Tianrui Yang

Glioblastoma (GBM) is the most malignant and lethal intracranial tumor, with extremely limited treatment options. Immunotherapy has been widely studied in GBM, but none can significantly prolong the overall survival (OS) of patients without selection. Considering that GBM cancer stem cells (CSCs) play a non-negligible role in tumorigenesis and chemoradiotherapy resistance, we proposed a novel stemness-based classification of GBM and screened out certain population more responsive to immunotherapy. The one-class logistic regression algorithm was used to calculate the stemness index (mRNAsi) of 518 GBM patients from The Cancer Genome Atlas (TCGA) database based on transcriptomics of GBM and pluripotent stem cells. Based on their stemness signature, GBM patients were divided into two subtypes via consensus clustering, and patients in Stemness Subtype I presented significantly better OS but poorer progression-free survival than Stemness Subtype II. Genomic variations revealed patients in Stemness Subtype I had higher somatic mutation loads and copy number alteration burdens. Additionally, two stemness subtypes had distinct tumor immune microenvironment patterns. Tumor Immune Dysfunction and Exclusion and subclass mapping analysis further demonstrated patients in Stemness Subtype I were more likely to respond to immunotherapy, especially anti-PD1 treatment. The pRRophetic algorithm also indicated patients in Stemness Subtype I were more resistant to temozolomide therapy. Finally, multiple machine learning algorithms were used to develop a 7-gene Stemness Subtype Predictor, which were further validated in two external independent GBM cohorts. This novel stemness-based classification could provide a promising prognostic predictor for GBM and may guide physicians in selecting potential responders for preferential use of immunotherapy.

Immune checkpoint inhibitors (CIs) have changed the landscape of tumor immunotherapy. Glioblastoma (GBM) remains the most common primary malignant brain tumor in adults and has a very poor prognosis. Due to the high invasiveness and aggressiveness of GBM, there is considerable interest in programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) treatment. However, the immunosuppressive and immune-privileged characteristics of GBM limit the efficacy of CIs. While clinical studies of CI monotherapies have shown unsatisfactory survival benefits, new treatment strategies have received attention. Multiple clinical studies have focused on combination of standard therapy (temozolomide, radiotherapy), targeted therapy and other immunotherapies, and some have reported results. Here, we reviewed recent clinical trials of anti-PD-1/PD-L1 monotherapy, studies with neoadjuvant strategies, and preclinical and clinical studies of combination immunotherapies for GBM. The preliminary clinical reports in certain subsets of patients with hypermutated or mismatch repair system deficiency GBM are also discussed.

Introduction: Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to the 2021 World Health Organization classification of central nervous system tumors. This study aimed to characterize the clinical, radiological, molecular, and survival features of GBM under the current classification scheme and explore survival determinants. Methods: We re-examined the genetic alterations of IDH-wildtype diffuse gliomas at our institute from 2011 to 2022, and enrolled GBMs for analysis after re-classification. Univariable and multivariable analyses were used to identify survival determinants. Results: Among 209 IDH-wildtype gliomas, 191 were GBMs, including 146 hist-GBMs (76%) and 45 mol-GBMs (24%). Patients with mol-GBMs were younger, less likely to develop preoperative motor dysfunction, and more likely to develop epilepsy than hist-GBMs. Mol-GBMs exhibited lower radiographic incidences of contrast enhancement and intratumoral necrosis. Common molecular features included copy-number changes in chromosomes 1, 7, 9, 10, and 19, as well as alterations in EGFR, TERT, CDKN2A/B, and PTEN, with distinct patterns observed between the two subtypes. The median overall survival (mOS) of GMB was 12.6 months. Mol-GBMs had a higher mOS than hist-GBMs, although not statistically significant (15.6 vs. 11.4 months, p=0.17). Older age, male sex, tumor involvement of deep brain structure or functional area, and genetic alterations in CDK4, CDK6, CIC, FGFR3, KMT5B, and MYB were predictors for a worse prognosis, while MGMT promoter methylation, maximal tumor resection, and treatment based on the Stupp protocol were predictive for better survival. Conclusion: The definition of GBM and its clinical, radiological, molecular, and prognostic characteristics have been altered under the current classification.

Background: The 5th edition of the World Health Organization (WHO) classification of central nervous system tumors incorporated specific molecular alterations into the categorization of gliomas. The major revision of the classification scheme effectuates significant changes in the diagnosis and management of glioma. This study aimed to depict the clinical, molecular, and prognostic characteristics of glioma and its subtypes according to the current WHO classification. Methods: hybridization methods and enrolled in the analysis. Results: The enrolled 452 gliomas were reclassified into adult-type diffuse glioma (ntotal=373; astrocytoma, n=78; oligodendroglioma, n=104; glioblastoma, n=191), pediatric-type diffuse glioma (ntotal=23; low-grade, n=8; high-grade, n=15), circumscribed astrocytic glioma (n=20), and glioneuronal and neuronal tumor (n=36). The composition, definition, and incidence of adult- and pediatric-type gliomas changed significantly between the 4th and the 5th editions of the classification. The clinical, radiological, molecular, and survival characteristics of each subtype of glioma were identified. Alterations in CDK4/6, CIC, FGFR2/3/4, FUBP1, KIT, MET, NF1, PEG3, RB1, and NTRK2 were additional factors correlated with the survival of different subtypes of gliomas. Conclusions: The updated WHO classification based on histology and molecular alterations has updated our understanding of the clinical, radiological, molecular, survival, and prognostic characteristics of varied subtypes of gliomas and provided accurate guidance for diagnosis and potential prognosis for patients.

Glioblastoma is the most common and aggressive malignancy in the adult central nervous system. Cytomegalovirus (CMV) plays a crucial role in the pathogenesis and treatment of glioblastoma. We reviewed the epidemiology of CMV in gliomas, the mechanism of CMV-related carcinogenesis, and its therapeutic strategies, offering further clinical practice insights. To date, the CMV infection rate in glioblastoma is controversial, while mounting studies have suggested a high infection rate. The carcinogenesis mechanism of CMV has been investigated in relation to various aspects, including oncomodulation, oncogenic features, tumor microenvironment regulation, epithelial-mesenchymal transition, and overall immune system regulation. In clinical practice, the incidence of CMV-associated encephalopathy is high, and CMV-targeting treatment bears both anti-CMV and anti-tumor effects. As the major anti-CMV treatment, valganciclovir has demonstrated a promising survival benefit in both newly diagnosed and recurrent glioblastoma as an adjuvant therapy, regardless of surgery and the MGMT promoter methylation state. Immunotherapy, including DC vaccines and adoptive CMV-specific T cells, is also under investigation, and preliminary results have been promising. There are still questions regarding the significance of CMV infection and the carcinogenic mechanism of CMV. Meanwhile, studies have demonstrated the clinical benefits of anti-CMV therapy in glioblastoma. Therefore, anti-CMV therapies are worthy of further recognition and investigation.