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Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array ( n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 ( n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation ( n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation ( n = 9), PPM1D mutation ( n = 2), and a novel type of PPM1D fusion ( n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the 'RTK I (PDGFRA)' group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs. [ABSTRACT FROM AUTHOR]

Purpose: Leptomeningeal enhancement (LME) suggests leptomeningeal dissemination (LMD) of tumor cells, which is a complication of end-stage glioblastoma, and is associated with a poor prognosis. However, magnetic resonance imaging (MRI) occasionally indicates the disappearance of peri-brainstem LME after surgical resection of glioblastoma. Since preoperative LMD may affect treatment indications, we aimed to analyze the clinical significance of preoperative LME of the brainstem in glioblastoma. Methods: We retrospectively collected clinical and radiological data from consecutive patients with glioblastoma and preoperative LME of the brainstem, who were treated at our hospital between 2017 and 2020. Results: Among 112 patients with glioblastoma, nine (8%) showed preoperative LME of the brainstem. In comparison with tumors without LME, tumor size was significantly associated with the preoperative LME of the brainstem (p = 0.016). In addition, there was a trend toward significance for a relationship between deep tumor location and preoperative LME of the brainstem (p = 0.058). Notably, among six patients who underwent surgical resection for glioblastoma with LME of the brainstem, four showed significant radiological disappearance of the LME on postoperative MRI. This suggests that the LME did not result from LMD in these cases. Moreover, these four patients lived longer than would be expected from the presence of LMD. However, this LME disappearance was not observed after biopsy or chemoradiotherapy. Conclusions: These findings suggest that preoperative LME does not necessarily indicate the presence of untreatable LMD; moreover, LME may disappear after surgical tumor resection. Thus, transient preoperative LME could be attributed to other mechanisms, including impaired venous flow due to intratumoral arteriovenous shunts, which can be resolved by reducing the tumor burden. [ABSTRACT FROM AUTHOR]

We conducted a feasibility study to predict malignant glioma grades via radiomic analysis using contrast-enhanced T1-weighted magnetic resonance images (CE-T1WIs) and T2-weighted magnetic resonance images (T2WIs). We proposed a framework and applied it to CE-T1WIs and T2WIs (with tumor region data) acquired preoperatively from 157 patients with malignant glioma (grade III: 55, grade IV: 102) as the primary dataset and 67 patients with malignant glioma (grade III: 22, grade IV: 45) as the validation dataset. Radiomic features such as size/shape, intensity, histogram, and texture features were extracted from the tumor regions on the CE-T1WIs and T2WIs. The Wilcoxon–Mann–Whitney (WMW) test and least absolute shrinkage and selection operator logistic regression (LASSO-LR) were employed to select the radiomic features. Various machine learning (ML) algorithms were used to construct prediction models for the malignant glioma grades using the selected radiomic features. Leave-one-out cross-validation (LOOCV) was implemented to evaluate the performance of the prediction models in the primary dataset. The selected radiomic features for all folds in the LOOCV of the primary dataset were used to perform an independent validation. As evaluation indices, accuracies, sensitivities, specificities, and values for the area under receiver operating characteristic curve (or simply the area under the curve (AUC)) for all prediction models were calculated. The mean AUC value for all prediction models constructed by the ML algorithms in the LOOCV of the primary dataset was 0.902 ± 0.024 (95% CI (confidence interval), 0.873–0.932). In the independent validation, the mean AUC value for all prediction models was 0.747 ± 0.034 (95% CI, 0.705–0.790). The results of this study suggest that the malignant glioma grades could be sufficiently and easily predicted by preparing the CE-T1WIs, T2WIs, and tumor delineations for each patient. Our proposed framework may be an effective tool for preoperatively grading malignant gliomas. [ABSTRACT FROM AUTHOR]

Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O- methylguanine- DNA methyltransferase ( MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]