W. Peter Vandertop

Bio: W. Peter Vandertop is an academic researcher from University of Amsterdam. The author has contributed to research in topics: Subarachnoid hemorrhage & Glioma. The author has an hindex of 44, co-authored 165 publications receiving 7355 citations. Previous affiliations of W. Peter Vandertop include VU University Medical Center & VU University Amsterdam.

Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up

Abstract: Summary Background Our previous study on cognitive functioning among 195 patients with low-grade glioma (LGG) a mean of 6 years after diagnosis suggested that the tumour itself, rather than the radiotherapy used to treat it, has the most deleterious effect on cognitive functioning; only high fraction dose radiotherapy (>2 Gy) resulted in significant added cognitive deterioration. The present study assesses the radiological and cognitive abnormalities in survivors of LGG at a mean of 12 years after first diagnosis. Methods Patients who have had stable disease since the first assessment were invited for follow-up cognitive assessment (letter–digit substitution test, concept shifting test, Stroop colour–word test, visual verbal learning test, memory comparison test, and categoric word fluency). Compound scores in six cognitive domains (attention, executive functioning, verbal memory, working memory, psychomotor functioning, and information processing speed) were calculated to detect differences between patients who had radiotherapy and patients who did not have radiotherapy. White-matter hyperintensities and global cortical atrophy were rated on MRI scans. Findings 65 patients completed neuropsychological follow-up at a mean of 12 years (range 6–28 years). 32 (49%) patients had received radiotherapy (three had fraction doses >2 Gy). The patients who had radiotherapy had more deficits that affected attentional functioning at the second follow-up, regardless of fraction dose, than those who did not have radiotherapy (−1·6 [SD 2·4] vs −0·1 [1·3], p=0·003; mean difference 1·4, 95% CI 0·5–2·4). The patients who had radiotherapy also did worse in measures of executive functioning (−2·0 [3·7] vs −0·5 [1·2], p=0·03; mean difference 1·5, 0·2–2·9) and information processing speed (−2·0 [3·7] vs −0·6 [1·5], p=0·05; mean difference 0·8, 0·009–1·6]) between the two assessments. Furthermore, attentional functioning deteriorated significantly between the first and second assessments in patients who had radiotherapy (p=0·25). In total, 17 (53%) patients who had radiotherapy developed cognitive disabilities deficits in at least five of 18 neuropsychological test parameters compared with four (27%) patients who were radiotherapy naive. White-matter hyperintensities and global cortical atrophy were associated with worse cognitive functioning in several domains. Interpretation Long-term survivors of LGG who did not have radiotherapy had stable radiological and cognitive status. By contrast, patients with low-grade glioma who received radiotherapy showed a progressive decline in attentional functioning, even those who received fraction doses that are regarded as safe (≤2 Gy). These cognitive deficits are associated with radiological abnormalities. Our results suggest that the risk of long-term cognitive and radiological compromise that is associated with radiotherapy should be considered when treatment is planned. Funding Kaptein Fonds; Schering Plough.

Treatment of Brain Arteriovenous Malformations A Systematic Review and Meta-analysis

Abstract: Context Outcomes following treatment of brain arteriovenous malformations (AVMs) with microsurgery, embolization, stereotactic radiosurgery (SRS), or combinations vary greatly between studies. Objectives To assess rates of case fatality, long-term risk of hemorrhage, complications, and successful obliteration of brain AVMs after interventional treatment and to assess determinants of these outcomes. Data Sources We searched PubMed and EMBASE to March 1, 2011, and hand-searched 6 journals from January 2000 until March 2011. Study Selection and Data Extraction We identified studies fulfilling predefined inclusion criteria. We used Poisson regression analyses to explore associations of patient and study characteristics with case fatality, complications, long-term risk of hemorrhage, and successful brain AVM obliteration. Data Synthesis We identified 137 observational studies including 142 cohorts, totaling 13 698 patients and 46 314 patient-years of follow-up. Case fatality was 0.68 (95% CI, 0.61-0.76) per 100 person-years overall, 1.1 (95% CI, 0.87-1.3; n = 2549) after microsurgery, 0.50 (95% CI, 0.43-0.58; n = 9436) after SRS, and 0.96 (95% CI, 0.67-1.4; n = 1019) after embolization. Intracranial hemorrhage rates were 1.4 (95% CI, 1.3-1.5) per 100 person-years overall, 0.18 (95% CI, 0.10-0.30) after microsurgery, 1.7 (95% CI, 1.5-1.8) after SRS, and 1.7 (95% CI, 1.3-2.3) after embolization. More recent studies were associated with lower case-fatality rates (rate ratio [RR], 0.972; 95% CI, 0.955-0.989) but increased rates of hemorrhage (RR, 1.02; 95% CI, 1.00-1.03). Male sex (RR, 0.964; 95% CI, 0.945-0.984), small brain AVMs (RR, 0.988; 95% CI, 0.981-0.995), and those with strictly deep venous drainage (RR, 0.975; 95% CI, 0.960-0.990) were associated with lower case fatality. Lower hemorrhage rates were associated with male sex (RR, 0.976, 95% CI, 0.964-0.988), small brain AVMs (RR, 0.988, 95% CI, 0.980-0.996), and brain AVMs with deep venous drainage (0.982, 95% CI, 0.969-0.996). Complications leading to permanent neurological deficits or death occurred in a median 7.4% (range, 0%-40%) of patients after microsurgery, 5.1% (range, 0%-21%) after SRS, and 6.6% (range, 0%-28%) after embolization. Successful brain AVM obliteration was achieved in 96% (range, 0%-100%) of patients after microsurgery, 38% (range, 0%-75%) after SRS, and 13% (range, 0%-94%) after embolization. Conclusions Although case fatality after treatment has decreased over time, treatment of brain AVM remains associated with considerable risks and incomplete efficacy. Randomized controlled trials comparing different treatment modalities appear justified.

IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors.

Abstract: Systematic sequence profiling of the Glioblastoma Multiforme (GBM) genome has recently led to the identification of somatic mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Interestingly, only the evolutionarily conserved residue R132 located in the substrate binding site of IDH1 was found mutated in GBM. At present, the occurrence and the relevance of p.R132 (IDH1R132) variants in tumors other than GBMs is largely unknown. We searched for mutations at position R132 of the IDH1 gene in a panel of 672 tumor samples. These included high-grade glioma, gastrointestinal stromal tumors (GIST), melanoma, bladder, breast, colorectal, lung, ovarian, pancreas, prostate, and thyroid carcinoma specimens. In addition, we assessed a panel of 84 cell lines from different tumor lineages. Somatic mutations affecting the IDH1R132 residue were detected in 20% (23 of 113) high-grade glioma samples. In addition to the previously reported p.R132H and p.R132S alleles, we identified three novel somatic mutations (p.R132C, p.R132G, and p.R132L) affecting residue IDH1R132 in GBM. Strikingly, no IDH1 mutations were detected in the other tumor types. These data indicate that cancer mutations affecting IDH1R132 are tissue-specific, and suggest that it plays a unique role in the development of high-grade gliomas. Hum Mutat 30, 7–11, 2009. © 2008 Wiley-Liss, Inc.

Epilepsy in low-grade gliomas: the impact on cognitive function and quality of life.

Abstract: Low-grade gliomas frequently are associated with epilepsy. The purpose of this study is to determine the impact of epilepsy and antiepileptic drug (AED) treatment on cognitive functioning and health-related quality of life (HRQOL) in these patients. One hundred fifty-six patients without clinical or radiological signs of tumor recurrence for at least 1 year after histological diagnosis and with an epilepsy burden (based on seizure frequency and AED use) ranging from none to severe were compared with healthy controls. The association between epilepsy burden and cognition/HRQOL was also investigated. Eighty-six percent of the patients had epilepsy and 50% of those using AEDs actually were seizure-free. Compared with healthy controls, glioma patients had significant reductions in information processing speed, psychomotor function, attentional functioning, verbal and working memory, executive functioning, and HRQOL. The increase in epilepsy burden that was associated with significant reductions in all cognitive domains except for attentional and memory functioning could primarily be attributed to the use of AEDs, whereas the decline in HRQOL could be ascribed to the lack of complete seizure control. In conclusion, low-grade glioma patients suffer from a number of neuropsychological and psychological problems that are aggravated by the severity of epilepsy and by the intensity of the treatment.

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

Abstract: In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

IDH1 and IDH2 Mutations in Gliomas

Abstract: Background A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). Methods We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. Results We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations h...

Regulation of cancer cell metabolism

Abstract: Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

Abstract: Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.

Patterns of Somatic Mutation in Human Cancer Genomes

Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore PL02-05 All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.