Genetic Clues to Meningioma: Meningiomas are the most common primary brain tumors in adults. Located within the layer of tissue covering the brain, these tumors are usually slow-growing and benign but can cause serious neurological complications. About half of these tumors have mutations in the neurofibromin 2 gene ( NF2 ). To identify other genes that contribute to meningioma pathogenesis, Clark et al. (p. 1077 , published online 24 January) performed genome sequence analysis on 300 tumors. Meningiomas fell into two general classes: benign tumors located at the skull base—which tend to harbor mutations in the TRAF7, KLF4, AKT1 , and SMO genes—and higher-grade tumors located in the cerebral and cerebellar hemispheres harbor mutations in NF2.

Murat Günel and colleagues use an integrated genomic approach to analyze the malignant progression of IDH1-mutant gliomas. They observe nonlinear clonal expansion of the original tumors and identify oncogenic pathways driving progression, including activation of MYC and RTK-RAS-PI3K pathways and epigenetic silencing of developmental transcription factors. Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors1. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.

Twenty years of oncolytic virus development have created a field that is driven by the potential promise of lasting impact on our cancer treatment repertoire. With the field constantly expanding—more than 20 viruses have been recognized as potential oncolytic viruses—new virus candidates continue to emerge even as established viruses reach clinical trials. They all share the defining commonalities of selective replication in tumors, subsequent tumor cell lysis, and dispersion within the tumor. Members from diverse virus classes with distinctly different biologies and host species have been identified. Of these viruses, 15 have been tested on human glioblastoma multiforme. So far, 20 clinical trials have been conducted or initiated using attenuated strains of 7 different oncolytic viruses against glioblastoma multiforme. In this review, we present an overview of viruses that have been developed or considered for glioblastoma multiforme treatment. We outline the principles of tumor targeting and selective viral replication, which include mechanisms of tumor-selective binding, and molecular elements usurping cellular biosynthetic machinery in transformed cells. Results from clinical trials have clearly established the proof of concept and have confirmed the general safety of oncolytic virus application in the brain. The moderate clinical efficacy has not yet matched the promising preclinical lab results; next-generation oncolytic viruses that are either “armed” with therapeutic genes or embedded in a multimodality treatment regimen should enhance the clinical results.

Object. Reports of outcomes for surgical treatment of cortical dysplasia associated with epilepsy are conflicting due to the inclusion of patients with a wide range of malformations of cortical development. The authors report their experience and the long-term outcome for a subgroup of patients with the histopathological diagnosis of focal cortical dysplasia of Taylor. Methods. The records of 22 patients with focal cortical dysplasia of Taylor (15 with the balloon-cell type and seven with the nonballoon-cell type) were reviewed. There were 11 female and 11 male patients whose mean age was 26 ± 17.6 years (mean ± standard deviation [SD]) at surgery. The details of their epilepsy evaluation and resection were analyzed. Extent of resection was preoperatively planned using information obtained from long-term intracranial monitoring (15 patients) and/or more definitively determined by histopathologically proven clear margins during resection when feasible (12 patients). The mean duration of follow up was 6.3 ± 5.1 years (mean ± SD, range 0.5–15.6 years). Risk factors for epilepsy were trauma (seven patients) or meningoencephalitis (one patient); 14 patients (64%) had no obvious risk factors. The mean age at seizure onset was 9.2 years and the mean duration of their epilepsy was 16.1 ± 9 years. In two patients there were no adverse findings on magnetic resonance (MR) imaging. In 15 patients (68%), the epileptogenic zone identified on long-term intracranial monitoring extended beyond the abnormality observed on MR images. Focal resection (lesion plus margins) was performed in 14 patients (64%), whereas eight (36%) underwent partial/tailored lobectomy. Two patients underwent multiple subpial transections in addition to partial lesionectomy because their lesions involved the sensorimotor cortex. In these two, functional MR imaging confirmed a normal functional anatomy despite the presence of the cortical dysplasia. Eleven (92%) of 12 patients who underwent resection guided by histopathologically proven clear margins and three (43%) of seven patients who underwent histopathologically proven subtotal resection have remained seizure free. Evidence of clear margins was significantly associated with an improved seizure outcome (p = 0.003). Postoperatively, expected deficits included nondisabling visual field defects, which occurred in three patients (14%), and transient sensorimotor deficits, which appeared in five (23%). Two patients had meningitis, which was successfully treated with antibiotics. Overall, 16 patients (73%) are either seizure free (13 patients), have rare nondisabling partial seizures (one patient), or had one seizure after their medication was changed (two patients). Thirteen patients (59%) have discontinued anticonvulsant medications or are being maintained on monotherapy. Of five patients (23%), two have had rare disabling seizures or significant reduction in their seizure frequency (three patients). One patient's seizures have remained the same. Conclusions. Focal cortical dysplasias are a distinct subgroup of malformations of cortical development and have a favorable outcome after resection. The epileptogenic zone often extends beyond the abnormality found on neuroimaging. Resection of the epileptogenic zone guided by histopathologically proven clear margins is associated with an improved seizure outcome.

Background Malignant high-grade gliomas (HGGs), including the most aggressive form, glioblastoma multiforme, show significant clinical and genomic heterogeneity. Despite recent advances, the overall survival of HGGs and their response to treatment remain poor. In order to gain further insight into disease pathophysiology by correlating genomic landscape with clinical behavior, thereby identifying distinct HGG molecular subgroups associated with improved prognosis, we performed a comprehensive genomic analysis. Methods We analyzed and compared 720 exome-sequenced gliomas (136 from Yale, 584 from The Cancer Genome Atlas) based on their genomic, histological, and clinical features. Results We identified a subgroup of HGGs (6 total, 4 adults and 2 children) that harbored a statistically significantly increased number of somatic mutations (mean = 9257.3 vs 76.2, P = .002). All of these “ultramutated” tumors harbored somatic mutations in the exonuclease domain of the polymerase epsilon gene (POLE), displaying a distinctive genetic profile, characterized by genomic stability and increased C-to-A transversions. Histologically, they all harbored multinucleated giant or bizarre cells, some with predominant infiltrating immune cells. One adult and both pediatric patients carried homozygous germline mutations in the mutS homolog 6 (MSH6) gene. In adults, POLE mutations were observed in patients younger than 40 years and were associated with a longer progression-free survival. Conclusions We identified a genomically, histologically, and clinically distinct subgroup of HGGs that harbored somatic POLE mutations and carried an improved prognosis. Identification of distinctive molecular and pathological HGG phenotypes has implications not only for improved classification but also for potential targeted treatments.