Search Results (172)

High-grade gliomas (HGGs) are aggressive brain tumors with limited treatment options and poor survival outcomes. Variants including isocitrate dehydrogenase (IDH)-wildtype, IDH-mutant, and histone 3 lysine to methionine substitution (H3K27M)-mutant subtypes demonstrate considerable tumor heterogeneity at the genetic, cellular, and microenvironmental levels. This presents a major barrier to the development of reliable models that recapitulate tumor heterogeneity, allowing for the development of effective therapies. Glioma tumor organoids (GTOs) have emerged as a promising model, offering a balance between biological relevance and practical scalability for precision medicine. In this study, we present a refined methodology for generating three-dimensional, multiregional, patient-derived GTOs across a spectrum of glioma subtypes (including primary and recurrent tumors) while preserving the transcriptomic and phenotypic heterogeneity of their source tumors. We demonstrate the feasibility of a high-throughput drug-screening platform to nominate multi-drug regimens, finding marked variability in drug response, not only between patients and tumor types, but also across regions within the tumor. These findings underscore the critical impact of spatial heterogeneity on therapeutic sensitivity and suggest that multiregional sampling is critical for adequate glioma model development and drug discovery. Finally, regional differential drug responses suggest that multi-agent drug therapy may provide better comprehensive oncologic control and highlight the potential of multiregional GTOs as a clinically actionable tool for personalized treatment strategies in HGG. Full article

Background/Objectives: Lower-grade gliomas, particularly IDH-mutant astrocytomas, represent a distinct molecular subtype with unique therapeutic challenges. Whole-genome sequencing (WGS) plays a crucial role in uncovering genetic alterations that drive glioma pathogenesis and therapeutic resistance. This study identifies and evaluates a novel GATA2 p.Arg396Trp mutation in a clinical sample of lower-grade glioma, assessing its structural impact and implications for drug binding. Methods: A WHO Grade II astrocytoma specimen from a 33-year-old female patient was analyzed using WGS with Oxford Nanopore sequencing, followed by comprehensive bioinformatics processing to identify genomic variants. The GATA2 p.Arg396Trp mutation was evaluated using protein modeling, structural analysis, and pathogenicity prediction tools. Drug affinity analysis was conducted using molecular docking simulations to assess the computational impact of the mutation on drug binding. Results: The GATA2 p.Arg396Trp mutation was identified as a computationally predicted pathogenic variant, potentially disrupting protein interactions within critical functional domains. Structural analysis revealed altered binding dynamics with key anti-neoplastic agents, suggesting potential implications for therapeutic response. These findings represent computational predictions requiring experimental validation. Conclusions: Our preliminary findings suggest a potential role of the GATA2 p.Arg396Trp mutation in lower-grade glioma pathogenesis. The mutation predicted impact on transcriptional regulation and drug affinity suggests GATA2 as a possible biomarker candidate. Extensive experimental validation in larger patient cohorts is needed to establish clinical relevance and explore targeted therapeutic strategies. Full article

Background: The incidence and prognosis of high-grade gliomas differ according to histopathological and molecular features. The WHO 2021 CNS classification emphasized IDH status, but historical cohorts often lacked systematic molecular profiling. Methods: We conducted a retrospective population-based study including adult patients diagnosed with IDH-wildtype glioblastoma or IDH-mutant astrocytoma in a Spanish tertiary center (2011–2021). Incidence trends and survival outcomes were analyzed according to treatment modality and sex. Results: A total of 1057 patients were included: 530 (50.1%) with IDH-wildtype glioblastoma and 137 (13%) with IDH-mutant astrocytoma. Incidence of both subtypes significantly increased during the study period (p < 0.01). Median overall survival (OS) was 12.3 months for IDH-wildtype glioblastoma and 38.4 months for IDH-mutant astrocytoma. Multimodal therapy (surgery, radiotherapy, chemotherapy) significantly improved OS and progression-free survival (PFS) in both subgroups (p < 0.001). Male sex was associated with longer OS in both tumor types (p < 0.05). Conclusions: IDH-wildtype glioblastoma shows persistently poor outcomes despite increasing incidence, while IDH-mutant astrocytoma demonstrates better survival, particularly in male patients and those receiving multimodal therapy. These findings reflect real-world practice and provide epidemiological and survival data from Southern Europe to guide future clinical and public health strategies. Full article

Diffuse gliomas are the most common primary brain tumors in adults in the Western world. According to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors, the assessment of isocitrate dehydrogenase (IDH1/2)-mutation status is essential for accurate patient stratification. In this study, we performed a comprehensive evaluation of IDH-mutation status in the intraoperative setting using the Idylla platform. The reference cohort comprised 30 formalin-fixed paraffin-embedded (FFPE) tissue samples with known IDH status, while the exploration cohort included 35 intraoperative snap-frozen and native-tissue specimens. The results were compared with those of a standard next-generation sequencing (NGS) analysis. Our findings demonstrate that the Idylla IDH-mutation assay provides 100% concordance compared with NGS analysis for both FFPE and intraoperative tissue samples. The Idylla system delivers results within approximately 90 min, significantly outperforming NGS, which requires between 7 and 27 days. This rapid turnaround facilitates timely interdisciplinary case discussions and enables timely therapy planning, within the framework of neuro-oncological molecular tumor boards. The ultra-fast intraoperative IDH-mutation analysis using the Idylla platform, in combination with intraoperative histopathological assessment, enables rapid patient stratification and treatment planning in diffuse gliomas. Full article

Background: The androgen receptor (AR) is a ligand-dependent transcription factor of the nuclear steroid receptor superfamily, implicated in the pathogenesis of various solid tumors. The AR gene, located on chromosome Xq11–12, is accompanied by several X-linked genes that modulate AR expression and function, including FLNA, UXT, and members of the melanoma antigen gene (MAGE) family (MAGEA1, MAGEA11, MAGEC1, MAGEC2). While the AR has been investigated in multiple tumor types, its role in adult-type diffuse gliomas remains largely unexplored. Here, we characterized AR protein expression and the promoter methylation status of the AR and associated regulatory genes in adult-type diffuse gliomas. Methods: A retrospective analysis was conducted on 50 patients with adult-type diffuse gliomas, including IDH-mutant gliomas (grades 2–4) and IDH-wildtype glioblastomas (GBMs), classified according to the 2021 WHO criteria. AR nuclear expression was assessed by immunohistochemistry (IHC). Methylation-specific PCR and quantitative DNA methylation analyses were employed to evaluate promoter methylation of the AR and selected co-regulatory genes. Results: AR nuclear positivity correlated significantly with male sex (p = 0.04) and higher tumor grade, with the highest expression in IDH-wildtype GBMs (p = 0.04). In IDH-mutant gliomas, AR immunoreactivity was more prevalent in astrocytomas than in 1p/19q codeleted oligodendrogliomas (p = 0.02). AR expression was associated with unmethylated MGMT promoter status (p = 0.02). DNA methylation analysis revealed AR gene hypomethylation in tumors displaying nuclear AR positivity and in IDH-wildtype GBMs (Kruskal–Wallis p < 0.05). Additionally, methylation patterns of AR co-regulators located on the X chromosome suggest epigenetic regulation of AR signaling in gliomas. Conclusions: The findings reveal distinct AR pathway activation patterns in adult-type diffuse gliomas, particularly IDH-wildtype GBMs, suggesting that further exploration of antiandrogen therapies is warranted. Full article

Background/Objectives: Methionine (MET) positron emission tomography (PET) and cerebral blood volume (CBV) imaging provide complementary glioma assessment. This study compared MET and CBV across glioma subtypes defined by the 2021 World Health Organization Classification. Methods: This retrospective study enrolled 106 patients (mean age 41.9 ± 12.4 years; 57 males) with MRI non-contrast-enhanced gliomas: 21 glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (G); 50 astrocytoma, IDH-mutant (A); and 35 oligodendrogliomas, IDH-mutant, and 1p/19q-codeleted (O). Relative CBVs (rCBVs) were measured in VOI-T2 and VOI-MET, and the MET tumor-to-normal (T/N) ratio was calculated. Results: MET and rCBV were significantly correlated (r = 0.5, p < 0.001); rCBV was higher in MET-positive tumors and predicted MET accumulation (area under the curve [AUC] = 0.72, cutoff = 2.99). In VOI-T2, rCBV and MET T/N ratio were the highest in G and lowest in A (p < 0.001). Receiver operating characteristic analyses showed no overall significant difference between MET and rCBV for differentiating G/A/O, but rCBV trended toward higher AUC values in key distinctions, such as G (0.736 vs. 0.612) or grade 4 (0.718 vs. 0.617). The increase in rCBV within the MET-positive region (VOI-MET/VOI-T2 rCBV ratio) was significantly higher in A (119.8%, p = 0.002) than in the other groups (p = 0.01). Conclusions: rCBV differentiated glioma subtype with accuracy comparable to MET and could predict MET accumulation. However, its reliability for identifying MET-positive regions varied by subtype, being useful in A but limited in O. Recognizing these subtype-specific differences, rCBV can serve as a practical tool for evaluating non-contrast-enhanced gliomas. Full article

Background: Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) enables the intraoperative visualization of glioma. However, its effectiveness varies based on tumor subtype and molecular profile, posing challenges for achieving complete resection. Our systematic review aims to explore the relationship between IDH mutation status and intraoperative fluorescence visualization. Importantly, this is the first study to propose that vorasidenib, an emerging IDH-targeting agent, could enhance 5-ALA-guided surgery, marking a novel direction for translational research. Methods: A systematic literature search was conducted using the PubMed, Cochrane Library, Scopus and Web of Science databases up to May 2025, following PRISMA guidelines. The primary outcomes included fluorescence detection rates across different glioma subtypes and their correlation with IDH mutation status. Secondary outcomes comprised surgical efficacy measures such as gross total resection (GTR), overall survival (OS), and progression-free survival (PFS). Additionally, we analyzed the metabolic consequences of IDH mutations and evaluated the potential role of vorasidenib in enhancing 5-ALA-induced fluorescence. Results: Seven studies including 621 patients included in the final analysis. Fluorescence detection was nearly universal in WHO grade 4 gliomas (94–100%), but lower in grade 3 (43–85%) and rare in grade 2 (7–26%). Several cohorts reported reduced fluorescence in IDH-mutant gliomas, although this was not consistent across all studies. In high-grade gliomas, visible fluorescence correlated with higher GTR rates and, in some series, longer OS. Conversely, in lower-grade IDH-mutant gliomas, fluorescence did not increase GTR and was associated with worse PFS and OS. Conclusions: The effectiveness of 5-ALA-guided fluorescence in glioma surgery is significantly influenced by both tumor grade and IDH mutation status. Vorasidenib may represent a potential avenue for modulating tumor metabolism and enhancing intraoperative fluorescence in IDH-mutant gliomas, a hypothesis that warrants further experimental validation. Full article

Isocitrate dehydrogenase 1 (IDH1) mutations are key drivers of glioma biology, influencing tumor aggressiveness and treatment response. To elucidate their molecular impact, we performed proteome analysis on patient-derived (PD) and U87MG glioma cell models with either mutant or wild-type IDH1. We quantified over 6000 protein groups per model, identifying 1594 differentially expressed proteins in PD-AS (IDH1_MUT) vs. PD-GB (IDH1_WT) and 904 in U87_MUT vs. U87_WT. Both IDH1_MUT models exhibited enhanced MHC antigen presentation and interferon signaling, indicative of an altered immune microenvironment. However, metabolic alterations were model-dependent: PD-AS cells shifted toward glycolysis and purine salvage, while U87_MUT cells retained oxidative phosphorylation, potentially due to D2-hydroxyglutarate (2OHG)-mediated HIF1A stabilization. We also observed a predominance of downregulated DNA repair proteins in IDH1_MUT models, particularly those involved in homologous recombination. In contrast, RB1 and ASMTL were strongly upregulated in both IDH1_MUT models, implicating them in DNA repair and cellular stress responses. We also found distinct expression patterns of proteins regulating histone methylation in IDH1_MUT cells, favoring increased methylation of H3K4, H3K9, and H3K36. A key driver of this may be the upregulation of SETD2 in PD-AS, an H3K4 and H3K36 trimethyltransferase linked to the recruitment of HIF1A as well as DNA mismatch repair proteins. This study uncovers candidate biomarkers and pathways relevant to glioma progression and therapeutic targeting, but also underscores the complexity of predicting glioma pathogenesis and treatment responses based on IDH1 mutation status. While proteome profiling provides valuable insights, a comprehensive understanding of IDH1_MUT gliomas will likely require integrative multi-omics approaches, including DNA/RNA methylation profiling, histone and protein post-translational modification analyses, and targeted DNA damage and repair assays. Full article

Objectives: To investigate the correlation between intraoperative conventional ultrasound, SWE, and SMI ultrasound manifestations of glioma and the expression of immunohistochemical markers. Methods: Patients with single superficial supratentorial glioma scheduled for brain tumor resection in our neurosurgery department from October 2020 to October 2022 were prospectively included. High-grade glioma (HGG) and low-grade glioma (LGG) were classified by pathological histological grading, and the differences in conventional ultrasound, SWE Young’s modulus, and SMI intratumoral and peritumoral blood flow architecture between HGG and LGG were analyzed, and the SWE diagnostic cut-off value was calculated by the Youdon index. Logistic regression models were used to analyze the independent predictive ultrasound signs associated with the diagnosis of HGG. HGG and LGG were classified by pathological histological grading. IDH1 expression was measured by immunohistochemical methods to analyze the correlation between IDH1 expression in glioma and clinical and ultrasound characteristics. Results: Forty-eight patients with glioma admitted to our hospital from October 2020 to October 2022 were included in this study, including 30 (62.5%) with HGG and 18 (37.5%) with LGG. For conventional ultrasound, HGG was often associated with severe peritumoral edema compared with LGG (p = 0.048). The sensitivity of HGG was 88.9%, the specificity was 86.7%, and the AUC was 0.855 (95% confidence interval: 0.741–0.968, p = 0.001) using Young’s mode 13.90 kPa as the threshold. Logistic analysis showed that SWE Young’s modulus values, and peritumoral and intratumoral SMI blood flow structures, were associated with the diagnosis of HGG. Among the 48 gliomas, 22 (45.8%) were IDH1-positive and 26 (54.2%) were IDH1-negative, with no statistical difference in age between the two groups and a statistical difference in histological grading (p < 0.05). There was a statistical difference between IDH1 mutant and wild type in terms of peritumoral edema and SMI intratumoral and peritumoral tissue vascular architecture. Logistic regression models showed that intratumoral and peritumoral tissue SMI vascular architecture was a valid predictor of IDH1 positivity, with a classification accuracy of 81.3%, sensitivity of 90.9%, and specificity of 73.1%. Further group analysis of mutant Young’s modulus values in LGG were higher than wild-type Young’s modulus values (p = 0.031). Conclusions: Peritumoral and intratumoral tissue SMI vascular architecture was a valid predictor of IDH1 positivity. Based on intraoperative ultrasound multimodality images, we can preoperatively determine the expression of molecular markers of lesions, which is of clinical significance for optimizing surgical strategies and predicting prognosis. Full article

Background/Objectives: Astrocytoma, IDH-mutant, CNS WHO grade 3, is a diffuse glioma with poor prognosis, molecularly defined by IDH mutations and frequently co-occurring TP53 and ATRX alterations. This study aimed to delineate the genomic landscape and identify clinically relevant molecular features of astrocytoma, IDH-mutant, CNS WHO grade 3 using this resource. Methods: Patients in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR Project GENIE) database were selected based on histological diagnosis of “anaplastic astrocytoma”, confirmed IDH1/2 mutation, and exclusion of CDKN2A/B homozygous deletions. We analyzed frequencies of somatic mutations, copy number alterations (CNAs), structural variants (SVs), assessed co-occurrence/exclusivity patterns, and explored associations with available demographic and limited survival data. Results: The most common somatic mutations were in IDH1 (98.0%), TP53 (94.8%), and ATRX (55.2%). The observed ATRX mutation frequency was lower than some historical reports (e.g., ~86%). Other recurrent alterations included phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (6.9%), Notch receptor 1 (NOTCH1) (6.9%), and platelet-derived growth factor receptor alpha (PDGFRA) (mutations 4.3%; CNAs also observed). Conclusions: This study provides a comprehensive genomic characterization of astrocytoma, IDH-mutant, CNS WHO grade 3 using the AACR GENIE database, confirming core mutational signatures while also highlighting potential variations in alteration frequencies, such as for ATRX. The findings establish a valuable real-world genomic benchmark for this tumor type, while promoting the need for continued data integration with robust clinical outcomes to identify actionable prognostic and therapeutic targets. Full article

Brain tumors elicit complex neuropsychiatric disturbances that frequently occur prior to radiological detection and hinder differentiation from major psychiatric disorders. These syndromes stem from tumor-dependent metabolic reprogramming, neuroimmune activation, neurotransmitter dysregulation, and large-scale circuit disruption. Dinucleotide hypermethylation (e.g., IDH-mutant gliomas), through the accumulation of 2-hydroxyglutarate (2-HG), execute broad DNA and histone hypermethylation, hypermethylating serotonergic and glutamatergic pathways, and contributing to a treatment-resistant cognitive-affective syndrome. High-grade gliomas promote glutamate excitotoxicity via system Xc⁻ transporter upregulation that contributes to cognitive and affective instability. Cytokine cascades induced by tumors (e.g., IL-6, TNF-α, IFN-γ) lead to the breakdown of the blood–brain barrier (BBB), which is thought to amplify neuroinflammatory processes similar to those seen in schizophrenia spectrum disorders and autoimmune encephalopathies. Frontal gliomas present with apathy and disinhibition, and temporal tumors lead to hallucinations, emotional lability, and episodic memory dysfunction. Tumor-associated neuropsychiatric dysfunction, despite increasing recognition, is underdiagnosed and commonly misdiagnosed. This paper seeks to consolidate the mechanistic understanding of these syndromes, drawing on perspectives from neuroimaging, molecular oncology, neuroimmunology, and computational psychiatry. Novel approaches, including lesion-network mapping, exosomal biomarkers or AI-based predictive modeling, have projected early detection and precision-targeted interventions. In the context of the limitations of conventional psychotropic treatments, mechanistically informed therapies, including neuromodulation, neuroimmune-based interventions, and metabolic reprogramming, are essential to improving psychiatric and oncological outcomes. Paraneoplastic neuropsychiatric syndromes are not due to a secondary effect, rather, they are manifestations integral to the biology of a tumor, so they require a new paradigm in both diagnosis and treatment. And defining their molecular and circuit-level underpinnings will propel the next frontier of precision psychiatry in neuro-oncology, cementing the understanding that psychiatric dysfunction is a core influencer of survival, resilience, and quality of life. Full article

Background/Objectives: Mutant isocitrate dehydrogenase (IDH) inhibitors represent a major advance in precision oncology. The recent Food and Drug Administration approval of vorasidenib for IDH-mutant glioma highlights its therapeutic potential in this setting. As this and other mutant IDH inhibitors enter the clinical setting, providers are tasked with staying informed of the evolving therapeutic landscape as more is learned about this unique class of medications. We aimed to summarize insights from preclinical studies and clinical trials exploring their use in IDH-mutant glioma. Methods: We reviewed notable preclinical studies establishing the rationale for targeting mutant IDH. We performed a systematic review of clincaltrials.gov to identify both completed and ongoing interventional IDH-directed trials in patients with IDH-mutant glioma. Results: We identified 8 published and 15 ongoing clinical trials evaluating IDH-directed therapies. IDH inhibitors have been shown to slow and, in some cases, reverse glioma tumor growth, with activity that may extend beyond their currently approved indications. The presence of contrast enhancement is consistently a negative predictor of response for ivosidenib and vorasidenib, although safusidenib and olutasidenib preliminarily may retain efficacy in these cases. Novel approaches such as IDH-directed vaccines and combination therapy using mutant IDH inhibitors with immunotherapy are currently under active investigation. Conclusions: Mutant IDH inhibition is a promising, well-tolerated, and evolving approach for many patients with IDH-mutant glioma. Ongoing research will clarify its optimal clinical utility and potentially expand its indication. Full article

Pediatric high-grade glioma (pHGG) is a devastating group of childhood cancers associated with poor outcomes. Traditionally, diagnosis was based on histologic and immunohistochemical characteristics, including high mitotic activity, presence of necrosis, and presence of glial cell markers (e.g., GFAP). With advances in molecular tumor profiling, these tumors have been recategorized based on specific molecular findings that better lend themselves to prediction of treatment response and prognosis. pHGG is now categorized into four subtypes: H3K27-altered, H3G34-mutant, H3/IDH-WT, and infant-type high-grade glioma (iHGG). Molecular profiling has not only increased the specificity of diagnosis but also improved prognostication. Additionally, these molecular findings provide novel targets for individual tumor-directed therapy. While these therapies are largely still under investigation, continued investigation of distinct molecular markers in these tumors is imperative to extending event-free survival (EFS) and overall survival (OS) for patients with pHGG. Full article

Gliomas, particularly IDH-wildtype ones, are associated with poor prognosis, yet their immunological landscape remains uncertain. We analyzed RNA sequencing data from 55 glioma patients, estimating immune infiltration with CIBERSORTx and immune cell states via Ecotyper. IDH-wildtype gliomas showed significantly higher immune cell infiltration (p = 0.002), notably of regulatory T cells (Tregs) and macrophages, and a greater proportion of exhausted T cells compared to IDH-mutant gliomas. Clustering based on immune profiles revealed two groups. Cluster A, enriched for IDH-wildtype cases, exhibited heightened immune infiltration but also marked immunosuppression. Cluster B, which included both IDH-wildtype and mutant cases, showed lower levels of immune infiltration. Tumor-infiltrating lymphocyte (TIL) cultured from IDH-wildtype tumors demonstrated limited expansion following anti-PD-1, a CSF1R inhibitor, or a STAT3 inhibitor treatment, without clear cluster-specific differences. Tumor-reactive TILs were mainly observed in cluster A. These findings highlight that IDH-wildtype gliomas have an immunosuppressive and heterogeneous microenvironment, potentially limiting responses to single-agent immunotherapies. A personalized, multi-targeted approach addressing multiple immunosuppressive mechanisms may be essential to improve immunotherapy outcomes in this aggressive glioma subgroup. Full article

Background/Objectives: Isocitrate dehydrogenase (IDH) mutations are hallmark features in subsets of gliomas, producing the oncometabolite D-2-hydroxyglutarate (2HG). Although IDH mutations are associated with better clinical outcomes, their relationship with tumor progression is complex. This study aimed to investigate, in vitro and in vivo, the phenotypic consequences of IDH mutation and 2HG exposure in glioblastoma (GBM) under normoxic and hypoxic conditions and under temozolomide (TMZ) and radiation exposure. Methods: Experiments were conducted using IDH-wildtype (IDH-wt) and IDH-mutant (IDH-mut) glioma cell lines under controlled oxygen conditions. Functional assays included cell viability, cell cycle analysis, apoptosis profiling, migration, and surface marker expression via flow cytometry. Orthotopic xenografts were established in immunocompromised mice to assess in vivo tumor growth and morphology, followed by MRI and histological analysis. Treatments included TMZ, radiation, and 2HG at varying concentrations. Statistical analyses were performed using SPSS and RStudio. Results:IDH-wt cells exhibited faster proliferation and greater adaptability under hypoxia, while IDH-mut cells showed cell cycle arrest and limited growth. 2HG recapitulated IDH-mut features in IDH-wt cells, including increased apoptosis under TMZ, reduced proliferation, and altered CD24/CD44 expression. In vivo, IDH-wt tumors were larger and more infiltrative, while 2HG administration reduced tumor volume and promoted compact morphology. Notably, migration was initially similar across genotypes but increased in IDH-mut and 2HG-treated IDH-wt cells over time, though suppressed under therapeutic stress. Conclusions: IDH mutation and 2HG modulate glioma cell biology, including cell cycle dynamics, proliferation rates, migration, and apoptosis. While the IDH mutation and its metabolic product confer initial growth advantages, they enhance treatment sensitivity and reduce invasiveness, highlighting potential vulnerabilities for targeted therapy. Full article