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Astrocytoma and glioblastoma (GB) are reclassified subtypes of adult diffuse gliomas based on distinct isocitrate dehydrogenase (IDH) mutation in the fifth edition of the WHO Classification of Tumors of the Central Nervous System. The recurrence of gliomas is a common and inevitable challenge, and analyzing the distinct genomic alterations in astrocytoma and GB could provide insights into their progression. This study conducted a longitudinal investigation, utilizing whole-exome sequencing, on 65 paired primary/recurrent gliomas. It examined chromosome arm aneuploidies, copy number variations (CNVs) of cancer-related genes and pathway enrichments during the relapse. The veracity of these findings was verified through the integration of our data with multiple public resources and by corroborative immunohistochemistry (IHC). The results revealed a greater prevalence of aneuploidy changes and acquired CNVs in recurrent lower grade astrocytoma than in relapsed grade 4 astrocytoma and GB. Larger aneuploidy changes were predictive of an unfavorable prognosis in lower grade astrocytoma (P < 0.05). Further, patients with acquired gains of 1q, 6p or loss of 13q at recurrence had a shorter overall survival in lower grade astrocytoma (P < 0.05); however, these prognostic effects were confined in grade 4 astrocytoma and GB. Moreover, acquired gains of 12 genes (including VEGFA) on 6p during relapse were associated with unfavorable prognosis for lower grade astrocytoma patients. Notably, elevated VEGFA expression during recurrence corresponded to poorer survival, validated through IHC and CGGA data. To summarize, these findings offer valuable insights into the progression of gliomas and have implications for guiding therapeutic approaches during recurrence. [ABSTRACT FROM AUTHOR]

Gliomas are aggressive brain tumors characterized by uncontrolled cell proliferation. FAM64A, a cell cycle-related gene, has been found to promote cell proliferation in various tumors, including gliomas. However, the regulatory mechanism and clinical significance of FAM64A in gliomas remain unclear. In this study, we investigated FAM64A expression in gliomas with different grades and constructed FAM64A silenced cell lines to study its functions. Our results demonstrated that FAM64A was highly expressed in glioblastoma (P < 0.001) and associated with a poor prognosis (P < 0.001). Expression profiles at the single-cell resolution indicated FAM64A could play a role in a cell-cycle-dependent way to promote glioma cell proliferation. We further observed that FAM64A silencing in glioma cells resulted in disrupted proliferation and migration ability, and increased cell accumulation in the G2/M phase (P = 0.034). Additionally, TGF-β signaling upregulates FAM64A expression, and SMAD4 and FAM64A co-localize in high-grade glioma tissues. We found FAM64A knockdown inhibited TGF-β-induced epithelial-mesenchymal transition in glioma. Our findings suggest that FAM64A could serve as a diagnostic and therapeutic target in gliomas. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma (GBM) is the most malignant primary tumor in the brain, with poor prognosis and limited effective therapies. Although Bevacizumab (BEV) has shown promise in extending progression-free survival (PFS) treating GBM, there is no evidence for its ability to prolong overall survival (OS). Given the uncertainty surrounding BEV treatment strategies, we aimed to provide an evidence map associated with BEV therapy for recurrent GBM (rGBM). Methods: PubMed, Embase, and the Cochrane Library were searched for the period from January 1, 1970, to March 1, 2022, for studies reporting the prognoses of patients with rGBM receiving BEV. The primary endpoints were overall survival (OS) and quality of life (QoL). The secondary endpoints were PFS, steroid use reduction, and risk of adverse effects. A scoping review and an evidence map were conducted to explore the optimal BEV treatment (including combination regimen, dosage, and window of opportunity). Results: Patients with rGBM could gain benefits in PFS, palliative, and cognitive advantages from BEV treatment, although the OS benefits could not be verified with high-quality evidence. Furthermore, BEV combined therapy (especially with lomustine and radiotherapy) showed higher efficacy than BEV monotherapy in the survival of patients with rGBM. Specific molecular alterations (IDH mutation status) and clinical features (large tumor burden and double-positive sign) could predict better responses to BEV administration. A low dosage of BEV showed equal efficacy to the recommended dose, but the optimal opportunity window for BEV administration remains unclear. Conclusions: Although OS benefits from BEV-containing regimens could not be verified in this scoping review, the PFS benefits and side effects control supported BEV application in rGBM. Combining BEV with novel treatments like tumor-treating field (TTF) and administration at first recurrence may optimize the therapeutic efficacy. rGBM with a low apparent diffusion coefficient (ADCL), large tumor burden, or IDH mutation is more likely to benefit from BEV treatment. High-quality studies are warranted to explore the combination modality and identify BEV-response subpopulations to maximize benefits. [ABSTRACT FROM AUTHOR]

Telomerase reverse transcriptase (TERT) promoter (pTERT) mutation has often been described as a late event in gliomagenesis and it has been suggested as a prognostic biomarker in gliomas other than 1p19q codeleted tumors. However, the characteristics of isocitrate dehydrogenase (IDH) wild type (wt) (IDHwt), pTERTwt glioblastomas are not well known. We recruited 72 adult IDHwt, pTERTwt glioblastomas and performed methylation profiling, targeted sequencing, and fluorescence in situ hybridization (FISH) for TERT structural rearrangement and ALT (alternative lengthening of telomeres). There was no significant difference in overall survival (OS) between our cohort and a the Cancer Genome Atlas (TCGA) cohort of IDHwt, pTERT mutant (mut) glioblastomas, suggesting that pTERT mutation on its own is not a prognostic factor among IDHwt glioblastomas. Epigenetically, the tumors clustered into classic‐like (11%), mesenchymal‐like (32%), and LGm6‐glioblastoma (GBM) (57%), the latter far exceeding the corresponding proportion seen in the TCGA cohort of IDHwt, pTERTmut glioblastomas. LGm6‐GBM‐clustered tumors were enriched for platelet derived growth factor receptor alpha (PDGFRA) amplification or mutation (p = 0.008), and contained far fewer epidermal growth factor receptor (EGFR) amplification (p < 0.01), 10p loss (p = 0.001) and 10q loss (p < 0.001) compared with cases not clustered to this group. LGm6‐GBM cases predominantly showed ALT (p = 0.038). In the whole cohort, only 35% cases showed EGFR amplification and no case showed combined chromosome +7/−10. Since the cases were already pTERTwt, so the three molecular properties of EGFR amplification, +7/−10, and pTERT mutation may not cover all IDHwt glioblastomas. Instead, EGFR and PDGFRA amplifications covered 67% and together with their mutations covered 71% of cases of this cohort. Homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A)/B was associated with a worse OS (p = 0.031) and was an independent prognosticator in multivariate analysis (p = 0.032). In conclusion, adult IDHwt, pTERTwt glioblastomas show epigenetic clustering different from IDHwt, pTERTmut glioblastomas, and IDHwt glioblastomas which are pTERTwt may however not show EGFR amplification or +7/−10 in a significant proportion of cases. CDKN2A/B deletion is a poor prognostic biomarker in this group. [ABSTRACT FROM AUTHOR]

Objective: We aimed to characterise glioblastomas of adolescents and young adults (AYAs) that were isocitrate dehydrogenase (IDH) wild type (wt) and H3wt. Materials and Methods: Fifty such patients (aged 16–32) were studied by methylation profiling, targeted sequencing and targeted RNA‐seq. Results: Tumours predominantly clustered into three methylation classes according to the terminology of Capper et al. (2018): (anaplastic) pleomorphic xanthoastrocytoma (PXA) (21 cases), GBM_midline (15 cases) and glioblastoma RTK/mesenchymal (seven cases). Two cases clustered with ANA_PA, four cases with LGG classes and one with GBM_MYCN. Only fifteen cases reached a calibrated score >0.84 when the cases were uploaded to DKFZ Classifier. GBM_midline‐clustered tumours had a poorer overall survival (OS) compared with the PXA‐clustered tumours (p = 0.030). LGG‐clustered cases had a significantly better survival than GBM_midline‐clustered tumours and glioblastoma RTK/mesenchymal‐clustered tumours. Only 13/21 (62%) of PXA‐clustered cases were BRAF V600E mutated. Most GBM_midline‐clustered cases were not located in the midline. GBM_midline‐clustered cases were characterised by PDGFRA amplification/mutation (73.3%), mutations of mismatch repair genes (40.0%), and all showed H3K27me3 and EZH1P loss, and an unmethylated MGMT promoter. Across the whole cohort, MGMT promoter methylation and wt TERT promoter were favourable prognosticators. Mismatch repair gene mutations were poor prognosticators and together with methylation class and MGMT methylation, maintained their significance in multivariate analyses. BRAF mutation was a good prognosticator in the PXA‐clustered tumours. Conclusion: Methylation profiling is a useful tool in the diagnosis and prognostication of AYA glioblastomas, and the methylation classes have distinct molecular characteristics. The usual molecular diagnostic criteria for adult IDHwt glioblastoma should be applied with caution within the AYA age group. [ABSTRACT FROM AUTHOR]

Background: The molecular profiling of glioblastoma (GBM) based on transcriptomic analysis could provide precise treatment and prognosis. However, current subtyping (classic, mesenchymal, neural, proneural) is time-consuming and cost-intensive hindering its clinical application. A simple and efficient method for classification was imperative.Methods: In this study, to simplify GBM subtyping more efficiently, we applied a random forest algorithm to conduct 26 genes as a cluster featured with hub genes, OLIG2 and CD276. Functional enrichment analysis and Protein-protein interaction were performed using the genes in this gene cluster. The classification efficiency of the gene cluster was validated by WGCNA and LASSO algorithms, and tested in GSE84010 and Gravandeel's GBM datasets.Results: The gene cluster (n = 26) could distinguish mesenchymal and proneural excellently (AUC = 0.92), which could be validated by multiple algorithms (WGCNA, LASSO) and datasets (GSE84010 and Gravandeel's GBM dataset). The gene cluster could be functionally enriched in DNA elements and T cell associated pathways. Additionally, five genes in the signature could predict the prognosis well (p = 0.0051 for training cohort, p = 0.065 for test cohort).Conclusions: Our study proved the accuracy and efficiency of random forest classifier for GBM subtyping, which could provide a convenient and efficient method for subtyping Proneural and Mesenchymal GBM. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the outcomes of patients with high-grade glioma who received treatment with particle radiotherapy.Methods: Between June 2015 and October 2018, 50 consecutive and nonselected patients with glioblastoma multiforme (n = 34) or anaplastic glioma (n = 16) were treated at the Shanghai Proton and Heavy Ion Center. Twenty-four patients received proton radiotherapy (at a dose of 60 gray-equivalents in 30 daily fractions), and 26 patients received proton radiotherapy plus a carbon-ion radiotherapy (CIRT) boost in various dose-escalating schemes. All patients received temozolomide because of their age or their O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Progression-free survival (PFS) and overall survival (OS) rates, as well as treatment-induced toxicities, were analyzed.Results: At a median follow-up of 14.3 months (range, 4.8-39.6 months), the 12-month and 18-month OS rates were 87.8% (95% CI, 77.6%-98.0%) and 72.8% (95% CI, 56.7%-88.9%), respectively, and the 12-month and 18-month PFS rates were 74.2% (95% CI, 60.9%-87.5%) and 59.8% (95% CI, 43.1%-76.5%), respectively. Univariate analyses revealed that age (>50 vs ≤50 years), World Health Organization grade (3 vs 4), and Karnofsky performance status (>80 vs ≤80) were significant prognosticators for OS, and IDH mutation and World Health Organization grade were significant for predicting PFS. Furthermore, MGMT promoter methylation, performance status, and age showed a trend toward predicting PFS. No significant predictive factors for PFS or OS were identified in multivariate analyses. Twenty-nine patients experienced grade 1 treatment-related acute adverse effects, and 11 developed grade 1 (n = 6) or grade 2 (n = 5) late adverse effect of radiation-induced brain necrosis. No grade 3, 4, or 5 toxicities were observed.Conclusions: Particle radiotherapy produced 18-month OS and PFS rates of 72.8% and 59.8%, respectively, with acceptable adverse effects in patients with high-grade glioma. Particle radiotherapy at a dose ≥60 gray-equivalents appears to be safe and potentially effective. [ABSTRACT FROM AUTHOR]

Giant cell glioblastoma (gcGBM) is a rare histological variant of GBM, accounting for about 1% of all GBM. The prognosis is poor generally though gcGBM does slightly better than the other IDH‐wild‐type GBM. Because of the rarity of the cases, there has been no comprehensive molecular analysis of gcGBM. Previously, single‐gene study identified genetic changes in TP53, PTEN and TERT promoter mutation in gcGBM. In this report, we performed whole‐exome sequencing (WES) to identify somatically acquired mutations and copy number variations (CNVs) in 10 gcGBM genomes. We also examined TERT promoter mutation and MGMT methylation in our cohort. On top of the reported mutations, WES revealed ATRX, PIK3R1, RB1 and SETD2 as the recurrent mutations in gcGBM. Notably, one tumor harbored a mutation in MutS homolog 6 (MSH6) that is a key mismatch repair (MMR) gene. This tumor demonstrated hypermutation phenotype and showed an increased number of somatic mutations. TERT promoter mutation and MGMT methylation were observed in 20% and 40% of our samples, respectively. In conclusion, we described relevant mutation profiling for developing future targeted therapies in gcGBM. [ABSTRACT FROM AUTHOR]

Aim Glioblastoma multiforme ( GBM) is one of the most frequent human brain tumor and causes dismal outcome. To identify tumor-associated antigens in GBM patients may find potential diagnostic markers and immunotherapeutic targets. In this study, we identified a gene termed URGCP using the serological identification of antigens by recombinant A2B5 positive glioma cDNA library. The gene product of URGCP is immunogenic in GBM after tested in allogenic patients serum screening. Methods and results GBM patients with an auto-antibody response against URGCP show longer survival than those without URGCP response. In additional, we show that URGCP was high expression in most GBM tissues and cell lines compared with normal brain tissues and majorly co-expressed with stem cell marker A2B5. Conclusion We identified a potential new biomarker of GBM, URGCP. The findings indicate that URGCP is immunogenic in human GBM and suggest its potential use as diagnostic and immunotherapeutic for GBM patients. [ABSTRACT FROM AUTHOR]

Brain stem gliomas are rare intracranial tumors, especially in adults. Malignant or high-grade brain stem gliomas are usually associated with a very poor prognosis. This case report documents an adolescent harboring brain stem glioblastoma who had complete radiological response to temozolomide after partial tumor resection and survived for more than 3 years. Radiological and pathological findings are described. To the best of our knowledge, no similar cases have been reported in the literature. [ABSTRACT FROM AUTHOR]

Glioblastoma cells secrete extra-cellular vesicles (EVs) containing microRNAs (miRNAs). Analysis of these EV miRNAs in the bio-fluids of afflicted patients represents a potential platform for biomarker development. However, the analytic algorithm for quantitative assessment of EV miRNA remains under-developed. Here, we demonstrate that the reference transcripts commonly used for quantitative PCR (including GAPDH, 18S rRNA, and hsa-miR-103) were unreliable for assessing EV miRNA. In this context, we quantitated EV miRNA in absolute terms and normalized this value to the input EV number. Using this method, we examined the abundance of miR-21, a highly over-expressed miRNA in glioblastomas, in EVs. In a panel of glioblastoma cell lines, the cellular levels of miR-21 correlated with EV miR-21 levels (p<0.05), suggesting that glioblastoma cells actively secrete EVs containing miR-21. Consistent with this hypothesis, the CSF EV miR-21 levels of glioblastoma patients (n=13) were, on average, ten-fold higher than levels in EVs isolated from the CSF of non-oncologic patients (n=13, p<0.001). Notably, none of the glioblastoma CSF harbored EV miR-21 level below 0.25 copies per EV in this cohort. Using this cut-off value, we were able to prospectively distinguish CSF derived from glioblastoma and non-oncologic patients in an independent cohort of twenty-nine patients (Sensitivity=87%; Specificity=93%; AUC=0.91, p<0.01). Our results suggest that CSF EV miRNA analysis of miR-21 may serve as a platform for glioblastoma biomarker development. [ABSTRACT FROM AUTHOR]

In recent years, numerous neurosurgical multimodal techniques have been utilized to maximize tumor resection safely and effectively. However, the synergetic effects of neurosurgical multimodalities on the survival of glioblastoma patients remain unclear. This study evaluated the role of intraoperative utilization of multimodalities in glioblastoma patients. Data of 912 adult patients with glioblastoma were obtained from the Huashan Glioma Registry. The utilization of fewer than 2 (multimodality value < 2) intraoperative multimodal techniques was defined as the nonmultimodal group. In contrast, the utilization of 2 or more (multimodality value ≥ 2) intraoperative multimodal techniques was regarded as the multimodal group. The prognosis of the 2 cohorts was compared and further stratified based on the diagnosis date (2010–2014 or 2015–2019) to reveal the role of the application of multimodal techniques. The median overall survival (OS) and progression-free survival of glioblastoma patients were 17.70 months and 12.03 months, respectively. The OS time of the multimodal group was noticeably longer than that of the nonmultimodal group (21.0 months vs. 16.0 months, P < 0.001). Multimodal techniques were more frequently applied in surgery in the 2015–2019 group than in the 2010–2014 group. The popularity of multimodal techniques contributed to significant improvement in the prognosis of glioblastoma patients from 2010–2014 to 2015–2019 (OS, 16.0 months vs. 22.0 months, P < 0.001). This study indicated that the utilization of intraoperative multimodal techniques improved the extent of resection and elevated the survival for adult glioblastoma patients. [ABSTRACT FROM AUTHOR]

Fewer than 5 % glioblastoma (GBM) patients survive over five years and are termed long-term survivors (LTS), yet their molecular background is unclear. The present cohort included 72 isocitrate dehydrogenase (IDH)-wildtype GBM patients, consisting of 35 LTS and 37 short-term survivors (STS), and we employed whole exome sequencing, RNA-seq and DNA methylation array to delineate this largest LTS cohort to date. Although LTS and STS demonstrated analogous clinical characters and classical GBM biomarkers, CASC5 (P = 0.002) and SPEN (P = 0.013) mutations were enriched in LTS, whereas gene-to-gene fusions were concentrated in STS (P = 0.007). Importantly, LTS exhibited higher tumor mutation burden (P < 0.001) and copy number (CN) increase (P = 0.013), but lower mutant-allele tumor heterogeneity score (P < 0.001) and CN decrease (P = 0.026). Additionally, LTS demonstrated hypermethylated genome (P < 0.001) relative to STS. Differentially expressed and methylated genes both enriched in olfactory transduction. Further, analysis of the tumor microenvironment revealed higher infiltration of M1 macrophages (P = 0.043), B cells (P = 0.016), class-switched memory B cells (P = 0.002), central memory CD4+ T cells (P = 0.031) and CD4+ Th1 cells (P = 0.005) in LTS. We also separately analyzed a subset of patients who were methylation class-defined GBM, contributing 70.8 % of the entire cohort, and obtained similar results relative to prior analyses. Finally, we demonstrated that LTS and STS could be distinguished using a subset of molecular features. Taken together, the present study delineated unique molecular attributes of LTS GBM. • LTS were characterized by hypermethylated genome, copy number increase and higher TMB. • LTS demonstrated distinct TME and olfactory transduction-related pathway enrichment. • STS showed heterogeneous tumor tissue, more gene fusion and copy number decrease. • Most LTS and STS were confirmed as methylation class-defined GBM (m-GBM). • The molecular features of m-GBM patients were in accordance with the entire cohort. [ABSTRACT FROM AUTHOR]

Objective Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with dismal survival. This study aims to examine the prognostic value of primary tumor sites and race on survival outcomes. Methods Patient data obtained from the Scott and White Hospital Brain Tumor Registry (1976–2013) were stratified according to sex, age, race, primary tumor site, vital status, and survival. Results Of the 645 patients, 580 (89.9%) were diagnosed with GBM not otherwise specified (GBM NOS), 57 (8.8%) with GBM, and 8 (1.2%) with giant-cell GBM. Most were male (53.5%), aged 50 years or older (78.7%). The white population had the highest GBM prevalence (87.1%) and the lowest overall survival versus all other race groups (6.6% vs. 30.1%; P < 0.01). The black population had a relatively low prevalence of GBM (5.9%) and the greatest overall survival versus all others (47.4% vs. 7.3%; P < 0.01). Primary tumor sites located in the temporal (25.8% vs. 20.2%; P = 0.03), occipital (8.1% vs. 2.9%; P = 0.05), and parietal lobes (24.2% vs. 20.8%; P = 0.05) had a greater occurrence in surviving individuals. The overall survival for men versus women was (62.9% vs. 37.1%; P = 0.12). Conclusions Black racial background and temporal, occipital, or parietal primary tumor sites are suggestive of positive survival outcomes. Conversely, white racial background with primary tumor sites in the brain overlapping and NOS areas seem to be associated with negative outcomes and decreased survival. Thus, racial background and primary tumor site may be useful prognostic factors in patients with GBM. [ABSTRACT FROM AUTHOR]