Search Results (154)

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

Pediatric high-grade gliomas (pHGGs), particularly diffuse midline gliomas (DMGs), are among the most lethal brain tumors due to poor survival and resistance to therapies. DMGs possess a distinct genetic profile, primarily driven by hallmark mutations such as H3K27M, ACVR1, and PDGFRA mutations/amplifications and TP53 inactivation, all of which contribute to tumor biology and therapeutic resistance. Developing physiologically relevant preclinical models that replicate both tumor biology and the tumor microenvironment (TME) is critical for advancing effective treatments. This review highlights recent progress in in vitro, ex vivo, and in vivo models, including patient-derived brain organoids, genetically engineered mouse models (GEMMs), and region-specific midline organoids incorporating SHH, BMP, and FGF2/8/19 signaling to model pontine gliomas. Key genetic alterations can now be introduced using lipofectamine-mediated transfection, PiggyBac plasmid systems, and CRISPR-Cas9, allowing the precise study of tumor initiation, progression, and therapy resistance. These models enable the investigation of TME interactions, including immune responses, neuronal infiltration, and therapeutic vulnerabilities. Future advancements involve developing immune-competent organoids, integrating vascularized networks, and applying multi-omics platforms like single-cell RNA sequencing and spatial transcriptomics to dissect tumor heterogeneity and lineage-specific vulnerabilities. These innovative approaches aim to enhance drug screening, identify new therapeutic targets, and accelerate personalized treatments for pediatric gliomas. Full article

High-grade gliomas (HGGs, WHO grades 3–4) are highly aggressive, with a poor prognosis and treatment resistance. Immune evasion may contribute to their progression, but the role of cytotoxic T-lymphocyte immune evasion (CTLE) is not well-validated. This study analyzed the transcriptomic data of 525 patients from TCGA-GBM-HG_U133A. Two molecular subtypes were identified based on 182 CTLE-associated genes, with 238 differentially expressed genes between them. A prognostic model was developed, identifying BST2 and DIRAS3 as key risk factors, and validated in multiple cohorts. The subtypes had distinct immune profiles, with Cluster 2 showing higher immune infiltration but a poorer prognosis. The model had a good predictive performance. High-risk patients had upregulated BST2 and DIRAS3, linked to immunosuppression and shorter survival. Knockdown experiments confirmed their roles in GBM cell migration and invasion. Mechanistically, they promote immune evasion. BST2 and DIRAS3 could be therapeutic targets for HGG immunotherapy. Full article

Background: High-grade glioma (HGG) is the most common primary malignant brain tumor, with peak incidence in the fifth and sixth decades of life. Although HGG is rare in children, the prognosis remains poor, with a median overall survival (OS) of less than two years. Recently, TRK inhibitors have been approved for the treatment of tumors harboring NTRK gene fusions. In this review, we analyzed data from early clinical trials investigating the use of these agents in patients with HGG. Methods: A systematic literature search was performed in the PubMed database. Studies involving patients with HGG treated with TRK inhibitors were included. We analyzed progression-free survival (PFS), 24-week disease control rate, and complete or partial radiological responses according to the Response Assessment in Neuro-Oncology (RANO) criteria. Results: Sixteen studies comprising 55 patients with HGG harboring NTRK gene fusions (19 adults and 36 children) were included. A statistically significant difference in PFS was observed between pediatric and adult patients treated with TRK inhibitors (17 vs. 8.5 months; p < 0.001). Pediatric patients also exhibited a higher rate of complete or partial radiological response compared to adults (94% vs. 57%). Discussion: Although the available evidence on TRK inhibitors in HGG is limited, the findings of this review highlight a potentially promising role for these agents, particularly in the treatment of pediatric HGGs. Full article

Background: Pediatric high-grade glioma (pHGG) is a highly aggressive cancer with unique biology distinct from adult high-grade glioma, limiting the effectiveness of standard treatment protocols derived from adult research. Objective: The purpose of this report is to present preliminary results from an ongoing pilot study integrating spectroscopic magnetic resonance imaging (sMRI) to guide proton beam therapy and longitudinal imaging analysis in pediatric patients with high-grade glioma (pHGG). Methods: Thirteen pediatric patients under 21 years old with supratentorial WHO grade III-IV glioma underwent baseline and serial whole-brain spectroscopic MRI alongside standard structural MRIs. Radiation targets were defined using T1-weighted contrast enhanced, T2-FLAIR, and Cho/NAA ≥ 2X maps. Longitudinal analyses included voxel-level metabolic change maps and spatial overlap metrics comparing pre-proton therapy and post-. Results: Six patients had sufficient longitudinal data; five received sMRI-guided PBT. Significant positive correlation (R² = 0.89, p < 0.0001) was observed between T2-FLAIR and Cho/NAA ≥ 2X volumes. Voxel-level difference maps of Cho/NAA and Choline revealed dynamic metabolic changes across follow-up scans. Analyzing Cho/NAA and Cho changes over time allowed differentiation between true progression and pseudoprogression, which conventional MRI alone struggles to achieve. Conclusions: Longitudinal sMRI enhanced metabolic tracking in pHGG, detects early tumor changes, and refines RT targeting beyond structural imaging. This first in-kind study highlights the potential of sMRI biomarkers in tracking treatment effects and emphasizes the complementary roles of metabolic and radiographic metrics in evaluating therapy response in pHGG. Full article

Background High-grade gliomas (HGGs) are aggressive brain tumors with poor prognoses. Maximizing the extent of resection (EOR) is a critical surgical goal. Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) has been proposed to enhance tumor visualization and resection. MethodsWe retrospectively analyzed 141 patients with histologically confirmed HGGs who underwent either 5-ALA-guided (n = 71) or conventional white-light (n = 70) resection between 2018 and 2023. Propensity score matching and multivariate Cox regression models were used to assess the impact of 5-ALA on surgical outcomes and survival. Results: Gross total resection (GTR) was significantly more common in the 5-ALA group than the conventional white-light group (28.17% vs. 12.86%, p = 0.0245). Kaplan–Meier analysis showed no statistically significant difference in overall survival between groups after matching (log-rank p = 0.6371). However, patients with GTR had significantly improved survival compared to those with subtotal resection (log-rank p = 0.0423). Multivariate Cox regression identified radiotherapy (HR = 0.291, 95% CI: 0.166–0.513, p < 0.001), higher Karnofsky Performance Status (HR = 0.962, 95% CI: 0.942–0.982, p = 0.0003), and GTR (HR = 0.476, 95% CI: 0.272–0.834, p = 0.0091) as independent predictors of improved survival. 5-ALA usage was not an independent predictor (HR = 0.885, 95% CI: 0.554–1.413, p = 0.612). Radiotherapy and chemotherapy were more frequently administered in the conventional white-light group (p = 0.0404 and p = 0.0085, respectively). Conclusions 5-ALA fluorescence-guided surgery significantly increases the rate of gross total resection in high-grade glioma patients but does not independently confer a survival advantage. Survival outcomes are primarily influenced by the extent of resection, adjuvant therapy, and functional status. Integration of 5-ALA within a comprehensive oncological framework may enhance its clinical utility. Full article

Background: High-grade gliomas (HGGs), particularly glioblastoma (GBM), are associated with exceptionally high mortality and inevitable recurrence. In considering novel treatment options for these devastating diseases, immunotherapies represent promising candidates. Immunotherapies have demonstrated efficacy for several advanced tumors outside the central nervous system, highlighting a potential role for these agents in treating HGGs. However, multiple challenges to immunotherapy efficacy have tempered therapeutic benefit in practice, including local and systemic immunosuppression, intratumoral heterogeneity, and various mechanisms of intrinsic and acquired resistance. In the past 30 years, diverse immunotherapeutic subclasses have been assessed for benefit against HGGs. Methods: We performed a PubMed search for randomized clinical trials performed within the last 30 years evaluating the following immunotherapy agents for high-grade gliomas: immune checkpoint inhibitors, vaccines, oncologic viruses, cytokines, and CAR T-cells. The present review offers a critical analysis of key pre-clinical and clinical trials that have shaped the immunotherapy landscape for high-grade gliomas over the past two decades. Results/Conclusions: Across the different immunotherapeutic methods and modalities explored thus far, a recurring theme emerges: while therapeutic strategies with a compelling conceptual basis are continually under development and even demonstrate a benefit in preclinical and early-phase trials, larger and later-phase trials consistently fail to produce concordantly significant outcomes. To date, no large-scale clinical trial has demonstrated a benefit of sufficient consequence to change practice. Continued critical appraisal of the strengths and pitfalls of prior investigative work, optimization of treatment development and delivery, and innovative approaches to combination therapy design will collectively be integral to future therapeutic advancement. Full article

Objectives: To assess amide proton transfer weighted (APTw) MR imaging capabilities in differentiating high-grade glial tumors across alpha-thalassemia/mental retardation X-linked (ATRX) expression, tumor-suppressor protein p53 expression (p53), O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation, isocitrate dehydrogenase (IDH) status, and proliferation marker Ki-67 (Ki-67 index) as a preoperative diagnostic aid. Material & Methods: A total of 42 high-grade glioma WHO grade 4 (HGG) patients were evaluated prospectively (30 males and 12 females). All patients were examined using conventional MRI, including the following: T1w-MPRAGE pre- and post-contrast administration, conventional T2w and 3D FLAIR, and APTw imaging with a 3T MR scanner. Receiver operating characteristic (ROC) curves were calculated for the APTw% mean, median, and max signal for the different molecular biomarkers. A logistic regression model was constructed for combined mean and median APTw% signals for p53 expression. Results: The whole-tumor max APTw% signal could significantly differentiate MGMTp from non-MGMTp HGG, p = 0.035. A cutoff of 4.28% max APTw% signal yielded AUC (area under the curve) = 0.702, with 70.6% sensitivity and 66.7% specificity. The mean/median APTw% signals differed significantly in p53 normal versus p53-overexpressed HGG s: 1.81%/1.83% vs. 1.15%/1.18%, p = 0.002/0.006, respectively. Cutoffs of 1.25%/1.33% for the mean/median APTw% signals yielded AUCs of 0.786/0.757, sensitivities of 76.9%/76.9%, and specificities of 50%/66.2%, p = 0.002/0.006, respectively. A logistic regression model with a combined mean and median APTw% signal for p53 status yielded an AUC = 0.788 and 76.9% sensitivity and 66.2% specificity. ATRX-, IDH- wild type (wt) vs. mutation (mut), and the level of Ki-67 did not differ significantly, but trends were found: IDH-wt and low Ki-67 showed higher mean/median/max APTw% signals vs. IDH-mut and high Ki-67, respectively. ATRX-wt vs. mutation showed higher mean and median APTw% signals but lower max APTw% signal. Conclusions: APTw imaging can potentially be a useful marker for the stratification of p53 expression and MGMT status in high-grade glioma in the preoperative setting and potentially aid surgical decision-making. Full article

Pediatric gliomas encompass the most common brain tumor in children and are subdivided into pediatric low-grade gliomas (pLGGs) and pediatric high-grade gliomas (pHGGs). The era of molecular diagnosis has shifted the treatment paradigms and management of these patients. RAS/MAPK pathway alterations serve as the driver in the majority of pLGGs, a subset of pHGG and NF1-related plexiform neurofibromas (PNs). The role of small molecule inhibitors in the treatment of these tumors has evolved in the past decade, facilitated through multiple clinical trials and moving into earlier stages of treatment. Although these developments hold promise, questions remain regarding targeted therapy, the long-term toxicities, the duration of treatment and the potential effects on the natural history of the tumor behavior. Full article

Background: 5-Aminolevulinic acid (5-ALA) serves as a precursor in the heme biosynthesis pathway, resulting in the selective accumulation of protoporphyrin IX (PpIX) within glioma cells. This property facilitates fluorescence-guided resection (FGR) in high-grade gliomas (HGGs), enhancing surgical precision and oncological results. Nonetheless, its clinical implementation is restricted by factors such as accessibility, cost, and technical limitations. Methods: A systematic review of PubMed literature (2019–2024) was conducted to assess the efficacy of 5-ALA in HGG surgery compared to conventional white light microscopy. Studies focusing on non-neurosurgical applications, pediatric populations, and non-HGG indications were excluded. Results: Nineteen articles met the criteria. Recent studies indicate that 5-ALA-guided resection significantly enhances gross total resection (GTR) rates compared to white light surgery (75.4% vs. 54.3%, p < 0.001). Patients receiving 5-ALA-assisted resection exhibit enhanced progression-free survival (PFS) at 6 months (median 8.1 months compared to 5.4 months, p = 0.002) and overall survival (OS) (median 15.2 months versus 12.3 months, p = 0.008). The necessity for specialized neurosurgical microscopes equipped with blue light filters restricts accessibility, especially in low-resource environments. Recent advancements in fluorescence-enhancing technologies, particularly loupe-based systems, have demonstrated increases in fluorescence intensity by up to tenfold through direct emission. Sodium fluorescein, originally designed for ophthalmological use, has been adapted for enhancing contrast in intracranial tumors; however, its non-specific binding to serum albumin restricts its accuracy in glioma resection. Conclusions: Recent publications demonstrate that 5-ALA fluorescence-guided surgery significantly improves gross total resection rates and survival outcomes in patients with high-grade gliomas. Although it offers clinical advantages, cost and equipment constraints continue to pose substantial obstacles to broad implementation. Additional research is required to enhance fluorescence-guided techniques and increase accessibility in resource-constrained environments. Full article

Background/Objectives: Glioblastoma IDH-wildtype CNS WHO grade 4 and astrocytoma IDH-mutant WHO grade 4 (together, high-grade gliomas: HGGs) are the most prevalent malignant brain tumors, carrying a poor prognosis despite multimodal treatment. Surgical site infections (SSIs) represent a relative frequent postoperative complication in HGG patients. Despite multimodal treatment protocols combining surgery, radiotherapy, and temozolomide chemotherapy, HGGs remain associated with a dismal prognosis, underscoring the need to evaluate how SSIs impact disease progression and survival outcomes. This study’s aim was to investigate the influence of SSIs on the clinical course of patients with HGGs. Methods: A comprehensive review of medical records for HGG patients treated at our institution between 2010 and 2024 identified 26 patients with SSIs. These patients were compared to an age-matched control group with the same histological diagnosis and treatment regimen. This study analyzed overall survival (OS), microbiological data, and pathological parameters to assess the impact of SSIs on patient outcomes. Survival differences between the infected and non-infected groups were evaluated using Kaplan–Meier survival curves. Remarkably, three patients with exceptionally long overall survival were highlighted in this study. Results: Among the cohort of 2008 patients with HGG surgery, 26 patients developed SSIs. An age-matched control group of 26 patients was identified, none of whom experienced SSIs. Comparing the OS between the infected and uninfected groups, a statistically significant improvement in OS was observed in the infected group (p = 0.049). The median OS in the infected group was 388 days, slightly shorter than the median OS of 422 days in the control group. However, the mean OS was markedly higher in the infected group (674 days) compared to the control group (442 days). The standard deviation of OS in the infected group was notably expansive, indicating substantial variability in survival outcomes. A cluster of infected patients with SSIs near the time of diagnosis had shorter OS, while other infected cases demonstrated significantly longer survival, exceeding both median and mean OS values. In contrast, the uninfected group showed limited standard deviation values, with uniformly distributed individual OS data around the median and mean values. Expectedly, IDH mutation status significantly influenced the survival in cohort patients. However, when stratified by infection status, no association between IDH mutation and improved infection-related survival was identified. The microbiological profile of SSIs was diverse, encompassing Gram-positive and Gram-negative bacteria as well as aerobic and anaerobic organisms. Conclusions: These findings underscore the heterogeneity of infection-related outcomes and their potential impact on survival in HGG patients. According to our knowledge, our study is one of the largest retrospective studies to date investigating and confirming the significant relationship between SSIs and HGG patients’ survival. Our results confirm the Janus Face phenomenon of infections, having both negative and positive effects depending on the context. Full article

Brain tumors, both primary and metastatic, represent a significant global health burden due to their high incidence, mortality, and the severe neurological deficits they frequently cause. Gliomas, especially high-grade gliomas (HGGs), rank among the most aggressive and lethal neoplasms, with only modest gains in long-term survival despite extensive molecular research and established standard therapies. In neurosurgical practice, maximizing the extent of safe resection is a principal strategy for improving clinical outcomes. Yet, the infiltrative nature of gliomas often complicates the accurate delineation of tumor margins. Confocal laser endomicroscopy (CLE), originally introduced in gastroenterology, has recently gained prominence in neuro-oncology by enabling real-time, high-resolution cellular imaging during surgery. This technique allows for intraoperative tumor characterization and reduces dependence on time-consuming frozen-section analyses. Recent technological advances, including device miniaturization and second-generation CLE systems, have substantially improved image quality and diagnostic utility. Furthermore, integration with deep learning algorithms and telepathology platforms fosters automated image interpretation and remote expert consultations, thereby accelerating surgical decision making and enhancing diagnostic consistency. Future work should address remaining challenges, such as mitigating motion artifacts, refining training protocols, and broadening the range of applicable fluorescent probes, to solidify CLE’s role as a critical intraoperative adjunct in neurosurgical oncology. Full article

Background/Objectives: Tumor interactions with their surrounding environment, particularly in the case of peritumoral edema, play a significant role in tumor behavior and progression. While most studies focus on the radiomic features of the tumor core, this work investigates whether peritumoral edema exhibits distinct radiomic fingerprints specific to glioma (GLI), meningioma (MEN), and metastasis (MET). By analyzing these patterns, we aim to deepen our understanding of the tumor microenvironment’s role in tumor development and progression. Methods: Radiomic features were extracted from peritumoral edema regions in T1-weighted (T1), post-gadolinium T1-weighted (T1-c), T2-weighted (T2), and T2 Fluid-Attenuated Inversion Recovery (T2-FLAIR) sequences. Three classification tasks using those features were then conducted: differentiating between Low-Grade Glioma (LGG) and High-Grade Glioma (HGG), distinguishing GLI from MET and MEN, and examining all four tumor types, i.e., LGG, HGG, MET, and MEN, to observe how tumor-specific signatures manifest in peritumoral edema. Model performance was assessed using balanced accuracy derived from 10-fold cross-validation. Results: The radiomic fingerprints specific to tumor types were more distinct in the peritumoral regions of T1-c images compared to other modalities. The best models, utilizing all features extracted from the peritumoral regions of T1-c images, achieved balanced accuracies of 0.86, 0.81, and 0.76 for the LGG-HGG, GLI-MET-MEN, and LGG-HGG-MET-MEN tasks, respectively. Conclusions: This study demonstrates that peritumoral edema, as characterized by radiomic features extracted from MRIs, contains fingerprints specific to tumor type, providing a non-invasive approach to understanding tumor-brain interactions. The results of this study hold the potential for predicting recurrence, distinguishing progression from pseudo-progression, and assessing treatment-induced changes, particularly in gliomas. Full article

BACKGROUND: Maximal safe resection is the objective of most neuro-oncological operations. Intraoperative magnetic resonance imaging (iMRI) may guide the surgeon to improve the extent of safe resection. There is limited evidence comparing the impact of iMRI on the rates of further resection between tumour types. AIM: To investigate the impact of iMRI on the rate of further resection following visualisation of residual tumour. METHODS: A retrospective cohort study identified all intracranial tumour operations performed in the 1.5 T iMRI machine of a single centre (2007–2023). Patients were identified using SurgiNet and were grouped according to their histopathological diagnosis in accordance with the WHO 2021 classification. The primary outcome was the rate of reoperation due to iMRI visualisation of residual tumours. RESULTS: A total of 574 cases were identified, including 152 low-grade gliomas (LGG), 108 high-grade gliomas (HGG), 194 pituitary neuroendocrine tumours (PitNETs), 15 metastases, and 6 meningiomas. Further resection following iMRI visualisation occurred in 45% of LGG cases, 47% of HGG cases, 29% of PitNET cases, and no meningioma or metastasis cases. Chi-square analysis showed that the rate of further resection after iMRI use across 2018–2023 was significantly higher than that across 2007–2012 (46% versus 33%, p = 0.036). CONCLUSION: Intraoperative MRI for guiding further resection was most useful in cases of LGG and HGG, possibly reflecting the difficulty of differentiating these tumour types from normal brain tissue. In addition, there was increased reliance on iMRI over time, which may represent our surgeons becoming accustomed to its use. Full article

Canine high-grade glioma (HGG) is among the deadliest and most treatment-resistant forms of canine cancer. Successful, widespread treatment is challenged by heterogeneity in tumor cells and the tumor microenvironment and tumor evolution following treatment. Immunotherapy is theoretically a strong novel therapy, since HGG-generated immunosuppression is a substantial malignancy mechanism. Immunotherapy has improved survival times overall, but has been associated with extremely poor outcomes in French bulldogs. Given this breed-specific observation, we hypothesized that within the French bulldog breed, there are key transcriptomic differences when compared to other breeds, and that their tumors change differently in response to immunotherapy. Using bulk RNA sequencing, French bulldog tumors were confirmed to differ substantially from boxer and Boston terrier tumors, with only 15.9% overlap in significant differentially expressed genes (DEGs). In upregulated DEGs, the magnitude of changes in expression post-treatment compared to pre-treatment was markedly greater in French bulldogs. Gene set enrichment analysis confirmed that following treatment, French bulldog tumors showed enrichment of key immune-associated pathways previously correlated with poor prognosis. Overall, this study confirmed that French bulldog HGG transcriptomes differ from boxer and Boston terrier transcriptomes, further refining description of the canine glioma transcriptome and providing important information to guide novel therapy development, both for specific dog breeds and for possible correlative variants of human glioblastoma. Full article