Temozolomide (TMZ), an oral alkylating agent, is a cornerstone of standard-of-care multimodality therapy for glioblastoma. In spite of significant efforts to treat this disease, the tumor carries a poor prognosis and is considered incurable largely due to the development of chemoresistance. One of the main mechanisms for this phenomenon is the activation of tumor DNA repair systems, such as O-6-methylguanine-DNA methyltransferase, that removes TMZ-induced DNA adducts and restores genomic integrity. Recent advances in the understanding of TMZ resistance oncobiology have introduced several novel independent molecular mechanisms involving epigenetic, transcriptomic, proteomic aberrations as well as alterations in apoptosis-autophagy processes, receptor tyrosine kinase activity, the tumor microenvironment, and the emergence of glioma stem cells. This article describes a multifaceted summary of the latest proposed causes for TMZ resistance and their complex interactions. It is believed that only by comprehending this growing network of interdependent mechanisms can effective combinatorial oncologic therapeutic strategies be developed to improve patient overall survival.

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Background and Aim: Guidelines recommend adjuvant treatment for patients with high-grade gliomas and low-grade gliomas with high risk of progression. In clinical practice, however, treatments may not conform to these suggested guidelines. In this study, we reviewed the treatments and outcomes in patients with gliomas at Sun Yat-Sen University Cancer Center (SYSUCC), China. Materials and Methods: Medical records and radiologic images of 1215 glioma patients who underwent surgery at the center from 2000 to 2017 were retrospectively reviewed, and their clinicopathological characteristics, treatment method, and overall survival (OS) were analyzed. The study was approved by the Ethics Committee of SYSUCC on February 20, 2019 (approval No. GZR2019-219). Results: A total of 1001 patients diagnosed with glioma (initially World Health Organization 2007 criteria, then 2016 criteria) were enrolled, including 90 patients with Grade I, 307 Grade II, 239 Grade III, and 365 Grade IV gliomas. A total of 331 of 604 patients with high-grade glioma (54.8%) and 159 of 397 with low-grade glioma (40.1%) received postsurgical radiotherapy, and 285 patients with high-grade tumors (47.1%) and 80 with low-grade tumors (20.2%) received adjuvant chemotherapy. The median OS was 17.5 months for Grade IV and 43.1 months for Grade III gliomas. The median OS of patients with low-grade glioma was not reached. The 5-year survival rates of patients with Grades I, II, III, and IV gliomas were 94.7%, 73.7%, 45.7%, and 18.6%, respectively. Multivariate analysis identified onset age, preoperative seizure, tumor location, pathological subtype, resection extent, and postsurgical treatment as independent predictors of OS in patients with high-grade gliomas. Patients with high-grade glioma who received postsurgical treatment had better survival than those without adjuvant therapy (Grade III: 52.6 vs. 20.3 months, P = 0.012; Grade IV: 22.6 vs. 12.1 months, P < 0.001). Among patients with diffuse low-grade gliomas, age, performance status, preoperative seizure, Ki-67 index, tumor subtype, and resection extent were associated with clinical outcomes. Conclusion: Glioma patients are not always treated according to guidelines. Although standard care may lead to favorable prognoses, individualized treatments may be more acceptable and result in better outcomes and should thus be considered in routine clinical practice.

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Gliosarcoma (GSM) is a rare primary neoplasm of the brain, characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation. GSM is usually treated as glioblastoma multiforme (GBM) and the prognosis is poor. Here, we discuss a 50-year-old male presenting with sudden decreased consciousness and a history of recent headache. A noncontrasted computed tomography of the brain revealed a well-circumscribed, hyperdense lesion in the left frontal lobe with significant perilesional edema, suggestive of an intracranial hemorrhage. The patient underwent emergency craniotomy to evacuate the hematoma. Intraoperatively, a mass was present, and fluid around the mass was collected and analyzed. Cytology revealed the presence of malignant cells. A 1-week postmagnetic resonance imaging (MRI) revealed a heterogenously enhancing mass in the left frontal lobe, suggestive of a high-grade glioma. The patient was then treated with radiation followed by adjuvant treatment with temozolomide plus bevacizumab. One year after the surgery, the patient was readmitted with headache, right-sided hemiparesis, and seizure. A follow-up MRI found a residual mass in the same region. A second surgery was performed. Histopathology examination showed GSM, and this was confirmed with an immunohistochemistry panel including glial fibrillary acid protein and vimentin. GSM is a rare variant of GBM. Intracranial hemorrhage is an uncommon clinical presentation of GSM. Diagnosis is established by histopathology. Treatment is surgery, followed by radiotherapy and chemotherapy. The study was approved by the Health Research Review Committee of Mohammad Hoesin Central General Hospital and Faculty of Medicine Sriwijaya University (No. 089/kepkrsmhunsri/2019) on March 1, 2019.

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Background and Aim: The overexpression and alternative splicing of calcium-activated potassium channel subunit alpha-1 (KCNMA1) that encodes large-conductance calcium-activated voltage-sensitive potassium (BK_Ca) channels are implicated in the development of human cancers. Dysfunctional angiogenesis in hypoxic tumors is a challenge to intravenous anticancer drug treatments. Hypoxic factors also lead to abnormal vascular functions posing hurdle for anticancer drug delivery to tumors. The aim of this study was to explore the role of BK_Cachannels in tumor angiogenesis, specifically with regard to release of vascular endothelial growth factor (VEGF). Materials and Methods: We subjected the glioma cells under hypoxia and normoxia and studied the expression and activity of BK_Cachannels in in vitro and in vivo tumor models. Then, we studied the proangiogenic factor, VEGF, in tumors and monitored the neoangiogenic process. The study protocol was approved by the Institutional Animal Care and Use Committee, Mercer University, Atlanta, GA, USA (approved No. A0706007_01) on July 20, 2007. Results: We presented in vivo and cell based in vitro experimental evidence on the direct and indirect interactions of BK_Cachannels with VEGF signaling. There was evidence that under hypoxia, glioma cells overexpressed KCNMA1 and increased VEGF secretion. By inhibiting KCNMA1, we showed that VEGF secretion was significantly reduced, thus potentially controlling angiogenesis, which has implications for vascular permeability and anticancer drug delivery. Moreover, there were differences in alternate splicing of KCNMA1 between normal and malignant cells under hypoxia and normoxia. Conclusion: We conclude that BK_Cachannels regulate hypoxia-induced angiogenesis. Therefore, serious effort is needed to better understand the molecular mechanisms of BK_Cachannelopathies triggering angiogenesis and progression of glioma. The modulators of BK_Cachannels could be viable in new anticancer therapeutics.

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Background and Aim: Cognitive deficits in low-grade glioma are well documented. Patients with glioma who are carriers of the apolipoprotein E (APOE) e4 allele may have increased memory problems and executive dysfunction. While APOE is ranked the number one Alzheimer's disease (AD) susceptibility gene, many other susceptibility genes have been identified in genome-wide association studies. This study aimed to analyze the expression of APOE and the next 23 ranked AD susceptibility genes in malignant gliomas to identify significantly co-occurrent genes. Materials and Methods: To identify the most important AD susceptibility genes, the AlzGene database (http://www.alzgene.org/) was consulted, which displays this information and regularly updates it. To analyze AD susceptibility genes in glioma, The Cancer Genome Atlas, a project begun in 2005, was used to catalog genetic mutations responsible for cancer, employing genome sequencing and bioinformatics. The cBioPortal for cancer genomics and the UCSC Xena browser were used to analyze the data in The Cancer Genome Atlas. Results: APOE and CD33 were the only significantly co-occurrent genes in 514 low-grade glioma tumor samples. APOE was altered in 1.8% of cases and CD33 in 3%. Heatmap indicates that the two genes tend to coexpress. The most common alteration was deep deletion. The cBioPortal and the Xena browser cannot distinguish or identify the alleles of APOE or CD33. Conclusions: AD patients with one or more APOE e4 alleles, having one or more copies of the CD33 risk allele (rs3865444 C), are at increased risk of cognitive decline compared to APOE E4 carriers, no doubt reflected by the co-occurrence of APOE and CD33 alterations in the gliomas. Better understanding of the interaction of genes and cognition in glioma patients may lead to new opportunities to personalize cancer therapy.

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Tumor treating fields are alternating electric fields that have a therapeutic effect on newly diagnosed and recurrent glioblastomas. The fields act on cellular proteins with large dipole moment that are critical for tumor cells undergoing mitosis. This putative mechanism of mitotic disruption translates into a superior survival benefit for newly diagnosed glioblastoma patients when tested in a randomized clinical trial comparing tumor treating fields and temozolomide with temozolomide alone in the adjuvant setting. This review provides an updated summary of preclinical and clinical data, including the cell biology effects of tumor treating fields, computer simulation of the electric field distribution in patients, and the clinical efficacy data of this new therapeutic modality against glioblastoma.

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Glioblastoma (GBM) is the most common malignant tumor of the central nervous system in adults. GBM is characterized by violent invasion and poor prognosis. Commonly, there are three main conventional methods to treat GBM, surgery, radiotherapy, and chemotherapy. GBM patients have a median survival ranging from 12 to 15 months, with all tumors developing, at some point, resistance to chemotherapy. There is recently growing interest in the relationship between microRNAs (miRNAs) and chemotherapy resistance in GBM. This paper aims to explore the molecular mechanism, by which miRNAs participate in the formation of chemotherapy resistance in GBM. Here, we summarize the published data relating miRNA to chemotherapy resistance in GBM. We discuss the relationship between mechanisms that miRNA impact upon and provide insight into potential future studies and clinical therapeutics.

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Chimeric antigen receptors (CARs) are genetically engineered transmembrane cell receptors consisting of an antigen-binding ectodomain fused to an activating intracellular T-cell signaling chain. Grafting CAR molecules on T-cells enables targeted killing of tumors. The gene therapy approach of modifying autologous patient immune cells with CARs has now moved from the research bench to early-phase clinical trials in patients with refractory, recurrent, and nonresectable glioblastoma. This is a review of the state of the science in the field of CAR T-cells for glioblastoma and an update on the completed and ongoing clinical trials available at the Clinical Trials Registry (www.clinicaltrials.gov). Here, we also discuss insights gained from the clinical trials of CAR T-cells against glioblastoma and innovative approaches to improve their efficacy.

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