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PURPOSE: The reliability and reproducibility of T2-weighted imaging/fluid-attenuated inversion recovery (T2/FLAIR) mismatch were investigated in the diagnosis of isocitrate dehydrogenase (IDH) mutant astrocytoma between WHO grade II and III diffuse hemispheric gliomas. METHODS: WHO grade II and grade III diffuse hemispheric gliomas (n=133) treated in our institute were included in the study. Pathological findings and molecular markers of the cases were reviewed with the criteria of WHO 2016. The finding of mismatch between T2-weighted and FLAIR images in preoperative magnetic resonance imaging (MRI) of the cases was evaluated by two different radiologists. The readers reviewed MRIs independently, blinded to the histopathologic diagnosis or molecular subset of tumors. The cases were classified as IDH-mutant astrocytoma, oligodendroglioma and IDH-wildtype (IDH-wt) astrocytoma according to molecular and genetic features. RESULTS: T2/FLAIR mismatch positivity was observed in 46 patients (34.6%). T2/FLAIR mismatch positivity was observed in 42 of 75 IDH-mutant astrocytomas (56%) and 4 of 43 oligodendrogliomas (9.30%), while it was not seen among IDH-wt astrocytomas (0/15, 0%). The T2/FLAIR mismatch ratio was significantly different between IDH-mutant astrocytomas (WHO grade II and grade III) and oligodendrogliomas (chi-square, p

OBJECTIVEProcesses that cause or contribute to cancer, such as aging, exposure to carcinogens, or DNA damage repair deficiency (DDRd), create predictable and traceable nucleotide alterations in one’s genetic code (termed “mutational signatures”). Large studies have previously identified various such mutational signatures across cancers that can be attributed to the specific causative processes. To gain further insight into the processes in glioma development, the authors analyzed mutational signatures in adult diffuse gliomas (DGs).METHODSTwenty-five DGs and paired blood samples were whole exome sequenced. Somatic mutational signatures were identified using 2 different methods. Associations of the signatures with age at diagnosis, molecular subset, and mutational load were investigated. As DDRd-related signatures were frequently observed, germline and somatic DDR gene mutations as well as microsatellite instability (MSI) status were determined for all samples. For validation of signature prevalence, publicly available data from The Cancer Genome Atlas (TCGA) were used.RESULTSEach tumor had a unique combination of signatures. The most common signatures were signature 1 (88%, aging related), signature 3 (52%, homologous recombination related), and signature 15 (56%, mismatch repair related). Eighty-four percent of the tumors contained at least 1 DDRd signature. The findings were validated using public TCGA data. The weight of signature 1 positively correlated with age (r = 0.43) while cumulative weight of DDRd signatures negatively correlated with age (r = −0.16). Each subject had at least 1 germline/somatic alteration in a DDR gene, the most common being the risk single nucleotide polymorphism rs1800734 in MLH1. The rs1800734-AA genotype had a higher cumulative DDRd weight as well as higher mutational load; TP53 was the most common somatically altered DDR gene. MSI was observed in 24% of the tumors. No significant associations of MSI status with mutational load, rs1800734, or the cumulative weight of DDRd signatures were identified.CONCLUSIONSCurrent findings suggest that DDRd may act as a fundamental mechanism in gliomagenesis rather than being a random, secondary event.

Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c) TERT promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.

Background Glioblastoma (GBM) is an aggressive tumor that frequently exhibits gain of chromosome 7, loss of chromosome 10, and aberrantly activated receptor tyrosine kinase signaling pathways. Previously, we identified Mesenchyme Homeobox 2 (MEOX2), a gene located on chromosome 7, as an upregulated transcription factor in GBM. Overexpressed transcription factors can be involved in driving GBM. Here, we aimed to address the role of MEOX2 in GBM. Methods Patient-derived GBM tumorspheres were used to constitutively knockdown or overexpress MEOX2 and subjected to in vitro assays including western blot to assess ERK phosphorylation. Cerebral organoid models were used to investigate the role of MEOX2 in growth initiation. Intracranial mouse implantation models were used to assess the tumorigenic potential of MEOX2. RNA-sequencing, ACT-seq, and CUT&Tag were used to identify MEOX2 target genes. Results MEOX2 enhanced ERK signaling through a feed-forward mechanism. We identified Ser155 as a putative ERK-dependent phosphorylation site upstream of the homeobox-domain of MEOX2. S155A substitution had a major effect on MEOX2 protein levels and altered its subnuclear localization. MEOX2 overexpression cooperated with p53 and PTEN loss in cerebral organoid models of human malignant gliomas to induce cell proliferation. Using high-throughput genomics, we identified putative transcriptional target genes of MEOX2 in patient-derived GBM tumorsphere models and a fresh frozen GBM tumor. Conclusions We identified MEOX2 as an oncogenic transcription regulator in GBM. MEOX2 increases proliferation in cerebral organoid models of GBM and feeds into ERK signaling that represents a core signaling pathway in GBM.

OBJECTIVE Gliomas frequently involve the insula both primarily and secondarily by invasion. Despite the high connectivity of the human insula, gliomas do not spread randomly to or from the insula but follow stereotypical anatomical involvement patterns. In the majority of cases, these patterns correspond to the intrinsic connectivity of the limbic system, except for tumors with aggressive biology. On the basis of these observations, the authors hypothesized that these different involvement patterns may be correlated with distinct outcomes and analyzed these correlations in an institutional cohort. METHODS Fifty-nine patients who had undergone surgery for insular diffuse gliomas and had complete demographic, pre- and postoperative imaging, pathology, molecular genetics, and clinical follow-up data were included in the analysis (median age 37 years, range 21–71 years, M/F ratio 1.68). Patients with gliomatosis and those with only minor involvement of the insula were excluded. The presence of T2-hyperintense tumor infiltration was evaluated in 12 anatomical structures. Hierarchical biclustering was used to identify co-involved structures, and the findings were correlated with established functional anatomy knowledge. Overall survival was evaluated using Kaplan-Meier and Cox proportional hazards regression analysis (17 parameters). RESULTS The tumors involved the anterior insula (98.3%), posterior insula (67.8%), temporal operculum (47.5%), amygdala (42.4%), frontal operculum (40.7%), temporal pole (39%), parolfactory area (35.6%), hypothalamus (23.7%), hippocampus (16.9%), thalamus (6.8%), striatum (5.1%), and cingulate gyrus (3.4%). A mean 4.2 ± 2.6 structures were involved. On the basis of hierarchical biclustering, 7 involvement patterns were identified and correlated with cortical functional anatomy (pure insular [11.9%], olfactocentric [15.3%], olfactoopercular [33.9%], operculoinsular [15.3%], striatoinsular [3.4%], translimbic [11.9%], and multifocal [8.5%] patterns). Cox regression identified hippocampal involvement (p = 0.006) and postoperative tumor volume (p = 0.027) as significant negative independent prognosticators of overall survival and extent of resection (p = 0.015) as a significant positive independent prognosticator. CONCLUSIONS The study findings indicate that insular gliomas primarily involve the olfactocentric limbic girdle and that involvement in the hippocampocentric limbic girdle is associated with a worse prognosis.

Glioblastoma (GBM) is an aggressive tumor that frequently exhibits gain of chromosome 7, loss of chromosome 10 and aberrantly activated receptor tyrosine kinase signaling pathways. Here, we identify mesenchyme homeobox 2 (MEOX2) on chromosome 7 with increased expression in GBM as a salient oncogenic transcription factor. Specifically, we show that MEOX2 overexpression leads to increased ERK phosphorylation, and we identify a phosphorylation site on MEOX2 that regulates its transcriptional activity by altering its subnuclear localization. We show that MEOX2 overexpression can lead to increased growth in GBM implantation models and cooperates with loss of p53 and PTEN in cerebral organoid models of human malignant gliomas to induce cell proliferation. Furthermore, using high-throughput genomics, we identify transcriptional target genes of MEOX2 in patient-derived GBM tumorsphere models and a fresh frozen GBM tumor. These analyses show that MEOX2 activates several oncogenic pathways involved in MAPK signaling and extracellular matrix organization. Furthermore, MEOX2 binds to oncogenic ETS factors and known glioma oncogenes such as FABP7. In total, we reveal a novel role for MEOX2 in GBM initiation and progression and demonstrate that MEOX2 can enhance ERK signaling through a feed-forward mechanism.Significance StatementGlioblastoma (GBM) harbors gain of chromosome 7 as an early driver event. In this study, we show that mesenchyme homeobox 2 (MEOX2), an aberrantly upregulated transcription factor on chromosome 7, is an oncogene in human glioblastoma. In contrast to GBM, MEOX2 expression is very low in normal brain. We show that MEOX2 cooperates with p53 and PTEN loss to promote tumor initiation in cerebral organoid models. In addition, we identify direct and indirect molecular targets of MEOX2 and demonstrate its role in activating the ERK signaling cascade. These findings identify a novel oncogene in GBM and highlight the transcriptional networks hijacked by these tumors to activate signaling pathways central to GBM biology.

Background There is a growing interest in noninvasively defining molecular subsets of hemispheric diffuse gliomas based on the isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase gene promoter (TERTp) mutation status, which correspond to distinct tumor entities, and differ in demographics, natural history, treatment response, recurrence, and survival patterns. Purpose To investigate whether metabolite levels detected with short echo time (TE) proton MR spectroscopy (1 H-MRS) at 3T can be used for noninvasive molecular classification of IDH and TERTp mutation-based subsets of gliomas. Study type Retrospective. Subjects In all, 112 hemispheric diffuse gliomas (70 males/42 females, mean age: 42.1 ± 13.9 years). Field strength/sequence Short-TE 1 H-MRS (repetition time (TR) = 2000 msec, TE = 30 msec, number of signal averages = 192) and routine clinical brain tumor MR protocols were acquired at 3T. Assessment 1 H-MRS data were quantified using LCModel software. TERTp and IDH1 or IDH2 (IDH1/2) mutations in the tissue were determined by either minisequencing or Sanger sequencing. Statistical tests Metabolic differences between IDH mutant and IDH wildtype gliomas were assessed by a Mann-Whitney U-test. A Kruskal-Wallis test followed by a Tukey-Kramer test was used to analyze metabolic differences between IDH and TERTp mutational molecular subsets of gliomas. A Spearman rank correlation coefficient was used to assess the correlations of metabolite intensities with the Ki-67 index. Furthermore, machine learning was employed to classify the IDH and TERTp mutational status of gliomas, and the accuracy, sensitivity, and specificity values were estimated. Results Short-TE 1 H-MRS classified the presence of an IDH mutation with 88.39% accuracy, 76.92% sensitivity, and 94.52% specificity, and a TERTp mutation within primary IDH wildtype gliomas with 92.59% accuracy, 83.33% sensitivity, and 95.24% specificity. Data conclusion Short-TE 1 H-MRS could be used to identify molecular subsets of hemispheric diffuse gliomas corresponding to IDH and TERTp mutations. Level of evidence 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1799-1809.

Background The aim of this study is to share our experiences on a series of 21 patients with intraventricular meningiomas (IVMs). Histopathologic examinations are reviewed in detail and the cell of origin of IVMs is discussed. Methods We retrospectively reviewed 1372 patients with intracranial meningioma who were surgically treated between September 1986 and July 2018. From this cohort, 21 patients with IVM were identified. The clinical, radiologic, surgical, and follow-up records were analyzed. The archival pathologic specimens were reviewed. Tissue microarray blocks were performed from the formalin-fixed, paraffin-embedded samples of all IVM cases, 2 choroid plexus tissue adjacent to the tumors, and 10 extraventricular fibrous meningioma cases selected as control randomly. Immunohistochemical staining with the antibodies S-100, SOX10, NGFR, and OTX2 was performed according to the protocols indicated by the manufacturers. Results Surgical complications included hemiparesis in 1 patient (5%), postoperative seizure in 1 patient (5%), sensorial aphasia in 1 patient (5%), and preexisting headache in 1 patient (5%). Seventeen (81%) of the IVMs had grade I pathology and 4 (19%) had grade II pathology. The immunoprofile of IVMs is identical to the immunoprofile of normal choroid plexus epithelium. Conclusions Transcortical approaches using intraoperative ultrasonography and intraoperative monitoring with avoidance of eloquent cortical areas can achieve good outcomes. Resection of the choroidal attachments should be attempted. Our results indicate that IVMs do not show arachnoid cap cell phenotype and the findings support that IVMs originate from the choroid plexus epithelium or the progenitors of the choroid plexus epithelium.

Background Meningiomas are heterogeneous, with differences in anatomical, histopathological, and clinical characteristics. Such spatial variability in meningioma biology is thought to result from differences in the expression of critical developmental regulators. We hypothesized that the variability in meningioma biology would follow gradients such as in embryology and tested a cohort of 366 meningiomas for histopathological and immunohistochemical gradients. Methods The medical records from 366 patients treated for meningiomas from 2003 to 2016 were retrospectively analyzed for age, gender, anatomical localization, recurrence-free survival, overall survival, histopathological diagnosis, and immunohistochemistry findings for 6 markers: epithelial membrane antigen (EMA), progesterone receptor (PR), CD34, S100, p53, and Ki-67 labeling index. Results EMA, PR, S100, p53, and CD34 were expressed in 94%, 73%, 49%, 26%, and 23% of the tumors, respectively. p53 expression correlated positively with Ki-67 and World Health Organization (WHO) grade (rτ = 0.31 and rτ = 0.4, respectively). PR positivity correlated inversely with S100, p53, Ki-67, and WHO grade (rτ = −0.19, rτ = −0.14, rτ = −0.15, and rτ = −0.16, respectively). All secretory meningiomas were positive for EMA and PR and negative for S100, and this pattern exhibited a rostrocaudal gradient. The overall proportion of EMA+PR+S100− cases was significantly lower in the cranial vault (30.3%) than in the skull base (45.89%; P = 0.021). The proportion of WHO grade II-III tumors was greater in cranial vault than in skull base meningiomas. Conclusions Unsupervised methods detected an association between the anatomical location and tumor biology in meningiomas. Unlike the categorical associations that former studies had indicated, the present study revealed a rostrocaudal gradient in both the cranial vault and the skull base, correlating with human developmental biology.

Background We and others have identified mutually exclusive molecular subgroups of meningiomas; however, the implications of this classification for clinical prognostication remain unclear. Integrated genomic and epigenomic analyses implicate unique oncogenic processes associated with each subgroup, suggesting the potential for divergent clinical courses. The aim of this study was to understand the associated clinical outcomes of each subgroup, as this could optimize treatment for patients. Methods We analyzed outcome data for 469 meningiomas of known molecular subgroup, including extent of resection, postoperative radiation, surveillance imaging, and time to recurrence, when applicable. Statistical relationships between outcome variables and subgroup were assessed. Features previously associated with recurrence were further investigated after stratification by subgroup. We used Kaplan–Meier analyses to compare progression-free survival, and identified factors significantly associated with recurrence using Cox proportional hazards modeling. Results Meningioma molecular subgroups exhibited divergent clinical courses at 2 years of follow-up, with several aggressive subgroups (NF2, PI3K, HH, tumor necrosis factor receptor–associated factor 7 [TRAF7]) recurring at an average rate of 22 times higher than others (KLF4, POLR2A, SMARCB1). PI3K-activated tumors recurred earlier than other subgroups but had intermediate long-term outcome. Among low-grade tumors, HH and TRAF7 meningiomas exhibited elevated recurrence compared with other subgroups. Recurrence of NF2 tumors was associated with male sex, high grade, and elevated Ki-67. Multivariate analysis identified molecular subgroup as an independent predictor of recurrence, along with grade and previous recurrence. Conclusion We describe distinct clinical outcomes and recurrence rates associated with meningioma molecular subgroups. Our findings emphasize the importance of genomic characterization to guide postoperative management decisions for meningiomas.

Little is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but IDH-mutant gliomas as well as diffuse midline gliomas H3-K27M were excluded to search for the possible presence of new entities among the very heterogenous group of IDH-WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including TERT promoter mutations, 7/10 pattern, or EGFR-amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and &ldquo, Others&rdquo, differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA.

Background In the clinical setting, workflows for analyzing individual genomics data should be both comprehensive and convenient for clinical interpretation. In an effort for comprehensiveness and practicality, we attempted to create a clinical individual whole exome sequencing (WES) analysis workflow, allowing identification of genomic alterations and presentation of neurooncologically-relevant findings. Methods The analysis workflow detects germline and somatic variants and presents: (1) germline variants, (2) somatic short variants, (3) tumor mutational burden (TMB), (4) microsatellite instability (MSI), (5) somatic copy number alterations (SCNA), (6) SCNA burden, (7) loss of heterozygosity, (8) genes with double-hit, (9) mutational signatures, and (10) pathway enrichment analyses. Using the workflow, 58 WES analyses from matched blood and tumor samples of 52 patients were analyzed: 47 primary and 11 recurrent diffuse gliomas. Results The median mean read depths were 199.88 for tumor and 110.955 for normal samples. For germline variants, a median of 22 (14–33) variants per patient was reported. There was a median of 6 (0–590) reported somatic short variants per tumor. A median of 19 (0–94) broad SCNAs and a median of 6 (0–12) gene-level SCNAs were reported per tumor. The gene with the most frequent somatic short variants was TP53 (41.38%). The most frequent chromosome-/arm-level SCNA events were chr7 amplification, chr22q loss, and chr10 loss. TMB in primary gliomas were significantly lower than in recurrent tumors (p = 0.002). MSI incidence was low (6.9%). Conclusions We demonstrate that WES can be practically and efficiently utilized for clinical analysis of individual brain tumors. The results display that NOTATES produces clinically relevant results in a concise but exhaustive manner.

Gamma knife radiosurgery (GKRS) delivers an unevenly distributed radiation dose to a tumor, with a sharp falloff outside the target. Although the dose inhomogeneity within a tumor is strongly influenced by its shape, routine GKRS dose planning does not account for it. We hypothesized that shape irregularity measures were correlated with treatment planning indices, and might provide insight during treatment planning. The aims of this study were to quantify the shape irregularity measures in vestibular schwannomas, estimate their correlations with core radiosurgical planning measures, and define the most predictive shape feature for dose effectiveness. METHODS: Four dose plan indices, which were the selectivity index (SI), gradient index (GI), efficiency index (EI), and Paddick’s conformity index (PCI) were estimated from the GKRS plans of 234 vestibular schwannomas. All dose plans were prepared using Gamma Plan 10.0 and above and all treatments were delivered using a perfexion/ICON platform. Three-dimensional (3D) tumor models were rendered using 3D Slicer Software from segmented T1-weighted MR images. Sixteen irregularity measures were calculated for each tumor using Radiomics in MATLAB. Spearman correlation coefficients (r) were computed to find associations of the dose plan indices with the irregularity descriptors. The most predictive shape feature for dose efficiency was identified using the least absolute shrinkage and selection operator (Lasso). RESULTS: The shape irregularity measures were negatively correlated with SI, EI, and PCI, and positively correlated with GI. Volumetric index of sphericity (VioS) had the highest correlations with SI (r = 0.63, p= 3.27E-23), GI (r= -0.58, p= 1.10E-19), EI (r = 0.69, p= 0.00), and PCI(r= 0.68, p = 6.73E-28), and Lasso feature selection identified VioS as the most important feature for predicting all dose plan indices. CONCLUSION: VioS provides a numerical quantification of tumor shape irregularity, and it is highly correlated with the GKRS dose planning indices. *indicates co-senior authors

The incidence of meningiomas is rising and the number of incidental cases is increasing steadily. The efficiency and the safety of each treatment strategy are also improving over time. Therefore the indications to treat meningiomas are constantly changing. The aim of meningioma treatment is keeping the patient fully functional while achieving long-term relief or prevention from problems related to intracranial tumor growth. This chapter reviews the natural history and treatment results and aims to put together the information for the most objective decision-making in treating meningiomas. Factors acting on the treatment decision such as anatomical localization, symptomatology, variations in tumor biology, recurrence status, age and co-morbidities, operative gains, and patient preference are individually discussed.

Aim Role of extrachromosomal DNA in cancer and the consequences of mutations are unclear. However, mitochondrial DNA (mtDNA) variants in the D-loop region have been suggested to be associated with different clinical parameters and proposed as controversial prognostic markers. Impaired function of mitochondria cannot be tolerated by highly energy requiring brain cells. Therefore, we have focused on the regulatory region D-loop which is thought to cause no growth disadvantage for cells. Our aim is to investigate the effect of mtDNA variants mainly in D-loop on glioma biology. Material and methods Sanger sequencing of D-loop (15971 - 16451 bp) for 52 glioma patients was performed and the variations were statistically analyzed for gender, WHO classification, morphological grade, IDH / TERT status. Results Total of 122 variations (51 unique) was identified in 52 patients. C16223T, T16189C, T16311C and T16126C variants were frequently detected. Total variation number was statistically non-significant among the analyzed categories. When individual variants were considered, T16311C and T16224C were statistically significant for WHO classification (p=0.033), morphological grade (p=0.036) and gender (p=0.039), respectively. Conclusion Total variation number in D-loop was not found to be related with clinical variables. Our data suggests that individual variants may play critical role in glioma biology.

The incidence of meningiomas is rising and the number of incidental cases is increasing steadily. The efficiency and the safety of each treatment strategy are also improving over time. Therefore the indications to treat meningiomas are constantly changing. The aim of meningioma treatment is keeping the patient fully functional while achieving long-term relief or prevention from problems related to intracranial tumor growth. This chapter reviews the natural history and treatment results and aims to put together the information for the most objective decision-making in treating meningiomas. Factors acting on the treatment decision such as anatomical localization, symptomatology, variations in tumor biology, recurrence status, age and co-morbidities, operative gains, and patient preference are individually discussed.

Up to 80% of meningiomas are classified as clinically low-grade, however, a subset of these ‘benign’ cases will ultimately recur and require additional treatment. The role of molecular subgroup in meningioma recurrence has not been thoroughly investigated, despite correlations of this variable with other clinical features. Indeed, epigenetic and transcriptional evidence supports involvement of distinct oncogenic processes within each subgroup, and as shown in other brain tumors, this may result in divergent clinical courses. In the present study, we classified 429 meningiomas into six established molecular subgroups based on genomic driver, and investigated associations of each subgroup with tumor recurrence. At two years of follow-up, we observed differences in progression free survival curves among relatively aggressive (NF2-loss, PI3K-activated, Hedgehog-activated) and quiescent (KLF4-mutant, SMARCB1-mutant, POLR2A-mutant) subgroups (log rank p = 4.3 x 10-2), with the former group recurring at a rate 14x higher. We found PI3K-activated meningiomas recurred significantly earlier than other subgroups (average time to recurrence of 19.2 months; p = 2.2 x 10-2), though we observed an intermediate long-term outcome relative to the Hedgehog and NF2 lesions. Overall, Hedgehog tumors recurred significantly more frequently than other low-grade meningiomas (adj. p = 3.1 x 10-2), and this subgroup was found to be an independent predictor of progression free survival using cox proportional hazards modelling (HR = 3.1; p = 2.4 x 10-2). By contrast, the aggressiveness of NF2 meningiomas was found to depend upon gender, WHO grade, and elevated Ki-67 index, and this subgroup was not an independent prognostic predictor. Our results suggest molecular subgroup is predictive of recurrence in low-grade meningiomas, and thus is an important consideration in post-operative management decisions. Routine genotyping to detect Hedgehog and PI3K mutant lesions may identify patients that would benefit from closer follow-up and consideration of adjuvant therapies.

OBJECTIVERecent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts.METHODSTargeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher’s exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features.RESULTSGenomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among “mutation unknown” samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor’s underlying driver mutation.CONCLUSIONSUsing a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.

Background Improved life expectancy and advanced diagnostic tools including computed tomography and magnetic resonance imaging have increased the awareness and diagnosis of intracranial meningiomas in the elderly population. The risk/benefit ratio of surgery in elderly patients with intracranial meningioma has not been clearly defined because of the lack of objective measurement tools. We aimed to understand the risk factors associated with postsurgical outcomes and how these risk factors affected postsurgical outcomes in elderly patients with intracranial meningioma. Methods We retrospectively evaluated 1372 patients, who were operated on for intracranial meningioma, using our prospectively collected database. The same senior author operated on all patients at 2 different tertiary clinics. Patients' clinical charts, presurgical postcontrast T1-weighted magnetic resonance images, operative reports, and pathology reports were reviewed. The relevant literature was also reviewed. Results Higher age, higher American Society of Anesthesiologists class, presence of comorbidities, tumor location, larger initial tumor size, and presence of peritumoral edema were all associated with postsurgical complications in elderly patients with intracranial meningioma. Age ≥50 years was the strongest predictor of postsurgical systemic complications, whereas higher American Society of Anesthesiologists class was the strongest predictor of postsurgical neurologic complications. A literature review showed higher morbidity and mortality of elderly patients with intracranial meningioma. Initial tumor size and postsurgical MIB-1 labeling index were higher in the elderly patients, both of which were predictors of tumor growth. Conclusions Even though elderly patients operated on for intracranial meningioma had higher morbidity and mortality compared with younger patients, surgery is still much more beneficial than wait-and-see strategy in elderly patients.

Telomerase reverse transcriptase promoter (TERTp) mutations in the absence of IDH mutations (TERTp-only) are recently proposed as a characteristic of glioblastoma regardless of the morphological grade. This study aims to analyze metabolic profiles of TERTp-only gliomas using proton magnetic resonance spectroscopy (1H-MRS) and evaluate the effect of metabolite concentrations on progression-free survival (PFS) and overall survival (OS). The patient cohort consisted of 56 TERTp-only gliomas (35M/21F, mean age: 58±10.37 years, 44 glioblastomas (GBM), and 12 lower-grade gliomas with TERTp-mutation but no IDH-mutations). All patients underwent preoperative diagnostic 1H-MRS using a 3T MR scanner with a 32-channel head coil. 1H-MRS was obtained from a manually placed region of interest with no necrosis, edema, and hemorrhage, using a Point Resolved Spectroscopy (PRESS) sequence (TR/TE=2000/30 ms, 1024 points). LCModel spectral fitting program was used for quantification of MR spectroscopic peak concentrations of 17 metabolites. The patients were divided into two groups using median values of the metabolite intensities, and Kaplan-Meier survival analysis followed by a log-rank test was used to determine the effects of metabolite concentrations on OS and PFS. Median PFS and OS of TERTp-only gliomas were 11 and 17 months, respectively. TERTp-only LGG patients had longer OS and PFS than TERTp-only GBM patients (p=0.022 for OS and p=0.018 for PFS). Significantly shorter OS and PFS were identified in TERTp-only gliomas, who had higher GSH/tCr (p=0.011 for OS and p=0.004 for PFS) and higher Lac/tCr (p=0.014 for OS and p=0.012 for PFS). Lactate is a marker of necrosis and a sign of malignancy. On the other hand, both tCr and GSH were lower, which resulted in higher GSH/tCr, in TERTp-only GBM. The results of this study indicate that high Lac/tCr and GSH/tCr might be indicators of poor prognosis in TERTp-only gliomas. This study has been supported by TUBITAK 1003 grant 216S432.

IDH mutation, a key factor in predicting glioma prognosis, alters the levels of some metabolites in brain, including 2-hydroxyglutarate (2HG), glutamine (Gln), and glutathione (GSH). While proton MR spectroscopy (1H-MRS) enables in-vivo detection of these metabolites, liquid chromatography-mass spectrometry (LC-MS/MS) is a sensitive in-vitro method to measure absolute metabolite concentrations. This study aims to examine the correlation of metabolic concentrations measured using 1H-MRS and LC-MS/MS in gliomas, and to detect IDH mutation with machine learning based on 1H-MRS and LC-MS/MS metabolic intensities. The patient cohort included 178 glioma patients (111M/67F, mean age:44.09±13.95 years, 100 IDH-mut, 78 IDH-wt). The patients were scanned pre-surgery by a 3T MR scanner with a 32-channel head coil. 1H-MRS was obtained from a manually placed region of interest with no necrosis, edema, and hemorrhage, using a Point Resolved Spectroscopy (PRESS) sequence (TR/TE=2000/30ms). LCModel software was used for quantification of eighteen metabolites of 1H-MRS data. Metabolite concentrations including creatine (Cr), choline (Cho), Gln, glutamate (Glu), gamma-aminobutyric acid (GABA), N-acetyl aspartate (NAA), myo-inositol (mIns), 2HG, and lactate (Lac) were also determined with LC-MS/MS for surgical specimen of the same patients. Spearman correlation coefficients were calculated between the metabolite concentrations measured with 1H-MRS and LC-MS/MS. Additionally, machine-learning algorithms were used to detect IDH mutation in gliomas based on metabolite concentrations obtained with 1H-MRS and LC-MS/MS. Consequently, there were statistically significant correlations between 1H-MRS and LC-MS/MS results for 2HG (p=0.036), Cr (p=0.009), mIns (p

Objective Sphenoid wing meningiomas are the third most common group of intracranial meningiomas. Their management is a challenge because of their bone invasion potential and their proximity to neurovascular structures and the cavernous sinus. Methods A cohort of 141 patients with sphenoid wing meningioma who were operated on and followed up between 1986 and 2018 were retrospectively analyzed. Demographic data, clinical and radiologic features, surgical results, and follow-up data are presented. The effects of adjuvant treatments (radiosurgery, radiotherapy, and chemotherapy) are reviewed. The invasion pattern of tumors and other factors were noted to analyze the extent of resection. Recurrence/regrowth rates were also analyzed. Results There were 96 female and 45 male patients with a median age of 51 years (range, 17–87 years). The median follow-up was 62 months (range, 1–303 months). Tumors were grouped as spheno-orbital (31 patients), lateral (34 patients), middle (35 patients), and medial (41 patients). Gross total resection was achieved in 98 patients, and 43 tumors were resected subtotally. One hundred and twenty of these cases had World Health Organization grade I pathology, whereas the remainder had grade II. In the follow-up, there were 14 recurrences of totally resected tumors, and 24 regrowths were observed in the subtotally resected group. No invasion pattern was strongly predictive of extent of resection alone, and a scoring system was built up and proposed. Conclusions Sphenoid wing meningioma is a large group with characteristics associated with skull base meningiomas and convexity meningiomas. The results of surgery and other adjuvant treatments are heterogeneous.

OBJECTIVERecent studies have established that hemispheric diffuse gliomas may be grouped into subsets on the basis of molecular markers; these subsets are loosely correlated with the histopathological diagnosis but are strong predictors of clinical tumor behavior. Based on an analysis of molecular and clinical parameters, the authors hypothesized that mutations of the telomerase promoter (TERTp-mut) mark separate oncogenic programs among isocitrate dehydrogenase 1 and/or 2 (IDH) mutant (IDH-mut) and IDH wild-type (IDH-wt) diffuse gliomas independent of histopathology or WHO grade.METHODSFour molecular subsets of the combined statuses of IDH and TERT-promoter mutations (double mutant, IDH only, TERT only, and double negative) were defined. Differences in age, anatomical location, molecular genetics, and survival rates in a surgical cohort of 299 patients with a total of 356 hemispheric diffuse gliomas (WHO Grade II, III, or IV) were analyzed.RESULTSTERTp-mut were present in 38.8% of IDH-mut and 70.2% of IDH-wt gliomas. The mutational status was stable in each patient at 57 recurrence events over a 2645-month cumulative follow-up period. Among patients with IDH-mut gliomas, those in the double-mutant subset had better survival and a lower incidence of malignant degeneration than those in the IDH-only subset. Of patients in the double-mutant subset, 96.3% were also positive for 1p/19q codeletions. All patients with 1p/19q codeletions had TERTp-mut. In patients with IDH-mut glioma, epidermal growth factor receptor or phosphatase and tensin homolog mutations were not observed, and copy-number variations were uncommon. Among IDH-wt gliomas, the TERT-only subset was associated with significantly higher age, higher Ki-67 labeling index, primary glioblastoma-specific oncogenic changes, and poor survival. The double-negative subset was genetically and biologically heterogeneous. Survival analyses (Kaplan-Meier, multivariate, and regression-tree analyses) confirmed that patients in the 4 molecular subsets had distinct prognoses.CONCLUSIONSMolecular subsets result in different tumor biology and clinical behaviors in hemispheric diffuse gliomas.

BACKGROUND Meningiomas can be classified into six genomic subgroups based on mutations in NF2, SMARCB1, KLF4, POLR2A, or activating variants in the PI3K or Hedgehog signaling pathways. Previous work has identified specific associations of driver events with clinical and molecular features, such as tumor location. However, their utility in predicting post-operative patient outcomes is not well-explored. Similar to recently described epigenetic signatures, underlying genomic subgroup may provide prognostic value in meningioma management. METHODS Targeted sequencing data was used to classify over 500 meningiomas into established genomic subgroups, and available patient outcome data was assembled based on retrospective chart reviews. Collected data included recurrence (based on imaging), extent of resection (EOR), use of post-operative radiation, and radiologic follow-up period. Statistical associations between genomic subgroup and recurrence were assessed using Fisher’s exact, Kaplan-Meier, and Cox proportional hazards modeling, including stratification based on use of radiation, EOR, grade, and location. RESULTS Meningiomas in the PI3K subgroup exhibited higher rates of early recurrence during the first five post-operative years. This subgroup affiliation was found to be an independent predictor of recurrence free survival from Ki-67, grade, and other clinical features. By contrast, recurrence was rare in the POLR2A, SMARCB1, and KLF4 subgroups, and was typically associated with use of post-operative radiation in these cases. The longest average recurrence free survival was observed in POLR2A mutant meningiomas. CONCLUSIONS Our analysis identifies divergence in meningioma patient outcomes based on genomic subgroup and suggests patients with PI3K activating events may require closer surveillance. These tumors, which often occur near and encase critical neurovascular structures along the sphenoid wing, may further benefit from consideration of radiation and emerging precision therapies. Conversely, other subgroups rarely recur, suggesting caution be invoked with use of potentially morbid adjuvant treatment.

Background Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy; however, individual tumors display immense variability in their response to these approaches. Genomic techniques such as whole-exome sequencing (WES) provide an opportunity to understand the molecular basis of this variability. Methods Here, we report WES-guided treatment of a patient with a primary GBM and two subsequent recurrences, demonstrating the dynamic nature of treatment-induced molecular changes and their implications for clinical decision-making. We also analyze the Yale-Glioma cohort, composed of 110 whole exome- or whole genome-sequenced tumor-normal pairs, to assess the frequency of genomic events found in the presented case. Results Our longitudinal analysis revealed how the genomic profile evolved under the pressure of therapy. Specifically targeted approaches eradicated treatment-sensitive clones while enriching for resistant ones, generated due to chromothripsis, which we show to be a frequent event in GBMs based on our extended analysis of 110 gliomas in the Yale-Glioma cohort. Despite chromothripsis and the later acquired mismatch-repair deficiency, genomics-guided personalized treatment extended survival to over 5 years. Interestingly, the case displayed a favorable response to immune checkpoint inhibition after acquiring mismatch repair deficiency. Conclusions Our study demonstrates the importance of longitudinal genomic profiling to adjust to the dynamic nature of treatment-induced molecular changes to improve the outcomes of precision therapies. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0401-9) contains supplementary material, which is available to authorized users.

Objective Clinical characteristics and management of hemangioblastomas of the spinal cord associated with von Hippel-Lindau syndrome have been extensively covered in the literature. This report aims to analyze the characteristics and surgical treatment results of sporadic spinal hemangioblastomas (SSHB). Methods This is a retrospective analysis of 14 patients with SSHB (8 men and 6 women) operated on during a span of 23 years. The median age was 41.5 years (24–70 years). von Hippel Lindau syndrome was excluded by imaging in all patients. The median follow-up was 4 years (1–23 years). We also conducted a meta-analysis of all 271 SSHB cases reported in the English-speaking language literature from 1967 to 2011. Results Nine (64.3%) lesions were cervical, 3 (28.5%) were thoracic, and 1 (7.1%) was lumbar. Eight (57.1%) tumors were dorsal intramedullary, 4 (28.6%) were exophytic, 1 (7.1%) was intradural extramedullary, and 1 (7.1%) was completely extradural. Diffuse segmental cord enlargement was present in 7 patients (50%) and a cyst/syrinx was present in 7 (50%). These 14 patients underwent 15 operations, and gross total resection was achieved in all operations. There was no mortality. Symptoms improved after 8 (53.3%) of 15 operations, remained the same after 5 (33.3%), and worsened after 2 (13.3%). The mean Karnofsky performance score improved from 79.3 (± 17.5) to 87.3 (± 12.2) after 6 months of follow-up. There was one recurrence 15 years after magnetic resonance imaging confirmed total resection. Conclusions The SSHBs occur most often in the upper spinal cord. Excellent surgical results and long-term outcome can be achieved using microsurgery alone with only rare recurrences.

Object The goal of surgery in high-grade gliomas is to maximize the resection of contrast-enhancing tumor without causing additional neurological deficits. Intraoperative MRI improves surgical results. However, when using contrast material intraoperatively, it may be difficult to differentiate between surgically induced enhancement and residual tumor. The purpose of this study was to assess the usefulness of intraoperative dynamic contrast-enhanced T1-weighted MRI to guide this differential diagnosis and test it against tissue histopathology. Methods Preoperative and intraoperative dynamic contrast-enhanced MRI was performed in 21 patients with histopathologically confirmed WHO Grade IV gliomas using intraoperative 3-T MRI. Standardized regions of interest (ROIs) were placed manually at 2 separate contrast-enhancing areas at the resection border for each patient. Time-intensity curves (TICs) were generated for each ROI. All ROIs were biopsied and the TIC types were compared with histopathological results. Pharmacokinetic modeling was performed in the last 10 patients to confirm nonparametric TIC analysis findings. Results Of the 42 manually selected ROIs in 21 patients, 25 (59.5%) contained solid tumor tissue and 17 (40.5%) retained the brain parenchymal architecture but contained infiltrating tumor cells. Time-intensity curves generated from residual contrast-enhancing tumor and their preoperative counterparts were comparable and showed a quick and persistently increasing slope (“climbing type”). All 17 TICs obtained from regions that did not contain solid tumor tissue were undulating and low in amplitude, compared with those obtained from residual tumors (“low-amplitude type”). Pharmacokinetic findings using the transfer constant, extravascular extracellular volume fraction, rate constant, and initial area under the curve parameters were significantly different for the tumor mass, nontumoral regions, and surgically induced contrast-enhancing areas. Conclusions Intraoperative dynamic contrast-enhanced MRI provides quick, reproducible, high-quality, and simply interpreted dynamic MR images in the intraoperative setting and can aid in differentiating surgically induced enhancement from residual tumor.

BACKGROUND Previous studies have established several meningioma genomic subgroups, defined by the mutually exclusive genomic drivers. However, we distinguished a small subset of meningiomas simultaneously harboring multiple drivers from different genomic subgroups, thus referred to as “multiple-driver meningiomas”, that has not been previously investigated. We aimed to characterize the genomic landscape and clinical features of multiple-driver meningiomas. METHODS We identified 42 cases of multiple-driver meningiomas from a cohort of 3,016 cases screened for genomic drivers via molecular inversion probe sequencing (MIPS) and/or whole-exome sequencing (WES) previously in our laboratory. All driver mutations were validated via Sanger sequencing and chromosome 22 loss was accessed with qPCR. Clinical information was collected and genome-to-clinical correlations were statistically analyzed. We selected 10 multiple-driver meningioma cases for tumor-normal WES for further characterization of genomic architecture. RESULTS Multiple-driver meningiomas were significantly enriched for NF2 alteration (p< 0.001), had significantly higher WHO grade (p= 0.005) and proportion of recurrent tumors (p= 0.007) when compared with “single-driver meningiomas”, i.e. harboring driver alterations from a single genomic subgroup. Among female cases, those with multiple drivers were nearly four times more likely to be high-grade (II or III) compared to single-driver female samples (48.6% vs. 12.6%, p< 0.001). Among tumors harboring NF2 alteration, multiple-driver meningiomas demonstrated skull base predilection compared with single-driver meningiomas (50.0% vs. 27.9%, p= 0.005). WES analysis of 10 multiple-driver meningiomas identified 1p and/or 14q loss in 60% of cases. Clonality analysis revealed the presence of sub-clonal cell populations in 9 cases with all driver mutations clustered into the founding clone in 7 cases, suggesting their acquisition in the early phase of tumor development. CONCLUSION Multiple-driver meningiomas demonstrate distinct genomic and clinical features that distinguish them as clinically aggressive. They frequently occur in surgically challenging skull base locations, and are more prevalent among high-grade and recurrent cases.

BACKGROUND Although the word “glioblastoma” still denotes a grade-IV pathology, basic molecular studies have clearly indicated that a significant proportion of lower-grade gliomas harbor genetic alterations typical of glioblastomas. Based on these findings cIMPACT-NOW update 3 has defined an entity called the “diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. A TERT-promoter mutation is one of these typical molecular markers of glioblastomas. In this study we analyzed IDH-wild type, TERT-mutant diffuse gliomas of different pathological grades to look for differences in demographic, clinical and survival characteristics. MATERIAL AND METHODS 147 adult hemispheric diffuse-gliomas with wild-type IDH1/2 and mutant TERT-promoter (C228T or C250T) were retrospectively analyzed. Primary thalamic, cerebellar brainstem or spinal cases were excluded. 126 (86%), 16(11%) and 5(3%) patients were WHO grade IV, III and II respectively. After surgical treatment or stereotactic biopsy all patients underwent chemoradiation. Median follow-up was 16mo (1–110). Tumors of different grades were compared for age, gender, multifocality, gliomatosis pattern, Ki-67 index, progression-free survival and overall-survival. RESULTS Mean age at presentation for grade II, III and IV were comparable (58.1, 58 and 58.1; ANOVA, p=0.72). There was a slight male predominance in both lower-grades and WHO-grade IV (M:F ratios 1.625 and 1.74). Mean Ki-67 index was significantly higher in higher grades (0.06, 0.14 and 0.25 for grades II, III and IV; ANOVA, p=0.001). Multifocality was comparable (chi-sq, p=1) in lower-grades (3/21; 14.3%) vs. WHO-grade IV (18/126; 14.3%). Gliomatosis pattern was comparable (chi-sq, p=0.095) in lower-grades (2/21; 9.5%) vs. (3/126; 2.3%). Median recurrence free survival (RFS) was 16 months (0–63) in lower-grades and 8months (1–50) in WHO-grade IV. PFS was significantly different between 3 WHO-grades (Log rank, p=0.007) and also between lower-grades and WHO-grade IV (Log rank, p=0.002). Median overall survival was 26 months(2–110) in lower-grades and 15mo(1–91) in WHO-grade IV. OS was significantly different between 3 WHO-grades (Log rank, p=0.014) and also between lower-grades and WHO-grade IV (Log rank, p=0.007). CONCLUSION Increasing pathological grades of hemispheric “IDH-wild type, TERT-mutant diffuse gliomas” have similar demographic and clinical characteristics but incrasing proliferation indices, decrasing progression free survival and shorter overall survival. The findings may be suggesitve of different grades of one common tumor entity.

The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17–16.52; 95% CI) for IDH-mutated gliomas and 12.85 (5.94–27.83; 95% CI) for IDH-mutated, 1p/19q co-deleted gliomas. Decreasing strength with increasing anaplasia implied a modulatory effect. No somatic mutations were noted at this locus in 114 blood-tumor pairs, nor was there a copy number difference between risk-allele and only-ancestral allele carriers. CCDC26 RNA-expression was rare and not different between the two groups. There were only minor subtype-specific differences in common glioma driver genes. RNA sequencing and LC-MS/MS comparisons pointed to significantly altered MYC-signaling. Baseline enhancer activity of the conserved region specifically on the MYC promoter and its further positive modulation by the SNP risk-allele was shown in vitro. Our findings implicate MYC deregulation as the underlying cause of the observed association., Scientific Reports, 6, ISSN:2045-2322

AIM: Olfactory groove meningiomas make up 4 to 13\% of meningiomas. The first line treatment of meningiomas is surgery, but the extent and types of approaches advised for olfactory groove meningiomas are diverse, from aggressive skull base approaches to standard or minimally invasive craniotomies and endoscopic approaches. We retrospectively reviewed our series of olfactory groove meningiomas that were operated microsurgically by standard pterional or unifrontal approaches. MATERIAL and METHODS: Our series of 61 olfactory groove meningioma patients operated through pterional or unifrontal approaches between March 1987 and September 2015 was reviewed and the clinical data, radiological findings, surgical treatment and clinical outcomes of the patients were retrospectively analyzed. RESULTS: Sixty-three craniotomies were performed in total. Pterional and unifrontal approaches were used in 38 (60.3\%) and 25 (39.7\%) surgical procedures, respectively. Overall, gross total tumor resection was achieved in 59 (93.7\%) cases. Complications were seen in 8 cases, and 2 of these patients underwent reoperation. Three of the 4 patients where only subtotal resection could be achieved underwent gamma knife radiosurgery. CONCLUSION: Pterional and unifrontal approaches, which are familiar and standard for neurosurgeons, can accomplish high rates of total resection with acceptable complication and recurrence rates for the treatment of olfactory groove meningiomas.

Gliomas represent approximately 30\% of all central nervous system tumors and 80\% of malignant brain tumors(1). 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.

Because productive infection by parvoviruses requires cell division and is enhanced by oncogenic transformation, some parvoviruses may have potential utility in killing cancer cells. To identify the parvovirus(es) with the optimal oncolytic effect against human glioblastomas, we screened 12 parvoviruses at a high multiplicity of infection (MOI). MVMi, MVMc, MVM-G17, tumor virus X (TVX), canine parvovirus (CPV), porcine parvovirus (PPV), rat parvovirus 1A (RPV1A), and H-3 were relatively ineffective. The four viruses with the greatest oncolytic activity, LuIII, H-1, MVMp, and MVM-G52, were tested for the ability, at a low MOI, to progressively infect the culture over time, causing cell death at a rate higher than that of cell proliferation. LuIII alone was effective in all five human glioblastomas tested. H-1 progressively infected only two of five; MVMp and MVM-G52 were ineffective in all five. To investigate the underlying mechanism of LuIII's phenotype, we used recombinant parvoviruses with the LuIII capsid replacing the MVMp capsid or with molecular alteration of the P4 promoter. The LuIII capsid enhanced efficient replication and oncolysis in MO59J gliomas cells; other gliomas tested required the entire LuIII genome to exhibit enhanced infection. LuIII selectively infected glioma cells over normal glial cells in vitro . In mouse models, human glioblastoma xenografts were selectively infected by LuIII when administered intratumorally; LuIII reduced tumor growth by 75%. LuIII also had the capacity to selectively infect subcutaneous or intracranial gliomas after intravenous inoculation. Intravenous or intracranial LuIII caused no adverse effects. Intracranial LuIII caused no infection of mature mouse neurons or glia in vivo but showed a modest infection of developing neurons.

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.

BACKGROUND: Experimental models to study cerebrovascular malformations are limited therefore we used the neonatal rodent retina as a model to study cerebral angiogenesis. OBJECTIVE: We performed a gene expression analysis to define temporal changes in the expression of 96 angiogenesis-related genes during retinal vascularization. METHODS: A total of 72 retinas from 36 newborn C57BL/6 mice were used. Sets of neonatal mouse retinas were surgically isolated by 2-day intervals starting from postnatal day 0 to day 20 and at the 32nd day (representing adult retinas). For each of these 12 time points in the postnatal developmental period of mouse retinas, separate sets of 6 retinas from 3 mice were pooled, and their RNA was hybridized to an angiogenesis-specific gene array. Temporal expression patterns of each of the 96 angiogenesis-related genes were analyzed. For confirmation, vascular endothelial growth factor protein expression was also studied by immunohistochemistry. RESULTS: Twenty-two of the 96 genes analyzed displayed a significantly different temporal expression profile, and the rest exhibited a static expression, as compared to the human glyceraldehyde-3-phosphate dehydrogenase gene. Among these genes, the temporal pattern of expression was variable, but peaks were seen mostly on days 8, 10, 12, and 16. This timing corresponds well to morphologic changes that occur in the retina during different stages of angiogenesis. CONCLUSION: The neonatal rodent retina, which has a cellular architecture similar to that of the brain, has active and quantifiable angiogenic activity during the neonatal period and can be used as a simple and convenient model to study cerebral angiogenesis.

Object The authors describe the first shared-resource, 3-T intraoperative MR (ioMR) imaging system and analyze its impact on low-grade glioma (LGG) resection with an emphasis on the use of intraoperative proton MR spectroscopy. Methods The Acibadem University ioMR imaging facility houses a 3-T Siemens Trio system and consists of interconnected but independent MR imaging and surgical suites. Neurosurgery is performed using regular ferromagnetic equipment, and a patient can be transferred to the ioMR imaging system within 1.5 minutes by using a floating table. The ioMR imaging protocol takes < 10 minutes including the transfer, and the authors obtain very high–resolution T2-weighted MR images without the use of intravenous contrast. Functional sequences are performed when needed. A new 5-pin headrest–head coil combination and floating transfer table were specifically designed for this system. Results Since the facility became operational in June 2004, 56 LGG resections have been performed using ioMR imaging, and > 19,000 outpatient MR imaging procedures have been conducted. First-look MR imaging studies led to further resection attempts in 37.5% of cases as well as a 32.3% increase in the number of gross-total resections. Intraoperative ultrasonography detected 16% of the tumor remnants. Intraoperative proton MR spectroscopy and diffusion weighted MR imaging were used to differentiate residual tumor tissue from peritumoral parenchymal changes. Functional and diffusion tensor MR imaging sequences were used both pre- and postoperatively but not intraoperatively. No infections or other procedure-related complications were encountered. Conclusions This novel, shared-resource, ultrahigh-field, 3-T ioMR imaging system is a cost-effective means of affording a highly capable ioMR imaging system and increases the efficiency of LGG resections.

Vesicular stomatitis virus (VSV) is the prototype virus for 75 or more negative-strand RNA viruses in the rhabdovirus family. Some of these viruses, including VSV, can cause neurological impairment or death upon brain infection. VSV has shown promise in the prevention and treatment of disease as a vaccine vector and an oncolytic virus, but infection of the brain remains a concern. Three VSV variants, the wild-type-related VSV-G/GFP and two attenuated viruses, VSV-CT1 and VSV-CT9-M51, were compared for neuroinvasiveness and neuromorbidity. In nonimmunized mice, direct VSV-G/GFP injection into the brain invariably resulted in lethal encephalitis; in contrast, partial survival was seen after direct injection of the attenuated VSV strains. In addition, both attenuated VSV strains showed significantly reduced neuroinvasiveness after intranasal inoculation of young postnatal day 16 mice. Of the three tested variants, VSV-CT9-M51 generated the lowest degree of neuropathology. Despite its attenuated state, peripheral inoculations of VSV-CT9-M51 targeted and killed human glioblastoma implanted into the mouse brain. Importantly, we show here that intranasal or intramuscular immunization prevents the lethal effects of subsequent VSV-G/GFP, VSV-CT1, and VSV-CT9-M51 injections into the brain. These results indicate that attenuated recombinant viruses show reduced neurovirulence and that peripheral immunization blocks the lethal actions of all VSVs tested.

Metastatic tumors and malignant gliomas make up the majority of cancers in the brain. They are invariably fatal and there is currently no cure. Fromin vitrocomparisons of a number of viruses, we selected one that appeared the best in selectively killing glioblastoma cells. This replication-competent virus, the glioma-adapted vesicular stomatis virus strain VSVrp30a, was used forin vivotests with the underlying view that infection of tumor cells will lead to an increase in the number of viruses subsequently released to kill additional tumor cells. Intravenous injection of VSVrp30a expressing a green fluorescent protein reporter, rapidly targeted and destroyed multiple types of human and mouse tumors implanted in the mouse brain, including glioblastoma and mammary tumors. When tumors were implanted both in the brain and peripherally, emulating systemic cancer metastasis, tumors inside and outside the brain were simultaneously infected. Intranasal inoculation, leading to olfactory nerve transport of the virus into the brain, selectively infected and killed olfactory bulb tumors. Neither control cortical wounds nor transplanted normal mouse or human cells were targeted, indicating viral tumor selectivity. Control viruses, including pseudorabies, adeno-associated, or replication-deficient VSV, did not infect the brain tumor. Confocal laser time-lapse imaging through a cranial window showed that intravenous VSV infects the tumor at multiple sites and kills migrating tumor cells. Disrupted tumor vasculature, suggested by dye leakage, may be the port of entry for intravenously delivered VSV. Quantitative PCR analysis of how VSVrp30a selectively infected tumor cells suggested multiple mechanisms, including cell surface binding and internalization.