Martin J van den Bent

Leiden University Medical Centre, Leyden, South Holland, Netherlands

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Publications (288)2067.45 Total impact

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    ABSTRACT: Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma. In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated. The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log10CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log10CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS. CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.British Journal of Cancer advance online publication, 4 June 2015; doi:10.1038/bjc.2015.191
    British Journal of Cancer 06/2015; DOI:10.1038/bjc.2015.191 · 4.82 Impact Factor
  • Martin J van den Bent, Jacoline E Bromberg
    Nature Reviews Neurology 05/2015; DOI:10.1038/nrneurol.2015.82 · 14.10 Impact Factor
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    Pieter Wesseling, Martin van den Bent, Arie Perry
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    ABSTRACT: For nearly a century, the diagnosis and grading of oligodendrogliomas and oligoastrocytomas has been based on histopathology alone. Roughly 20 years ago, the first glioma-associated molecular signature was found with complete chromosome 1p and 19q codeletion being particularly common in histologically classic oligodendrogliomas. Subsequently, this codeletion appeared to not only carry diagnostic, but also prognostic and predictive information, the latter aspect only recently resolved after carefully constructed clinical trials with very long follow-up times. More recently described biomarkers, including the non-balanced translocation leading to 1p/19q codeletion, promoter hypermethylation of the MGMT gene, mutations of the IDH1 or IDH2 gene, and mutations of FUBP1 (on 1p) or CIC (on 19q), have greatly enhanced our understanding of oligodendroglioma biology, although their diagnostic, prognostic, and predictive roles are less clear. It has therefore been suggested that complete 1p/19q codeletion be required for the diagnosis of 'canonical oligodendroglioma'. This transition to an integrated morphological and molecular diagnosis may result in the disappearance of oligoastrocytoma as an entity, but brings new challenges as well. For instance it needs to be sorted out how (histopathological) criteria for grading of 'canonical oligodendrogliomas' should be adapted, how pediatric oligodendrogliomas (known to lack codeletions) should be defined, which platforms and cut-off levels should ideally be used for demonstration of particular molecular aberrations, and how the diagnosis of oligodendroglioma should be made in centers/countries where molecular diagnostics is not available. Meanwhile, smart integration of morphological and molecular information will lead to recognition of biologically much more uniform groups within the spectrum of diffuse gliomas and thereby facilitate tailored treatments for individual patients.
    Acta Neuropathologica 05/2015; 129(6). DOI:10.1007/s00401-015-1424-1 · 9.78 Impact Factor
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    ABSTRACT: With the rapid discovery of prognostic and predictive molecular parameters for glioma, the status of histopathology in the diagnostic process should be scrutinized. Our project aimed to construct a diagnostic algorithm for gliomas based on molecular and histologic parameters with independent prognostic values. The pathology slides of 636 patients with gliomas who had been included in EORTC 26951 and 26882 trials were reviewed using virtual microscopy by a panel of six neuropathologists who independently scored 18 histologic features and provided an overall diagnosis. The molecular data for IDH1, 1p/19q loss, EGFR amplification, loss of chromosome 10 and chromosome arm 10q, gain of chromosome 7, and hypermethylation of the promoter of MGMT were available for some of the cases. The slides were divided in discovery (n = 426) and validation sets (n = 210). The diagnostic algorithm resulting from analysis of the discovery set was validated in the latter. In 66% of cases, consensus of overall diagnosis was present. A diagnostic algorithm consisting of two molecular markers and one consensus histologic feature was created by conditional inference tree analysis. The order of prognostic significance was: 1p/19q loss, EGFR amplification, and astrocytic morphology, which resulted in the identification of four diagnostic nodes. Validation of the nodes in the validation set confirmed the prognostic value (P < .001). We succeeded in the creation of a timely diagnostic algorithm for anaplastic glioma based on multivariable analysis of consensus histopathology and molecular parameters. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 04/2015; 33(17). DOI:10.1200/JCO.2014.59.0166 · 17.88 Impact Factor
  • Walter Taal, Jacoline Ec Bromberg, Martin J van den Bent
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    ABSTRACT: SUMMARY The treatment of glial brain tumors begins with surgery, and standard adjuvant treatment at the end of the past millennium for high-grade glioma and high-risk low-grade glioma was radiotherapy and chemotherapy was given at recurrence. However, over the past 10 years much has changed regarding the role of chemotherapy in gliomas and it is now clear that chemotherapy has a role in the treatment of almost all newly diagnosed diffuse gliomas (WHO grade II-IV). This is the result of several prospective studies that showed survival benefit after combined chemoradiotherapy with temozolomide in glioblastoma (WHO grade IV) or after procarbazine, CCNU (lomustine) and vincristine chemotherapy in diffuse low-grade (WHO grade II) and anaplastic (WHO grade III) glioma. The current standard of treatment for diffuse gliomas is described in this overview and in addition some attention is given to targeted therapies.
    04/2015; DOI:10.2217/cns.15.2
  • Annals of Oncology 04/2015; 26(suppl 1):i42-i42. DOI:10.1093/annonc/mdv050.42 · 6.58 Impact Factor
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    ABSTRACT: The BELOB study, a randomised controlled phase 2 trial comparing lomustine, bevacizumab and combined lomustine and bevacizumab in patients with recurrent glioblastoma, showed that the 9-month overall survival rate was most promising in the combination arm. Here we report the health-related quality of life (HRQoL) results, a secondary trial end-point.
    European Journal of Cancer 04/2015; 51(10). DOI:10.1016/j.ejca.2015.03.025 · 4.82 Impact Factor
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    ABSTRACT: The efficacy of novel targeted therapies is often tested at the time of tumor recurrence. However, for glioblastoma (GBM) patients, surgical resections at recurrence are performed only in a minority of patients; therefore, molecular data are predominantly derived from the initial tumor. Molecular data of the initial tumor for patient selection into personalized medicine trials can therefore be used only when the specific genetic change is retained in the recurrent tumor. In this study we determined whether EGFR amplification and expression of the most common mutation in GBMs (EGFRvIII) is retained at tumor recurrence. Because retention of genetic changes may be dependent on the initial treatment, we only used a cohort of GBM samples that were uniformly treated according to the current standard of care (ie, chemo-irradiation with temozolomide). Our data show that, in spite of some quantitative differences, the EGFR amplification status remains stable in the majority (84%) of tumors evaluated. EGFRvIII expression remained similar in 79% of GBMs. However, within the tumors expressing EGFRvIII at initial diagnosis, approximately one-half lose their EGFRvIII expression at tumor recurrence. The relative stability of EGFR amplification indicates that molecular data obtained in the primary tumor can be used to predict the EGFR status of the recurrent tumor, but care should be taken in extrapolating EGFRvIII expression from the primary tumor, particularly when expressed at first diagnosis. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail:
    Neuro-Oncology 02/2015; DOI:10.1093/neuonc/nov013 · 5.29 Impact Factor
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    ABSTRACT: Background HOX genes are a family of developmental genes that are neither expressed in the developing forebrain nor in normal brain. Aberrant expression of a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistance to chemo-radiotherapy and sustained proliferation of glioma initiating cells. Here we describe the epigenetic and genetic alterations and their interactions associated with the expression of this signature in glioblastoma.ResultsWe observe prominent hypermethylation of the HOXA locus 7p15.2 in glioblastoma in contrast to non-tumoral brain. Hypermethylation is associated with a gain of chromosome 7, a hallmark of glioblastoma, and may compensate for tumor-driven enhanced gene dosage as a rescue mechanism by preventing undue gene expression. We identify the CpG island of the HOXA10 alternative promoter that appears to escape hypermethylation in the HOX-high glioblastoma. An additive effect of gene copy gain at 7p15.2 and DNA methylation at key regulatory CpGs in HOXA10 is significantly associated with HOX-signature expression. Additionally, we show concordance between methylation status and presence of active or inactive chromatin marks in glioblastoma-derived spheres that are HOX-high or HOX-low, respectively.Conclusions Based on these findings, we propose co-evolution and interaction between gene copy gain, associated with a gain of chromosome 7, and additional epigenetic alterations as key mechanisms triggering a coordinated, but inappropriate, HOX transcriptional program in glioblastoma.
    Genome Biology 01/2015; 16(1):16. DOI:10.1186/s13059-015-0583-7 · 10.47 Impact Factor
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    ABSTRACT: This edition of CCR Focus provides critical reviews of several important areas in the field, including the application of findings from genomic investigations of brain tumors to improve diagnosis, clinical trial design, and ultimately optimizing individual patient treatment. Another article is a critical review provided by experts in the field that discusses the recent clinical trials using angiogenesis inhibitors, possible explanations for the results, and how to move forward. There is a concise discussion of the application of immunotherapy to brain tumors by key investigators in this field, reflecting the potential opportunities as well as the disease-specific challenges. Finally, leading pediatric brain tumor investigators provide an overview of the field and insights about the recent seminal discoveries in two pediatric brain tumors, supporting the paradigm that laboratory investigations lead to more precise diagnosis, prognosis, and ultimately better treatment. Herein, an overview of the recent advances and challenges in the area of clinical and translational brain tumor research is provided to set the stage for the contributions that follow. See all articles in this CCR Focus section, "Discoveries, Challenges, and Progress in Primary Brain Tumors." Clin Cancer Res; 20(22); 5591-600. ©2014 AACR.
    Clinical Cancer Research 11/2014; 20(22):5591-600. DOI:10.1158/1078-0432.CCR-14-0835 · 8.19 Impact Factor
  • European Journal of Cancer 11/2014; 50. DOI:10.1016/S0959-8049(14)70283-7 · 4.82 Impact Factor
  • Martin J van den Bent
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    ABSTRACT: The long-term follow-up of the RTOG 9802 trial that compared 54 Gy of radiotherapy (RT) with the same RT followed by adjuvant procarbazine, CCNU, and vincristine (PCV) chemotherapy in high-risk low-grade glioma shows a major increase in survival after adjuvant PCV chemotherapy. Median overall survival increased from 7.8 years to 13.3 years, with a hazard ratio of death of 0.59 (log rank: P = .002). This increase in survival was observed despite the fact that 77% of patients who progressed after RT alone received salvage chemotherapy. With this outcome, RT + PCV is now to be considered standard of care for low-grade glioma requiring postsurgical adjuvant treatment. Unfortunately, studies on molecular correlates associated with response are still lacking. This is now the third trial showing benefit from the addition of PCV to RT in grade II or III diffuse glioma. The optimal parameter for selecting patients for adjuvant PCV has not yet been fully elucidated, but several candidate markers have so far emerged. It is still unclear whether temozolomide can replace PCV and whether initial management with chemotherapy only is a safe initial treatment. Potentially, that may adversely affect overall survival, but concerns for delayed RT-induced neurotoxicity may limit acceptance of early RT in patients with expected long term survival. The current evidence supports that in future trials, grades II and III tumors with similar molecular backgrounds should be combined, and trials should focus on molecular glial subtype regardless of grade.
    Neuro-Oncology 10/2014; 16(12). DOI:10.1093/neuonc/nou297 · 5.29 Impact Factor
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    ABSTRACT: We treated patients with newly diagnosed and large low-grade oligodendroglial tumors with upfront procarbazine, CCNU and vincristine (PCV) in order to delay radiotherapy. Patients were treated with PCV for a maximum of 6 cycles. The response to treatment was defined according to the RANO criteria; in addition change over time of mean tumor diameters (growth kinetics) was calculated. Thirty-two patients were treated between 1998 and 2006, 18 of which were diagnosed with 1p/19q co-deleted tumors. Median follow-up duration was 8 years (range 0.5-13 years). The median overall survival (mOS) was 120 months and the median progression-free survival (mPFS) was 46 months. Growth kinetics showed an ongoing decrease of the mean tumor diameter after completion of chemotherapy, during a median time of 35 months, but an increase of the mean tumor diameter did not herald progression as detected by RANO criteria. 1p/19q co-deletion was associated with a significant increase in OS (mOS 83 months versus not reached for codeleted tumors; p = 0.003)) and PFS (mPFS 35 months versus 67 months for codeleted tumors; p = 0.024). Patients with combined 1p/19q loss had a 10 year PFS of 34 % and the radiotherapy in these patients was postponed for a median period of more than 6 years. This long-term follow-up study indicates that upfront PCV chemotherapy is associated with long PFS and OS and delays radiotherapy for a considerable period of time in patients with low-grade oligodendroglial tumors, in particular with combined 1p/19q loss.
    Journal of Neuro-Oncology 10/2014; DOI:10.1007/s11060-014-1641-9 · 2.79 Impact Factor
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    ABSTRACT: Purpose In cancer research, outcome measures may co-vary. Treatment and treatment related impairment of health-related quality of life (HRQoL) may affect survival. When these effects are analyzed separately, bias may arise. Therefore, we investigated the combined effect of treatment and longitudinally measured HRQoL on survival. Methods Patients with anaplastic oligodendrogliomas (n = 288) who were randomized (EORTC 26951) to radiotherapy (RT) alone or RT plus procarbazine, lomustine, and vincristine (PCV) chemotherapy were analyzed. HRQoL [appetite loss (AP)] was assessed with the EORTC QLQ-C30. We compared survival results from different analysis strategies: Cox model with treatment only [model 1 (M1)] or with treatment and time-dependent AP score [model 2 (M2)] and the joint model combining longitudinal AP score and survival [model 3 (M3)]. Results The estimated hazard ratio (HR) for RT plus PCV was 0.76 (95 % CI 0.58–1.00) for M1, 0.72 (0.55–0.96) for M2, and 0.69 (0.52–0.92) for M3. This corresponds to a lower risk of death of 24 % in M1, 28 % in M2, and 31 % in M3, for patients treated with RT plus PCV chemotherapy. AP resulted in an increased risk of death, with estimated HR of 1.06 (1.01–1.12) for M2 and 1.13 (1.03–1.23) for M3: Every 10-point increase of AP resulted in a 13 % increased risk of death in M3 as compared to 6 % in M2. Conclusion Part of the survival benefit of treatment with RT plus PCV chemotherapy can be masked by the negative effect that this treatment has on patients’ HRQoL. In our study, up to 7 % of the theoretical treatment efficacy was lost when AP was not adjusted through joint modeling.
    Quality of Life Research 10/2014; 24(4). DOI:10.1007/s11136-014-0821-6 · 2.86 Impact Factor
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    ABSTRACT: HDAC inhibitors have radiosensitizing effects in established cancer cell lines. This study was conducted to compare the efficacy of SAHA, LBH589, Valproic Acid (VPA), MS275 and Scriptaid in the patient-derived glioblastoma model. In more detail, SAHA and LBH589 were evaluated to determine predictors of response. Acetylated-histone-H3, γH2AX/53BP1, (p)Chek2/ATM, Bcl-2/Bcl-XL, p21(CIP1/WAF1) and caspase-3/7 were studied in relation to response. SAHA sensitized 50% of cultures, LBH589 45%, VPA and Scriptaid 40% and MS275 60%. Differences after treatment with SAHA/RTx or LBH589/RTx in a sensitive and resistant culture were increased acetylated-H3, caspase-3/7 and prolonged DNA damage repair γH2AX /53BP1 foci. pChek2 was found to be associated with both SAHA/RTx and LBH589/RTx response with a positive predictive value (PPV) of 90%. Bcl-XL had a PPV of 100% for LBH589/RTx response. Incubation with HDACi 24 and 48hours pre-RTx resulted in the best efficacy of combination treatment. In conclusion a subset of patient-derived glioblastoma cultures were sensitive to HDACi/RTx. For SAHA and LBH589 responses were strongly associated with pChek2 and Bcl-XL, which warrant further clinical exploration. Additional information on responsiveness was obtained by DNA damage response markers and apoptosis related proteins.
    Cancer Letters 10/2014; DOI:10.1016/j.canlet.2014.09.049 · 5.02 Impact Factor
  • Martin J van den Bent, Walter Taal
    The Lancet Oncology 10/2014; 15(11):e473–e474. DOI:10.1016/S1470-2045(14)70453-X · 24.73 Impact Factor
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    ABSTRACT: On January 30, 2014, a workshop was held on neuroimaging endpoints in high-grade glioma. This workshop was sponsored by the Jumpstarting Brain Tumor Drug Development Coalition, consisting of the National Brain Tumor Society, the Society for Neuro-Oncology, Accelerate Brain Cancer Cure, and the Musella Foundation for Research and Information, and conducted in collaboration with the Food and Drug Administration. The workshop included neuro-oncologists, neuroradiologists, radiation oncologists, neurosurgeons, biostatisticians, patient advocates, and representatives from industry, clinical research organizations, and the National Cancer Institute. This report summarizes the presentations and discussions of that workshop and the proposals that emerged to improve the Response Assessment in Neuro-Oncology (RANO) criteria and standardize neuroimaging parameters.
    Neuro-Oncology 10/2014; 16(suppl 7):vii36-vii47. DOI:10.1093/neuonc/nou226 · 5.29 Impact Factor
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    ABSTRACT: Over the past 20 years, very few agents have been approved for the treatment of brain tumors. Recent studies have highlighted some of the challenges in assessing activity in novel agents for the treatment of brain tumors. This paper reviews some of the key challenges related to assessment of tumor response to therapy in adult high-grade gliomas and discusses the strengths and limitations of imaging-based endpoints. Although overall survival is considered the "gold standard" endpoint in the field of oncology, progression-free survival and response rate are endpoints that hold great value in neuro-oncology. Particular focus is given to advancements made since the January 2006 Brain Tumor Endpoints Workshop, including the development of Response Assessment in Neuro-Oncology criteria, the value of T2/fluid-attenuated inversion recovery, use of objective response rates and progression-free survival in clinical trials, and the evaluation of pseudoprogression, pseudoresponse, and inflammatory response in radiographic images.
    Neuro-Oncology 10/2014; 16(suppl 7):vii2-vii11. DOI:10.1093/neuonc/nou224 · 5.29 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):5543-5543. DOI:10.1158/1538-7445.AM2014-5543 · 9.28 Impact Factor
  • 39th ESMO Congress (ESMO); 09/2014

Publication Stats

17k Citations
2,067.45 Total Impact Points


  • 2009–2015
    • Leiden University Medical Centre
      • Department of Pathology
      Leyden, South Holland, Netherlands
    • University of Virginia
      • Department of Neurology
      Charlottesville, VA, United States
  • 1994–2015
    • Erasmus MC
      • • Department of Neurology
      • • Daniel den Hoed Centre
      • • Department of Medical Oncology
      Rotterdam, South Holland, Netherlands
  • 2009–2013
    • University of Lausanne
      • Centre hospitalier universitaire vaudois (CHUV)
      Lausanne, Vaud, Switzerland
  • 1996–2013
    • Netherlands Cancer Institute
      • Department of Medical Oncology
      Amsterdamo, North Holland, Netherlands
  • 1994–2013
    • Erasmus Universiteit Rotterdam
      • • Department of Neurology
      • • Daniel den Hoed Cancer Center
      Rotterdam, South Holland, Netherlands
  • 2009–2011
    • University of Zurich
      • Division of Neuropsychology
      Zürich, ZH, Switzerland
  • 2008
    • European Organisation for Research and Treatment of Cancer
      Bruxelles, Brussels Capital Region, Belgium
  • 2007
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
    • University Medical Center Utrecht
      • Department of Neurology
      Utrecht, Provincie Utrecht, Netherlands
  • 2006
    • The University of Calgary
      Calgary, Alberta, Canada
  • 2005
    • University Hospital of Lausanne
      • Service de radio-oncologie
      Lausanne, Vaud, Switzerland
  • 2003
    • Utrecht University
      Utrecht, Utrecht, Netherlands