Neuro-oncology最新文献

Background: The oncological role of resection in elderly patients with glioblastoma remains controversial. We evaluated the value of resection in patients ≥65 years with (I) newly diagnosed and (II) recurrent glioblastoma by comparing the prognostic relevance of extent of resection to patients <65 years.

Methods: The international RANO resect group retrospectively collected patients with newly diagnosed and recurrent IDH-wildtype glioblastoma from ten neuro-oncological centers. Associations of residual tumor with molecular and clinical markers and survival were analyzed.

Results: 1260 patients with newly diagnosed glioblastoma were identified, including 512 patients ≥65 years. Lower postoperative contrast-enhancing tumor volumes were favorably associated with survival on uni- and multivariate analyses; however, the associations with outcome were more pronounced in younger patients. Only in patients <65 years, supramaximal resection was associated with more favorable survival (40 vs. 20 months, p=0.001). In 310 patients with first recurrence (≥65 years: 92), maximal resection of contrast-enhancing tumor was associated with favorable outcomes, particularly in younger patients. Neither older nor younger patients had favorable outcome associations of supramaximal resection in the recurrent setting. All findings were confirmed in propensity-score-matched analyses to minimize confounding effects of inherent differences in demographic and clinical markers (including second-line treatments) between older and younger patients.

Conclusions: While complete contrast-enhancing tumor resection is prognostic for favorable outcomes in older patients, associations of supramaximal resection with improved outcomes were only retained in younger patients with newly diagnosed disease. Those findings support stratified surgical approaches.

Background: The identification of clinical and molecular heterogeneity in medulloblastoma has produced risk-stratified therapy, but establishing the most effective yet least toxic regimens has remained elusive owing to numerous treatment options. To improve risk-stratification, we performed an integrated analysis from three clinical trials.

Methods: Medulloblastoma patients from ACNS0331/NCT00085735, ACNS0332/NCT00392327, and SJMB03/NCT00085202 were included if they had methylation profiling. Molecular groups [WNT, SHH, Group 3 (G3) and Group 4 (G4)], subgroups, and copy number variations were procured from methylation profiles and mutations from next-generation sequencing. Data was assembled into an interactive portal to capture patient characteristics. Cross-trial comparisons, univariable, and multivariable analyses were conducted and used to derive a risk-stratification schema.

Results: 898 patients (WNT = 131, SHH = 151, G3 = 220, G4 = 396) were included. Progression-free-survival (PFS) distributions among analogous cross-trial cohorts were not different, demonstrating no survival advantage of any one therapy over another. The addition of carboplatin to high-dose craniospinal irradiation (HDCSI) containing regimen was selectively superior in PFS in G3/G4 subgroup 3 (p = 0.048) and G3/G4 subgroup 2 (p = 0.035) to HDCSI regimens without carboplatin. Nine actionable risk-stratified groups were identified consisting of 2 WNT groups (low, high-risk), 3 SHH groups (low-, average-, very-high-risk) and 4 G3/G4 groups (low-, average-, high-, and very-high-risk).

Conclusions: Our integrated cross-trial analysis suggests toxicity can be reduced by eliminating disproportionate differences in therapy in favor of a more uniform treatment backbone. Moreover, we propose and model a risk-classification system that identifies the most appropriate cohorts on which to trial significant dose reductions in craniospinal irradiation or select treatment intensifications.

Background: Craniopharyngioma presents malignant clinical manifestations with severe symptoms and higher incidence of hypothalamic dysfunction. The pathogenesis of craniopharyngioma remains unclear, which impedes the development of effective treatments and preventive measures. Comprehensively understanding the neoplastic programming and tumoral evolution may contribute to the improvement of prognosis for craniopharyngioma.

Methods: Using the single cell RNA-sequencing and high-resolution spatial transcriptomics analysis on adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP) and Rathke cleft cyst (RCC) to depict the cellular hierarchies and neoplastic evolution. Multiplex immunohistochemistry and ex vivo pituitary culture from animal model were used to identify the putative therapeutic targets.

Results: Cellular hierarchy analysis uncovered a more inflammatory tumor microenvironment in PCP compared to ACP. Parallel genomic variation and gene expression patterns were revealed between PCP and RCC, suggesting a continuum of the same disease spectrum that evolutes from RCC to PCP. Furthermore, we identified the disease-type-unique structures composed of various cellular states, including the tumoral progenitors surrounding the fibrovascular cores in PCP and senescence associated secretory phenotype (SASP)-related cellular hierarchy in ACP, respectively. In addition, SASP-related fibroblast growth factor (FGF) signaling was identified as a potential therapeutic target for ACP and inhibition of it led to decreased tumor cell proliferation in murine model.

Conclusions: Our study reveals the neoplastic programming and evolution of craniopharyngioma at single cell and spatial levels. Notably, SASP-related FGF signaling is identified as a potential therapeutic target for ACP and inhibition of it reduces tumor cell proliferation in murine model.

Background: Medulloblastoma and ependymoma are common pediatric central nervous system tumors with significant molecular and clinical heterogeneity. While molecular subgrouping has enabled classification into molecular subtypes, the extent of heterogeneity within these subgroups remains poorly defined.

Methods: We collected bulk RNA sequencing data from 888 medulloblastoma and 370 ependymoma tumors to establish a comprehensive reference landscape. After rigorous batch effect correction, normalization, and dimensionality reduction, we generated a unified landscape to explore gene expression, signaling pathways, RNA fusions, and copy number variations.

Results: Our transcriptional analysis revealed distinct clustering patterns, including two primary ependymoma compartments, EPN-E1 and EPN-E2, each with specific RNA fusions and molecular signatures. In medulloblastoma, we observed precise stratification of Group 3/4 tumors by subtype and in SHH tumors by patient age. We also identified subtype-specific pathways and gene fusions, enriched in each group.

Conclusions: This transcriptomic landscape serves as a resource for biomarker discovery, diagnostic refinement, and prediction of tumor biology and outcome. By enabling projection of new patients' bulk RNA-seq data onto the reference map using nearest neighbor analysis, the framework supports accurate subtype classification. The landscape is publicly available via Oncoscape, an interactive platform for global exploration and application.

Background: Pediatric-type low-grade gliomas (PLGG) are the most common central nervous system (CNS) tumor in children. Many are indolent and have excellent outcomes, however some inexplicably spread throughout the CNS leading to increased morbidity and mortality.

Methods: To better understand this rare and difficult-to-treat entity, as well as the features associated with dissemination in CNS tumors, we assembled a large international cohort (n = 269) of patients with disseminated PLGG with detailed clinical and molecular characterization, including DNA sequencing and methylome profiling.

Results: We identified three subgroups of patients based on the temporal and spatial distribution of dissemination. Tumors with diffuse leptomeningeal spread without a primary tumor mass and those occurring in infants had the worst clinical outcomes. The genetics overlapped substantially with that of non-disseminated PLGG, suggesting that non-genetic mechanisms are an important contributor to dissemination. Therapeutically, targeted RAS/MAPK-pathway inhibition was more effective than conventional chemotherapy as first or second-line treatment.

Conclusion: In sum, this cohort increases our clinical and biological understanding of this rare disease, provides insights for improving patient care, and directs future clinical trials and basic science research.

Background: T cell-based immunotherapies have had limited success in glioma thus far. Here, we evaluate the literature on abundance, spatial distribution and phenotypical characteristics of T cells in the tumor micro-environment (TME) of IDH-mutant and IDH-wildtype glioma, with the aim to understand how these measures relate to immunotherapy resistance and to aid the development of immunotherapies for glioma.

Methods: Medline, Embase, Web of Science Core Collection, Google Scholar and the Cochrane Central Register of Controlled Trials were systematically searched up to May 6th, 2025. Out of 4,303 articles screened, 85 studies examining T cell immunity in human glioma were selected. We collected information about tumor subtype, grade, methods, T cell abundance, spatial distribution, phenotypes and prognostic significance.

Results: T cells are present in the glioma TME, but at heterogeneous and generally low densities, especially in IDH-mutant glioma. T cell abundance increases with higher WHO grade and upon recurrence. T cells cluster around blood vessels, especially in IDH-mutant glioma. Glioma-infiltrating T cells largely display a late-differentiated phenotype (CD45RA-CCR7-C62L-), expressing markers that signify sustained antigen activation and exhaustion (PD-1, CTLA-4, TIM-3, LAG-3, CD39 and TIGIT). This phenotype coincides with decreased anti-tumor cytotoxicity and is spatially enriched in the myeloid-rich, hypoxic tumor core. Prognostic significance remains controversial.

Conclusions: T cells in glioma are scarce, generally fully differentiated and functionally inert. Understanding and reinvigorating the deficient T cell response will be essential for successful immunotherapies. Future research should incorporate functional and spatial immune profiling to optimize and personalize immunotherapeutic strategies for glioma patients.

Background: Preclinical studies demonstrate activity of PARP inhibitors in IDH mutant gliomas. We investigated safety, tolerability, pharmacokinetics, and efficacy of the PARP inhibitor pamiparib in conjunction with metronomic low-dose temozolomide in patients with recurrent IDH mutant (IDHmt) gliomas in a multicenter Phase I/II/window of opportunity study.

Methods: Patients received pamiparib in conjunction with daily temozolomide. Following Phase I determination of MTD, we enrolled two patient cohorts (Arm A, multiple prior chemotherapy regimens; Arm B, single prior regimen) in a two-stage design. Exploratory cohorts examined grade 4 IDHmt patients and intratumoral pharmacokinetics of pamiparib. The primary endpoint was objective radiographic response (ORR) by RANO criteria.

Results: 66 subjects were enrolled. We established pamiparib 60 mg twice daily with temozolomide 20 mg daily as the phase II dose. In non-enhancing and enhancing tumor, pamiparib exhibited an unbound tumor/plasma ratio of 0.92 and 0.98 respectively. 0/15 Arm A and 1/24 Arm B patients achieved a centrally confirmed partial response. Median progression-free survival for Arm A was 5.9 months (95% CI, 1.2-14.8 months), and for Arm B 9.7 months (95% CI, 5.7-21.7 months). Grade 3+ anemia and neutropenia affected 24% and 33% of patients respectively. Twenty-two of 66 patients (33.3%) discontinued study treatment for reasons other than tumor progression.

Conclusion: Pamiparib appeared to achieve sufficient pharmacologically active concentrations in both enhancing and non-enhancing tumors. While some patients achieved prolonged progression-free survival, combination with temozolomide did not produce a meaningful ORR in IDHmt recurrent gliomas. Cumulative hematologic toxicity was substantial and impacted long-term tolerability.

Background: The tumor microenvironment (TME) represents a promising avenue to understand gonadotroph tumors and develop therapeutic tools. Here, we aimed to gain insight into the tumorigenesis mechanisms driven by the gonadotoph TME.

Methods:  Single-cell and spatial-omics were combined with histological analysis. Mice engrafted with tumor cells were used for functional validation.

Results:  using single-cell and spatial transcriptomic data from gonadotroph tumors and normal tissues, we identified mast cells in the microenvironment of gonadotroph tumors and confirmed their physical and functional interaction with endothelial cells. Quantification of mast cells in 40 patients suggested their pro-tumoral role as tumors relapsing after surgery harbored more mast cells. More interestingly, the distribution of mast cells was associated with the presence of a higher number of blood vessels, with an increased microvessel density (MVD), and with blood vessels with thicker walls. Ligand-receptor network analysis highlighted VEGFA as a modulator of mast/endothelial cell communication, a result confirmed by the identification of intratumoral mast cells expressing VEGFA in mouse and human gonadotroph tumors. Finally, using mice engrafted with gonadotroph tumor cells, we demonstrated that the depletion of mast cells reduces tumor volume through increased apoptosis. These observations were associated with increased hemorrhagic areas and a significant reduction of the number of blood vessels and MVD as evidenced in human gonadotroph tumors.

Conclusion:  we demonstrate that mast cells represent a new actor of the gonadotroph TME, and highlight their pro-angiogenic and pro-tumorigenic roles as potential targets for the therapeutic treatment of gonadotroph tumors.