http://repub.eur.nl/res/aut/22226/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39690/ 2013-03-25T00:00:00Z Primary intracranial germ-cell tumors are rare tumors primarily of adolescence, and literature on this disease in adults is scarce. The available evidence on intracranial germ-cell tumors is reviewed with a focus on adult patients whenever possible, and used to make suggestions for diagnosis and treatment. Diagnostic and treatment algorithms were developed to provide an evidence-based backbone to base treatment on in adult patients with a (suspected) primary intracranial germ-cell tumor. http://repub.eur.nl/res/pub/34990/ 2012-01-16T00:00:00Z 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. http://repub.eur.nl/res/pub/34132/ 2011-11-15T00:00:00Z Purpose: The MGMT promoter methylation status has been suggested to be predictive for outcome to temozolomide chemotherapy in patients with glioblastoma (GBM). Subsequent studies indicated that MGMT promoter methylation is a prognostic marker even in patients treated with radiotherapy alone, both in GBMs and in grade III gliomas. Experimental Design: To help determine the molecular mechanism behind this prognostic effect, we have conducted genome-wide methylation profiling and determined the MGMT promoter methylation status, 1p19q LOH, IDH1 mutation status, and expression profile on a series of oligodendroglial tumors [anaplastic oligodendrogliomas (AOD) and anaplastic oligoastrocytomas (AOA)] within EORTC study 26951. The series was expanded with tumors of the same histology and treatment from our own archive. Results: Methylation profiling identified two main subgroups of oligodendroglial brain tumors of which survival in the CpG island hypermethylation phenotype (CIMP+) subgroup was markedly better than the survival of the unmethylated (CIMP-) subgroup (5.62 vs. 1.24 years; P < 0.0001). CIMP status correlated with survival, MGMT promoter methylation, 1p19q LOH, and IDH1 mutation status. CIMP status strongly increases the predictive accuracy of survival in a model including known clinical prognostic factors such as age and performance score. We validated our results on an independent data set from the Cancer Genome Atlas (TCGA). Conclusion: The strong association between CIMP status andMGMTpromoter methylation suggests that the MGMT promoter methylation status is part of a more general, prognostically favorable genome-wide methylation profile. Methylation profiling therefore may help identify AODs and AOAs with improved prognosis. http://repub.eur.nl/res/pub/34570/ 2011-11-01T00:00:00Z Gliomas form a heterogeneous group of tumours of the central nervous system. Most gliomas, the so-called 'diffuse gliomas', are characterized by diffuse infiltrative growth in the neuropil. Based on histopathological analysis, diffuse gliomas are subdivided in astrocytic, oligodendroglial, and oligoastrocytic tumours and graded as WHO grade II (low grade), WHO grade III (anaplastic), or WHO grade IV (glioblastoma). Accurate distinction between the different diffuse glioma types and malignancy grades has significant prognostic and therapeutic implications. This review describes essential aspects of the microscopic diagnosis of diffuse gliomas. Because of problems with tissue sampling and imprecise criteria for typing and grading, unequivocal histopathological classification of diffuse gliomas can be challenging. The addition of molecular parameters contributes to a more objective pathological diagnosis of diffuse gliomas. A multidisciplinary approach is mandatory for achieving an optimal diagnosis for patients with these tumours. http://repub.eur.nl/res/pub/26559/ 2011-07-01T00:00:00Z BACKGROUND: Although it has been demonstrated that the neuronal intermediate filament alpha-internexin (INA) is closely related to 1p19q codeletion in gliomas, its prognostic and predictive value has not yet been confirmed in a prospective trial. The authors of this report assessed the prognostic significance of INA expression and its correlation with relevant clinical and molecular characteristics in the prospective, randomized European Organization for Research and Treatment of Cancer (EORTC) 26951 trial of adjuvant procarbazine, lomustine, and vincristine (PCV) in patients with anaplastic oligodendroglial tumors (AOTs). METHODS: INA immunohistochemistry expression in tumors from 92 patients who were included in the EORTC 26951 trial was analyzed independently by 2 observers and was correlated with relevant clinical characteristics, including progression-free survival (PFS) and overall survival (OS), and with molecular features, including 1p/19q codeletion, isocitrate dehydrogenase 1 and 2 gene (IDH1/IDH2) mutation, and O-6 methylguanine-DNA methyltransferase (MGMT) promoter methylation status. RESULTS: INA expression was observed in 33 tumors and was strongly correlated with 1p/19q codeletion, IDH1 mutations, and MGMT promoter methylation. It was associated with significantly better PFS and OS independent of the treatment received. By using Cox proportional hazard modeling for OS with stepwise selection, INA expression, patient age, and performance status were identified as independent prognostic factors. The results indicated that INA expression may have an impact on the efficacy of combined radiotherapy plus PCV. CONCLUSIONS: In a homogeneously treated group of patients with grade III AOTs, INA expression had strong favorable prognostic significance for OS and may have predictive value for sensitivity to chemotherapy. Copyright http://repub.eur.nl/res/pub/26702/ 2011-06-01T00:00:00Z Paragangliomas (PGLs) have widely different metastastic potentials. Two different types of PGLs can be defined by expression profiling. Cluster 1 PGLs exhibit VHL and/or succinate dehydrogenase (SDH) mutations and a pseudohypoxic phenotype. RET and neurofibromatosis type 1 (NF1) mutations occur in cluster 2 tumors characterized by deregulation of the RAS/RAF/MAP kinase signaling cascade. Sporadic PGLs can exhibit either profile. During sustained hypoxia, a natural antisense transcript of hypoxia-inducible factor 1 (aHIF) is expressed. The role of aHIF in the metastatic potential of PGL has not yet been investigated. The aim was to test the hypothesis that genotype-specific overexpression of aHIF is associated with an increased metastatic potential. Tumor samples were collected from87 patients with PGL. Quantitative PCR was performed for aHIF, vascular endothelial growth factor (VEGF), aquaporin 3, cytochrome b561, p57Kip2, slit homolog 3, and SDHC. Expression was related to mutation status, benign versus malignant tumors, and metastasis-free survival. We found that both aHIF and VEGF were overexpressed in cluster 1 PGLs and inmetastatic tumors. In contrast, slit homolog 3, p57Kip2, cytochrome b561, and SDHC showed overexpression in non-metastatic tumors, whereas no such difference was observed for aquaporin 3. Patients with higher expression levels of aHIF and VEGF had a significantly decreased metastasis free survival. Higher expression levels of SDHC are correlated with an increased metastasis-free survival. In conclusion, we not only demonstrate a higher expression of VEGF in cluster 1 PGL, fitting a profile of pseudohypoxia and angiogenesis, but also of aHIF. Moreover, overexpression of aHIF and VEGF marks a higher metastatic potential in PGL. http://repub.eur.nl/res/pub/19912/ 2010-03-01T00:00:00Z Purpose: Recent studies have shown the prognostic significance of IDH1 mutations in glioma. It is yet unclear if IDH1 mutations are predictive for outcome to chemotherapy. We determined the effect of IDH1 mutations on progression-free survival and overall survival (OS), and its correlation with other clinical and molecular features in the prospective randomized European Organization for Research and Treatment of Cancer study 26951 on adjuvant procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-L-nitrosourea, and vincristine (PCV) in anaplastic oligodendroglioma. Experimental Design: IDH1 and IDH2 alterations of the mutational hotspot codons R132 and R172 were assessed by the bidirectional cycle sequencing of PCR-amplified fragments. MGMT promoter methylation was assessed using methylation-specific multiplex ligation-dependant probe amplification based on methylation-sensitive restriction analysis. Loss of chromosomes 1p, 19q, 10, and 10q and the gain of 7 and the EGFR gene were assessed with fluorescence in situ hybridization. Results: From 159 patients, sufficient material was available for IDH1 analysis. In 151 and 118 of these patients, respectively, the 1p/19q status and the MGMT promoter methylation status were known. In 73 cases (46%), an IDH1 mutation was found and only one IDH2 mutation was identified. The presence of IDH1 mutations correlated with 1p/19q codeletion and MGMT promoter methylation, and inversely correlated with loss of chromosome 10, EGFR amplification, polysomy of chromosome 7, and the presence of necrosis. IDH1 mutations were found to be prognostic in the radiotherapy- and the radiotherapy/PCV-treated patients, for both progression-free survival and OS. With Cox proportional hazard modeling for OS with stepwise selection, IDH1 mutations and 1p/19q codeletion but not MGMT promoter methylation were independent prognostic factors. Conclusion: In this homogeneously treated group of anaplastic oligodendroglioma patients, the presence of IDH1 mutations was found to carry a very strong prognostic significance for OS but without evidence of a predictive significance for outcome to PCV chemotherapy. IDH1 mutations were strongly associated with 1p/ 19q codeletion and MGMT promoter methylation. ©2010 AACR. http://repub.eur.nl/res/pub/25381/ 2009-12-01T00:00:00Z 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 (EGFRamp), 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 (1ploss19qloss) were histopathologically diagnosed as anaplastic oligodendroglioma, were more frequently located in the frontal lobe, and had a better outcome. Anaplastic oligodendroglial tumors with EGFRamp 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 1ploss19qloss 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. Copyright 2009 by the Society for Neuro-Oncology. http://repub.eur.nl/res/pub/24538/ 2009-05-01T00:00:00Z Background: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. Methods: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. Findings: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27·2% (95% CI 22·2-32·5) at 2 years, 16·0% (12·0-20·6) at 3 years, 12·1% (8·5-16·4) at 4 years, and 9·8% (6·4-14·0) at 5 years with temozolomide, versus 10·9% (7·6-14·8), 4·4% (2·4-7·2), 3·0% (1·4-5·7), and 1·9% (0·6-4·4) with radiotherapy alone (hazard ratio 0·6, 95% CI 0·5-0·7; p<0·0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. Interpretation: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. Funding: EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.