Publications by authors named "Mathilde Kouwenhoven"

25 Publications

  • Page 1 of 1

Longitudinal molecular trajectories of diffuse glioma in adults.

Nature 2019 12 20;576(7785):112-120. Epub 2019 Nov 20.

The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.
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http://dx.doi.org/10.1038/s41586-019-1775-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897368PMC
December 2019

To Combine or Not Combine: Drug Interactions and Tools for Their Analysis. Reflections from the EORTC-PAMM Course on Preclinical and Early-phase Clinical Pharmacology.

Anticancer Res 2019 Jul;39(7):3303-3309

Department of Medical Oncology, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands

Combination therapies are used in the clinic to achieve cure, better efficacy and to circumvent resistant disease in patients. Initial assessment of the effect of such combinations, usually of two agents, is frequently performed using in vitro assays. In this review, we give a short summary of the types of analyses that were presented during the Preclinical and Early-phase Clinical Pharmacology Course of the Pharmacology and Molecular Mechanisms Group, European Organization for Research and Treatment on Cancer, that can be used to determine the efficacy of drug combinations. The effect of a combination treatment can be calculated using mathematical equations based on either the Loewe additivity or Bliss independence model, or a combination of both, such as Chou and Talalay's median-drug effect model. Interactions can be additive, synergistic (more than additive), or antagonistic (less than additive). Software packages CalcuSyn (also available as CompuSyn) and Combenefit are designed to calculate the extent of the combined effects. Interestingly, the application of machine-learning methods in the prediction of combination treatments, which can include pharmacogenomic, genetic, metabolomic and proteomic profiles, might contribute to further refinement of combination regimens. However, more research is needed to apply appropriate rules of machine learning methods to ensure correct predictive models.
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http://dx.doi.org/10.21873/anticanres.13472DOI Listing
July 2019

The TICking clock of EGFR therapy resistance in glioblastoma: Target Independence or target Compensation.

Drug Resist Updat 2019 03 22;43:29-37. Epub 2019 Apr 22.

Department of Neurosurgery, Brain Tumor Center Amsterdam, Amsterdam University Medical Center, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HZ, Amsterdam, the Netherlands. Electronic address:

Targeted therapy against driver mutations responsible for cancer progression has been shown to be effective in many tumor types. For glioblastoma (GBM), the epidermal growth factor receptor (EGFR) gene is the most frequently mutated oncogenic driver and has therefore been considered an attractive target for therapy. However, so far responses to EGFR-pathway inhibitors have been disappointing. We performed an exhaustive analysis of the mechanisms that might account for therapy resistance against EGFR inhibition. We define two major mechanisms of resistance and propose modalities to overcome them. The first resistance mechanism concerns target independence. In this case, cells have lost expression of the EGFR protein and experience no negative impact of EGFR targeting. Loss of extrachromosomally encoded EGFR as present in double minute DNA is a frequent mechanism for this type of drug resistance. The second mechanism concerns target compensation. In this case, cells will counteract EGFR inhibition by activation of compensatory pathways that render them independent of EGFR signaling. Compensatory pathway candidates are platelet-derived growth factor β (PDGFβ), Insulin-like growth factor 1 (IGFR1) and cMET and their downstream targets, all not commonly mutated at the time of diagnosis alongside EGFR mutation. Given that both mechanisms make cells independent of EGFR expression, other means have to be found to eradicate drug resistant cells. To this end we suggest rational strategies which include the use of multi-target therapies that hit truncation mutations (mechanism 1) or multi-target therapies to co-inhibit compensatory proteins (mechanism 2).
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http://dx.doi.org/10.1016/j.drup.2019.04.002DOI Listing
March 2019

Comparing Glioblastoma Surgery Decisions Between Teams Using Brain Maps of Tumor Locations, Biopsies, and Resections.

JCO Clin Cancer Inform 2019 01;3:1-12

Vrije Universiteit Medical Center, Amsterdam, the Netherlands.

Purpose: The aim of glioblastoma surgery is to maximize the extent of resection while preserving functional integrity, which depends on the location within the brain. A standard to compare these decisions is lacking. We present a volumetric voxel-wise method for direct comparison between two multidisciplinary teams of glioblastoma surgery decisions throughout the brain.

Methods: Adults undergoing first-time glioblastoma surgery from 2012 to 2013 performed by two neuro-oncologic teams were included. Patients had had a diagnostic biopsy or resection. Preoperative tumors and postoperative residues were segmented on magnetic resonance imaging in three dimensions and registered to standard brain space. Voxel-wise probability maps of tumor location, biopsy, and resection were constructed for each team to compare patient referral bias, indication variation, and treatment variation. To evaluate the quality of care, subgroups of differentially resected brain regions were analyzed for survival and functional outcome.

Results: One team included 101 patients, and the other included 174; 91 tumors were biopsied, and 181 were resected. Patient characteristics were largely comparable between teams. Distributions of tumor locations were dissimilar, suggesting referral bias. Distributions of biopsies were similar, suggesting absence of indication variation. Differentially resected regions were identified in the anterior limb of the right internal capsule and the right caudate nucleus, indicating treatment variation. Patients with (n = 12) and without (n = 6) surgical removal in these regions had similar overall survival and similar permanent neurologic deficits.

Conclusion: Probability maps of tumor location, biopsy, and resection provide additional information that can inform surgical decision making across multidisciplinary teams for patients with glioblastoma.
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http://dx.doi.org/10.1200/CCI.18.00089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873995PMC
January 2019

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with -mutated or -mutated solid tumours.

BMJ Open 2017 06 10;7(6):e014961. Epub 2017 Jun 10.

Department of Medical Oncology, University of Amsterdam, Meibergdreef, Amsterdam, The Netherlands.

Introduction: High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes and (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. -mutated cancer cells produce the oncometabolite -2-hydroxyglutarate (-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine.

Methods And Analysis: We describe a dose-finding phase Ib/II clinical trial, in which patients with -mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in -mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive -2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for -mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications.

Ethics And Dissemination: This study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal.

Trial Registration Number: This article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2016-014961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541450PMC
June 2017

New clinical, pathological and molecular prognostic models and calculators in patients with locally diagnosed anaplastic oligodendroglioma or oligoastrocytoma. A prognostic factor analysis of European Organisation for Research and Treatment of Cancer Brain Tumour Group Study 26951.

Eur J Cancer 2013 Nov 26;49(16):3477-85. Epub 2013 Jul 26.

EORTC Headquarters, Brussels, Belgium. Electronic address:

Background: The prognosis of patients with anaplastic oligodendrogliomas (AOD) and oligoastrocytomas (AOA) is variable. Biomarkers might be helpful to identify more homogeneous disease subtypes and improve therapeutic index. The aim of this study is to develop new clinical, pathological and molecular prognostic models for locally diagnosed anaplastic gliomas with oligodendroglial features (AOD or AOA).

Methods: Data from 368 patients with AOD or AOA recruited in The European Organisation for Research and Treatment of Cancer (EORTC) trial 26951 on adjuvant PCV (Procarbazine, CCNU, Vincristine) chemotherapy in anaplastic oligodendroglial tumours were used to develop multifactor models to predict progression free survival (PFS) and overall survival (OS). Different models were compared by their percentage of explained variation (PEV). Prognostic calculators were derived from these new models.

Results: Treatment (for PFS only), younger age, confirmed absence of residual tumour on imaging, frontal location, good World Health Organisation (WHO) performance status, absence of endothelial abnormalities and/or necrosis, 1p/19q codeletion and Isocitrate dehydrogenase 1 (IDH1) mutation were independent factors that predicted better PFS and OS.

Conclusions: We identified important prognostic factors for AOD and AOA and showed that molecular markers added a major contribution to clinical and pathological factors in explaining PFS and OS. With a positive predictive value of 92% for PFS and 94% for OS, our models allow physicians to precisely identify high risk patients and aid in making therapeutic decisions.
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http://dx.doi.org/10.1016/j.ejca.2013.06.039DOI Listing
November 2013

Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951.

J Clin Oncol 2013 Jan 15;31(3):344-50. Epub 2012 Oct 15.

Neuro-Oncology Unit, Erasmus MC-Daniel den Hoed Cancer Center, PO Box 5201, 3008AE Rotterdam, The Netherlands.

Purpose: Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT).

Patients And Methods: Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis.

Results: A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance.

Conclusion: The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.
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http://dx.doi.org/10.1200/JCO.2012.43.2229DOI Listing
January 2013

Prognostic value of Ki67 index in anaplastic oligodendroglial tumours--a translational study of the European Organization for Research and Treatment of Cancer Brain Tumor Group.

Histopathology 2012 May 15;60(6):885-94. Epub 2012 Feb 15.

Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Aims: To evaluate the prognostic value and clinical utility of Ki67 tumour cell proliferation index in anaplastic oligodendroglial tumours (AOT).

Methods And Results: We performed anti-Ki67 immunostaining (MIB-1 antibody) of formalin-fixed and paraffin-embedded tumour tissue specimens of 128 patients with newly diagnosed AOT that were treated in a randomized Phase III trial. Ki67 index was assessed by three independent observers and was correlated to clinical, histopathological and molecular features (including 1p/19q co-deletion, epithelial growth factor receptor gene (EGFR) amplification, isocitrate dehydrogenase (IDH1) mutations, O6-methylguanine-DNA methyltransferase gene (MGMT) promoter methylation, and patient survival times. Intra- and inter-observer agreement of Ki67 index assessment was excellent. Univariable analysis (n = 79) showed that patients with a low Ki67 index had significantly more favourable progression-free survival (PFS) (P-value = 0.004, log-rank test) and overall survival (OS) (P-value = 0.003, log-rank test) than patients with a high Ki67 index, respectively. On multivariable analysis (n = 43), Ki67 index showed no independent association with PFS or OS.

Conclusions: In AOT the Ki67 index has a strong prognostic impact on univariable analysis, but no independent influence on multivariable analysis. However, further prospective studies including larger numbers of cases and standardized evaluation of Ki67 index in conjunction with other relevant prognostic parameters are needed to draw definitive conclusions.
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http://dx.doi.org/10.1111/j.1365-2559.2011.04134.xDOI Listing
May 2012

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial.

Acta Neuropathol 2012 Jun 15;123(6):841-52. Epub 2012 Jan 15.

Department of Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland.

Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy.
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http://dx.doi.org/10.1007/s00401-011-0938-4DOI Listing
June 2012

Pathway analysis of glioblastoma tissue after preoperative treatment with the EGFR tyrosine kinase inhibitor gefitinib--a phase II trial.

Mol Cancer Ther 2011 Jun 6;10(6):1102-12. Epub 2011 Apr 6.

Laboratory of Brain Tumor Biology and Genetics, Department of Neurosurgery, LausanneUniversity Hospital and University of Lausanne, Lausanne, Switzerland.

Amplification of the epidermal growth factor receptor (EGFR) gene is one of the most common oncogenic alterations in glioblastoma (45%) making it a prime target for therapy. However, small molecule inhibitors of the EGFR tyrosine kinase showed disappointing efficacy in clinical trials for glioblastoma. Here we aimed at investigating the molecular effects of the tyrosine kinase inhibitor gefitinib on the EGFR signaling pathway in human glioblastoma. Twenty-two patients selected for reoperation of recurrent glioblastoma were treated within a phase II trial for 5 days with 500 mg gefitinib before surgery followed by postoperative gefitinib until recurrence. Resected glioblastoma tissues exhibited high concentrations of gefitinib (median, 4.1 μg/g), 20 times higher than respective plasma. EGFR-pathway activity was evaluated with phosphorylation-specific assays. The EGFR was efficiently dephosphorylated in treated patients as compared to a control cohort of 12 patients. However, no significant effect on 12 pathway constituents was detected. In contrast, in vitro treatment of a glioblastoma cell line, BS-153, with endogenous EGFRwt amplification and EGFRvIII expression resulted not only in dephosphorylation of the EGFR, but also of key regulators in the pathway such as AKT. Treating established xenografts of the same cell line as an in vivo model showed dephosphorylation of the EGFR without affecting downstream signal transductors, similar to the human glioblastoma. Taken together, gefitinib reaches high concentrations in the tumor tissue and efficiently dephosphorylates its target. However, regulation of downstream signal transducers in the EGFR pathway seems to be dominated by regulatory circuits independent of EGFR phosphorylation.
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http://dx.doi.org/10.1158/1535-7163.MCT-11-0048DOI Listing
June 2011

First-line temozolomide chemotherapy in progressive low-grade astrocytomas after radiotherapy: molecular characteristics in relation to response.

Neuro Oncol 2011 Feb 21;13(2):235-41. Epub 2010 Dec 21.

Department of Neuro-oncology/Neurology, Erasmus MC, Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands.

Only a few studies examined the effect of temozolomide (TMZ) in recurrent low-grade astrocytoma (LGA) after surgery, none of which included a homogeneous and sufficiently sized group of patients with progression after radiotherapy (RT). We evaluated a cohort of 58 patients treated with TMZ for progression after RT of a previous LGA and investigated the relation between outcome and mutations in the IDH1, IDH2, and TP53 genes, O⁶-methylguanine-methyltransferase (MGMT) promoter methylation, trisomy of chromosome 7, and loss of chromosomes 1p and 19q. All patients received first-line TMZ 200 mg/m²/day on days 1-5 every 4 weeks for a progressive LGA with a contrast-enhancing lesion on MRI after RT. Six months progression-free survival (PFS) was 67%, and the median overall survival was 14 months. An objective response was obtained in 54%. TP53 mutations and loss of chromosome 19q showed a borderline association with PFS, but none of the other molecular characteristics were correlated with the outcome to TMZ. Both a methylated MGMT promoter gene and IDH1 mutations were found in 86% of the tumor samples. A correlation was found between IDH1 mutations and MGMT promoter methylation (P < .001). Neither MGMT promoter methylation nor IDH1 mutations correlated with PFS, but the interval between the very first symptom of the LGA and the start of the TMZ was significantly longer in the patients with IDH1 mutations (P = .01) and a methylated MGMT promoter (P = .02). We conclude that MGMT promoter methylation and IDH1 mutations seem to predict survival from the time of diagnosis, but not PFS to TMZ.
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http://dx.doi.org/10.1093/neuonc/noq177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064627PMC
February 2011

Genomic aberrations associated with outcome in anaplastic oligodendroglial tumors treated within the EORTC phase III trial 26951.

J Neurooncol 2011 Jun 6;103(2):221-30. Epub 2010 Sep 6.

INSERM, U975, Université Pierre & Marie Curie Paris VI, Faculté de médecine Pitié-Salpêtrière, CNRS UMR 7225, Paris, France.

Despite similar morphological aspects, anaplastic oligodendroglial tumors (AOTs) form a heterogeneous clinical subgroup of gliomas. The chromosome arms 1p/19q codeletion has been shown to be a relevant biomarker in AOTs and to be perfectly exclusive from EGFR amplification in gliomas. To identify new genomic regions associated with prognosis, 60 AOTs from the EORTC trial 26951 were analyzed retrospectively using BAC-array-based comparative genomic hybridization. The data were processed using a binary tree method. Thirty-three BACs with prognostic value were identified distinguishing four genomic subgroups of AOTs with different prognosis (p < 0.0001). Type I tumors (25%) were characterized by: (1) an EGFR amplification, (2) a poor prognosis, (3) a higher rate of necrosis, and (4) an older age of patients. Type II tumors (21.7%) had: (1) loss of prognostic BACs located on 1p tightly associated with 19q deletion, (2) a longer survival, (3) an oligodendroglioma phenotype, and (4) a frontal location in brain. Type III AOTs (11.7%) exhibited: (1) a deletion of prognostic BACs located on 21q, and (2) a short survival. Finally, type IV tumors (41.7%) had different genomic patterns and prognosis than type I, II and III AOTs. Multivariate analysis showed that genomic type provides additional prognostic data to clinical, imaging and pathological features. Similar results were obtained in the cohort of 45 centrally reviewed-validated cases of AOTs. Whole genome analysis appears useful to screen the numerous genomic abnormalities observed in AOTs and to propose new biomarkers particularly in the non-1p/19q codeleted AOTs.
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http://dx.doi.org/10.1007/s11060-010-0380-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3097344PMC
June 2011

MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation.

J Neurooncol 2011 Feb 1;101(3):405-17. Epub 2010 Jul 1.

Department of Pathology, Josephine Nefkens Institute, Be320a, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.

Hypermethylation of the MGMT gene promoter and mutation of the TP53 tumor-suppressor gene are frequently present in diffuse astrocytomas. However, there is only anecdotal information about MGMT methylation status and TP53 mutations during progression of low-grade diffuse astrocytoma (AII) to anaplastic astrocytoma (AIII) and secondary glioblastoma (sGB). In this study biopsy specimens from 51 patients with astrocytic tumors with radiologically proved progression from low to high-grade malignancy were investigated for the presence and consistency of MGMT promoter hypermethylation and TP53 mutations. For 27 patients biopsy samples both of primary tumors and their recurrences were available. For the other 24 patients histology of either the low-grade lesion or the high-grade recurrence was available. It was found that MGMT promoter hypermethylation and TP53 mutations are both frequent and early events in the progression of astrocytomas and that their status is consistent over time. No correlation was found between MGMT methylation status and the presence of TP53 mutations. In addition, no correlation was found between MGMT promoter hypermethylation and the type of TP53 mutations. These results argue against the putative TP53 G:C>A:T transition mutations suggested to occur preferentially in MGMT hypermethylated tumors.
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http://dx.doi.org/10.1007/s11060-010-0274-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024495PMC
February 2011

Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology.

Cancer Res 2009 Dec 17;69(23):9065-72. Epub 2009 Nov 17.

Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.

Gliomas are the most common primary brain tumors with heterogeneous morphology and variable prognosis. Treatment decisions in patients rely mainly on histologic classification and clinical parameters. However, differences between histologic subclasses and grades are subtle, and classifying gliomas is subject to a large interobserver variability. To improve current classification standards, we have performed gene expression profiling on a large cohort of glioma samples of all histologic subtypes and grades. We identified seven distinct molecular subgroups that correlate with survival. These include two favorable prognostic subgroups (median survival, >4.7 years), two with intermediate prognosis (median survival, 1-4 years), two with poor prognosis (median survival, <1 year), and one control group. The intrinsic molecular subtypes of glioma are different from histologic subgroups and correlate better to patient survival. The prognostic value of molecular subgroups was validated on five independent sample cohorts (The Cancer Genome Atlas, Repository for Molecular Brain Neoplasia Data, GSE12907, GSE4271, and Li and colleagues). The power of intrinsic subtyping is shown by its ability to identify a subset of prognostically favorable tumors within an external data set that contains only histologically confirmed glioblastomas (GBM). Specific genetic changes (epidermal growth factor receptor amplification, IDH1 mutation, and 1p/19q loss of heterozygosity) segregate in distinct molecular subgroups. We identified a subgroup with molecular features associated with secondary GBM, suggesting that different genetic changes drive gene expression profiles. Finally, we assessed response to treatment in molecular subgroups. Our data provide compelling evidence that expression profiling is a more accurate and objective method to classify gliomas than histologic classification. Molecular classification therefore may aid diagnosis and can guide clinical decision making.
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http://dx.doi.org/10.1158/0008-5472.CAN-09-2307DOI Listing
December 2009

Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951.

Neuro Oncol 2009 Dec;11(6):737-46

Department of Neurology, Daniel den Hoed Cancer Center, Erasmus University Hospital, Rotterdam, The Netherlands.

Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFR(amp)), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, we used the clinical data and tumor samples of the patients included in multicenter prospective phase III European Organisation for Research and Treatment of Cancer (EORTC) study 26951 on the effects of adjuvant procarbazine, chloroethyl cyclohexylnitrosourea (lomustine), and vincristine chemotherapy in anaplastic oligodendroglial tumors. Fluorescence in situ hybridization was used to assess copy number aberrations of chromosome 1p, 19q, 7, 10, and 10q and EGFR. Three different analyses were performed: on all included patients based on local pathology diagnosis, on the patients with confirmed anaplastic oligodendroglial tumors on central pathology review, and on this latter group but after excluding anaplastic oligoastrocytoma (AOA) with necrosis. As a reference set for glioblastoma multiforme (GBM), patients from the prospective randomized phase III study on GBM (EORTC 26981) were used as a benchmark. In 257 of 368 patients, central pathology review confirmed the presence of an anaplastic oligodendroglial tumor. Tumors with combined 1p and 19q loss (1p(loss)19q(loss)) were histopathologically diagnosed as anaplastic oligodendroglioma, were more frequently located in the frontal lobe, and had a better outcome. Anaplastic oligodendroglial tumors with EGFR(amp) were more frequently AOA, were more often localized outside the frontal lobe, and had a survival similar to that for GBM. Survival of patients with AOA harboring necrosis was in a similar range as for GBM, while patients with AOA with only endothelial proliferation had better overall survival. In univariate analyses, all molecular factors except loss of 10q were of prognostic significance, but on multivariate analysis a histopathological diagnosis of AOA, necrosis, and 1p(loss)19q(loss) remained independent prognostic factors. AOA tumors with necrosis are to be considered WHO grade IV tumors (GBM). Of all molecular markers analyzed in this study, especially loss of 1p/19q carried prognostic significance, while the others contributed little prognostic value to classical histology.
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http://dx.doi.org/10.1215/15228517-2009-011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802394PMC
December 2009

Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034.

J Clin Oncol 2009 Mar 9;27(8):1268-74. Epub 2009 Feb 9.

Neuro-Oncology Unit, Daniel den Hoed Cancer Center, PO Box 5201, 3008AE Rotterdam, the Netherlands.

Purpose: Approximately 50% of glioblastomas (GBMs) are characterized by overexpression of the epidermal growth factor receptor (EGFR) and EGFR gene amplification. In approximately 25% of instances, constitutively activated EGFR mutants are present. These observations make EGFR-inhibiting drugs a logical approach for trials in recurrent GBM.

Patients And Methods: In a randomized, controlled, phase II trial, 110 patients with progressive GBM after prior radiotherapy were randomly assigned to either erlotinib or a control arm that received treatment with either temozolomide or carmustine (BCNU). The primary end point was 6-month progression-free survival (PFS). Tumor specimens obtained at first surgery were investigated for EGFR expression; EGFRvIII mutants; EGFR amplification; EGFR mutations in exons 18, 19, and 21; and pAkt. These results were correlated with outcome. Pharmacokinetic analysis was part of the study. RESULTS; Treatment was well tolerated in general; skin toxicity was the most frequent adverse effect of erlotinib. The 6-month PFS rate in the erlotinib arm was 11.4% (95% CI, 4.6% to 21.5%), and it was 24% in the control arm. Of all explored biomarkers, only low pAkt expression appeared to be of borderline significance to an improved outcome. None of the eight patients who had tumors with EGFRvIII mutant presence and PTEN expression had 6-month PFS. The use of enzyme-inducing anticonvulsants significantly increased erlotinib clearance, but pharmacokinetic findings were not related to outcome.

Conclusion: Erlotinib has insufficient single-agent activity in unselected GBM. No clear biomarker associated with improved outcome to erlotinib was identified.
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http://dx.doi.org/10.1200/JCO.2008.17.5984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667826PMC
March 2009

Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma.

J Clin Oncol 2008 Jun;26(18):3015-24

Laboratory of Tumor Biology and Genetics, Centre Universitaire Romand de Neurochirurgie, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne 1011, Switzerland.

Purpose: Glioblastomas are notorious for resistance to therapy, which has been attributed to DNA-repair proficiency, a multitude of deregulated molecular pathways, and, more recently, to the particular biologic behavior of tumor stem-like cells. Here, we aimed to identify molecular profiles specific for treatment resistance to the current standard of care of concomitant chemoradiotherapy with the alkylating agent temozolomide.

Patients And Methods: Gene expression profiles of 80 glioblastomas were interrogated for associations with resistance to therapy. Patients were treated within clinical trials testing the addition of concomitant and adjuvant temozolomide to radiotherapy.

Results: An expression signature dominated by HOX genes, which comprises Prominin-1 (CD133), emerged as a predictor for poor survival in patients treated with concomitant chemoradiotherapy (n = 42; hazard ratio = 2.69; 95% CI, 1.38 to 5.26; P = .004). This association could be validated in an independent data set. Provocatively, the HOX cluster was reminiscent of a "self-renewal" signature (P = .008; Gene Set Enrichment Analysis) recently characterized in a mouse leukemia model. The HOX signature and EGFR expression were independent prognostic factors in multivariate analysis, adjusted for the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status, a known predictive factor for benefit from temozolomide, and age. Better outcome was associated with gene clusters characterizing features of tumor-host interaction including tumor vascularization and cell adhesion, and innate immune response.

Conclusion: This study provides first clinical evidence for the implication of a "glioma stem cell" or "self-renewal" phenotype in treatment resistance of glioblastoma. Biologic mechanisms identified here to be relevant for resistance will guide future targeted therapies and respective marker development for individualized treatment and patient selection.
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http://dx.doi.org/10.1200/JCO.2007.15.7164DOI Listing
June 2008

Chromosome 1p loss evaluation in anaplastic oligodendrogliomas.

Neuropathology 2008 Aug 26;28(4):440-3. Epub 2008 Feb 26.

INSERM, Unité 711, Paris, France.

The chromosome (chr) 1p deletion is a favorable biomarker in oligodendroglial tumors and is even more powerful a marker when combined with chr 19q loss. As a result, the 1p deletion is taken into account more and more in clinical trials and the management of patients. However, the laboratory technique implemented for detection of this biomarker has been a topic of debate. To illustrate the usefulness of evaluating multiple loci, we here report two anaplastic oligodendrogliomas that were investigated using fluorescent in situ hybridization (FISH) and bacterial artificial chromosome (BAC)-array-based comparative genomic hybridization (aCGH). Indeed, segmental analysis using FISH, limited to chr 1p36 was unable to discriminate between complete and partial deletions of chrs 1p. However, complete and partial deletions of 1p are reported to have distinct clinical outcomes. Our results illustrate that aCGH (or other multiple loci technologies) provide complementary information to single locus technologies such as FISH because multiple loci technologies can evaluate the extent of the chr 1p deletion.
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http://dx.doi.org/10.1111/j.1440-1789.2008.00863.xDOI Listing
August 2008

Intratumoral distribution of 1p loss in oligodendroglial tumors.

J Neuropathol Exp Neurol 2007 Dec;66(12):1118-23

Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.

The favorable response of oligodendrogliomas correlates well with characteristic chromosomal losses, of which loss of the short arm of chromosome 1 is most predictive. Oligodendrogliomas are histopathologically heterogeneous tumors and, in addition to the classic honeycomb histology, fields of nonclassic histology are often encountered. Information about the distribution of 1p loss in various regions of oligodendroglioma is, therefore, important to interpret findings in tumor biopsies. In this study we investigated the distribution of 1p loss in multiple fields in 24 biopsy specimens of oligodendroglioma consisting of classic and nonclassic histology by fluorescent in situ hybridization and loss of heterozygosity analysis. By fluorescent in situ hybridization analysis, loss of 1p was found in all fields examined in 37% of the tumor samples, and no loss was detected in 46%. In fields of classic oligodendroglial and polar spongioblastoma-like histology, significantly more loss for 1p was found (p < 0.001 and p < 0.01, respectively). Although fluorescent in situ hybridization analysis indicated heterogeneity for 1p loss in the other 17% of tumors, loss of heterozygosity analysis of these samples pointed to homogeneity of 1p status in all fields. The 1p status of the fields with classic histology significantly correlated with the status of the other fields in the same tumors (Spearman's rho 0.918, p < 0.001). These results point to genotypic homogeneity for 1p in oligodendroglial tumors.
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http://dx.doi.org/10.1097/nen.0b013e31815c254dDOI Listing
December 2007

Panel review of anaplastic oligodendroglioma from European Organization For Research and Treatment of Cancer Trial 26951: assessment of consensus in diagnosis, influence of 1p/19q loss, and correlations with outcome.

J Neuropathol Exp Neurol 2007 Jun;66(6):545-51

Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands.

The diagnosis of anaplastic oligodendroglioma (AOD) or anaplastic oligoastrocytoma (AOA) is subject to interobserver variation. The aim of this study was to estimate consensus in typing and grading of these tumors using tumor material collected in a large prospective randomized phase III study and to correlate the consensus diagnosis with the 1p/19q status of the tumors and the clinical outcome. The available pathology material of the first 150 patients, randomized into the European Organization for Research and Treatment of Cancer Trial 26951, was reviewed by an independent panel of 9 neuropathologists. The presence of deletions of 1p and 19q was assessed by fluorescence in situ hybridization with locus-specific probes. The panel reached consensus on the diagnosis of AOD in 52% of the tumors that had been diagnosed as AOD by the local pathologists, whereas only 8% of the local diagnosis of AOA was confirmed with consensus. The concordance on the panel diagnosis of AOD was high (intraclass correlation = 86%). The survival curves for AOD with 1p/19q loss, AOD without these losses, and AOA without 1p/19q loss ran separately in this order. The absence of necrosis and the presence of endothelial abnormalities were correlated with better outcomes. In multivariate analysis, patients' age, 1p/19q loss, and necrosis were identified as independent prognostic factors.
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http://dx.doi.org/10.1097/01.jnen.0000263869.84188.72DOI Listing
June 2007

1p/19q loss within oligodendroglioma is predictive for response to first line temozolomide but not to salvage treatment.

Eur J Cancer 2006 Oct 17;42(15):2499-503. Epub 2006 Aug 17.

Department of Neuro-Oncology, Daniel den Hoed Oncology Center, P.O. Box 5201, 3008AE Rotterdam, The Netherlands.

Background: Combined loss of 1p/19q predicts an almost 100% response rate to first line procarbazine, CCNU and vincristine chemotherapy (PCV) chemotherapy in oligodendroglial tumours. We assessed the impact of 1p and 19q loss on the outcome to first line temozolomide (TMZ) chemotherapy and to second line PCV or TMZ in progressive oligodendroglial tumours.

Materials And Methods: Tumour samples from patients included in two prospective EORTC studies on first line and second line TMZ chemotherapy in recurrent oligodendroglioma were used for this study. Most patients in the first line TMZ trial received PCV at further progression. Loss of 1p and 19q was assessed on paraffin embedded tumour samples by fluorescent in situ hybridisation with locus specific probes for 1p36 and 19q13.

Results: Losses of 1p and 19q were mainly observed in morphologically classical oligodendrogliomas (OD). Thirteen out of 18 patients with 1p loss (72%) responded to first line temozolomide (p<0.01). Both response to second line salvage PCV or to second line temozolomide was limited, even in patients with combined 1p/19q loss. Patients with tumours with 1p loss treated with salvage PCV had improved PFS (p<0.05). More patients with 1p loss were alive at 60 and 120 months after initial surgery (p<0.001).

Conclusion: Combined 1p/19q loss is mainly observed in classical OD. Responses to first line temozolomide are strongly correlated to loss of 1p. Response to second line alkylating treatment is modest even in tumours with 1p/19q loss. For further improvement of outcome in OD novel treatments are needed.
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http://dx.doi.org/10.1016/j.ejca.2006.05.021DOI Listing
October 2006

Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial.

J Clin Oncol 2006 Jun;24(18):2715-22

Departments of Neurology and Pathology, Daniel den Hoed Cancer Center/Erasmus University Hospital, Rotterdam, The Netherlands.

Purpose: Anaplastic oligodendrogliomas are more responsive to chemotherapy than high-grade astrocytomas. We investigated, in a multicenter randomized controlled trial, whether adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy improves overall survival (OS) in newly diagnosed patients with anaplastic oligodendrogliomas or anaplastic oligoastrocytomas.

Patients And Methods: The primary end point of the study was OS; secondary end points were progression-free survival (PFS) and toxicity. Patients were randomly assigned to either 59.4 Gy of radiotherapy (RT) in 33 fractions only or to the same RT followed by six cycles of standard PCV chemotherapy (RT/PCV). 1p and 19q deletions were assessed with fluorescent in situ hybridization.

Results: A total of 368 patients were included. The median follow-up time was 60 months, and 59% of patients have died. In the RT arm, 82% of patients with tumor progression received chemotherapy. In 38% of patients in the RT/PCV arm, adjuvant PCV was discontinued for toxicity. OS time after RT/PCV was 40.3 months compared with 30.6 months after RT only (P = .23). RT/PCV increased PFS time compared with RT only (23 v 13.2 months, respectively; P = .0018). Twenty-five percent of patients were diagnosed with combined 1p/19q loss; 74% of this subgroup was still alive after 60 months. RT/PCV did not improve survival in the subgroup of patients with 1p/19q loss.

Conclusion: Adjuvant PCV chemotherapy does not prolong OS but does increase PFS in anaplastic oligodendroglioma. Combined loss of 1p/19q identifies a favorable subgroup of oligodendroglial tumors. No genetic subgroup could be identified that benefited with respect to OS from adjuvant PCV.
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http://dx.doi.org/10.1200/JCO.2005.04.6078DOI Listing
June 2006

Gene expression profiles associated with treatment response in oligodendrogliomas.

Cancer Res 2005 Dec;65(24):11335-44

Department of Neurology, Cancer Genomics Center, Erasmus Medical Center, Rotterdam, the Netherlands.

Oligodendrogliomas are a specific subtype of brain tumor of which the majority responds favorably to chemotherapy. In this study, we made use of expression profiling to identify chemosensitive oligodendroglial tumors. Correlation of expression profiles to loss of heterozygosity on 1p and 19q, common chromosomal aberrations associated with response to treatment, identified 376, 64, and 60 differentially expressed probe sets associated with loss of 1p, 19q or 1p, and 19q, respectively. Correlation of expression profiles to the tumors' response to treatment identified 16 differentially expressed probe sets. Because transcripts associated with chemotherapeutic response were identified independent of common chromosomal aberrations, expression profiling may be used as an alternative approach to the tumors' 1p status to identify chemosensitive oligodendroglial tumors. Finally, we correlated expression profiles to survival of the patient after diagnosis and identified 103 differentially expressed probe sets. The observation that many genes are differentially expressed between long and short survivors indicates that the genetic background of the tumor is an important factor in determining the prognosis of the patient. Furthermore, these transcripts can help identify patient subgroups that are associated with favorable prognosis. Our study is the first to correlate gene expression with chromosomal aberrations and clinical performance (response to treatment and survival) in oligodendrogliomas. The differentially expressed transcripts can help identify patient subgroups with good prognosis and those that will benefit from chemotherapeutic treatments.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-1886DOI Listing
December 2005

Monocyte-derived dendritic cells express and secrete matrix-degrading metalloproteinases and their inhibitors and are imbalanced in multiple sclerosis.

J Neuroimmunol 2002 May;126(1-2):161-71

Neuroimmunology Unit, Division of Neurology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.

Dendritic cells (DC) are antigen-presenting cells (APC) that most efficiently initiate and control immune responses. Migration processes of blood DC are crucial to exert their professional antigen-presenting functions. Matrix-degrading metalloproteinases (MMP) are proteolytic enzymes, which are considered to be key enzymes in extracellular matrix (ECM) turnover and mediators of cell migration. Tissue inhibitors of metalloproteinases (TIMP) are important regulators of MMP activity. Here we investigate whether blood monocyte-derived immature DC (iDC) and mature DC (mDC) express, produce and secrete functionally active MMP-1, -2, -3 and -9 and their inhibitors TIMP-1 and -2, and examine their involvement in multiple sclerosis (MS). On mRNA level, we observed high numbers of MMP-2 and TIMP-2 mRNA expressing iDC in MS. On protein level, high percentages of MMP-1, -2 and -9 expressing iDC by flow cytometry, and high MMP-1 secretion by Western blot together with high MMP-2 and -9 activities in iDC supernatants as studied with zymography were observed. Similarly, MS is associated with high percentages of MMP-2 and -3 and of TIMP-1 expressing mDC by flow cytometry together with high MMP-3 secretion and high MMP-9 activity in culture supernatants. Spontaneous migratory capacity of both iDC and mDC over ECM-coated filters was higher in MS compared to healthy controls (HC). In conclusion, blood monocyte-derived iDC and mDC express, produce and secrete several MMP and TIMP. Alterations in these molecules as observed in MS may be functionally important for DC functioning.
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http://dx.doi.org/10.1016/s0165-5728(02)00054-1DOI Listing
May 2002

Recruitment of dendritic cells to the cerebrospinal fluid in bacterial neuroinfections.

J Neuroimmunol 2002 Jan;122(1-2):106-16

Division of Neurology, Karolinska Institute, Huddinge University Hospital R54, SE-14186, Stockholm, Sweden.

Dendritic cells (DC) accumulate in the CNS during inflammation and may contribute to local immune responses. Two DC subsets present in human cerebrospinal fluid (CSF) are probably recruited from myeloid (CD11c(+)CD123(dim)) and plasmacytoid (CD11c(-)CD123(high)) blood DC. In bacterial meningitis and especially in Lyme meningoencephalitis, numbers of myeloid and plasmacytoid DC in CSF were increased, compared to non-inflammatory neurological diseases, and correlated with chemotactic activity of CSF for immature monocyte-derived DC (moDC). Multiple DC chemoattractants, including macrophage inflammatory protein (MIP)-1beta, monocyte chemotactic protein (MCP)-1, MCP-3, RANTES and stromal cell-derived factor (SDF)-1alpha were elevated in CSF in these two neuroinfections. Chemotaxis of immature moDC induced by these CSFs could be partially inhibited by mAbs against CXCR4, the receptor for SDF-1alpha, and CD88, the receptor for C5a. SDF-1alpha present in CSF also chemoattracted mature moDC, which in vivo could correspond to a diminished migration of antigen-bearing DC from the CSF to secondary lymphoid organs. Regulation of DC trafficking to and from the CSF may represent a mechanism of controlling the CNS inflammation.
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http://dx.doi.org/10.1016/s0165-5728(01)00451-9DOI Listing
January 2002