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The diagnosis and prognostication of glioblastoma (GBM) remain to be solely dependent on histopathological findings and few molecular markers, despite the clinical heterogeneity in this entity. To address this issue, we investigated the prognostic impact of copy number alterations (CNAs) using two population-based IDH -wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). The molecular disproportions between these cohorts were dissected in light of cohort differences in GBM. The Japanese cohort was collected from cases registered in Kansai Molecular Diagnosis Network for CNS tumors (KNBTG). The somatic landscape around CNAs was analyzed for 212 KNBTG cases and 359 TCGA cases. Next, the clinical impacts of CNA profiles were investigated for 140 KNBTG cases and 152 TCGA cases treated by standard adjuvant therapy using temozolomide-based chemoradiation. The comparative profiling indicated unequal distribution of specific CNAs such as EGFR , CDKN2A , and PTEN among the two cohorts. Especially, the triple overlap CNAs in these loci (triple CNA) were much higher in frequency in TCGA (70.5%) than KNBTG (24.3%), and its prognostic impact was independently validated in both cohorts. The KNBTG cohort significantly showed better prognosis than the TCGA cohort (median overall survival 19.3 vs 15.6 months). This survival difference between the two cohorts completely resolved after subclassifying all cases according to the triple CNA status. The prognostic significance of triple CNA was identified in IDH -wild-type GBM. Distribution difference in prognostic CNA profiles potentially could cause survival differences across cohorts in clinical studies. Electronic supplementary material The online version of this article (10.1186/s40478-019-0749-8) contains supplementary material, which is available to authorized users.

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Background/Aim: Glioblastoma (GBM) is one of the most lethal solid cancers due to its highly invasive nature. The malignant potential of GBM cells might be partially regulated by surrounding normal cells, such as oligodendrocytes or fibroblasts. The aim of this study was to examine the interaction between stromal cells and GBM cells. Materials and Methods: Two GBM cell lines were used. The effect of stromal cells, oligodendrocytes or fibroblasts, on the invasive ability of GBM cells was examined by wound-healing assay and invasion assay. Results: Oligodendrocytes, in contrast to fibroblasts, significantly increased the migration and invasive ability of GBM cells. Angiopoietin-2 levels were high in the conditioned medium obtained from oligodendrocytes. Angiopoietin-2 significantly increased the motility of GBM, and the motilitystimulating activity of the oligodendrocytes-derived conditioned medium was significantly decreased by anti-angiopoietin-2neutralizing antibody. Conclusion: Glioma stromal cells, oligodendrocytes, might up-regulate the invasiveness of GBM cells via angiopoietin-2 signaling.Diffuse glioma comprises the majority of primary brain tumors (1, 2). Recently, diffuse gliomas were classified as WHO grade II, III, and Ⅳ, based not only on their growth pattern and behavior, but also on genetic driver mutations in IDH1 and IDH2 genes (3). The current classification is based on the theory that primary glioblastoma (GBM) occurs de novo without the need of a less malignant precursor tumor, whereas secondary GBM arises from a lower-grade diffuse glioma (WHO grade II or III) (4). In spite of the standard multimodal treatments including surgical resection, chemotherapy, and radiotherapy, the median survival time of GBM patients is only around 14.6 months (1, 2). Surgical resection of diffuse gliomas is frequently non-curative because of their highly invasive nature (5). Therefore, a more thorough investigation of the invasive ability of GBM cells is of utmost importance for the discovery of novel therapies to improve the prognosis of patients with diffuse glioma.Tumor development is not only determined by malignant tumor cells themselves, but also by the tumor stroma. Recently, it was reported that tumor progression depends on the interactions between tumor cells and its surrounding tumor stromal cells (6, 7). Oligodendrocytes, fibroblasts, and astrocytes are considered stroma cells for diffuse glioma, especially GBM (8,9). However, the correlation between diffuse glioma cells and its surrounding tumor stroma cells has not been fully clarified. This study aimed to investigate the effect of stromal cells on the invasion of GBM cells and identify factors/signaling pathways that regulate migration and invasiveness of GBM. To the best of our knowledge, this is the first study to show that oligodendrocyte cells might up-regulate the invasive ability of GBM cells via angiopoietin-2 signaling. Materials and MethodsCell culture and cell lines. Two glioblastoma (GBM) cell lines, T98G and U251 were purchased from the J...

OBJECTIVEEpileptic spasms (ESs) are classified as focal, generalized, or unknown onset ESs. The classification of ESs and surgery in patients without lesions apparent on MRI is challenging. Total corpus callosotomy (TCC) is a surgical option for diagnosis of the lateralization and possible treatment for ESs. This study investigated phase-amplitude coupling (PAC) of fast activity modulated by slow waves on scalp electroencephalography (EEG) to evaluate the strength of the modulation index (MI) before and after disconnection surgery in children with intractable nonlesional ESs. The authors hypothesize that a decreased MI due to surgery correlates with good seizure outcomes.METHODSThe authors studied 10 children with ESs without lesions on MRI who underwent disconnection surgeries. Scalp EEG was obtained before and after surgery. The authors collected 20 epochs of 3 minutes each during non–rapid eye movement sleep. The MI of the gamma (30–70 Hz) amplitude and delta (0.5–4 Hz) phase was obtained in each electrode. MIs for each electrode were averaged in 4 brain areas (left/right, anterior/posterior quadrants) and evaluated to determine the correlation with seizure outcomes.RESULTSThe median age at first surgery was 2.3 years (range 10 months–9.1 years). Two patients with focal onset ESs underwent anterior quadrant disconnection (AQD). TCC alone was performed in 5 patients with generalized or unknown onset ESs. Two patients achieved seizure freedom. Three patients had residual generalized onset ESs. Disconnection surgeries in addition to TCC consisted of TCC + posterior quadrant disconnection (PQD) (1 patient); TCC + AQD + PQD (1 patient); and TCC + AQD + hemispherotomy (1 patient). Seven patients became seizure free with a mean follow-up period of 28 months (range 5–54 months). After TCC, MIs in 4 quadrants were significantly lower in the 2 seizure-free patients than in the 6 patients with residual ESs (p < 0.001). After all 15 disconnection surgeries in 10 patients, MIs in the 13 target quadrants for each disconnection surgery that resulted in freedom from seizures were significantly lower than in the 26 target quadrants in patients with residual ESs (p < 0.001).CONCLUSIONSIn children with nonlesional ESs, PAC for scalp EEG before and after disconnection surgery may be a surrogate marker for control of ESs. The MI may indicate epileptogenic neuronal modulation of the interhemispheric corpus callosum and intrahemispheric subcortical network for ESs. TCC may be a therapeutic option to disconnect the interhemispheric modulation of epileptic networks.