Gertjan J L Kaspers

VU University Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (315)1664.7 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Wilms tumour postoperative chemotherapy is ideally stratified according to the pathologist's assessment of tumour stage and risk classification (tumour type). In sub-Saharan Africa results are often not available in time to influence therapy and in Malawi surgical staging has been used to stratify postoperative chemotherapy. Here we compare the results from surgical and both local pathology and central pathology review.ProcedureChildren diagnosed with a Wilms tumour in Blantyre, Malawi between 2007 and 2011 were included if they had a nephrectomy and the pathology slides were available. All tumour specimens were assessed in three different ways: the local surgeon documented the surgical stage of the tumour, and the risk classification and pathology stage were assessed both by the local pathologist and by a SIOP central review pathologist in Europe.ResultsFifty patients had complete data available and were included in the analyses. Tumour risk classification differed between the local and central pathology review in only two patients (4%). Using central pathology review as the gold standard 60% of patients received the correct postoperative chemotherapy treatment based on surgical staging and 84% based on the local pathology stage and risk classification.Conclusion Local pathology capacity building is needed to enable timely assessment and reporting. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 09/2014; · 2.35 Impact Factor
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    ABSTRACT: Improvement in survival of pediatric acute lymphoblastic leukemia (ALL) has increased the attention to quality of life (QoL) . QoL is impaired during maintenance treatment, but little is known about QoL during induction therapy. Identification of patients with poor QoL during induction will provide opportunities for early interventions, and may subsequently improve future QoL. This national multi-center study aimed to assess QoL and its determinants during ALL induction treatment.
    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 07/2014;
  • Pediatric hematology and oncology. 07/2014;
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    ABSTRACT: Outcome for relapsed paediatric acute myeloid leukaemia (AML) remains poor. Strong prognostic factors at first relapse are lacking, which hampers optimization of therapy. We assessed the frequency of molecular aberrations (FLT3, NRAS, KRAS, KIT, WT1 and NPM1 genes) at first relapse in a large set (n = 198) of relapsed non-French-American-British M3, non-Down syndrome AML patients that received similar relapse treatment. We correlated molecular aberrations with clinical and biological factors and studied their prognostic relevance. Hotspot mutations in the analysed genes were detected in 92 out of 198 patients (46·5%). In 72 of these 92 patients (78%), molecular aberrations were mutually exclusive for the currently analysed genes. FLT3-internal tandem repeat (ITD) (18% of total group) mutations were most frequent, followed by NRAS (10·2%), KRAS (8%), WT1 (8%), KIT (8%), NPM1 (5%) and FLT3-tyrosine kinase domain (3%) mutations. Presence of a WT1 aberration was an independent risk factor for second relapse (Hazard Ratio [HR] = 2·74, P = 0·013). In patients who achieved second complete remission (70·2%), WT1 and FLT3-ITD aberrations were independent risk factors for poor overall survival (HR = 2·32, P = 0·038 and HR = 1·89, P = 0·045 respectively). These data show that molecular aberrations at first relapse are of prognostic relevance and potentially useful for risk group stratification of paediatric relapsed AML and for identification of patients eligible for personalized treatment.
    British Journal of Haematology 06/2014; · 4.94 Impact Factor
  • Acta neuropathologica. 06/2014;
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    ABSTRACT: Although diffuse intrinsic pontine glioma (DIPG) carries the worst prognosis of all pediatric brain tumors, studies on prognostic factors in DIPG are sparse. To control for confounding variables in DIPG studies, which generally include relatively small patient numbers, a survival prediction tool is needed.
    Neuro-oncology. 06/2014;
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    ABSTRACT: Background: Chemotherapy and radiotherapy for childhood cancer can result in a decreased reproductive function. It is therefore important that paediatric oncologists discuss the possible impact of treatment on female fertility and available fertility preservation options with their patients. However, it is unknown what Dutch paediatric oncologists know about of the effect of cancer treatment on female fertility, whether or not they address this issue in clinical practice, what their attitudes are towards addressing fertility after cancer treatment and fertility preservation options, and to what extent they require additional information resources. Methods: In this nationwide quantitative cross-sectional study a survey was sent to all registered paediatric oncologists in the Netherlands (n=64). Results: Thirty-seven paediatric oncologists participated (participation rate 58%). Fertility issues were discussed with patients and÷or parents by 97%. Of the paediatric oncologists, 54-76% were aware of possibilities for fertility preservation; however only.
    The Netherlands Journal of Medicine 06/2014; 72(5):264-70. · 2.38 Impact Factor
  • Gertjan Kaspers
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    ABSTRACT: The prognosis of paediatric acute myeloid leukaemia (AML) has improved significantly over the recent decades, but still about one-third of patients relapse. These patients have a relatively poor prognosis, with a probability of long-term survival from relapse of about 35%. This can only be achieved with very intensive chemotherapy and, usually, allogeneic stem cell transplantation, leading to very significant toxicity and even treatment-related mortality. Major improvements in the treatment of paediatric relapsed AML thus are required still, and several possibilities are discussed. In case of a suspected relapse, a comprehensive diagnostic work-up has to be undertaken, because significant changes in the biological features of the AML cells may have occurred between initial diagnosis and relapse. This review discusses many practical issues that one encounters in the treatment of children with relapsed AML. It will also be of interest for those involved in translational research in AML.
    British Journal of Haematology 05/2014; · 4.94 Impact Factor
  • Haematologica 05/2014; · 5.94 Impact Factor
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    ABSTRACT: Background The principal reason for childhood cancer treatment failure in low-income countries is treatment abandonment, the most severe form of nonadherence. Two often neglected factors that may contribute to treatment abandonment are as follows: (a) lack of information and guidance by doctors, along with the negative beliefs of family and friends advising parents, which contributes to misconceptions regarding cancer and its treatment, and (b) a widespread policy in public hospitals by which children are retained after doctor's discharge until medical bills are settled.Objective This study explored parents' experiences with hospital retention policies in a Kenyan academic hospital and the impact of attitudes of family and friends on parents' decisions about continuing cancer treatment for their child.Methods Home visits were conducted to interview parents of childhood cancer patients who had been diagnosed between 2007 and 2009 and who had abandoned cancer treatment.ResultsRetrospective chart review revealed 98 children diagnosed between 2007 and 2009 whose parents had made the decisions to abandon treatment. During 2011–2012, 53 families (54%) could be reached, and 46 (87%) of these agreed to be interviewed. Parents reported the attitudes of community members (grandparents, relatives, friends, villagers, and church members); 61% believed that the child had been bewitched by some individual, and 74% advised parents to seek alternative treatment or advised them to stop medical treatment (54%). Parents also reported that they were influenced by discussions with other parents who had a child being treated, including that their child's life was in God's hands (87%), the trauma to the child and family of forced hospital stays (84%), the importance of completing treatment (81%), the financial burden of treatment (77%), and the incurability of cancer (74%). These discussions influenced their perceptions of cancer treatment and its usefulness (65%). Thirty-six families (78%) had no health insurance, and 19 of these parents (53%) could not pay their medical bills and were not allowed to take their child home when treatment ended. Parents reported feelings of desperation (95%), powerlessness (95%), and sadness (84%) and that their child has been imprisoned (80%), during the period of retention. The majority of parents (87%) felt that hospital retention of children must cease.Conclusions The attitudes and beliefs of parents of children with cancer are impacted by those close to them and their community and may influence their perceptions of cancer treatment and decisions to stop treatment. Hospital retention policies are highly distressing for parents and may contribute to both treatment delays and treatment abandonment. These factors jeopardize treatment outcomes for young patients and require attention and modification. Copyright © 2014 John Wiley & Sons, Ltd.
    Psycho-Oncology 05/2014; · 3.51 Impact Factor
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    ABSTRACT: Diffuse intrinsic pontine glioma (DIPG), with a median survival of only 9 months, is the leading cause of pediatric brain cancer mortality. Dearth of tumor tissue for research has limited progress in this disease until recently. New experimental models for DIPG research are now emerging. To develop preclinical models of DIPG, two different methods were adopted: cells obtained at autopsy (1) were directly xenografted orthotopically into the pons of immunodeficient mice without an intervening cell culture step or (2) were first cultured in vitro and, upon successful expansion, injected in vivo. Both strategies resulted in pontine tumors histopathologically similar to the original human DIPG tumors. However, following the direct transplantation method all tumors proved to be composed of murine and not of human cells. This is in contrast to the indirect method that included initial in vitro culture and resulted in xenografts comprising human cells. Of note, direct injection of cells obtained postmortem from the pons and frontal lobe of human brains not affected by cancer did not give rise to neoplasms. The murine pontine tumors exhibited an immunophenotype similar to human DIPG, but were also positive for microglia/macrophage markers, such as CD45, CD68 and CD11b. Serial orthotopic injection of these murine cells results in lethal tumors in recipient mice. Direct injection of human DIPG cells in vivo can give rise to malignant murine tumors. This represents an important caveat for xenotransplantation models of DIPG. In contrast, an initial in vitro culture step can allow establishment of human orthotopic xenografts. The mechanism underlying this phenomenon observed with direct xenotransplantation remains an open question.
    Acta Neuropathologica 04/2014; · 9.73 Impact Factor
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    ABSTRACT: Salinosporamide A (NPI-0052, marizomib) is a naturally-occurring proteasome inhibitor derived from the marine actinobacterium Salinispora tropica and represents a promising clinical agent in the treatment of hematologic malignancies. Recently, these actinobacteria were shown to harbor self-resistance properties to salinosporamide A by expressing redundant catalytically-active mutants of the 20S proteasome β-subunit, reminiscent of PSMB5 mutations identified in cancer cells with acquired resistance to the founding proteasome inhibitor, bortezomib. Here, we assessed the growth inhibitory potential of salinosporamide A in human acute lymphocytic leukemia CCRF-CEM cells, and its 10-fold (CEM/BTZ7), and 123-fold (CEM/BTZ200) bortezomib-resistant sublines harboring PSMB5 mutations. Parental cells displayed sensitivity to salinosporamide A (IC50= 5.1 nM), whereas their bortezomib-resistant sublines were 9- and 17-fold cross-resistant to salinosporamide A, respectively. Notably, combination experiments of salinosporamide A and bortezomib showed synergistic activity in CEM/BTZ200 cells. CEM cells gradually exposed to 20 nM salinosporamide A (CEM/S20) displayed stable 5-fold acquired resistance to salinosporamide A and were 3-fold cross-resistant to bortezomib. Consistent with the acquisition of a PSMB5 point mutation (Met45Val) in CEM/S20 cells, salinosporamide A displayed a markedly impaired capacity to inhibit β5-associated catalytic activity. Lastly, compared to parental CEM cells, CEM/S20 cells exhibited up to 2.5-fold upregulation of constitutive proteasome subunits, while retaining unaltered immunoproteasome subunit expression. In conclusion, salinosporamide A displayed potent antileukemic activity against bortezomib-resistant leukemia cells. β-subunit point mutations as a common feature of acquired resistance to salinosporamide A and bortezomib in hematologic cells and Salinispora tropica suggest an evolutionarily conserved mechanism of resistance to proteasome inhibitors.
    Molecular pharmacology 04/2014; · 4.53 Impact Factor
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    ABSTRACT: Pediatric acute lymphoblastic leukemia (ALL) is treated with combination chemotherapy including mercaptopurine (6MP) as an important component. Upon its uptake, 6MP undergoes a complex metabolism involving many enzymes and active products. The prognostic value of all the factors engaged in this pathway still remains unclear. This study attempted to determine which components of 6MP metabolism in leukemic blasts and red blood cells are important for 6MP's sensitivity and toxicity. In addition, changes in the enzymatic activities and metabolite levels during the treatment were analyzed. In a cohort (N = 236) of pediatric ALL patients enrolled in the Dutch ALL-9 protocol, we studied the enzymes inosine-5'-monophosphate dehydrogenase (IMPDH), thiopurine S-methyltransferase (TPMT), hypoxanthine guanine phosphoribosyl transferase (HGPRT), and purine nucleoside phosphorylase (PNP) as well as thioguanine nucleotides (TGN) and methylthioinosine nucleotides (meTINs). Activities of selected enzymes and levels of 6MP derivatives were measured at various time points during the course of therapy. The data obtained and the toxicity related parameters available for these patients were correlated with each other. We found several interesting relations, including high concentrations of two active forms of 6MP-TGN and meTIN-showing a trend toward association with better in vitro antileukemic effect of 6MP. High concentrations of TGN and elevated activity of HGPRT were found to be significantly associated with grade III/IV leucopenia. However, a lot of data of enzymatic activities and metabolite concentrations as well as clinical toxicity were missing, thereby limiting the number of assessed relations. Therefore, although a complex study of 6MP metabolism in ALL patients is feasible, it warrants more robust and strict data collection in order to be able to draw more reliable conclusions.
    Nucleosides Nucleotides &amp Nucleic Acids 04/2014; 33(4-6):422-433. · 0.71 Impact Factor
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    ABSTRACT: The most important reason for childhood cancer treatment failure in low-income countries is treatment abandonment. The aim of this study was to explore reasons for childhood cancer treatment abandonment and assess the clinical condition of these children. This was a descriptive study using semistructured questionnaires. Home visits were conducted to interview families of childhood cancer patients, diagnosed between January 2007 and January 2009, who had abandoned treatment at the Moi Teaching and Referral Hospital (MTRH). Between January 2007 and January 2009, 222 children were newly diagnosed with a malignancy at MTRH. Treatment outcome was documented in 180 patients. Of these 180 patients, 98 (54%) children abandoned treatment. From December 2011 until August 2012, 53 (54%) of the 98 families were contacted. Due to lack of contact information, 45 families were untraceable. From 53 contacted families, 46 (87%) families agreed to be interviewed. Reasons for abandonment were reported by 26 families, and they were diverse. Most common reasons were financial difficulties (46%), inadequate access to health insurance (27%) and transportation difficulties (23%). Most patients (72%) abandoned treatment after the first 3 months had been completed. Of the 46 children who abandoned treatment, 9 (20%) were still alive: 6 (67%) of these children looked healthy and 3 (33%) ill. The remaining 37 (80%) children had passed away. Prevention of childhood cancer treatment abandonment requires improved access to health insurance, financial or transportation support, proper parental education, psychosocial guidance and ameliorated communication skills of healthcare providers.
    Archives of Disease in Childhood 03/2014; · 3.05 Impact Factor
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    ABSTRACT: Cellular folate concentration was earlier reported to be a critical factor in the activity and expression of the multidrug resistance protein MRP1 (ABCC1). Since MRP1 mediates resistance to a variety of therapeutic drugs, we investigated whether the cellular folate concentration influences the MRP1-mediated cellular resistance against drugs. As a model system, we used the human ovarian carcinoma cell line 2008wt, and its stably MRP1/ABCC1-transfected subline 2008/MRP1. These cell types have a moderate and high expression of MRP1, respectively. In folate-deprived 2008/MRP1 cells, the MRP1-mediated efflux of its model substrate calcein decreased to ~55 % of the initial efflux rate under folate-rich conditions. In 2008wt cells, only a small decrease in efflux was observed. Folate depletion for 5-10 days markedly increased (~500 %) cellular steady-state accumulation of calcein in 2008/MRP1 cells and moderately in 2008wt cells. A subsequent short (24 h) exposure to 2.3 μM L-leucovorin decreased calcein levels again in MRP1-overexpressing cells. Folate deprivation markedly increased growth inhibitory effects of the established MRP1 substrates daunorubicin (~twofold), doxorubicin (~fivefold), and methotrexate (~83-fold) in MRP1-overexpressing cells, proportional to MRP1 expression. In conclusion, this study demonstrates that increased cellular folate concentrations induce MRP1/ABCC1-related drug efflux and drug resistance. These results have important implications in the understanding of the role of MRP1 and its homologs in clinical drug resistance.
    Cancer Chemotherapy and Pharmacology 03/2014; · 2.80 Impact Factor
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    ABSTRACT: Several studies in adults have shown patient reported outcomes (PROs) to be effective in enhancing patient-physician communication and discussion of Health Related Quality of Life outcomes. Although less studied, positive results have been demonstrated in children. A PRO-intervention needs to be feasible in clinical practice to be successful. In the current study, 74 parents of children who successfully completed their cancer treatment and 21 pediatric oncologists (POs) evaluated a PRO-intervention and gave recommendations for future use in their practice. Most parents and POs suggested PROs to be an important part of standard care, starting during treatment, with an assessment frequency of every 3 months. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 03/2014; · 2.35 Impact Factor
  • Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2014; · 10.16 Impact Factor
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    ABSTRACT: This study prospectively analyzed the efficacy of very prolonged PEGasparaginase and Erwinia asparaginase (Erwinia-asp) courses in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2,500 IU/m2 q2 weeks) in intensification after receiving native E.coli asparaginase in induction. In case of allergy to or silent inactivation of PEGasparaginase, Erwinia-asp (20,000 IU/m2 2-3 times weekly) was given. Eighty-nine patients were enrolled in the "PEGasparaginase study". Twenty(22%) of the PEGasparaginase-treated patients developed an allergy; seven (8%) showed silent inactivation. PEGasparaginase level was zero in all allergic patients (grade 1-4). Patients without hypersensitivity to PEGasparaginase had serum mean trough levels of 899 U/L. Fifty-nine patients were included in the "Erwinia-asp study", two (3%) developed an allergy and none silent inactivation. Ninety-six percent had at least one trough level ≥100 U/L. Serum asparagine level was not always completely depleted with Erwinia-asp in contrast to PEGasparaginase. Presence of asparaginase-antibodies was related to allergies and silent inactivation, but with low specificity (64%). Use of native E.coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Therefore, PEGasparaginase should be used already in induction and we suggest that the dose could be lowered. Switching to Erwinia-asp leads to effective asparaginase levels in most patients. Therapeutic drug monitoring has been added to our ALL-11-protocol to individualize asparaginase therapy.
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    ABSTRACT: Background Glial brain tumors cause considerable mortality and morbidity in children and adults. Innovative targets for therapy are needed to improve survival and reduce long-term sequelae. The aim of this study was to find a candidate tumor-promoting protein, abundantly expressed in tumor cells but not in normal brain tissues, as a potential target for therapy.Methods In silico proteomics and genomics, immunohistochemistry, and immunofluorescence microscopy validation were performed. RNA interference was used to ascertain the functional role of the overexpressed candidate target protein.ResultsIn silico proteomics and genomics revealed pre-B-cell leukemia homeobox (PBX) interacting protein 1 (PBXIP1) overexpression in adult and childhood high-grade glioma and ependymoma compared with normal brain. PBXIP1 is a PBX-family interacting microtubule-binding protein with a putative role in migration and proliferation of cancer cells. Immunohistochemical studies in glial tumors validated PBXIP1 expression in astrocytoma and ependymoma but not in oligodendroglioma. RNAi-mediated PBXIP1-knockdown in glioblastoma cell lines strongly reduced proliferation and migration and induced morphological changes, indicating that PBXIP1 knockdown decreases glioma cell viability and motility through rearrangements of the actin cytoskeleton. Furthermore, expression of PBXIP1 was observed in radial glia and astrocytic progenitor cells in human fetal tissues, suggesting that PBXIP1 is an astroglial progenitor cell marker during human embryonic development.ConclusionPBXIP1 is a novel protein overexpressed in astrocytoma and ependymoma, involved in tumor cell proliferation and migration, that warrants further exploration as a novel therapeutic target in these tumors.
    Neuro-Oncology 01/2014; · 6.18 Impact Factor
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    ABSTRACT: This study prospectively analyzed the efficacy of very prolonged PEGasparaginase and Erwinia-asparaginase (Erwinia-asp) courses in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2,500IU/m(2) q2 weeks) in intensification after receiving native E.coli-asparaginase in induction. In case of allergy to or silent-inactivation of PEGasparaginase, Erwinia-asp(20,000IU/m(2) 2-3 times weekly) was given. Eighty-nine patients were enrolled in the "PEGasparaginase study". Twenty(22%) of the PEGasparaginase-treated patients developed an allergy; seven(8%) showed silent inactivation. PEGasparaginase level was zero in all allergic patients(grade 1-4). Patients without hypersensitivity to PEGasparaginase had serum mean trough levels of 899 U/L. Fifty-nine patients were included in the "Erwinia-asp study", two(3%) developed an allergy and none silent-inactivation. Ninety-six percent had at least one trough level ≥100 U/L. Serum asparagine level was not always completely depleted with Erwinia-asp in contrast to PEGasparaginase. Presence of asparaginase-antibodies was related to allergies and silent-inactivation, but with low specificity(64%). Use of native E.coli-asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Therefore, PEGasparaginase should be used already in induction and we suggest that the dose could be lowered. Switching to Erwinia-asp leads to effective asparaginase levels in most patients. Therapeutic-drug-monitoring has been added to our ALL-11-protocol to individualize asparaginase therapy.
    Blood 01/2014; · 9.78 Impact Factor

Publication Stats

5k Citations
1,664.70 Total Impact Points

Institutions

  • 1991–2014
    • VU University Amsterdam
      • • Department of Neurosurgery
      • • Department of Pediatric Hematology/Oncology
      Amsterdamo, North Holland, Netherlands
  • 2013
    • Sydney Children's Hospital
      Sydney, New South Wales, Australia
  • 2012–2013
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 2002–2013
    • VU University Medical Center
      • • Department of Pediatrics
      • • Department of Haematology
      Amsterdamo, North Holland, Netherlands
  • 2010–2012
    • Erasmus MC
      Rotterdam, South Holland, Netherlands
    • Hannover Medical School
      • Department of Paediatric Haematology and Oncology
      Hannover, Lower Saxony, Germany
  • 2009–2012
    • Dutch Childhood Oncology Group
      Rotterdam, South Holland, Netherlands
    • Aarhus University Hospital
      • Department of Pediatrics
      Aarhus, Central Jutland, Denmark
  • 2011
    • Leiden University Medical Centre
      • Department of Pediatrics
      Leiden, South Holland, Netherlands
    • Massachusetts General Hospital
      • Department of Neurology
      Boston, MA, United States
  • 2008–2009
    • Charles University in Prague
      Praha, Praha, Czech Republic
    • Childrens Hospital of Pittsburgh
      Pittsburgh, Pennsylvania, United States
    • Università degli Studi di Milano-Bicocca
      Milano, Lombardy, Italy
    • Carl Gustav Carus-Institut
      Pforzheim, Baden-Württemberg, Germany
  • 2005
    • Gesellschaft für Pädiatrische Onkologie und Hämatologie
      Muenster, North Rhine-Westphalia, Germany
  • 2004
    • University of Münster
      Muenster, North Rhine-Westphalia, Germany
  • 2003
    • Kent Hospital
      Warwick, Rhode Island, United States
  • 1991–1995
    • University of Amsterdam
      • Department of Paediatrics
      Amsterdamo, North Holland, Netherlands
  • 1994
    • Post University
      Post, Texas, United States