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Glioblastoma is characterized by a pronounced resistance to therapy with dismal prognosis. Transcriptomics classify glioblastoma into proneural (PN), mesenchymal (MES) and classical (CL) subtypes that show differential resistance to targeted therapies. The aim of this study was to provide a viable approach for identifying combination therapies in glioblastoma subtypes. Proteomics and phosphoproteomics were performed on dasatinib inhibited glioblastoma stem cells (GSCs) and complemented by an shRNA loss-of-function screen to identify genes whose knockdown sensitizes GSCs to dasatinib. Proteomics and screen data were computationally integrated with transcriptomic data using the SamNet 2.0 algorithm for network flow learning to reveal potential combination therapies in PN GSCs. In vitro viability assays and tumor spheroid models were used to verify the synergy of identified therapy. Further in vitro and TCGA RNA-Seq data analyses were utilized to provide a mechanistic explanation of these effects. Integration of data revealed the cell cycle protein WEE1 as a potential combination therapy target for PN GSCs. Validation experiments showed a robust synergistic effect through combination of dasatinib and the WEE1 inhibitor, MK-1775, in PN GSCs. Combined inhibition using dasatinib and MK-1775 propagated DNA damage in PN GCSs, with GCSs showing a differential subtype-driven pattern of expression of cell cycle genes in TCGA RNA-Seq data. The integration of proteomics, loss-of-function screens and transcriptomics confirmed WEE1 as a target for combination with dasatinib against PN GSCs. Utilizing this integrative approach could be of interest for studying resistance mechanisms and revealing combination therapy targets in further tumor entities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Several studies have investigated the role of HIF-1α in predicting the prognosis of patients with glioblastoma, yielding contradictory results. Therefore, we performed a meta-analysis to document the correlation between HIF-1α and glioblastoma in individuals diagnosed with glioblastoma. We searched the PubMed, Cochrane Library, EMBASE, and Web of Science by January 25, 2024. Hazard Ratio (HR) was used to evaluate the relationship between HIF-1α and survival outcome, and Odds Ratio (OR) was adopted for tumor features.There was incorporation of nine observational studies with 607 individuals. The total prevalence of HIF-1α (higher than cut-off values) among individuals with glioblastoma was 0.72 (95% confidence interval (CI) = 0.68-0.75, I 2  = 95.1%). There is a strong association between increased levels of HIF-1α in tumour tissues and shorter Overall Survival (OS) (HR = 1.82, 95% CI = 1.41-2.34, I 2  = 13.7%). Subgroup analysis also indicated a correlation between higher levels of HIF-1α and reduced OS, specifically in the Asian population (HR = 1.48, 95% CI = 1.13-1.83, I 2  = 41.5%). In addition, there was a correlation between HIF-1α and age (older vs. younger, OR = 2.19, 95% CI = 1.25-3.86, P = 0.260). High levels of HIF-1α expression were associated with poorer survival outcomes and other clinicopathological characteristics of glioblastoma. Integrating HIF-1α into prognostic tools for glioblastoma aids in predicting survival, categorising risk, and advising patients on suitable treatment regimens., Competing Interests: Declarations Ethical approval This study did not require ethics approval. Consent to publish This study did not include any personal data, including personal details, images or videos, and no children participated. Therefore, consent for publication is not applicable in this context. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Although most pilocytic astrocytomas grow slowly, their progression in critical sites such as the brainstem or hypothalamus may prove fatal much more rapidly. Cystic progression may be more problematic than solid tumor. Patients with progressive cystic PAs located in eloquent deep areas of the brain are the best candidates for stereotactic radiosurgery., Objective: This retrospective case series aims to present the effective outcomes obtained from GKRS, targeting the mural nodules of symptomatic eloquently deep-seated cystic PAs in 9 consecutive patients treated at the IMC Gamma Knife Centre in Cairo, Egypt, between 2003 and 2021., Patient and Methods: The median follow-up period was 84 months (range 24-240 months). The median treated mural nodule volume was 1.25 cm 3 (range 0.32-1.97 cm 3 ), treated with a median peripheral prescription dose of 12 Gy and a median maximum dose of 24 Gy. The median cyst volume in treated patients was 7.64cm 3 (range 1.66-40.6cm 3 )., Results: At the last follow-up, 7 out of 9 patients (78%) achieved tumor control (marked reduction > 50% of the entire tumor volume in 6 patients and moderate tumor reduction < 50% in one patient) in addition to clinical improvement. The median time of confirmed tumor reduction was 18 months (range 12-32 months). Two patients reported progression of the treated tumor. The overall tumor control rates at 2, 5, and 7 years of follow-up were 88.9%, 78%, and 78%, respectively., Conclusion: The encouraging results of this series indicate that limiting the GKRS to the mural nodule of eloquently deep-seated cystic PAs may be a practical and effective pattern in the salvage of its treatment. Our data do not support radiation for extensive, large symptomatic cysts in deep-seated cystic PA or patients where microsurgical removal is feasible., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Retrospective study: "For this type of retrospective study, formal consent or committee approval is not required, it does not contain any studies with human participants", (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

The objective of this study was to explore the potential of machine-learning techniques in the automatic identification and classification of brain metastases from a radiomic perspective, aiming to improve the accuracy of tumor volume assessment for radiotherapy. By using various machine-learning algorithms, including random forest, support vector machine, gradient boosting machine, XGBoost, decision tree, artificial neural network, k-nearest neighbors, LightGBM, and CatBoost algorithms, a stacking ensemble model was developed to classify gross tumor volume (GTV), brainstem, and normal brain tissue based on radiomic features. Multiple evaluation metrics, including the specificity, sensitivity, negative predictive value, positive predictive value, accuracy, Matthews correlation coefficient, and the Youden index, were used to assess the model's performance. The stacked ensemble model integrated the strengths of the nine base models and consistently outperformed individual base models in classifying GTV (area under the curve [AUC] = 0.928), brainstem (AUC = 0.932), and normal brain tissue (AUC = 0.942). Among the base models, the support vector machine model demonstrated the best performance in the three classifications (AUC = 0.922, 0.909, and 0.928). The higher performance of the stacked ensemble model highlighted the low performance of other models, including the decision tree (AUC = 0.709, 0.706, 0.804) and k-nearest neighbors (AUC = 0.721, 0.663, 0.729) models in certain contexts, such as when faced with high-dimensional feature spaces. While machine learning shows significant promise in medical image analysis, relying solely on a single model may lead to suboptimal results. By combining the strengths of various algorithms, the stacking ensemble model offers a better solution for the classification of brain metastases based on radiomic features., Competing Interests: Declarations Ethics approval and consent to participate According to the ethical guide-lines of the Helsinki Declaration and was approved by the institutional review board of Jiang-xi Cancer Hospital. Written informed consents were obtained from all patients prior to treatment. Informed consent forms were signed by all patients. The study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Jiang-xi Cancer Hospital (ethics number:2023KY082). Consent for publication Consent for publication is not applicable in this study, because there is not any individual person’s data. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Gliomas exhibit high heterogeneity and poor prognosis. Despite substantial progress has been made at the genomic and transcriptomic levels, comprehensive proteomic characterization and its implications remain largely unexplored. In this study, we perform proteomic profiling of gliomas using 343 formalin-fixed and paraffin-embedded tumor samples and 53 normal-appearing brain samples from 188 patients, integrating these data with genomic panel information and clinical outcomes. The proteomic analysis uncovers two distinct subgroups: Subgroup 1, the metabolic neural subgroup, enriched in metabolic enzymes and neurotransmitter receptor proteins, and Subgroup 2, the immune subgroup, marked by upregulation of immune and inflammatory proteins. These proteomic subgroups show significant differences in prognosis, tumorigenesis, microenvironment dysregulation, and potential therapeutics, highlighting the critical roles of metabolic and immune processes in glioma biology and patient outcomes. Through a detailed investigation of metabolic pathways guided by our proteomic findings, dihydropyrimidine dehydrogenase (DPYD) and thymidine phosphorylase (TYMP) emerge as potential prognostic biomarkers linked to the reprogramming of nucleotide metabolism. Functional validation in patient-derived glioma stem cells and animal models highlights nucleotide metabolism as a promising therapy target for gliomas. This integrated multi-omics analysis introduces a proteomic classification for gliomas and identifies DPYD and TYMP as key metabolic biomarkers, offering insights into glioma pathogenesis and potential treatment strategies., Competing Interests: Competing interests T.G. is a shareholder of Westlake Omics Inc. The other authors declare no potential competing of interest., (© 2024. The Author(s).)

Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed. We added 14 epigenetically defined pedHGG-RTK2A/B tumors to this GC series and provided centrally reviewed radiological, histological, and molecular characterization. The final cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 pedHGG-RTK2A (78%) and seven pedHGG-RTK2B (22%) cases. The median age was 11.6 years (range, 4-17) with a median overall survival of 16.0 months (range 10.9-28.2). Seven of 11 of the newly added cases with imaging available showed a GC phenotype at diagnosis or follow-up. PedHGG-RTK2B tumors exhibited frequent bithalamic involvement (6/7, 86%). Central neuropathology review confirmed a diffuse glial neoplasm in all tumors with prominent angiocentric features in both subclasses. Most tumors (24/27 with available data, 89%) diffusely expressed EGFR with focal angiocentric enhancement. PedHGG-RTK2A tumors lacked OLIG2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed this glial transcription factor. ATRX loss occurred in 3/6 pedHGG-RTK2B samples with available data (50%). DNA sequencing (pedHGG-RTK2A: n = 18, pedHGG-RTK2B: n = 5) found EGFR alterations (15/23, 65%; predominantly point mutations) in both subclasses. Mutations in BCOR (14/18, 78%), SETD2 (7/18, 39%), and the hTERT promoter (7/19, 37%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 alterations (4/5, 80%). In conclusion, pedHGG-RTK2A/B tumors are characterized by highly diffuse-infiltrating growth patterns and specific radiological and histo-molecular features. By comprehensively characterizing methylation-based tumors, the chance to develop specific and effective therapy concepts for these detrimental tumors increases., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Medical University of Graz (35–085 ex 22/23). Consent for publication Not applicable. Competing interests The authors declare that they have no conflicts of interest directly related to the topic of this article., (© 2024. The Author(s).)

High-frequency irreversible electroporation (H-FIRE), a nonthermal brain tumor ablation therapeutic, generates a central tumor ablation zone while transiently disrupting the peritumoral blood-brain barrier (BBB). We hypothesized that bystander effects of H-FIRE tumor cell ablation, mediated by small tumor-derived extracellular vesicles (sTDEV), disrupt the BBB endothelium. Monolayers of bEnd.3 cerebral endothelial cells were exposed to supernatants of H-FIRE or radiation (RT)-treated LL/2 and F98 cancer cells. Endothelial cell response was evaluated microscopically and via flow cytometry for apoptosis. sTDEV were isolated following H-FIRE and RT, characterized via nanoparticle tracking analysis (NTA) and transmission electron microscopy, and applied to a Transwell BBB endothelium model to quantify permeability changes. Supernatants of H-FIRE-treated tumor cells, but not supernatants of sham- or RT-treated cells, disrupted endothelial cell monolayer integrity while maintaining viability. sTDEV released by glioma cells treated with 3000 V/cm H-FIRE increased permeability of the BBB endothelium model compared to sTDEV released after lower H-FIRE doses and RT. NTA revealed significantly decreased sTDEV release after the 3000 V/cm H-FIRE dose. Our results demonstrate that sTDEV increase permeability of the BBB endothelium after H-FIRE ablation in vitro. sTDEV-mediated mechanisms of BBB disruption may be exploited for drug delivery to infiltrative margins following H-FIRE ablation., Competing Interests: Competing interests Davalos, Aycock, Dervisis, and Rossmeisl have pending and issued patents related to electroporation. Murphy, Marsh, Hay, Athanasiadi, Bracha, Chang, and Gourdie declare no potential conflicts of interest., (© 2024. The Author(s).)

Glioma refers to a highly prevalent type of brain tumor that is strongly associated with a high mortality rate. During the treatment process of the disease, it is particularly important to accurately perform segmentation of the glioma from Magnetic Resonance Imaging (MRI). However, existing methods used for glioma segmentation usually rely solely on either local or global features and perform poorly in terms of capturing and exploiting critical information from tumor volume features. Herein, we propose a local and global dual transformer with an attentional supervision U-shape network called DTASUnet, which is purposed for glioma segmentation. First, we built a pyramid hierarchical encoder based on 3D shift local and global transformers to effectively extract the features and relationships of different tumor regions. We also designed a 3D channel and spatial attention supervision module to guide the network, allowing it to capture key information in volumetric features more accurately during the training process. In the BraTS 2018 validation set, the average Dice scores of DTASUnet for the tumor core (TC), whole tumor (WT), and enhancing tumor (ET) regions were 0.845, 0.905, and 0.808, respectively. These results demonstrate that DTASUnet has utility in assisting clinicians with determining the location of gliomas to facilitate more efficient and accurate brain surgery and diagnosis., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Glioblastoma (GBM) is the most frequent and aggressive malignant primary tumor of the central nervous system in adults, with an incidence of 3.23 per 100,000 people. Despite the existence of various therapeutic approaches, the absence of a cure and the unfavorable prognosis persist for this neoplasm, with a median survival of approximately 8-15 months and a 5-year survival rate of 6.9%. In this review, we address the epidemiology, histopathology, molecular characteristics, and treatment of GBM. We highlight the relationship of GBM with the microenvironment in the lateral ventricle wall and the cerebrospinal fluid. The location of GBM in this region results in more aggressive tumors and shorter life expectancy for patients. Understanding the malignancy mechanisms that hinder remission, treatment, and positive prognosis opens the possibility of improving diagnostic and therapeutic interventions against GBM.

Glioblastoma (GBM), an aggressive brain malignancy with a cellular hierarchy dominated by GBM stem cells (GSCs), evades antitumor immunity through mechanisms that remain incompletely understood. Like most cancers, GBMs undergo metabolic reprogramming toward glycolysis to generate lactate. Here, we show that lactate production by patient-derived GSCs and microglia/macrophages induces tumor cell epigenetic reprogramming through histone lactylation, an activating modification that leads to immunosuppressive transcriptional programs and suppression of phagocytosis via transcriptional upregulation of CD47, a "don't eat me" signal, in GBM cells. Leveraging these findings, pharmacologic targeting of lactate production augments efficacy of anti-CD47 therapy. Mechanistically, lactylated histone interacts with the heterochromatin component chromobox protein homolog 3 (CBX3). Although CBX3 does not possess direct lactyltransferase activity, CBX3 binds histone acetyltransferase (HAT) EP300 to induce increased EP300 substrate specificity toward lactyl-CoA and a transcriptional shift toward an immunosuppressive cytokine profile. Targeting CBX3 inhibits tumor growth by both tumor cell-intrinsic mechanisms and increased tumor cell phagocytosis. Collectively, these results suggest that lactate mediates metabolism-induced epigenetic reprogramming in GBM that contributes to CD47-dependent immune evasion, which can be leveraged to augment efficacy of immuno-oncology therapies.

Glioma is a common primary nervous system malignant tumor with poor overall cure rate and low survival rate, yet successful treatment still remains a challenge. Here, we demonstrated that amantadine (AMT) exhibits the powerful anti-glioma effect by promoting apoptosis and autophagy in vivo and in vitro. Mechanistically, amantadine induces a large amount of reactive oxygen species (ROS) accumulation in glioma cells, and then triggers apoptosis by destroying mitochondria. In addition, amantadine induces the initiation of autophagy and inhibits the fusion of autophagosome and lysosome, consequently performing an anti-glioma role. Taken together, our findings suggest that amantadine could be a promising anti-glioma drug that inhibits glioma cells by inducing apoptosis and autophagy, which may provide a novel potential treatment option for patients., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval All animal studies were approved by the Institutional Ethics Committee of Lanzhou University Second Hospital., (© 2024. The Author(s).)

Aims: The incidence of recurrent gliomas is high, exerting low survival rates and poor prognoses. Transcription factor AP-2α has been reported to regulate the progression of primary glioblastoma (GBM). However, the function of AP-2α in recurrent gliomas is largely unclear., Methods: The expression of AP-2α and O6-methylguanine DNA-methyltransferase (MGMT) was detected in recurrent glioma tissues and cell lines by Western blots, the regulation mechanisms between AP-2α/MGMT promoter and RA/AP-2α promoter were studied by luciferase reporter assays, EMSA, and chIP assays. The effects of AP-2α and TMZ/RA treatment on cell viability in vitro and in vivo were investigated by MTT assays, γH 2 AX staining, comet assays and intracranial injection., Key Findings: AP-2α expression negatively correlates with the expression of MGMT in glioma samples. AP-2α could directly bind with the promoter of the MGMT gene, suppresses transcriptional levels of MGMT and downregulate MGMT expression in TMZ-resistant U87MG-R and T98G cells, but TMZ treatment decreases AP-2α expression and increases MGMT expression. The extended TMZ treatment and increased TMZ concentrations reversed these effects. Moreover, AP-2α overexpression combines with TMZ to decrease cell viability, concurrently with improved DNA damage marker γH 2 AX. Furthermore, retinoic acid (RA) activates RAR/RXR heterodimers, which bind to RA-responsive elements (RAREs) of the AP-2α promoter, and activates AP-2α expression in recurrent glioma cells. Finally, in intracranial relapsed glioma mouse model, both RA and TMZ could retard tumor development and prolong the mouse survival., Significance: AP-2α activation by gene overexpression or RA treatment reveals the suppressive effects on glioma relapse, providing a novel therapeutic strategy against malignant refractory gliomas., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM), also known as grade IV astrocytoma, is the most common and deadly brain tumour. It has a poor prognosis and a low survival rate. GBM cells' immunological escape mechanism helps them resist advanced multimodal therapy. In physiological homeostasis, brain astrocytes and microglia suppress infections and clear the potential pathogen from the system. However, in severe pathological conditions like cancer, the immune response fails to eliminate mutated and rapidly over-proliferating GBM cells. The malignant cells' interactions with immune cells and the neoplasm's immunosuppressive environment enable the avoidance and their clearance. Immunotherapy efficiently addresses these difficulties, as shown by sufficient evidence. This review discusses how GBM cells inhibit and elude the immune system. These include MHC molecule expression alteration and PD-L1 and CTLA-4 immune checkpoint overexpression. Without co-stimulation, these changes induce effector T-cell tolerance and anergy. The review also covers how MDSCs, TAMs, Herpes Virus Entry Mediators, and Human cytomegalovirus protein decrease the effector immune response against glioblastoma. The latter part discusses various therapies that are available in the market or under clinical trials which revolves around combating resistance against the available multimodal therapies. The recent trends indicate that there are various monoclonal antibodies and peptide-based vaccines that can be utilized to overcome the immune evasion technique harbored by GBM cells. A strategic development of Immunotherapy considering these hallmarks of immune evasion may help in designing a therapy that may prove to be effective in killing the GBM cells thereby, improving the overall survival of GBM-affected patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: This study aimed to investigate the role of gamma-aminobutyric acid (GABA) in the glioblastoma (GBM) tumor immune microenvironment (TIME) and its impact on prognosis and response to immunotherapy., Main Methods: This study employed single-cell RNA sequencing (scRNA-seq) to delineate the TIME of GBM, utilized non-negative matrix factorization (NMF) for GABA-associated cell clustering, and performed pseudotime analysis for cellular trajectories. Additionally, we integrated immunohistochemistry (IHC), immunofluorescence (IF), and protein-protein interaction (PPI) analysis to explore the regulatory mechanisms within the tumor microenvironment., Key Findings: The study identified distinct GABA-associated immune cell subtypes, particularly macrophages and T-cells, with unique gene expression and developmental trajectories. The development of the GABA-associated scoring model (GABAAS), introduced novel prognostic indicators, enhancing our ability to predict patient outcomes. This study also suggests that GABA-related genes, including NDRG2 and TIMP1, play a crucial role in immune modulation, with potential implications for immunotherapy responsiveness., Significance: The findings underscore the potential of targeting GABA-related genes (NDRG2 and TIMP1) and M2 macrophage to reshape the glioblastoma immune landscape, offering a new frontier in personalized neuro-immunotherapy. This approach holds promise to counter individual tumor immunosuppressive mechanisms, enhancing patient outcomes., Competing Interests: Declaration of competing interest All authors agree to publish. The authors declare that they have no conflicts of interest for this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tumor-associated microglia and macrophages (TAM) make up the largest immune cell population in the glioblastoma (GBM) tumor microenvironment. Given the heterogeneity and plasticity of TAMs in the GBM tumor microenvironment, understanding the context-dependent cancer cell-TAM symbiotic interaction is crucial for understanding GBM biology and developing effective therapies. In a recent issue of Cell, Kloosterman and colleagues identified a subpopulation of glycoprotein nonmetastatic melanoma protein Bhigh lipid-laden microglia and macrophages (LLM) in GBM. Mesenchymal-like GBM cells help generate the LLM phenotype. Reciprocally, LLMs are epigenetically rewired to recycle myelin and transfer the lipid from myelin to cancer cells, fueling mesenchymal-like GBM progression in a liver X receptor/ABCA1-dependent manner. Together, leveraging LLMs opens new therapeutic possibilities for rewiring the metabolism-mediated tumor-TAM interaction during GBM progression., (©2024 American Association for Cancer Research.)

Glioblastoma multiforme (GBM) is a highly aggressive form of primary brain tumor in adults, which unfortunately has an abysmal prognosis and poor survival rates. The reason behind the poor success rate of several FDA-approved drug is mainly attributed to insufficient drug distribution to the tumor site across the blood-brain barrier (BBB) and induction of resistance. In this study, we have developed a novel nanotherapeutic approach to achieve our goal. PLGA-based nanoencapsulation of both Temozolomide (TMZ) and EGFR inhibitor 3,3'-diindoyl methane (DIM) in a combinatorial approach enhances the delivery of them together. Their synergistic mode of actions, significantly enhances the cytotoxic effect of TMZ in vitro and in vivo. Moreover, the dual-loaded nanoformulation works more efficiently on DNA damage and apoptosis, resulting in a several-fold reduction in tumor burden in vivo, systemic drug toxicity, and increased survival. These findings suggest the preclinical potential of this new treatment strategy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Galectin-9 (Gal-9) is a multifaceted regulator of various pathophysiologic processes that exerts positive or negative effects in a context-dependent manner. In this study, we elucidated the distinctive functional properties of Gal-9 on myeloid cells within the brain tumor microenvironment (TME). Gal-9-expressing cells were abundant at the hypoxic tumor edge in the tumor-bearing ipsilateral hemisphere compared with the contralateral hemisphere in an intracranial mouse brain tumor model. Gal-9 was highly expressed in microglia and macrophages in tumor-infiltrating cells. In primary glia, both the expression and secretion of Gal-9 were influenced by tumors. Analysis of a human glioblastoma bulk RNA sequencing dataset and a single-cell RNA sequencing dataset from a murine glioma model revealed a correlation between Gal-9 expression and glial cell activation. Notably, the Gal-9high microglial subset was functionally distinct from the Gal-9neg/low subset in the brain TME. Gal-9high microglia exhibited properties of inflammatory activation and higher rates of cell death, whereas Gal-9neg/low microglia displayed a superior phagocytic ability against brain tumor cells. Blockade of Gal-9 suppressed tumor growth and altered the activity of glial and T cells in a mouse glioma model. Additionally, glial Gal-9 expression was regulated by hypoxia-inducible factor-2α in the hypoxic brain TME. Myeloid-specific hypoxia-inducible factor-2α deficiency led to attenuated tumor progression. Together, these findings reveal that Gal-9 on myeloid cells is an immunoregulator and putative therapeutic target in brain tumors. Significance: Galectin-9 serves as an immune checkpoint molecule that modulates the functional properties of microglia in the brain tumor microenvironment and could potentially be targeted to effectively treat brain tumors., (©2024 American Association for Cancer Research.)

Glioma, a common primary brain tumor, is highly infiltrative and invasive, often leading to drug resistance and recurrence. Therefore, the development of novel therapeutic agents is urgently needed. Pseudellone C is a novel marine triindole alkaloid. Screening of its antiproliferative activity against 55 cell lines revealed its anti-CNS cancer potential. A total of 42 derivatives of Pseudellone C were designed and synthesized, and their inhibitory activities against two human glioma cell lines (U-87MG and LN-229) were evaluated using the CCK-8 assay. Ten derivatives exhibited potent antiproliferative activity with IC 50 values below 10 μmol, which are 18- to 39- fold more potent than Pseudellone C. Among these, derivative 4o demonstrated favorable blood-brain barrier permeability. Mechanistic studies revealed that 4o induces apoptosis primarily by activating the downstream caspase 3 cascade via the TNF/TNFR pathway. Structure-activity relationship correlations were systematically analyzed, and a pharmacophore model for further rational design was constructed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Glioblastoma multiforme (GBM) is the most common primary intracranial tumor with characteristics of high aggressiveness and poor prognosis. Deguelin, a component from the bark of Leguminosae Mundulea sericea (African plant), displays antiproliferative effects in some tumors, however, the inhibitory effect and mechanism of deguelin on GBM were still poorly understood. At first, we found that deguelin reduced the viability of GBM cells by causing cell cycle arrest in G2/M phase and inducing their apoptosis. Secondly, deguelin inhibited the migration of GBM cells. Next, RNA-seq analysis identified that CCL2 (encoding chemokine CCL2) was downregulated significantly in deguelin-treated GBM cells. As reported, CCL2 promoted the cell growth, and CCL2 was associated with regulating NFκB signaling pathway, as well as involved in modulating tumor microenvironment (TME). Furthermore, we found that deguelin inactivated CCL2/NFκB signaling pathway, and exougous CCL2 could rescue the anti-inhibitory effect of deguelin on GBM cells via upregulating NFκB. Finally, we established a syngeneic intracranial orthotopic GBM model and found that deguelin regressed the tumor growth, contributed to an anti-tumorigenic TME and inhibited angiogenesis of GBM by suppressing CCL2/NFκB in vivo. Taken together, these results suggest the anti-GBM effect of deguelin via inhibiting CCL2/NFκB pathway, which may provide a new strategy for the treatment of GBM., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Prognosis of glioblastoma patients is still poor despite multimodal therapy. The highly brain-infiltrating growth in concert with a pronounced therapy resistance particularly of mesenchymal glioblastoma stem-like cells (GSCs) has been proposed to contribute to therapy failure. Recently, we have shown that a mesenchymal-to-proneural mRNA signature of patient derived GSC-enriched (pGSC) cultures associates with in vitro radioresistance and gel invasion. Importantly, this pGSC mRNA signature is prognostic for patients' tumor recurrence pattern and overall survival. Two mesenchymal markers of the mRNA signature encode for IK Ca and BK Ca Ca 2+ -activated K + channels. Therefore, we analyzed here the effect of IK Ca - and BK Ca -targeting concomitant to (fractionated) irradiation on radioresistance and glioblastoma spreading in pGSC cultures and in pGSC-derived orthotopic xenograft glioma mouse models. To this end, in vitro gel invasion, clonogenic survival, in vitro and in vivo residual DNA double strand breaks (DSBs), tumor growth, and brain invasion were assessed in the dependence on tumor irradiation and K + channel targeting. As a result, the IK Ca - and BK Ca -blocker TRAM-34 and paxilline, respectively, increased number of residual DSBs and (numerically) decreased clonogenic survival in some but not in all IK Ca - and BK Ca -expressing pGSC cultures, respectively. In addition, BK Ca - but not IK Ca -blockade slowed-down gel invasion in vitro. Moreover, systemic administration of TRAM-34 or paxilline concomitant to fractionated tumor irradiation increased in the xenograft model(s) residual number of DSBs and attenuated glioblastoma brain invasion and (numerically) tumor growth. We conclude, that K Ca -blockade concomitant to fractionated radiotherapy might be a promising new strategy in glioblastoma therapy., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

In this study, we have synthesized novel 4-acetophenone moiety-bearing functionalized imidazole derivatives containing S-, and N-ethyl substituents and evaluated their anticancer activity. Their anticancer activity was studied against human breast carcinoma (MDA-MB-231), human prostate carcinoma (PPC-1), and human glioblastoma (U-87). Compounds 4, 9, 14, and 22 were identified as the most promising anticancer agents from a series of imidazole derivatives. They showed the highest cytotoxicity by MTT assay against MDA-MB-231, PPC-1 and U-87 cell lines. Compounds 14 and 22 were most selective against PPC-1 and U-87 cell lines, and their EC 50 values against these cell lines ranged from 3.1 to 47.2 µM. Most tested compounds showed lower activity against the triple-negative breast cancer MDA-MB-231 cell line. None of the imidazole derivatives possessed an inhibiting effect on the migration of PPC-1 and U-87 cells by 'wound' healing assay. In spheroid assay, the most promising were compounds 14 and 22, especially in PPC-1 3D cultures. They efficiently reduced both the size and the viability of PPC-1 spheroid cells., Competing Interests: Declarations Competing interests The authors declare no competing interests. Informed consent Not applicable., (© 2024. The Author(s).)

Background: The interaction between mesenchymal stem cells (MSC) and Glioblastoma (GBM), although potentially of the highest importance, is ill-understood. This is due, in part, to the lack of relevant experimental models. The similarity between the in vitro situations and the in vivo situation can be improved by 3D co-culture as it reproduces key cell-cell interactions between the tumor microenvironment (TME) and cancer cells., Methods: MSC Can acquired characteristics of cancer associated fibroblasts (CAF) by being cultured with conditioned medium from GBM cultures and thus are called MSC CAF . We co Cultured MSC CAF with patient derived GBM in a scaffold 3D bioprinted model. We studied the response to current GBM therapy (e.g. Temozolomide + /Radiation) on the co cultures by bulk transcriptomic (RNA Seq) and epigenetic (ATAC Seq) analyses RESULTS: The transcriptomic modifications induced by standard GBM treatment in bioprinted scaffolds of mono- or co-cultures of GBM ± MSC can be analyzed. We found that mitochondrial encoded OXPHOS genes are overexpressed under these conditions and are modified by both co-culture and treatment (chemotherapy ± radiation). We have identified two new markers of MSC/GBM interactions, one epigenetically regulated (i.e. TREM-1) associated with an increased overall survival in GBM patients and another implicated in post-transcriptional regulation (i.e. the long non-coding RNA, miR3681HG), which is associated with a reduced overall survival in GBM patients., Competing Interests: Declarations Ethics approval and consent to participate The bio-collection used for this analysis is the Glioblastoma collection belonging to the approved project, “pediatric research program of the University Hospital of Nantes, France (Ref. MESR DC-2014–2206)”, having obtained an institutional approval from committee patients protection board, “CPP Ouest IV, approval number “Dossier 06/15”, date of approval 08/04/2015. The patients or their guardians/legally authorized representatives/next of kin provided written informed consent for participation in the use of samples. After informed consent, tumor samples classified as GBM, based on the World Health Organization criteria, were obtained from patients undergoing surgical intervention at the Department of Neurosurgery at “Centre Hospitalier Universitaire de Nantes” and the “Tumorothèque IRCNA”. Declaration of use of AI The authors declare that artificial intelligence is not used in this study. Competing Interests The authors declare that they have no competing of interest., (© 2024. The Author(s).)

Cytokines, tumor cells, and tumor-associated macrophages play crucial roles in the composition of glioma tissue. Studies have demonstrated that certain cytokines can induce M2 polarization of tumor-associated macrophages and contribute to the progression of glioma. Nonetheless, the intricate molecular interactions among cytokines, glioma cells, and tumor-associated macrophages remain largely unexplored. To investigate this cross-talk, a combination of RNA-sequencing, chromatin immunoprecipitation, immunoprecipitation, exosome isolation, and biological experiments were employed. Treatment with IL-6 significantly increased circ-001422 expression in glioma cells. A poorer prognosis was associated with elevated levels of circ-001422 in glioma tissues. Circ-001422 was transcribed directly by STAT3 through binding to its promoter. Circ-001422 exerted cancer-promoting functions when co-cultured with M2 macrophages. Furthermore, glioma cells were found to transfer circ-001422 to macrophages via an exosomal pathway, promoting M2 polarization. Mechanically, circ-001422 interacted with p300, resulting in STAT3 acetylation, thus promoting nuclear localization and transcriptional activity of STAT3/NF-κB and M2 macrophage polarization. In conclusion, glioma cells released exosomes enriched with circ-001422, which in turn induce M2 macrophage polarization by activating the STAT3/NF-κB pathway, thereby enhancing the aggressive characteristics of glioma cells. Targeting circ-001422 may represent a potential therapeutic approach for glioma., Competing Interests: Competing interests The authors declare no competing interests. Ethics The Human Research Ethics Review Committee of Guizhou Medical University approved the application of these clinical samples, which was performed according to the tenets of the Declaration of Helsinki. The process of animal experiments was approved by Animal Ethics Committee of Guizhou Medical University., (© 2024. The Author(s).)

Purpose: Extent of resection, MGMT promoter methylation status, age, functional level, and residual tumor volume are established prognostic factors for overall survival in glioblastoma patients. Preoperative tumor volume has also been investigated, but the results have been inconclusive. We hypothesized that the surface area and the shape were more representative of the tumor's infiltrative capacities, and thus, the purpose of this study was to assess the prognostic value of tumor size and shape in patients with glioblastoma., Methods: In total, 271 patients with primary, unifocal glioblastoma were included from two centers in Norway and Sweden, respectively. All tumors were automatically segmented on preoperative MRI scans and manually validated. Tumor volume was used as a measurement of size, whereas sphericity index and area-to-volume ratio defined the shape complexity of the tumor. Contact surface area of the tumor was considered a measurement of both size and shape. Multivariable Cox proportional hazards models were used to assess the prognostic value of the respective tumor measurements, with previously established prognostic factors as covariates., Results: There were no associations between preoperative tumor volume and overall survival. Contact surface area (HR = 1.013, p = 0.002) and sphericity index (HR = 2.223, p = 0.001) were both significant independent prognostic factors for survival in the multivariable Cox models. Contact surface area was also associated with MGMT promoter methylation (p = 0.039) and extent of resection (p = 0.017)., Conclusion: Tumor shape complexity appears to be an independent prognostic factor in glioblastoma patients and may also be associated with MGMT promoter methylation status and extent of surgical resection., Competing Interests: Declarations Ethical approval The project was approved by the Regional Committee for Medical and Health Research Ethics (REK) in Norway (REK-reference 2019/510) and the Swedish Ethical Review Authority (Dnr: 702 − 18). The study was conducted in accordance with the Declaration of Helsinki, and all patients provided either written informed consent (Norway) or passive consent (Sweden). Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Brain tumor stem cells (BTSCs) are a population of self-renewing malignant stem cells that play an important role in glioblastoma tumor hierarchy and contribute to tumor growth, therapeutic resistance, and tumor relapse. Thus, targeting of BTSCs within the bulk of tumors represents a crucial therapeutic strategy. Here, we report that edaravone is a potent drug that impairs BTSCs in glioblastoma. We show that edaravone inhibits the self-renewal and growth of BTSCs harboring a diverse range of oncogenic mutations without affecting non-oncogenic neural stem cells. Global gene expression analysis revealed that edaravone significantly alters BTSC transcriptome and attenuates the expression of a large panel of genes involved in cell cycle progression, stemness, and DNA repair mechanisms. Mechanistically, we discovered that edaravone directly targets Notchless homolog 1 (NLE1) and impairs Notch signaling pathway, alters the expression of stem cell markers, and sensitizes BTSC response to ionizing radiation (IR)-induced cell death. Importantly, we show that edaravone treatment in preclinical models delays glioblastoma tumorigenesis, sensitizes their response to IR, and prolongs the lifespan of animals. Our data suggest that repurposing of edaravone is a promising therapeutic strategy for patients with glioblastoma., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pediatric high-grade gliomas (pHGGs), including hemispheric pHGGs and diffuse midline gliomas (DMGs), harbor mutually exclusive tumor location-specific histone mutations. Using immunocompetent de novo mouse models of pHGGs, we demonstrated that myeloid cells were the predominant infiltrating non-neoplastic cell population. Single-cell RNA sequencing (scRNA-seq), flow cytometry, and immunohistochemistry illustrated the presence of heterogeneous myeloid cell populations shaped by histone mutations and tumor location. Disease-associated myeloid (DAM) cell phenotypes demonstrating immune permissive characteristics were identified in murine and human pHGG samples. H3.3K27M DMGs, the most aggressive DMG, demonstrated enrichment of DAMs. Genetic ablation of chemokines Ccl8 and Ccl12 resulted in a reduction of DAMs and an increase in lymphocyte infiltration, leading to increased survival of tumor-bearing mice. Pharmacologic inhibition of chemokine receptors CCR1 and CCR5 resulted in extended survival and decreased myeloid cell infiltration. This work establishes the tumor-promoting role of myeloid cells in DMG and the potential therapeutic opportunities for targeting them., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glioblastoma multiforme (GBM) represents one of the most prevailing and aggressive primary brain tumors among adults. Despite advances in therapeutic approaches, the complex microenvironment of GBM poses significant challenges in its optimal therapy, which are attributed to immune evasion, tumor repopulation by stem cells, and limited drug penetration across the blood-brain barrier (BBB). Nanotechnology has emerged as a promising avenue for GBM treatment, offering biosafety, sustained drug release, enhanced solubility, and improved BBB penetrability. In this review, a comprehensive overview of recent advancements in nanocarrier-based drug delivery systems for GBM therapy is emphasized. The conventional and novel treatment modalities for GBM and the potential of nanocarriers to overcome existing limitations are comprehensively covered. Furthermore, the updates in the clinical landscape of GBM therapeutics are presented in addition to the current status of drugs and patents in the same context. Through a critical evaluation of existing literature, the therapeutic prospect and limitations of nanocarrier-based drug delivery strategies are highlighted offering insights into future research directions and clinical translation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

To improve immunotherapy for brain tumors, it is important to determine the principal intracranial site of T cell recruitment from the bloodstream and their intracranial route to brain tumors. Using intravital microscopy in mouse models of intracranial melanoma, we discovered that circulating T cells preferably adhered and extravasated at a distinct type of venous blood vessel in the tumor vicinity, peritumoral venous vessels (PVVs). Other vascular structures were excluded as alternative T cell routes to intracranial melanomas. Anti-PD-1/CTLA-4 immune checkpoint inhibitors increased intracranial T cell motility, facilitating migration from PVVs to the tumor and subsequently inhibiting intracranial tumor growth. The endothelial adhesion molecule ICAM-1 was particularly expressed on PVVs, and, in samples of human brain metastases, ICAM-1 positivity of PVV-like vessels correlated with intratumoral T cell infiltration. These findings uncover a distinct mechanism by which the immune system can access and control brain tumors and potentially influence other brain pathologies., Competing Interests: Declaration of interests F.W. reports receiving research grants from Boehringer, Genentech, Roche, and Divide and Conquer Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Glioblastoma is a highly aggressive brain tumor with limited survival that poses challenges in predicting patient outcomes. The Karnofsky Performance Status (KPS) score is a valuable tool for assessing patient functionality and contributes to the stratification of patients with poor prognoses. This study aimed to develop a 6-month postoperative KPS prediction model by combining clinical data with deep learning-based image features from pre- and postoperative MRI scans, offering enhanced personalized care for glioblastoma patients., Materials and Methods: Using 1,476 MRI datasets from the Brain Tumor Segmentation Challenge 2020 public database, we pretrained two variational autoencoders (VAEs). Imaging features from the latent spaces of the VAEs were used for KPS prediction. Neural network-based KPS prediction models were developed to predict scores below 70 at 6 months postoperatively. In this retrospective single-center analysis, we incorporated clinical parameters and pre- and postoperative MRI images from 150 newly diagnosed IDH wild-type glioblastoma, divided into training (100 patients) and test (50 patients) sets. In training set, the performance of these models was evaluated using the area under the curve (AUC), calculated through fivefold cross-validation repeated 10 times. The final evaluation of the developed models assessed in the test set., Results: Among the 150 patients, 61 had 6-month postoperative KPS scores below 70 and 89 scored 70 or higher. We developed three models: a clinical-based model, an MRI-based model, and a multimodal model that incorporated both clinical parameters and MRI features. In the training set, the mean AUC was 0.785±0.051 for the multimodal model, which was significantly higher than the AUCs of the clinical-based model (0.716±0.059, P = 0.038) using only clinical parameters and the MRI-based model (0.651±0.028, P<0.001) using only MRI features. In the test set, the multimodal model achieved an AUC of 0.810, outperforming the clinical-based (0.670) and MRI-based (0.650) models., Conclusion: The integration of MRI features extracted from VAEs with clinical parameters in the multimodal model substantially enhanced KPS prediction performance. This approach has the potential to improve prognostic prediction, paving the way for more personalized and effective treatments for patients with glioblastoma., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sasagasako et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Astroblastoma, MN1-altered, is a rare circumscribed glial neoplasm that is composed of round, cuboidal, orcolumnar cells with astroblastic perivascular pseudorosettes, often associated with MN1::BEND2 and MN1::CXXC5 fusions. Atroblastoma-like gliomas harbouring EWSR1::BEND2 have been reported that they defined an epigenetically distinct subtype of astroblastoma. We report a case of a 19-year-old female with an intracranial neuroepithelial tumor featuring a novel TCF3::BEND2 fusion. This tumor, while classified as EWSR1::BEND2 gliomas based on DNA methylation, did not exhibit the MN1 alteration or typical astroblastoma morphology. The patient, initially diagnosed as ependymoma WHO grade 2 following surgery for an intracranial tumor four years prior, presented with a suspected recurrence. Magnetic resonance imaging identified a mixed solid-cystic lesion in the temporal area of the left lateral ventricle. For the recurrent tumor, the histological examination revealed the tumor cells predominantly exhibited a solid arrangement, with the solid areas primarily consisting of oval and short-spindle cells. In certain regions, loosely arranged short-spindle cells was observed. The tumor exhibited high cellular density, nuclear atypia, and frequent mitoses, but lacked the hallmark features typically associated with astroblastoma. Immunohistochemistry revealed patchy positivity for GFAP and OLIG2, diffuse positivity for EMA, and a high MIB-1 labeling index. Genome-wide DNA methylation profiling confirmed the tumor's classification as EWSR1::BEND2 gliomas with a high-confidence match and revealed focal deletion of chromosome 9q. Targeted next-generation sequencing identified a TCF3::BEND2 fusion, validated by reverse transcription polymerase chain reaction and Sanger sequencing. This case broadens the genetic spectrum of high-grade neuroepithelial tumor and suggests that BEND2 alterations may serve as critical determinants for this EWSR1::BEND2 glioma subgroup within the methylation classifier., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by Clinical Ethics Committee of West China Hospital of Sichuan University and patient gave consent. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Adult glioblastoma (GBM) is a highly aggressive primary brain tumor, accounting for nearly half of all malignant brain tumors, with a median survival rate of only 8 months. Treatment for GBM is largely ineffective due to the highly invasive nature and complex tumor composition of this malignancy. MicroRNAs (miRNA) are short, non-coding RNAs that regulate gene expression by binding to messenger RNAs (mRNA). While specific miRNA have been associated with GBM, their precise roles in tumor development and progression remain unclear. In this study, the analysis of miRNA expression data from 743 adult GBM cases and 59 normal brain samples identified 94 downregulated miRNA and 115 upregulated miRNA. Many of these miRNA were previously linked to GBM pathology, confirming the robustness of our approach, while we also identified novel miRNA that may act as potential regulators in GBM. By integrating miRNA predictions with gene expression data, we were able to associate downregulated miRNA with tumor microenvironment factors, including extracellular matrix remodeling and signaling pathways involved in tumor initiation, while upregulated miRNA were found to be associated with essential neuronal processes. This analysis highlights the significance of miRNA in GBM and serves as a foundation for further investigation., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Following the publication of the 2021 WHO Classification of Central Nervous System Tumors (CNS5), Following the publication of the 2021 WHO Classification of Central Nervous System Tumors (CNS5), prognostic markers of glioblastoma (GBM) need to be further explored. Radiomics is a non-invasive and reproducible method for the prognostic assessment of multiple solid tumors. This study aimed to explore the prognostic value and biological significance of MRI T1-weighted enhancement (CE-T1) based radiomics in GBM (CNS5). A six-features radiomics prognostic model was created to calculate the radiomics score (RS). High RS (HR = 3.718, 95%CI: 2.222 - 6.220, P < 0.001) was an independent risk factor for overall survival (OS). The correlation between RS and OS was externally verified based on the First Affiliated Hospital of Fujian Medical University cohorts (n = 93; HR = 2.015, 95% CI: 1.079 - 3.762, P = 0.028) and the Second Affiliated Hospital of Zhejiang University School of Medicine cohorts (n = 126; HR = 1.779, 95% CI: 1.023 - 3.091, P = 0.041). Through biological significance exploration, RS was found to be significantly correlated with DNA repair (P = 0.009) and glycolysis (P = 0.001) pathway enrichment scores. RS was associated with γδT cell infiltration and the expression of LAG3. The MRI CE-T1 based radiomics models can predict GBM (CNS5) prognosis noninvasively. RS is relevant to DNA repair, and may guide the screening of radiosensitive populations., Competing Interests: Declarations Consent for publication All authors of this paper have read and approved the final version submitted. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Comprehensive and non-invasive preoperative molecular diagnosis is important for prognostic and therapy decision-making in adult-type diffuse gliomas. We employed a deep learning method for automatic segmentation of brain gliomas directly from conventional magnetic resonance imaging (MRI) scans of the tumor core and peritumoral edema regions based on available glioma MRI data provided in the BraTS2021. Three-dimensional volumes of interest were segmented from 424 cases of glioma imaging data retrospectively obtained from two medical centers using the segmentation method and radiomic features were extracted. We developed a subtype prediction model based on extracted radiomic features and analyzed significance and correlations between glioma morphological characteristics and pathological features using data from patients with adult-type diffuse glioma. The automated segmentation achieved mean Dice scores of 0.884 and 0.889 for the tumor core and whole tumor, respectively. The area under the receiver operating characteristic curve for the prediction of adult-type diffuse gliomas subtypes was 0.945. "Glioblastoma, IDH-wildtype", "Astrocytoma, IDH-mutant", and "Oligodendroglioma, IDH-mutant, 1p/19q-coded" showed AUCs of 0.96, 0.914, and 0.961, respectively, for subtype prediction. Glioma morphological characteristics, molecular and pathological levels, and clinical data showed significant differences and correlations. An automatic segmentation model for gliomas based on 3D U-Nets was developed, and the prediction model for gliomas built using the parameters obtained from the automatic segmentation model showed high overall performance., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Nervous system cancers exhibit diverse transcriptional cell states influenced by normal development, injury response, and growth. However, the understanding of these states' regulation and pharmacological relevance remains limited. Here we present "single-cell regulatory-driven clustering" (scregclust), a method that reconstructs cellular regulatory programs from extensive collections of single-cell RNA sequencing (scRNA-seq) data from both tumors and developing tissues. The algorithm efficiently divides target genes into modules, predicting key transcription factors and kinases with minimal computational time. Applying this method to adult and childhood brain cancers, we identify critical regulators and suggest interventions that could improve temozolomide treatment in glioblastoma. Additionally, our integrative analysis reveals a meta-module regulated by SPI1 and IRF8 linked to an immune-mediated mesenchymal-like state. Finally, scregclust's flexibility is demonstrated across 15 tumor types, uncovering both pan-cancer and specific regulators. The algorithm is provided as an easy-to-use R package that facilitates the exploration of regulatory programs underlying cell plasticity., (© 2024. The Author(s).)

Glioma associated macrophages/microglia (GAMs) play an important role in glioblastoma (GBM) progression, due to their massive recruitment to the tumor site and polarization to a tumor promoting phenotype. GAMs secrete a variety of cytokines, which facilitate tumor cell growth and invasion, and prevent other immune cells from mounting an immune response against the tumor. Here, we demonstrate that zinc finger and BTB containing domain 18 (ZBTB18), a transcriptional repressor with tumor suppressive function in glioblastoma, impairs the production of key cytokines, which function as chemoattractant for GAMs. Consistently, we observe a reduced migration of GAMs when ZBTB18 is expressed by glioblastoma cells, both in cell culture and in vivo experiments. Moreover, RNA sequencing analysis shows that the presence of ZBTB18 in glioblastoma cells alters the commitment of conditioned microglia, suggesting the loss of the immune-suppressive phenotype and the acquisition of pro-inflammatory features. Thus, therapeutic approaches to increase ZBTB18 expression in GBM cells could represent an effective adjuvant to immune therapy in GBM., (© 2024. The Author(s).)

A hallmark of glioma cells, particularly glioblastoma multiforme (GBM) cells, is their resistance to apoptosis. Accumulating evidences has demonstrated that CARD16, a caspase recruitment domain (CARD) only protein, enhances both anti-apoptotic and tumorigenic properties. Nevertheless, there is a limited understanding of the expression and functional role of CARD16 in glioma. This study seeks to investigate, through in silico analysis and clinical specimens, the role of CARD16 as a potential tumor promoter in glioma. Functional assays and molecular studies revealed that CARD16 promotes tumorigenesis and suppresses apoptosis in glioma cells. Moreover, knockdown of CARD16 enhances the expression of the FOXO1/TRAIL axis in GBM cells. Additionally, FOXO1 downregulation in CARD16 knockdown GBM cells restores proliferation and reduces apoptosis. Further investigation demonstrated that elevated P21 expression inhibits CDK2-mediated FOXO1 phosphorylation and ubiquitination in CARD16-knockdown GBM cells. Collectively, these findings suggest that CARD16 is a tumor-promoting molecular in glioma via downregulating FOXO1/TRAIL axis, and suppressing TRAIL-induced apoptosis. The CARD16 gene presents significant potential for prognostic prediction and advances in innovative apoptotic therapeutics., (© 2024. The Author(s).)

Glioblastoma is one of the most common and aggressive primary brain tumors. The aberration of metabolism is the important character of GBM cells and is tightly related to the malignancy of GBM. We mainly verified the regulatory effects of KHDRBS1, SNORD51 and ZBED6 on pentose phosphate pathway and malignant biological behavior in glioblastoma cells, such as proliferation, migration and invasion. KHDRBS1 and SNORD51 were upregulated in GBM tissues and cells. But ZBED6 had opposite tendency in GBM tissues and cells. KHDRBS1 may improve the stability of SNORD51 by binding to SNORD51, thus elevating the expression of SNORD51. More importantly, SNORD51 can competitively bind to WDR33 with 3'UTR of ZBED6 pre-mRNA which can inhibit the 3' end processing of ZBED6 pre-mRNA, thereby inhibiting the expression of ZBED6 mRNA. ZBED6 inhibited the transcription of G6PD by binding to the promoter region of G6PD. Therefore, the KHDRBS1/SNORD51/ZBED6 pathway performs an important part in regulating the pentose phosphate pathway to influence malignant biological behavior of GBM cells, providing new insights and potential targets for the treatment of GBM., (© 2024. The Author(s).)

Radiotherapy (RT) remains a primary treatment modality for glioblastoma (GBM), but it induces cellular senescence and is strongly implicated in GBM progression and RT-related injury. Recently, eliminating senescent cells has emerged as a promising strategy for treating cancer and for mitigating radiation-induced brain injury (RBI). Here, we investigated the impact of all-trans retinoic acid (RA) on radiation-induced senescence. The findings of this study revealed that RA effectively eliminated astrocytes, which are particularly prone to senescence after radiation, and that the removal of senescence-associated secretory phenotype factor-producing astrocytes inhibited GBM cell proliferation in vitro. Moreover, RA-mediated clearance of senescent cells improved survival in GBM-bearing mice and alleviated radiation-induced cognitive impairment. Through RNA sequencing, we found that the AKT/mTOR/PPARγ/Plin4 signaling pathway is involved in RA-mediated clearance of senescent cells. In summary, these results suggest that RA could be a potential senolytic drug for preventing GBM progression and improving RBI.

Background and Purpose: World Health Organization (WHO) grade 2 and 3 diffuse gliomas account for approximately 5% of primary brain tumors. They are invasive and infiltrative tumors and have considerable morbidity, causing progressive neurologic deterioration. The mean survival time is <10 years from diagnosis. Surgical debulking represents first-line management. The extent of resection is associated with progression-free and overall survival. Radiologic assessment of the extent of resection is challenging. This can be underestimated on early postoperative MRI, meaning that accurate assessment may be achieved only on delayed follow-up imaging. We hypothesized that DWI may help facilitate more reliable estimates of the extent of resection on early postoperative MRI. This study aimed to assess the utility of DWI in early postoperative MRI to evaluate the extent of resection., Materials and Methods: A single-center observational cohort study was performed. All patients with histologically confirmed WHO grade 2 and 3 gliomas managed with surgical debulking between January 2015 and December 2020 were identified. Preoperative, early postoperative, and follow-up imaging were reviewed independently by 2 consultant neuroradiologists. The extent of resection was estimated with and without DWI sequences for each case., Results: Two hundred twenty-four patients with WHO grade 2 and 3 gliomas were managed with surgical debulking between 2015 and 2020. DWI was not performed on early postoperative MRI in 2 patients. With the use of DWI, the extent of resection was upgraded in 30% of cases ( n  =   66/222) and classified as "complete" or "supramaximal" in 58% of these patients ( n  =   38/66). In cases in which the extent of resection was upgraded with the use of DWI, signal abnormality was stable or reduced at follow-up in 78% ( n  =   49/63). In cases with worsening signal abnormality, 64% were deemed to be secondary to adjuvant radiation therapy ( n = 9/14). Eight percent ( n  =   5/63) of patients with an increased estimated extent of resection using DWI demonstrated signal progression attributed to true disease progression at follow-up., Conclusions: DWI is a helpful and reliable adjunct in differentiating residual tumor from marginal ischemia in early postoperative MRI in WHO grade 2 and 3 diffuse gliomas and increases the accuracy in assessing the extent of resection. It should be used routinely in these cases., (© 2024 by American Journal of Neuroradiology.)

The 2021 World Health Organization Classification of Tumors of the Central Nervous System (CNS5), introduced significant changes, impacting tumors ranging from glial to ependymal neoplasms. Ependymal tumors were previously classified and graded based on histopathology, which had limited clinical and prognostic utility. The updated CNS5 classification now divides ependymomas into 10 subgroups based on anatomic location (supratentorial, posterior fossa, and spinal compartment) and genomic markers. Supratentorial tumors are defined by zinc finger translocation associated ( ZFTA ) (formerly v-rel avian reticuloendotheliosis viral oncogene [ RELA ]), or yes-associated protein 1 ( YAP1 ) fusion; posterior fossa tumors are classified into groups A (PFA) and B (PFB), spinal ependymomas are defined by MYCN amplification. Subependymomas are present across all these anatomic compartments. The new classification kept an open category of "not elsewhere classified" or "not otherwise specified" if no pathogenic gene fusion is identified or if the molecular diagnosis is not feasible. Although there is significant overlap in the imaging findings of these tumors, a neuroradiologist needs to be familiar with updated CNS5 classification to understand tumor behavior, for example, the higher tendency for tumor recurrence along the dural flap for ZFTA fusion-positive ependymomas. On imaging, supratentorial ZFTA -fused ependymomas are preferentially located in the cerebral cortex, carrying predominant cystic components. YAP1-MAMLD1 -fused ependymomas are intra- or periventricular with prominent multinodular solid components and have significantly better prognosis than ZFTA -fused counterparts. PFA ependymomas are aggressive paramedian masses with frequent calcification, seen in young children, originating from the lateral part of the fourth ventricular roof. PFB ependymomas are usually midline, noncalcified solid-cystic masses seen in adolescents and young adults arising from the fourth ventricular floor. PFA has a poorer prognosis, higher recurrence, and higher metastatic rate than PFB. Myxopapillary spinal ependymomas are now considered grade II due to high recurrence rates. Spinal- MYCN ependymomas are aggressive tumors with frequent leptomeningeal spread, relapse, and poor prognosis. Subependymomas are noninvasive, intraventricular, slow-growing benign tumors with an excellent prognosis. Currently, the molecular classification does not enhance the clinicopathologic understanding of subependymoma and myxopapillary categories. However, given the molecular advancements, this will likely change in the future. This review provides an updated molecular classification of ependymoma, discusses the individual imaging characteristics, and briefly outlines the latest targeted molecular therapies., (© 2024 by American Journal of Neuroradiology.)

Pituitary carcinoma (metastatic neuroendocrine tumor of the pituitary gland) is the pituitary tumor with confirmed craniospinal and/or systemic metastases. These tumors are extremely rare accounting for only 0.1% to 0.5% of all pituitary tumours and are characterized by high mortality. In the presented case, pituitary carcinoma with intracranial metastasis was diagnosed in a young patient 25 years after manifestation of an aggressive recurrent prolactin-secreting pituitary tumor. Standard therapy (removal of metastasis, radiation therapy, cabergoline therapy) resulted in a long-term remission of the disease.

Background: Resistance acquired after radiotherapy is directly related to the failure of various cancer treatments, including GBM. Because the mechanism for overcoming radioresistance has not yet been clearly identified, the development of diagnostic and therapeutic markers to treat radioresistance is necessary. Since increased expression of stemness- and EMT-related markers are reported to be closely correlated with radioresistance, research is underway to develop new drugs targeting these factors., Methods: To develop an anticancer drug that overcomes radioresistance, a library of drugs already approved by the FDA was used. After treating radioresistant GBM cells with each drug, the expression of stemness- and EMT-related markers was confirmed by qRT-PCR, and as a result, Atomoxetine (ATX) was selected. It was confirmed that radioresistance-induced cell migratory, invasive, sphere formation abilities, and tumor growth using a xenograft mouse model were suppressed upon ATX treatment. Using a miRNA prediction tool, we discovered miR-520d-5p, which targets Notch2 and Hey1, key factors in radioresistance, and discovered circATIC targeting this miRNA, revealing its relationship with ATX. We demonstrated the expression regulation mechanism and signaling mechanism between circATIC, miR-520d-5p, Notch2, and Hey1 factors using a luciferase reporter assay. In addition, the results at the cellular level were clinically verified by confirming the correlation between radiation, miR-520d-5p, and circATIC using patient plasma by qRT-PCR., Results: ATX showed potential as a treatment for radioresistance by suppressing the malignant phenotype by regulating the circATIC/miR-520d-5p/Notch2-Hey1 signaling mechanism in vitro and in vivo using radioresistant GBM cells., Conclusions: This study revealed that ATX suppresses radioresistance through the circATIC/miR-520d-5p/Notch2-Hey1 signaling pathway. These results showed the potential of ATX as a new drug that can overcome radioresistance, a major challenge in cancer treatment, and the signaling factors identified in this mechanism suggest the possibility of use as potential targets for the diagnosis and treatment of radioresistance., (© 2024. The Author(s).)

The isocitrate dehydrogenase (IDH) mutation status is one of the most important markers according to the 2021 WHO classification of CNS tumors. Preoperatively, this information is usually obtained based on invasive biopsies, contrast-enhanced MR images or PET images generated using radioactive tracers. However, the completely non-invasive determination of IDH mutation status using routinely acquired preoperative native CT images has hardly been investigated to date. In our study, we show that radiomics-based machine learning allows to determine IDH mutation status based on preoperative native CT images both with very high accuracy and completely non-invasively. Based on independent test data, we are able to correctly identify 91.1% of cases with an IDH mutation. Our final model, containing only six features, exhibits a high area under the curve of 0.847 and an excellent area under the precision-recall curve of 0.945. In the future, such models may be used for a completely non-invasive prediction of important genetic markers, potentially allowing treating physicians to reduce the number of biopsies and speed up further treatment planning., (© 2024. The Author(s).)

Glioma stem cells have been recognized as key players in glioma recurrence and therapeutic resistance, presenting a promising target for novel treatments. However, the limited understanding of the role glioma stem cells play in the glioma hierarchy has drawn controversy and hindered research translation into therapies. Despite significant advances in our understanding of gene regulatory networks, the dynamics of these networks and their implications for glioma remain elusive. This study employs a systemic theoretical perspective to integrate experimental knowledge into a core endogenous network model for glioma, thereby elucidating its energy landscape through network dynamics computation. The model identifies two stable states corresponding to astrocytic-like and oligodendrocytic-like tumor cells, connected by a transition state with the feature of high stemness, which serves as one of the energy barriers between astrocytic-like and oligodendrocytic-like states, indicating the instability of glioma stem cells in vivo. We also obtained various stable states further supporting glioma's multicellular origins and uncovered a group of transition states that could potentially induce tumor heterogeneity and therapeutic resistance. This research proposes that the transition states linking both glioma stable states are central to glioma heterogeneity and therapy resistance. Our approach may contribute to the advancement of glioma therapy by offering a novel perspective on the complex landscape of glioma biology., (© 2024. The Author(s).)

Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate. Targeting MDH2 induced accumulation of alpha-ketoglutarate (αKG), a critical co-factor for dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5). Forced expression of MDH2 increased m6A levels and inhibited ALKBH5 activity, both rescued by αKG supplementation. Reciprocally, targeting MDH2 reduced global m6A levels with platelet-derived growth factor receptor-β (PDGFRβ) as a regulated transcript. Pharmacological inhibition of MDH2 in GSCs augmented efficacy of dasatinib, an orally bioavailable multi-kinase inhibitor, including PDGFRβ. Collectively, stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Brain metastasis (BM) is one of the main causes of death in patients with non-small cell lung carcinoma. The specific pathological processes of BM, which are inextricably linked to the brain tumor microenvironment, such as the abundance of astrocytes, lead to limited treatment options and poor prognosis. Reactive astrocytes are acquired in the BM; however, the underlying mechanisms remain unclear. This study aimed to explore the mechanisms by which astrocytes promote BM development. We determined the crucial role of reactive astrocytes in promoting the proliferation and migration of brain metastatic lung tumor cells by upregulating protocadherin 1 (PCDH1) expression in an in vitro co-culture model. The overexpression of PCDH1 was confirmed in clinical BM samples using immunohistochemical staining. Survival analysis indicated that high-PCDH1 expression was associated with poor survival in patients with lung adenocarcinoma. In vivo assays further showed that silence of PCDH1 effectively inhibited the tumor progression of brain metastases and prolonged the survival of animals. RNA sequencing has revealed that PCDH1 plays an important role in cell proliferation and adhesion. In conclusion, the present study revealed the promoting role of astrocytes in enhancing the aggressive phenotype of brain metastatic tumor cells by regulating the expression of PCDH1, which might be a biomarker for BM diagnosis and prognosis, suggesting the potential efficacy of targeting important astrocyte-tumor interactions in the treatment of patients with non-small cell lung carcinoma with BM., Competing Interests: Declaration of competing interest All authors have read and approved the content, and agree to submit it for consideration for publication in your journal. There are no ethical/legal conflicts involved in the article. The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: This study investigated the interfractional volume changes of large (≥ 10 cm 3 ) brain metastases (BMs) during fractionated gamma knife radiosurgery (FGKRS) to assess its predictive value for tumor control outcomes., Methods: The patients who underwent FGKRS for large BMs between January 2017 and December 2022 in our center were reviewed. The interfractional volume change was defined as the disparity in tumor volume (TV) measured between the magnetic resonance images acquired on the first treatment day and those obtained after 2 or 3 fractions during the course of FGKRS., Results: A total of 73 lesions in 70 patients with various primary pathologies were included. Over a median follow-up period of 11 months (range 1-77), the tumor control rate was 63%. Initial TV (cm 3 ) was associated with progression free survival (PFS) and overall survival (OS) in both univariate and multivariate analyses (p = 0.01). Interfractional TV changes revealed an increase in 13 (17.8%) lesions, no change in 14 (19.2%) lesions, and a decrease in 46 (63.0%) lesions, with a mean volume reduction of 5% ± 0.12. Three cut-offs (5%, 10% and 15% volume decrement) were established and patients were divided into two groups based on each reference point. However, there were no significant differences in PFS and OS between the two groups, irrespective of the chosen cut-off value used., Conclusion: Interfractional volume changes of large BMs were not found to be associated with tumor control outcomes. Neither significant interfractional volume reduction nor significant volume increase necessarily predicts the tumor control, making early close monitoring essential after FGKRS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Stereotactic radiosurgery (SRS) is an effective therapy for brain metastases. Response is assessed with serial 1H magnetic resonance imaging (MRI). Early markers for response are desirable to allow for individualized treatment adaption. Previous studies indicated that radiotherapy might have impact on tissue sodium concentration. Thus, 23Na MRI could provide early quantification of response to SRS., Purpose: We investigated whether longitudinal detection of tissue sodium concentration alteration within brain metastases and their peritumoral tissue after SRS with 23Na MRI was feasible., Study Type: Prospective., Population: Twelve patients with a total of 14 brain metastases from various primary tumors., Assessment: 23Na MRI scans were acquired from patients 2 days before, 5 days after, and 40 days after SRS. Gross tumor volume (GTV) and healthy-appearing regions were manually segmented on the MPRAGE obtained 2 days before SRS, onto which all 23Na MR images were coregistered. Radiation isodose areas within the peritumoral tissue were calculated with the radiation planning system. Tissue sodium concentration before and after SRS within GTV, peritumoral tissue, and healthy-appearing regions as well as the routine follow-up with serial MRI were evaluated., Statistical Tests: Results were compared using Student's t-test and correlation was evaluated with Pearson's correlation coefficient., Results: We found a positive correlation between the tissue sodium concentration within the peritumoral tissue and radiation dosage. Two patients showed local progression and a differing tissue sodium concentration evolution within GTV and the peritumoral tissue compared to mean tissue sodium concentration of the other patients. No significant tissue sodium concentration changes were observed within healthy-appearing regions., Conclusion: Tissue sodium concentration assessment within brain metastases and peritumoral tissue after SRS with 23Na MRI is feasible and might be able to quantify tissue response to radiation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ruder et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The recent discovery of the pivotal role of the central nervous system in controlling tumor initiation and progression has opened a new field of research. Increasing evidence suggests a bidirectional interaction between the brain and tumors. The brain influences the biological behavior of tumor cells through complex neural networks involving the peripheral nervous system, the endocrine system, and the immune system, whereas tumors can establish local autonomic and sensory neural networks to transmit signals into the central nervous system, thereby affecting brain activity. This review aims to summarize the latest research in brain-tumor cross-talk, exploring neural circuitries between the brain and various peripheral solid tumors, analyzing the roles in tumor development and the related molecular mediators and pathologic mechanisms, and highlighting the critical impact on the understanding of cancer biology. Enhanced understanding of reciprocal communication between the brain and tumors will establish a solid theoretical basis for further research and could open avenues for repurposing psychiatric interventions in cancer treatment., (©2024 The Authors; Published by the American Association for Cancer Research.)

Brain tumors, particularly glioblastoma (GBM), are devastating and challenging to treat, with a low 5-year survival rate of only 6.6%. Mouse models are established to understand tumorigenesis and develop new therapeutic strategies. Large-scale genomic studies have facilitated the identification of genetic alterations driving human brain tumor development and progression. Genetically engineered mouse models (GEMMs) with clinically relevant genetic alterations are widely used to investigate tumor origin. Additionally, syngeneic implantation models, utilizing cell lines derived from GEMMs or other sources, are popular for their consistent and relatively short latency period, addressing various brain cancer research questions. In recent years, the success of immunotherapy in specific cancer types has led to a surge in cancer immunology-related research which specifically necessitates the utilization of immunocompetent mouse models. In this review, we provide a comprehensive summary of GEMMs and syngeneic mouse models for adult brain tumors, emphasizing key features such as model origin, genetic alteration background, oncogenic mechanisms, and immune-related characteristics. Our review serves as a valuable resource for the brain tumor research community, aiding in the selection of appropriate models to study cancer immunology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)