Glioma

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Pediatric high-grade gliomas (pHGGs) are the leading cause of tumor-related death in children, with diffuse midline gliomas representing the worst prognoses. Despite decades of clinical trials, no effective treatment has been found, and we are in desperate need of novel therapeutics. The discovery of highly recurrent histone H3 mutations in pHGGs represents a major breakthrough in our understanding of tumor initiation and development. In this review, we summarize our current knowledge of the molecular pathology of these tumors, including their genomic/epigenetic alterations, mechanism of action, and partner mutations contributing to tumor progression.

Significant new progress was made 10 years ago in the hypothesis that neuroglial cells, neural stem cells, and glioma stem cells (GSCs) depend on the tumor microenvironment (TME) transformation: (1) Because GSCs also have heterogeneity, they are a state, not an entity. (2) The importance of the border niche among many tumor niches is emphasized because it is a shelter for tumor resistance to radiotherapy and chemotherapy. (3) The plasticity of GSCs and TME cells allows TME cells to become GSC-initiating cells. (4) Future development will entail a close interaction between high-throughput molecular biology and artificial intelligence. In this review, we summarize recent advances in GSCs and their microenvironment from the following three aspects: the constantly updated of concept of stem cells, the concept of TME and niche, and the plasticity of GSCs and TME cells.

Background and Aim: Glioblastoma (GBM) is the most lethal primary brain tumor. Patients with unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter have higher MGMT expression, are less sensitive to temozolomide (TMZ), and are linked to poor prognosis. The aim of this study was to identify patients from this population with a better prognosis, explore the molecular mechanism, and provide a theoretical basis for the formulation of treatment strategies. Materials and Methods: Prognostic genes involved in the DNA damage response (DDR) pathway were screened, and the risk score of each GBM patient undergoing TMZ chemotherapy from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) database was calculated. A comprehensive prognostic nomogram model was constructed by combining the risk score and other clinical features. Results: Two DDR-related genes (replication factor C subunit 2 [RFC2] and methyl-CpG binding domain 4, DNA glycosylase [MBD4]) were identified as having a prognostic value in GBM patients with unmethylated MGMT promoter. Patients were classified into high- and low-risk groups using the risk score based on the expression of these two genes. The median overall survival of patients in the low-risk group was significantly longer than that recorded in the high-risk group in the TCGA cohort (15.95 vs. 11.90 months, respectively, P = 0.027) and CGGA cohort (25.90 vs. 11.87 months, respectively, P = 0.0082). The expression of those two genes was confirmed in tissue samples, and the risk scoring model showed that their prognostic value was independent of other clinical characteristics (P = 0.032), such as age. A final nomogram model was constructed, and its good performance was validated (concordance-index = 0.6656). Conclusions: A comprehensive prognostic model for patients with MGMT unmethylated GBM receiving TMZ chemotherapy was constructed using RFC2 and MBD4 gene expression, age, sex, and isocitrate dehydrogenase. The model showed good performance.

Background and Aim: High-grade glioma is the most common malignant primary brain tumor in the central nervous system. Multiple strategies such as surgery, radiotherapy, and chemotherapy have been used, but the prognosis of patients with high-grade glioma remains poor. No standard treatment exists for recurrent gliomas; however, combination therapies of programmed cell death protein 1 blockades with antiangiogenic agents have demonstrated promising effects in different solid tumors. Therefore, since the end of 2020, a clinical trial designed to evaluate the safety and efficiency of neoadjuvant therapy using camrelizumab and apatinib in patients with recurrent high-grade gliomas has been carried out in our institution. Methods/Design: In this prospective, Phase II, single-arm study, patients with recurrent high-grade gliomas will receive single-dose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before reoperation for tumor resection. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab and 4 weeks after surgery with the daily administration of apatinib. Treatment of camrelizumab and apatinib will be continued until disease progression or unacceptable toxicity or death. The primary outcome measure will be the median overall survival rate. Secondary outcome measures will include progression-free survival rate at 6 months and at 12 months and other measures. The trial is planned to enroll 30 patients. This study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (Guangzhou, China; approval No. SL-B2020-149-01) on July 27, 2020. Results and Conclusions: Although an evaluation is still impossible to be conducted yet, 11 patients had been enrolled by the end of January 2022. Some patients have shown a promising outcome. These preliminary data suggest that this study would be worthwhile. We hope that this study will provide scientific evidence to better care of patients with recurrent high-grade glioma. Trial registration: This study was registered with ClinicalTrials.gov under identifier NCT04588987 on October 19, 2020.

The clinical hallmarks of tumor growth, angiogenesis, and invasion were identified in a patient with isocitrate dehydrogenase-1 wild-type glioblastoma at initial diagnosis and management issues were examined. The head magnetic resonance imaging (MRI) showed multiple solid and cystic contrast enhancements in the rostral portion of the tumor located within the left motor gyrus and the adjacent brain. Extensive tumor invasion was noted along the left corticospinal tract extending into the cerebral peduncle and pons. After an open craniotomy for tissue biopsy, the patient underwent external beam radiotherapy and concomitant temozolomide, and his motor deficit was stabilized with concurrent bevacizumab infusion while dexamethasone was weaned off. After two cycles of adjuvant temozolomide, the patient experienced worsening motor deficit in the right hand. A repeat gadolinium-enhanced head MRI revealed increased fluid-attenuated inversion recovery hyperintensity in the left cerebral peduncle indicating tumor progression. This case illustrates the extensive invasion from a glioblastoma that cannot be adequately quantified or effectively treated. A wider margin of radiation may be needed to cover microscopic and infiltrative tumor cells. The early use of bevacizumab can also reverse neurological deficits and obviate the long-term use of dexamethasone and insulin in this patient. This study was approved by the Institutional Review Board at Dana Farber Cancer Institute #12-519 onMay 5, 2020.

Online since 6^th Sep 2017.