Neuro-oncology最新文献

Abstract: BackgroundThe oncological role of resection in elderly patients with glioblastoma remains controversial. We evaluated the value of resection in patients ≥65 years with (1) newly diagnosed and (2) 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: A total of 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 = .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: Chordomas are locally aggressive notochordal tumors with no systemic therapy options. As an ultra-rare cancer type, our understanding of its immune landscape is limited. While tumor-associated macrophages (TAMs) and T cells are critical components of the immune landscape, their functional states and interactions remain poorly understood.

Methods: We conducted an integrative analysis of 35 chordoma samples and six paired tumor-PBMC samples using single-cell RNA sequencing (scRNA-seq), T-cell receptor (TCR) profiling, and multiplex immunofluorescence. Immune cell phenotypes, spatial distribution, TCR motif diversity, and functional states were assessed using unbiased co-expression network analysis and predictive modeling.

Results: Chordomas exhibited remarkable immune cell heterogeneity, ranging from highly infiltrated to immune--desert tumors. Tumor-associated macrophages dominated the tumor microenvironment (TME) and were enriched for antigen-processing pathways. T-cell receptor profiling revealed clonal overlap between tumor-infiltrating and peripheral T cells, suggesting systemic anti-tumor responses. Exhausted CD8+ T cells exhibited restricted clonality and tumor-specific amino acid motifs. Weighted gene co-expression network analysis (WGCNA) identified gene modules associated with immune activation and suppression, underscoring the dual roles of immune cells in the TME. Spatial analysis revealed fibrous septa as immune interaction hubs, where immune cell clustering was significantly higher than in tumor regions.

Conclusions: This study advances understanding of the chordoma immune landscape by integrating spatial, transcriptomic, and TCR data. The findings highlight systemic and local immune dynamics, reveal tumor-specific TCR motifs, and identify potential therapeutic targets. These insights provide a foundation for developing personalized immunotherapies to overcome immune suppression and enhance anti-tumor immunity in chordomas.

Background: Methotrexate-based chemoradiotherapy is effective in primary central nervous system lymphoma (PCNSL) but carries a risk of severe neurotoxicity. In a single-arm study, a regimen with methotrexate, procarbazine, vincristine, and cytarabine was combined with rituximab (R-MPV-A) and substantially reduced doses of whole-brain radiotherapy (LD-WBRT), resulting in excellent progression-free survival (PFS) and overall survival (OS). Because R-MPV-A had never been tested without radiation, we sought to evaluate the efficacy of R-MPV-A with and without LD-WBRT, as well as determining if such low radiotherapy doses influenced disease control and/or neurotoxicity.

Methods: Patients were randomized to receive R-MPV-A alone (Chemo arm) or combined with LD-WBRT (ChemoRT arm), given at 2,340 cGy (180cGy X13). Primary endpoint was intent-to-treat (ITT) PFS. A sample size of 89 would provide 80% power to detect a hazard ratio (HR) of 0.63 (one-sided alpha = 0.15).

Results: Ninety-one patients were randomized, with 44 analyzed in the ChemoRT and 46 in the Chemo arm. Median age was 66 and 59.5, respectively. R-MPV-A was well tolerated, achieving a complete response rate of 92.3% (ChemoRT) and 76.3% (Chemo). After median follow-up of 4.6 years, median PFS was not reached (ChemoRT) vs 2.1 years (Chemo), HR = 0.47 (P = .007; 95% CI, 0.26-0.87). The 2-year PFS was 78.7% vs 54%, respectively. Differences in OS did not reach statistical significance (HR = 0.71; P = .33). Neuropsychological evaluation showed no differences in cognitive outcomes, with several tests favoring ChemoRT.

Conclusions: R-MPV-A is a highly efficacious and safe regimen with or without LD-WBRT. LD-WBRT contributes to disease control and increases PFS in PCNSL.

Background: No standardized method exists for seizure assessment in glioma clinical trials. We describe the development and evaluation of RANO-TREAT (Tumor Related Epilepsy Assessment Tool) for seizure assessment and its association with changes on brain MRI.

Methods: Patients with glioma/glioneuronal tumors and ≥ 1 prior seizure along with clinicians completed RANO-TREAT in conjunction with brain MRIs, yielding multiple RANO-TREAT scores at clinic visits over time. Unweighted (primary) and weighted (post-hoc) scores were correlated with disease progression via MRI in all patients and patients with IDHmt tumors, separately. Cohorts were randomly split by patient into cohort-specific training and validation sets. Weights for RANO-TREAT items were defined by multivariable generalized estimating equation models in cohort-specific training sets and validated in cohort-specific validation sets. A nomogram was developed using overall cohort training and validation sets.

Results: Four hundred and ninety patients (310 IDHmt tumors) had ≥ 1 visits and 285 patients (168 IDHmt tumors) had ≥ 2 visits. Unweighted RANO-TREAT scores (OR:1.01; 95%CI:0.998-1.02; P = .13) and score changes (OR:1.00; 95%CI:0.99-1.02; P = .63) were not associated with progressive disease on MRI. Post-hoc analysis using training and validation sets demonstrated weighted RANO-TREAT scores were correlated with progressive disease in both overall cohort validation set (OR:2.51; 95%CI:1.80-3.52; P < .0001) and IDHmt cohort validation set (OR:4.53; 95%CI:2.11-9.75; P = .0001). Weighted analyses for patients with ≥ 2 visits showed similar associations in validation sets.

Conclusions: This prospective study suggests an association of seizure control evaluated by a new standardized tool with disease progression in glioma. This tool requires further systematic evaluation in glioma clinical trials alongside more traditional endpoints.

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 Sonic Hedgehog (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: Studies of hormonal contraceptives and the risk of meningioma has often relied on self-reported information, primarily focusing on oral contraceptives. Recently, an association between progestins and meningioma was suggested. We aimed to analyze the association between hormonal contraceptives and meningioma using data from Swedish national registries.

Methods: We used the Swedish Cancer Register to identify women born 1955-1995, diagnosed with meningioma at age ≥20 years, between 2007 and 2015 (N = 1055). Twenty controls per case were randomly selected from the Swedish population register, matched by birth year and county of residence. We retrieved information regarding prescriptions of hormonal contraceptives from the National Prescribed Drug Register. Adjusted conditional logistic regression models were used to evaluate the association between hormonal contraceptive use and meningioma occurrence.

Results: Women prescribed hormonal contraceptives ≥1 year before the index date had an odds ratio (OR) of meningioma of 1.76 (95% CI, 1.53-2.03). For contraceptives containing medroxyprogesterone the OR was 5.49 (95% CI, 4.51-6.67), while the association was weaker for other progesterone contraceptives (OR = 1.34, 95% CI, 1.09-1.65). No association was found for intrauterine devices, vaginal rings, and subdermal implants.

Conclusions: This large register-based case-control study show a strong association between injectable hormonal contraceptives containing medroxyprogesterone and meningioma risk. The results add to the growing body of evidence of an association between meningiomas and progestins in general and the strong, consistent associations suggest a causal role of injectable medroxyprogesterone in meningioma growth. Our results correspond to 2 additional cases of meningioma per 10 000 women exposed to medroxyprogesterone per year.

Background: Immunotherapies have improved outcomes in many cancers but remain largely ineffective in glioblastoma (GBM). We investigated whether immunotherapy could be rationally tailored to GBM by functionally subtyping the tumor immune microenvironment (TIME) and associated vascular landscapes.

Methods: Single-cell and single-nucleus RNA sequencing, multiplex immunohistochemistry and flow cytometry were used to define TIME subtypes in human and murine GBMs. Therapeutic responses to anti-angiogenic and immunomodulatory therapies, including CD40 agonism, anti-PDL1, and PI3Kγ/δ inhibition, were assessed in orthotopic syngeneic GBM mouse models.

Results: Three distinct functional TIME subtypes with unique vascular-immune landscapes were identified in human and murine GBM. TIME-low tumors were immune-low/deserted with a leaky vasculature. TIME-med GBM exhibited intermediate immune-infiltration, prominent angiogenesis and active immune responses. TIME-high tumors showed dense infiltration of immunosuppressive myeloid cells and dysfunctional T cells. Representative mouse models demonstrated subtype-specific sensitivities to anti-angiogenic immunomodulating therapies. TIME-low GBMs exhibited transient T-cell activation but relapsed due to myeloid-driven immunosuppression and mesenchymal transition. TIME-med tumors displayed the most favorable responses across anti-angiogenic immunomodulating therapies. TIME-high GBMs were largely resistant, although therapeutic efficacy improved with myeloid-targeted PI3Kγ inhibition. In contrast, CD40 agonist therapy worsened survival by enhancing angiogenesis, amplifying immunosuppression, impairing T cell function, reducing NK-cell recruitment, and promoting tumor propagation.

Conclusions: GBM comprise three functional TIME subtypes with divergent vascular-immune landscapes that require subtype-specific therapeutic strategies. TIME-med tumors are most amenable to immunotherapies. TIME-low tumors derive transient effects with anti-angiogenic immunomodulating therapies, and TIME-high are resistant or even experience worse outcome without targeted reversal of myeloid immunosuppression.

Background: Genomic stability is essential for cell survival, particularly under stress conditions like hypoxia, which disrupt DNA repair. Glioblastoma (GBM) is markedly resistant to DNA-damaging therapies, primarily due to glioma stem cells (GSCs) and the hypoxic tumor microenvironment. Long non-coding RNAs (lncRNAs) play a significant role in maintaining genome integrity, but their involvement in the DNA damage response (DDR) under hypoxic conditions in GSCs remains unclear. We previously identified LUCAT1 as the most highly induced lncRNA in GSCs under hypoxia and a key regulator HIF1α activity. We now investigate its role in DDR regulation.

Methods: LUCAT1-interacting proteins in GSCs under hypoxia were identified using identification of direct RNA interacting proteins (iDRIP) and mass spectrometry. Interactions were confirmed by RNA pulldown and RNA immunoprecipitation. Mechanistic studies involved immunoprecipitation, proximity ligation assays, comet assays, immunostaining, and LUCAT1 knockdown using shRNA. Gene expression changes were evaluated via RNAseq in GSCs and TCGA datasets. Functional assays were conducted in GSCs and orthotopic xenografts with LUCAT1 depletion alone or in combination with PARP or DNA-PK inhibition or radiation.

Results: LUCAT1 directly interacts with the DNA-PK holoenzyme, modulating its assembly and function in the non-homologous end joining (NHEJ) pathway. It also regulates BRCA1 and RAD51, key proteins in homologous recombination (HR). Depletion of LUCAT1 increased DNA damage, sensitized GSCs to DDR inhibitors, and improved survival in mice treated with radiotherapy.

Conclusions: LUCAT1 is a critical DDR regulator in GSCs under hypoxia and a promising target to enhance the efficacy of DDR inhibitors and radiotherapy in GBM.