, Prof. Dr. A van Belkum, Center for Biomics, Dr. T.M. Luider and obstetrics, Dr. T Schneider. Urodynamic investigations, in connection to the other projects the value of urodynamic evaluations is investigated in cooperation with FURORE Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot urology 1,2 0 0 0 1,2 Total 1,2 0 0 0 1,2 0 0 0 0 4 1 0 5 Article/Letter to the editor Cools, M.B.C., Looijenga, L.H.J., Wolffenbuttel, K.P. & Drop, S.L.S. (2009). Disorders of sex development: update on the genetic background, terminology and risk for the develoment of germ cell tumors. World Journal of Pediatrics, 5(2), 93-102. Goossens, K., Juniarto, A.Z., Timmerman, M.A., Faradz, SMH, Wolffenbuttel, K.P., Drop, S.L.S. & Jong, F.H. de (2009). Lack of correlation between phenotype and genotype in untreated 21-hydroxylase-deficient Indonesian patients. Clinical Endocrinology, 71, 628-635. Hoek, J. van den, Krijger, R.R. de, Ven, C.P. van de, Lequin, M.H. & Heuvel-Eibrink, M.M. van den (2009). Cystic nephroma, cystic partially differentiated nephroblastoma and cystic Wilm's tumor in children: a spectrum with therapeutic dilemmas. Urologia Internationalis, 82, 65-70. Hoek, J. van den, Beckers, G.M.A., Gier, R.P. de & Jong, T.P. de (2009). One sided multiscystic dysplastic kidney in children. Nederlands Tijdschrift voor Geneeskunde, 153(16), 768-771. Wielen, G.J. van der, Vermeij, M., Jong, B.W.D. de, Schuit, M.R.H., Marijnissen, J.P.A., Kok, D.J., Weerden, W.M. van & Incrocci, L. (2009). Changes in the Penile Arteries of the Rat after Fractionated Irradiation of the Prostate: A Pilot Study. Journal of Sexual Medicine, 6(7), 1908-1913.

EMC MM-04-54-07 - Disorders of the gastrointestinal tract in childhood Programme design in brief The digestive tract is under constant attack by bacteria, viruses and other noxious agents in the lumen of the gastrointestinal tract. The gastrointestinal mucosa, consisting of the epithelium and the underlying immune cells in the lamina propria, forms an important line of defence against these potential harmful agents. Mucosal damage may lead to malabsorption and diarrhea, since the gastrointestinal epithelium is essential for the digestion and uptake of nutrients and for the maintenance of the liquid balance in the human body. Many types of gastrointestinal diseases lead to mucosal damage. The mission of the research program is to unravel the mechanisms underlying normal function and disorders of the gastrointestinal tract including the liver, in childhood by means of integrated pre-clinical and clinical research. This research aims at the development of strategies for prevention, diagnosis, and treatment of gastrointestinal diseases. In particular, research is focussed on mechanisms responsible for damage and subsequent regeneration of the gastrointestinal tract in 1. Inflammatory bowel diseases (Crohn and ulcerative colitis), 2. Infectious diseases (rotavirus or norovirus, E. coli) 3. Inherited diseases (cystic fibrosis, CrigIer Najjar), and 4. after chemotherapy. The relevance is perhaps best illustrated by the high incidence of each of the studied diseases. Possibilities are evaluated of intervention using dietary components, probiotics, or drugs, either to prevent mucosal damage or to stimulate the recovery of mucosal functions after an insult. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot pediatrics 4 1 3 0,14 8,14 Total 4 1 3 0,14 8,14 0 0 0 0 14 2 0 16 Article/Letter to the editor Berg, A. van den, Elburg, R.M. van, Vermeij, L., Zwol, A.L. van, Brink, G.R. van den, Twisk, J.W.R., Nieuwenhuis, E.E.S. & Fetter, W.P.F. (2009). Cytokine responses in very low birth weight infants receiving glutamine-enriched enteral nutrition. Journal of Pediatric Gastroenterology and Nutrition, 48, 94-101. Bijvelds, M.J.C., Bot, A.G.M., Escher, J.C. & Jonge, H.R. de (2009). Activation of intestinal CI-secretion by lubiprostone requires the cystic fibrosis transmembrane conductance regulator. Gastroenterology, 137, 976-985. Broere, F., Pre, M.F. du, Berkel, L.A. van, Garssen, J., Schmid-Weber, CB, Lambrecht, B.N., Hendriks, R.W., Nieuwenhuis, E.E.S., Kraal, G. & Samsom, J.N. (2009). Cyclooxygenase-2 in mucosal DC mediates induction of regulatory T cells in the intestine through suppression of IL-4. Mucosal Immunology, 2(3), 254-264. Brugman, S., Liu, K.Y., Lindenbergh-Kortleve, D.J, Samsom, J.N., Furuta, G.T., Renshaw, S.A., Willemsen, R. & Nieuwenhuis, E.E.S. (2009). Oxazolone-induced enterocolitis in zebrafish depends on the composition of the intestinal microbiota. Gastroenterology, 137, 1757-1767. Cucchiara, S, Escher, J.C., Hildebrand, H, Amil-Dias, J., Stronati, L. & Ruemmele, F.M. (2009). Pediatric inflammatory bowel disease and the risk of lymphoma: should we revise our treatment strategies? Journal of Pediatric Gastroenterology and Nutrition, 48, 257-267. Deutekom, A.W. van, Beukenhorst, H.L., Ridder, L. de & Kuip, M. v.d. (2009). Een adolescent met ondervoeding, purpura en chronische diarree bij wie colitis ulcerosa werd aangetroffen. Nederlands Tijdschrift voor Geneeskunde, 153(4), 142-146. Dieren, J.M. van, Bodegraven, A.A. van, Kuipers, E.J., Bakker, E.N., Poen, A.C., Dekken, H. van, Nieuwenhuis, E.E.S. & Woude, C.J. van der (2009). Local application of tacrolimus in distal colitis: feasible and safe. Inflammatory Bowel Diseases, 15(2), 193-198. Escher, J.C. (2009). Transition form pediatric to adult health care in inflammatory bowel disease. Digestive Diseases, 27, 382-386. Groeneweg, M., Poley, J.W., Dansen, M.J., Brinkman, J.G., Escher, J.C. & Nieuwenhuis, E.E.S. (2009). Chronic hereditary pancretatitis in a girl with a serine protease inhibitor Kazal type I (SPINK-1) gene mutation an a Coxsackie type B5 infection. Pediatric Infectious Disease Journal, 28(2), 169-170. Ham, S.M. van, Samsom, J.N., Bos, N.A., Damoiseaux, J., Laman, J.D. & Wauben, M.H.M. (2009). Vaccination immunology: Prevention and beyond. NVVI-Dutch society for immunology course Lunteren, 2008, April 3-4. Immunology Letters, 122, 101-103. Hol, J., Jongste, J.C. de & Nieuwenhuis, E.E.S. (2009). Quoting a landmark paper on the beneficial effects of probiotics. Journal of Allergy and Clinical Immunology, 124(6), 1354-1355. Lierop, P.P.E. van, Samsom, J.N., Escher, J.C. & Nieuwenhuis, E.E.S. (2009). Role of the innate immune system in the pathogenesis of inflammatory bowel disease. Journal of Pediatric Gastroenterology and Nutrition, 48, 142-151. Middendorp, S. & Nieuwenhuis, E.E.S. (2009). NKT cells in mucosal immunity. Mucosal Immunology, 2(5), 393-402. Nieuwenhuis, E.E.S., Matsumoto, T., Lindenbergh-Kortleve, D.J, Willemsen, R., Kaser, A., Oosterhuis, Y., Brugman, S., Yamaguchi, K., Ishikawa, H., Aiba, Y., Koga, Y., Samsom, J.N., Oshima, K., Kikuchi, M., Escher, J.C., Hattori, M., Onderdonk, A.B. & Blumberg, R.S. (2009). Cd1d-dependent regulation of bacterial colonization in the intestine of mice. Journal of Clinical Investigation, 119(5), 1241-1250.

Vervloessem, D.M.A., Leersum, F.S. van, Boer, D., Hop, W.C.J., Escher, J.C., Madern, G.C., Ridder, L. de & Bax, N.M.A. (2009). Percutaneous endoscopic gastrostomy (PEG) in children is not a minor procedure: risk factors for major complications. Seminars in Pediatric Surgery, 18, 93-97. Zwol, A.L. van, Berg, A. van den, Nieuwenhuis, E.E.S., Twisk, J.W.R., Fetter, W.P.F. & Elburg, R.M. van (2009). Cytokine profiles in 1-year-old very low birth weight infants after enteral glutamine supplementation in the neonatal periode. Pediatric Allergy and Immunology, 20, 467-470.

EMC MM-04-54-08-A - Clinical, epidemiological and basic research of infectious diseases and immunological diseases in children Programme design in brief This programme aims to enhance the understanding of the (molecular) pathogenesis, pathobiology, epidemiology, diagnosis, therapy and prevention of infectious diseases and immunological disorders in children by means of clinical and basic research. Infectious diseases are the major cause of morbidity in children and contribute substantially towards mortality in children needing topclinical care including those with AIDS, meningococcal sepsis and immunocompromised children with sepsis. Primary and secondary (acquired) immunodeficiencies as well as immunodysregulations, in particular auto-immunity, are frequent diagnostic and therapeutic challenges and often complicated by (serious) infections. The studies carried out within this project aim to increase the understanding of interactions between host and micro-organisms and to improve the diagnostic, therapeutic and preventive modalities of infectious diseases and immunological disorders. Key figures Department SP1 SP2 SP3 SP4 SPtot T1 T2 T3 Ttot IS FS OP Ptot Generation R 2 0 0 0 2 pediatrics 5,86 0 8,8 3 17,66 Total 7,86 0 8,8 3 19,66 1 0 0 1 60 8 3 72 Thesis Kampen, J.J.A. van (2009, oktober 21). Mass spectrometry to determine intracellular concentrations of antiretroviral drugs. EUR (216 pag.) (Rotterdam: Optima Grafische Communicatie). Prom./coprom.: Prof.Dr. P.A.E. Sillevis Smitt, Prof.Dr. R. de Groot & Dr. T.M. Luider. Article/Letter to the editor Albers, H.M., Kurreeman, FAS, Stoeken-Rijsbergen, G., Brinkman, D.M.C., Kamphuis, S.S.M., Rossum, M.A.J. van, Girschick, H.J., Wouters, C., Saurenmann, R.K., Hoppenreijs, E.P.A.H., Slagboom, P.E., Houwing-Duistermaat, J.J., Verduijn, W., Huizinga, T.W.J., Cate, R. ten, Toes, R.E.M. & Schilham, M.W. (2009). Association of the autoimmunity locus 4q27 with juvenile idiopathic arthritis. Arthritis & Rheumatism, 60(3), 901-904. Albers, H.M., Kurreeman, FAS, Houwing-Duistermaat, J.J., Brinkman, D.M.C., Kamphuis, S.S.M., Girschick, H.J., Wouters, C., Rossum, M.A.J. van, Verduijn, W., Toes, R.E.M., Huizinga, T.W.J., Schilham, M.W. & Cate, R. ten (2008). The TRAF1/C5 region is a risk factor for polyarthritis in juvenile idiopathic arthritis. Annals of the Rheumatic Diseases, 67, 1578-1580. Albers, H.M., Wessels, J.A.M., Straaten, R.J.H.M. van der, Brinkman, D.M.C., Suijlekom-Smit, L.W.A. van, Kamphuis, S.S.M., Girschick, H.J., Wouters, C., Schilham, M.W., Cessie, S. le, Huizinga, T.W.J., Cate, R. ten & Guchelaar, HJ (2009). Time to treatment as an important factor for the response to methotrexate in juvenile idiopathic arthritis. Arthritis & Rheumatism, 61(1), 46-51. Ay, L., Houten, V.A.A. van, Steegers, E.A.P., Hofman, A., Witteman, J.C.M., Jaddoe, V.W.V. & Hokken-Koelega, A.C.S. (2009). Fetal and Postnatal Growth and Body Composition at 6 Months of Age. Journal of Clinical Endocrinology and Metabolism, 94(6), 2023-2030. Ay, L., Kruithof, C.J., Bakker, R., Steegers, E.A.P., Witteman, J.C.M., Moll, H.A., Hofman, A., Mackenbach, J.P., Hokken- Koelega, A.C.S. & Jaddoe, V.W.V. (2009). Maternal anthropometrics are associated with fetal size in different periods of pregnancy and at birth. The Generation R Study. Bjog-An International Journal of Obstetrics and Gynaecology, 116(7), 953-963. Batenburg-Eddes, T. van, Groot, L. de, Huizink, A.C., Steegers, E.A.P., Hofman, A., Jaddoe, V.W.V., Verhulst, F.C. & Tiemeier, H. (2009). Maternal Symptoms of Anxiety During Pregnancy Affect Infant Neuromotor Development: The Generation R Study. Developmental Neuropsychology, 34(4), 476-493. Been, J.V., Kornelisse, R.F., Rours, G.I.J.G., Lima Passos, V., Krijger, R.R. de & Zimmermann, L.J.I. (2009). Early postnatal blood pressure in preterm infants: effects of chorioamnionitis and timing of antenatal steriods. Pediatric Research, 66(5), 571-576. Been, J.V., Rours, G.I.J.G., Kornelisse, R.F., Lima Passos, V., Kramer, B.W., Schneider, T.A.J., Krijger, R.R. de & Zimmermann, L.J.I. (2009). Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants. American Journal of Obstetrics and Gynecology, 201, 587.e1-587.e8. Beersma, M.F.C., Schutten, M., Vennema, H., Hartwig, N.G., Mes, T.H.M., Osterhaus, A.D.M.E., Doornum, G.J.J. van & Koopmans, M.P.G. (2009). Norovirus in a Dutch tertiary care hospital (2002-2007): frequent nosocomial transmission and dominance of GIIb strains in young children. Journal of Hospital Infection, 71, 199-205. Berg, M.P. van den, Ende, J. van der, Crijnen, A.A.M., Jaddoe, V.W.V., Moll, H.A., Mackenbach, J.P., Hofman, A., Hengeveld, M.W., Tiemeier, H. & Verhulst, F.C. (2009). Paternal Depressive Symptoms During Pregnancy Are Related to Excessive Infant Crying. Pediatrics, 124(1), E96-E103. Coulier, L, Kampen, J.J.A. van, Groot, R. de, Gerritsen, HW, Bas, RC, Dongen, WD van, Brull, LP & Luider, T.M. (2009). Simultaneous detemination of endogenous deoxynucleotides and phosphorylated nucleoside reverse transcriptase inhibitors in peripheral blood mononuclear cells using ion-pair liquid chromatography coupled to mass spectrometry. Proteomics Clinical Applications, 2, 1557-1562.

Dierckx, B., Tulen, J.H.M., Berg, M.P. van den, Tharner, A., Jaddoe, V.W.V.K., Moll, H.A., Hofman, A., Verhulst, F.C. & Tiemeier, H. (2009). Maternal Psychopathology Influences Infant Heart Rate Variability: Generation R Study. Psychosomatic Medicine, 71(3), 313-321. Duijts, L., Ramadhani, M.K. & Moll, H.A. (2009). Breastfeeding protecs against infectious diseases during infancy in industrialized countries. A systematic review. Maternal and Child Nutrition, 5, 199-210. Duijts, L., Bakker-Jonges, L.E., Labout, J.A.M., Jaddoe, V.W.V., Hofman, A., Steegers, E.A.P., Dongen, J.J.M. van, Hooijkaas, H. & Moll, H.A. (2009). Fetal Growth Influences Lymphocyte Subset Counts at Birth: The Generation R Study. Neonatology, 95(2), 149-156. Duijts, L., Bakker-Jonges, L.E., Mook, D.O., Labout, J.A.M., Hofman, A., Duijn, C.M. van, Dongen, J.J.M. van, Hooijkaas, H., Moll, H.A. & Jaddoe, V.W.V.K. (2009). Variation in the IGF-1 gene is associated with lymphocyte subset counts in neonates: The Generation R study. Clinical Endocrinology, 70, 53-59. Elfrink, M.E.C., Veerkamp, J.S.J., Aartman, IHA, Moll, H.A. & Cate, J.M. ten (2009). Validity of scoring caries and primary molar hypomineralization (DMH) on intraoral photographs. European Archives of Paediatric Dentistry, 10(supl. 1), 5-9. Geelhoed, J.J.M., Steegers, E.A.P., Osch-Gevers, M. van, Verburg, B.O., Hofman, A., Witteman, J.C.M., Heijden, A.J. van der, Helbing, W.A. & Jaddoe, V.W.V. (2009). Cardiac structures track during the first 2 years of life and are associated with fetal growth and hemodynamics: The Generation R Study. American Heart Journal, 158(1), 71-77. Geelhoed, J.J.M., Verburg, B.O., Nautal, J, Lequin, M., Hofman, A., Moll, H.A., Witteman, J.C.M., Heijden, A.J. van der, Steegers, E.A.P. & Jaddoe, V.W.V. (2009). Tracking and Determinants of Kidney Size From Fetal Life Until the Age of 2 Years: The Generation R Study. American Journal of Kidney Diseases, 53(2), 248-258. Geelhoed, M.J.J., Snijders, S.P.E., Kleyburg-Linkers, V.E., Steegers, E.A.P., Osch-Gevers, M. van & Jaddoe, V.W.V.K. (2009). Reliability of echocardiographic measurements of left cardiac structures in healthy children. Cardiology in the Young, 19(5), 494-500. Geerdink, L.M., Prince, F.H.M., Looman, C.W.N. & Suijlekom-Smit, L.W.A. van (2009). Development of a digital Childhood Health Assessment Questionnaire for systematic monitoring of disease activity in daily practice. Rheumatology, 48(8), 958-963. Goetghebuer, T. (2009). Effect of early antiretroviral therapy on the risk of AIDS/death in HIV-infected infants. European Infant Collaboration group. Aids, 23, 597-604. Goossens, L.M.A., Standaert, B., Hartwig, N.G., Hovels, A.M. & Maiwenn, AL (2009). Conclusions on cost-effectiveness of rotavirus vaccination highly dependent on assumptions. Vaccine, 27, 2531-2532. Hartwig, N.G., Rumke, H.C. & Visser, H.K.A. (2009). Vaccineren tegen waterpokken, gordelroos en rotavirus-infectie. Nederlands Tijdschrift voor Geneeskunde, 153(44), 2157-2161. Hendriksen, W.T., Bootsma, H.J., Diepen, A. van, Estevao, S.C., Kuipers, OP, Groot, R. de & Hermans, P.W.M. (2009). Strainspecific impct of PsaR of Streptococcus pneumoniae on global gene expression and virulence. Microbiology, 155, 1569-1579. Henrichs, J., Schenk, J.J.A.M., Schmidt, H.G., Arends, L.R., Steegers, E.A.P., Hofman, A., Jaddoe, V.W.V., Verhulst, F.C. & Tiemeier, H. (2009). Fetal Size in Mid- and Late Pregnancy Is Related to Infant Alertness: The Generation R Study. Developmental Psychobiology, 51(2), 119-130. Holzhauer, S., Hokken-Koelega, A.C.S., Ridder, M de, Hofman, A., Moll, H.A., Steegers, E.A.P., Witteman, J.C.M. & Jaddoe, V.W.V. (2009). Effect of birth weight and postnatal weight gain on body composition in early infancy The Generation R Study. Early Human Development, 85(5), 285-290. 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