Search Results (684)

Thalamic gliomas are among the most challenging pediatric brain tumors due to the delicate functions of the thalamus. Limited surgical intervention leads to the use of adjuvant therapies, including targeted therapy. Thalamic gliomas can be divided into two distinct groups: diffuse midline glioma (DMG) and low-grade glioma (LGG). The most common mutations that can be targeted for treatment are the KIAA1549-BRAF fusion; BRAF V600E mutation; EGFR, FGFR, PDGFR, NTRK, and CDK4/6 mutations; other MAP kinase pathway alterations; and PI3K/AKT/mTOR activation. The bithalamic high-grade glioma especially demonstrates EGFR mutations which makes it a distinct entity. Targeted therapy, including tyrosine kinas inhibitors has been shown to improve the overall survival compared to conventional therapy in certain situations. Demonstrating the mutation carried by the tumor is very critical in this regard. The purpose of this article is to focus on the treatment of thalamic glioma in pediatric patients in light of molecular information. Full article

While research on high-incidence tumors such as breast, prostate, and lung cancer has led to significant increases in patient survival in recent years, this has not been the case for low-incidence tumors such as high-grade gliomas, the most common and lethal brain tumors, for which the last significant therapeutic advance dates back to 2005. The high infiltration capacity of these tumors into normal brain tissue essential for both vegetative and relational life, the tumor microenvironment, with poor immunological activity, the multiple resistance mechanisms, and the unattractiveness of research investments due to the limited number of patients have made, and continue to make, the path to achieving significant improvements in the survival of patients with high-grade gliomas long and arduous. The objective of this article is to update the slow but continuous radiotherapeutic progress for adult and pediatric high-grade gliomas to the second half of 2023. We analyzed the progress of preclinical and clinical research on both adult and pediatric high-grade gliomas, with a particular focus on improvements in radiotherapy. Interactions between non-radiant new therapies and radiotherapy were also covered. A literature search was conducted in PubMed using the terms (“glioma* and radio*”) and the time limit of 1 July 2023 to 31 December 2023. The inclusion and exclusion criteria for the review were relevance to advances in radiotherapy for high-grade gliomas in adults and children. Treating patients with advanced disease progression only, using “historical” data as controls, as well as repurposing drugs developed for purposes completely different from their intended use, were the major (but not the only) methods to assess risk of bias in the included studies. The effect measures used in the synthesis or presentation of the results were tabulated and/or displayed in figures. A total of 100 relevant references were reviewed. Advances in preclinical studies and in clinical radiotherapy treatment planning, innovative fractionation, use of radioisotopes/radiopharmaceuticals, radiosensitization procedures, and radiation-induced damage were focused on. While this analysis may be limited by the relatively short publication period, high-grade glioma research remains impacted, especially at the clinical level, by potential issues with trial design, such as treating patients with advanced disease progression, using “historical” data as controls, and repurposing drugs developed for completely different purposes than intended. Addressing these aspects of high-grade glioma research could improve its efficacy, which often remains low despite the associated costs. Full article

Background/Objectives: Although Tumor-Treating Fields (TTFields) therapy is an established treatment modality for adult glioblastoma, clinical data on its efficacy in pediatric brain tumors are extremely scarce. The present study aimed to evaluate the safety of TTFields therapy for pediatric diffuse high-grade glioma (HGG) and to conduct an exploratory analysis of its efficacy. Methods: A prespecified, interim analysis was performed to determine whether the study should be continued on the basis of safety and feasibility data on the first three patients. The target population was children aged 5 to 17 years with newly diagnosed, supratentorial HGG or its first recurrence following frontline therapy. After completion of initial, local treatment for the tumor (surgical removal and/or radiotherapy), all patients received TTFields therapy using Optune^TM for 28 days per course for up to 26 courses until disease progression. Results: The interim analysis, which was completed in October 2022, included three female patients aged 14, 17, and 9 years. All had a histological grade 4 tumor, two of which were radiation-induced, secondary HGG. No serious, treatment-related toxicities or device-related issues were observed. All three patients were able to continue using the device for 75% or more of the time in accordance with the protocol, suggesting that the treatment was feasible. The MRI findings of two patients indicated that the treatment has a potential antitumor effect. Based on these results, the study was resumed and is currently being continued at multiple centers. Conclusions: The initial results of the prespecified, interim analysis demonstrated that TTFields therapy was safe and feasible for children with HGG. This study was funded by the Japan Agency for Medical Research and Development (AMED) and was registered with the Japan Registry of Clinical Trials (jRCTs032200423). Full article

Gliomas are the most common malignant primary brain tumors in adults. The treatment of high-grade gliomas is very limited due to their diffuse infiltration, high plasticity, and resistance to conventional therapies. Although they were long considered passive massive lesions, they are now regarded as functionally integrated components of neural circuits, as they form authentic electrochemical synapses with neurons. This allows them to mimic neuronal activity to drive tumor growth and invasion. Ultrastructural studies show presynaptic vesicles in neurons and postsynaptic densities in glioma cell membranes, while electrophysiological recordings detect postsynaptic currents in tumor cells. Tumor microtubules (TMs), dynamic cytoplasmic protrusions enriched in AMPA receptors, are the structures responsible for glioma–glioma and glioma–neuron connectivity, also contributing to treatment resistance and tumor network integration. In these connections, neurons release glutamate that mainly activates their AMPA receptors in glioma cells, while gliomas release excess glutamate, causing excitotoxicity, altering the local excitatory-inhibitory balance, and promoting a hyperexcitable and pro-tumorigenic microenvironment. In addition, certain gliomas, such as diffuse midline gliomas, have altered chloride homeostasis, which makes GABAergic signaling depolarizing and growth promoting. Synaptogenic factors, such as neuroligin-3 and BDNF, further enhance glioma proliferation and synapse formation. These synaptic and paracrine interactions contribute to cognitive impairment, epileptogenesis, and resistance to surgical and pharmacological interventions. High functional connectivity within gliomas correlates with shorter patient survival. Therapies such as AMPA receptor antagonists (perampanel), glutamate release modulators (riluzole or sulfasalazine), and chloride cotransporter inhibitors (NKCC1 blockers) aim to improve outcomes for patients. Full article

Background: Emerging evidence suggests that biological sex shapes glioma biology and therapeutic response. Methods: We performed a sex-stratified analysis of CGGA (Chinese Glioma Genome Atlas) RNA sequencing data comparing low-grade glioma (LGG) with high-grade glioma (HGG) and glioblastoma (GBM). Using the 3PodR framework, we integrated differential expression analysis with Gene Set Enrichment Analysis (GSEA), EnrichR, leading-edge analysis, and iLINCS drug repurposing. Results: These comparisons provide a proxy for biological processes underlying malignant transformation. In LGG vs. HGG, 973 significantly differentially expressed genes (DEGs) were identified in females and 1236 in males, with 15.5% and 33.5% unique to each sex, respectively. In LGG vs. GBM, 2011 DEGs were identified in females and 2537 in males, with 12.6% and 30.7% being unique. Gene-level contrasts included GLI1 upregulation in males and downregulation in females, GCGR upregulation in males, MYOD1 upregulation in females, and HIST1H2BH downregulation in males. Additional top DEGs included PRLHR, DGKK, DNMBP-AS1, HOXA9, CTB-1I21.1, RP11-47I22.1, HPSE2, SAA1, DLK1, H19, PLA2G2A, and PI3. In both sexes, LGG–HGG and LGG–GBM grade comparisons converged on neuronal and synaptic programs, with enrichment of glutamatergic receptor genes and postsynaptic modules, including GRIN2B, GRIN2A, GRIN2C, GRIN1, and CHRNA7. In contrast, collateral pathways diverged by sex: females showed downregulation of mitotic and chromosome-segregation programs, whereas males showed reduction of extracellular matrix and immune-interaction pathways. Perturbagen analysis nominated signature-reversing compounds across sexes, including histone deacetylase inhibitors, Aurora kinase inhibitors, microtubule-targeting agents such as vindesine, and multi-kinase inhibitors targeting VEGFR, PDGFR, FLT3, PI3K, and MTOR. Conclusions: Glioma grade comparisons reveal a shared neuronal–synaptic program accompanied by sex-specific transcriptional remodeling. These findings support sex-aware therapeutic strategies that pair modulation of neuron–glioma coupling with chromatin- or receptor tyrosine kinase/angiogenic-targeted agents, and they nominate biomarkers such as GLI1, MYOD1, GCGR, PRLHR, and HIST1H2BH for near-term validation. Full article

Background/Objectives: High-grade glioma shows marked metabolic heterogeneity. We performed a PRISMA-guided systematic review and meta-analysis to quantify PET accuracy for pseudoprogression (PsP) and for recurrence/progression versus treatment-related change (TRC), assess pool baseline associations with overall (OS) and progression-free survival (PFS), summarize PET-based prediction of molecular markers, and assess the PET–stereotactic biopsy–ex vivo metabolomics workflow. Methods: We searched PubMed/MEDLINE and the Web of Science Core Collection (Clarivate) from inception to 1 September 2025 for HGG cohorts with baseline PET. Eligibility: Adults with HGG; diagnostic syntheses required per-patient 2 × 2; prognostic syntheses required for HR with 95% CI. Risk of bias: QUADAS-2 (diagnostic) and QUIPS (prognostic). Random-effects models pooled log-HRs and sensitivity/specificity; molecular studies were summarized by AUCs. Imaging-to-omics concordance was reviewed narratively owing to the absence of co-registered PET–metabolite maps in human HGG. Results: The results included the following: OS k = 10; PFS k = 3; PsP k = 2 (N = 76); and TRC k = 3 (N = 152). For PsP, two amino acid PET cohorts yielded a sensitivity of 0.943 and a specificity of 0.826. For TRC, pooled FDOPA across two cohorts gave rise to a sensitivity of 0.879 and a specificity of 0.771. OS meta-analyses were non-significant under Hartung–Knapp modification—FDG HR of 1.09 (95% CI 0.69–1.73) and amino acid HR of 1.03 (0.72–1.46)—with substantial heterogeneity. PFS effects varied by tracer/metric; examples include FDOPA HR of 7.92 (2.17–28.90) and MET metabolic tumor volume HR of 1.60 (1.20–2.30). Conclusions: Amino acid PET is sensitive to PsP and, with FDOPA, aids TRC discrimination when MRI is equivocal, whereas baseline PET–survival associations are weak and heterogeneous. Prospective co-registered PET/MR with stereotactic biopsies and HR-MAS NMR spectroscopy/MALDI-MSI is required to quantify imaging-to-omics concordance and standardize spatial endpoints. Study registration: PROSPERO CRD420251113416. Funding: none. Full article

High-grade gliomas in children continue to have a dismal prognosis. This case is of a child with a diffuse pediatric-type high-grade glioma H3 and IDH-wildtype, treated with surgery, radiation, chemotherapy, and a targeted agent without success. Physician and family perspectives are also presented. Options for treatment and research participation are limited, but there is a strong desire from patients and families to access new treatment modalities and take part in clinical trials. Treating teams and families remain hopeful that in the future, tumours like the one described in this report will be treated with much greater success. Full article

Background/Objective: Gliomas are the most common primary brain tumors in adults, with recurrence rates varying by tumor grade and initial treatment. Reoperation is a key strategy for managing recurrence; however, its impact on functional status and health-related quality of life (HRQoL) remains insufficiently defined. While HRQoL and neurocognitive outcomes have been described after primary treatment, far less is known following reoperation. This systematic review synthesizes available evidence on postoperative functional outcomes and summarizes HRQoL reporting in the reoperation literature. Methods: A systematic search of PubMed and Google Scholar retrieved 1336 articles. After removing duplicates (n = 76) and screening full texts (n = 42), 15 studies (total n = 1934; reoperation group n = 947) met the inclusion criteria. Studies were eligible if they employed validated functional or HRQoL instruments (e.g., Karnofsky Performance Status [KPS], FACT-G, SF-36, and EQ-5D-L). Due to limited and heterogeneous HRQoL reporting, only KPS could be aggregated for meta-analysis, and HRQoL measures were descriptively summarized. Results: Fixed-effect meta-analysis demonstrated a modest decline in postoperative KPS compared with preoperative scores (−3.28, 95% CI: −3.69 to −2.86; p < 0.001), though heterogeneity was high (I² ≈ 97%). The random-effects model, accounting for interstudy variability, showed no significant overall change (+0.16 KPS, 95% CI: −4.04 to +4.35; p = 0.94; I² ≈ 48%). The 95% prediction interval (−14.1 to +14.4) indicated that individual centers may observe either improvement or decline. Sensitivity analyses identified a small outlier study as a major contributor to heterogeneity; its exclusion did not materially alter the results. Conclusions: Across heterogeneous observational cohorts, reoperation for recurrent glioma was not associated with a consistent decline in functional status as measured by KPS, although substantial variability and uncertainty in outcomes remain. HRQoL reporting remains sparse and inconsistent, underscoring the need for prospective, multicenter studies employing standardized HRQoL instruments to better define quality-of-life trajectories after reoperation. Full article

Background and Objectives: Grade 4 adult-type diffuse gliomas remain the most aggressive primary central nervous system malignancies, with limited prognostic tools beyond molecular classification. This study introduces the HALLMOUNT score, a multidimensional prognostic index integrating hematologic, biochemical, and clinical parameters to capture the interplay between tumor biology and systemic host response. Materials and Methods: A total of 227 patients with histologically confirmed grade 4 adult-type diffuse glioma were retrospectively analyzed. The HALLMOUNT score incorporated nine pretreatment variables: hemoglobin, albumin, lactate dehydrogenase (LDH), lymphocyte, monocyte, Eastern Cooperative Oncology Group (ECOG) performance status, uric acid, neutrophil, and thrombocyte counts. Receiver operating characteristic (ROC) analyses determined optimal cut-offs, and Cox regression models evaluated prognostic performance for overall (OS) and progression-free survival (PFS). Results: High HALLMOUNT scores (≥2.5) were significantly associated with older age, comorbidities, poor ECOG status, isocitrate dehydrogenase (IDH)-wild phenotype, lower resection rates, and reduced treatment responses. ROC analysis showed predictive accuracy comparable to CAR and PIV (AUC = 0.650). High scores independently predicted inferior OS (HR = 2.78, p < 0.001) and PFS (HR = 2.76, p < 0.001). Conclusions: The HALLMOUNT score provides a simple, cost-effective, and biologically grounded biomarker reflecting both tumor aggressiveness and host vulnerability. It enables refined risk stratification, supports individualized therapeutic planning, and warrants prospective validation in molecularly defined and multicenter cohorts. Full article

Background and Clinical Significance: DNA methylation profiling has revolutionized the classification of central nervous system (CNS) tumors, providing insights into tumor prognosis, recurrence, and personalized treatments. However, a significant challenge remains in classifying rare or molecularly undefined high-grade gliomas (HGGs) that fail to match existing methylation reference classes. This study evaluates the clinical, histopathological, and molecular characteristics of three unclassifiable cases through a retrospective analysis. Methylation profiling was performed by the National Institute of Health based on the 11b6 and 12b6 of the Heidelberg classifier, as well as the National Cancer Institute/Bethesda classifier. The cases were evaluated for histopathological features, molecular markers, and clinical outcomes. Case Presentation: We present three adult patients with histologically confirmed HGGs that were unclassifiable by standard DNA methylation profiling. All patients presented with diverse clinical and radiographic findings. Histopathological examination confirmed high-grade glial neoplasms in each case. However, methylation profiling failed to yield clear matches for any known class. Instead, profiling suggested indeterminate IDH-wildtype neoplasms with aggressive clinical courses. Following treatment, one patient experienced disease progression and died, while the other two remained without evidence of recurrence at follow-up. Conclusions: These cases underscore the persistent diagnostic challenges posed by CNS tumors that are unclassifiable by current DNA methylation, highlighting the urgent need for expanded reference datasets. While methylation profiling has transformed the field of tumor diagnostics, its limitations still exist. Enhanced collaboration to broaden diagnostic categories is essential to broaden diagnostic classifiers. Until these tools are refined, integration of clinical, histological, and molecular findings is imperative to optimize patient management, improve classification accuracy, and optimize therapeutic outcomes. Unclassifiable HGGs represent a critical gap in CNS tumor diagnostics. Addressing this requires global collaboration to enrich methylation databases. In the interim, a multimodal diagnostic strategy remains essential for the management of these challenging tumors. Full article

The high attrition rates in glioblastoma (GB) therapeutic development stem largely from preclinical models that fail to adequately recapitulate the dynamic tumor–host ecosystem. Unlike previous reviews that characterize glioma cell lines in isolation, this article integrates tumor biology with the distinct neuro-immune–endocrine landscapes of major laboratory rat strains. We critically evaluate standard rat malignant glioma cell lines (C6, F98, RG2, 9L) alongside transplantable tissue models (GB 101.8, GB 15/47), which offer enhanced translational relevance, demonstrating that the predictive value of any model is contingent upon the specific “glioma model and host strain” pairing and the individual physiological characteristics of the host. We provide evidence that strain-specific hypothalamic–pituitary–adrenal (HPA) axis reactivity (e.g., hyper-reactive Fischer 344 versus normo-reactive Wistar) acts as a decisive, yet often overlooked, modulator of the tumor microenvironment and therapeutic response. The review delineates the utility and limitations of these models, specifically addressing the MHC incompatibilities of the widely used C6 model in immunotherapy research, while contrasting it with the immune-evasive phenotypes of RG2 and the GB 101.8 tissue model. Furthermore, we highlight the superiority of tissue transplants in preserving cellular polyclonality and diffuse infiltration patterns compared to the circumscribed growth often observed in cell line-derived tumors. Consequently, we propose a strategic selection paradigm wherein immunogenic models serve as bioindicators of host immunocompetence, while invasive, non-immunogenic systems (F98, RG2, and GB 101.8) are utilized to investigate therapeutic resistance and systemic host-tumor interactions. Full article

High-grade gliomas—particularly glioblastoma (GBM)—remain refractory to standard-of-care surgery followed by chemoradiation, with a median overall survival of ~15 months. Oncolytic viruses (OVs), which selectively infect and lyse tumor cells while engaging antitumor immunity, offer a mechanistically distinct therapeutic modality. This review synthesizes clinical progress of OVs in GBM, with emphasis on oncolytic herpes simplex virus (oHSV) and coverage of other vectors (adenovirus, reovirus, Newcastle disease virus, vaccinia virus) across phase I–III trials, focusing on efficacy and safety. Key observations include the encouraging clinical trajectory of oHSV exemplars—T-VEC (approved for melanoma) and G47Δ (approved in Japan for recurrent GBM)—the multi-center exploration of the adenovirus DNX-2401 combined with programmed death-1 (PD-1) blockade, and the early-stage status of reovirus (pelareorep) and Newcastle disease virus programs. Emerging evidence indicates that oHSV therapy augments immune infiltration within the tumor microenvironment and alleviates immunosuppression, with synergy when combined with chemotherapy or immune checkpoint inhibitors. Persistent challenges include GBM’s inherently immunosuppressive milieu, limitations imposed by the blood–brain barrier, intrapatient viral delivery and biodistribution, and concerns about viral shedding. Future directions encompass programmable vector design, optimization of systemic delivery, biomarker-guided patient selection, and rational combination immunotherapy. Collectively, OVs represent a promising immunotherapeutic strategy in GBM; further gains will hinge on vector engineering and precision combinations to translate mechanistic promise into durable clinical benefit. Full article

Background: This study explores the therapeutic potential of radiodynamic therapy (RDT), a combination of the photosensitizer 5-aminolevulinic acid (5-ALA) administration and X-ray irradiation, for high-grade glioma (HGG). The research aims to verify the RDT efficacy in both normoxic and hypoxic environments, examine its mechanisms, and assess its impact on the tumor micro-immune environment to address resistance to RDT. Methods: Glioma cell lines U87MG and U251MG were used in experiments in vitro. The cells were divided into four groups with or without 5-ALA and X-ray exposure. Results: Results demonstrated that RDT was effective under normoxia (20% O₂), increasing reactive oxygen species (ROS) production and significantly decreasing U87MG cell viability in a 5-ALA concentration-dependent manner at 2 Gy and 6 Gy. However, under hypoxic conditions (3% O₂) or long-term 3% O₂ exposure, the RDT effect was not significant compared to controls. The study also found that RDT under normoxia influenced immune reaction-related gene expression, while under hypoxia, it primarily affects genes related to epithelial–mesenchymal transition (EMT). Further analysis revealed that RDT reduces the secretion of soluble PD-L1, a marker of immune checkpoint inhibition, in a 20% O₂ environment. Additionally, RDT suppressed the vascular endothelial growth factor (VEGF), an angiogenesis marker, under 3% O₂ conditions. RDT also reduced the secretion of colony-stimulating factor -1 (CSF-1), a differentiation inhibitory marker for macrophages, in a 20% O₂ environment. Conclusion: In conclusion, this study provides evidence that RDT, combining 5-ALA and X-ray irradiation, has potential as a therapeutic strategy for HGG, especially under normoxic conditions. It may also offer benefits under hypoxia, particularly in inhibiting angiogenesis. The study also highlights the importance of understanding the role of oxygen levels in the efficacy of RDT and its potential impact on immune responses, angiogenesis, and macrophage differentiation in the tumor microenvironment. Further research is needed to fully elucidate the underlying mechanisms and optimize RDT for clinical application. Full article

Purpose: The aim of this review is to evaluate the role of intraoperative flow cytometry (IFC) in tumor surgery. Methods: The Medline, Scopus, and Cochrane databases were searched up to 21 June 2025 to identify all available studies that met the inclusion criteria for final evaluation. To assess the risk of bias and applicability concerns, the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool was used. Results: A total of 22 studies involving 1511 patients with various tumor types were analyzed to assess the utility of IFC in the rapid diagnosis of tumors. The studies investigated IFC’s role in tumor grading, margin delineation, prognostic evaluation, and in differentiating neoplastic from benign lesions, as well as normal from cancerous tissues. In brain tumors, particularly gliomas and meningiomas, IFC demonstrated high diagnostic performance, with reported sensitivities ranging from 61% to 100% and specificities from 66% to 100%. Studies on non-brain tumors also showed high accuracy in distinguishing neoplastic from normal tissues, with sensitivities and specificities exceeding 85% in most cases. The most promising results were observed in brain tumor surgery, although its application in other tumor types continues to expand. Conclusions: IFC appears to be a valuable intraoperative tool in surgical oncology, providing rapid results within minutes and assisting in surgical and therapeutic decision-making. Nonetheless, studies remain limited, and further research is needed, particularly for non-brain tumors, to establish standardized cut-off values and enhance diagnostic reliability. Full article

Advances in neuroimaging and intraoperative mapping have transformed brain tumour surgery from anatomy-based resection to function-guided intervention. This review synthesises current evidence on multimodal strategies for maximising tumour removal while preserving cognitive and neurological function. Integrating task-based and resting-state functional MRI (fMRI), diffusion tensor imaging (DTI), tractography, and connectomic analysis enables personalised mapping of eloquent and cognitive networks. Intraoperatively, awake craniotomy with direct electrical stimulation (DES) remains the gold standard for real-time functional validation, while adjuncts such as intraoperative MRI (iMRI), 5-aminolevulinic acid (5-ALA) fluorescence, and ultrasound-based extended resection accuracy. However, these technologies present unique limitations, including neurovascular uncoupling in fMRI, tract distortion in DTI, and resource constraints in low-income settings. Our review differentiates their application across low-grade and high-grade gliomas, emphasising that tumour biology determines the balance between neuroplasticity-driven mapping and imaging-guided radicality. Key future priorities include validation of multimodal imaging protocols, integration of longitudinal neuropsychological outcomes, and development of interpretable connectomic models. Addressing the technological and ethical challenges of high-field MRI, data standardisation, and cost-effective implementation will be essential for equitable global adoption. Ultimately, the evolution of functional neurosurgery depends not only on new technologies but on integrating multimodal evidence and patient-centred outcome measures to achieve reproducible, safe, and personalised brain tumour surgery. Full article