Neuro-oncology advances最新文献

Purpose: High-grade gliomas are among the most treatment-resistant cancers, with few therapies improving survival despite hundreds of clinical trials. The biostatistical parameters used to design these trials are critical but uncharacterized in aggregate. Currently, no data-driven benchmarks exist to inform these parameters, including the target effect size. This study therefore aimed to analyze trends in their use across neuro-oncology trials.

Methods: We systematically searched PubMed for publications of phase 2 and 3 high-grade glioma or medulloblastoma trials comparing two or more arms with a time-to-event primary endpoint. Key biostatistical parameters were extracted from each study, including trial phase, endpoints, effect size, control arm survival assumptions, Type I error, power, sample size, and accrual time.

Results: We analyzed 210 trials published between 1976 and 2025, evaluating 254 primary time-to-event endpoints (overall, OS, or progression-free survival or similar). Survival assumptions and target effect sizes (ie, hazard ratios, HRs) used for trial powering varied substantially. Assumed control arm OS was often lower than observed OS, and the application of type I error rates did not consistently reflect the stated hypothesis directionality. Trials with planned sample sizes below 500 and lower HR targets were less likely to meet accrual goals. Trials generally aimed to complete accrual by 36 months with a median follow up of 24 months.

Conclusion: This study provides historical benchmarks for sample size assumptions to support more transparent, data-driven, and context-aware trial design. They may also serve as a resource for feasibility planning, protocol development, and statistical justification in future trials.

Background: Monitoring diffuse lower-grade glioma (DLGG) evolution on MRI is challenging due to their infiltrative nature and post-surgical deformations. The RANO criteria recommend assessing the 2D tumor size, but volume analysis remains the gold standard for calculating growth rate. Manual tumor segmentation, however, is time-consuming, limiting its use in clinical practice. Automated segmentation tools like nnU-Net are promising but require clinical validation.

Methods: We used 1971 MRI exams from 207 DLGG patients to train and validate an in house-developed nnU-Net al.orithm. The dataset included scans from various MRI systems, with 2D and 3D FLAIR and T1-weighted acquisitions, that were divided into derivation (N = 1771) and validation (N = 200) sets with matching 2D and 3D FLAIR ratios. The algorithm's automated segmentations (AS) were compared with manual segmentations (MS) by expert neuroradiologists using the dice similarity coefficient (DSC) and Intersection over Union (IoU). Tumor volume and mean tumor diameter (MTD) were compared using Lin's concordance correlation coefficient (CCC) and Bland-Altman tests.

Results: The median nnU-Net DSC and IoU were 0.93 and 0.86, respectively. In the validation cohort, 64% of exams had excellent (≥0.9), 31% good ([0.7-0.9]), 3.5% unsatisfactory ([0.5-0.7]), and 1.5% poor DSC (<0.5). Higher DSC correlated with larger tumor volumes (P < .001). Tumor volume and MTD showed near-perfect concordance between AS and MS (CCC: 0.991 and 0.989, respectively).

Conclusions: Our automated nnU-Net segmentation tool demonstrates high accuracy and potential for clinical integration, enhancing DLGG monitoring and management.

Background: Glioblastoma (GBM) is the most common primary brain tumor with an overall survival under 21 months. Despite extensive research effort, patient outcomes have improved minimally over the past several decades. The Inhibitor of Apoptosis (IAP) proteins are critical survival factors implicated in both immune regulation and gliomagenesis. Small molecule IAP antagonists called SMAC mimetic compounds (SMCs) are under investigation as cancer therapeutics across multiple malignancies, including GBM. SMCs induce GBM cell death in the presence of inflammatory cytokines, synergize with immune checkpoint inhibitors (ICI), and induce death of microglia and macrophages. Although SMCs show significant efficacy in murine models, complete eradication is not achieved. Here, we aimed to understand the limitations of SMCs in murine GBM and identify strategies to enhance efficacy of combination treatment with ICIs with the goal of informing future translational efforts.

Methods: We use animal models, co-culture systems, flow cytometry, and multiplex immunohistochemistry to optimize SMC dosing and delivery, uncovering resistance mechanisms that address key unmet research needs.

Results: We demonstrate that although GBM cells are immunologically recognizable, their location within the central nervous system (CNS) limits effective anti-GBM immunity following SMC and ICI combination therapy. Increasing SMC dose potently improves overall survival, which is associated with reduced intratumoral macrophage content, increased microglial involvement, and peripheral immunoactivation. Given the immunosuppressive role of TGFβ, the incorporation of TGFβ blockade further enhances survival outcomes.

Conclusion: We comprehensively outline how SMCs can be used in conjunction with ICIs to treat GBM and propose strategies to maximize SMC efficacy.

Background: The developmental context in which genetic alterations occur is crucial to understand disease progression. In pediatric cancer, modeling tumor formation in the right cell type is necessary to faithfully recapitulate the unique nature of pediatric tumors. The Cre-LoxP system is a powerful tool to modulate gene expression in specific cell types at discrete developmental time windows.

Methods: We used Cre-LoxP mouse models to study the role of the oncofetal transcription factor PLAG1 in pediatric brain tumor formation. We characterized our model using histology, DNA methylation based copy number variant (CNV) analysis on fresh frozen and FFPE derived samples, RNA sequencing, whole genome sequencing and whole genome CRISPR Cas9 screening.

Results: We generated a new model for PLAG1 overexpressing brain tumors, but discovered an unexpected CNV at the Nras locus by DNA methylation analysis. We confirmed the CNV via whole genome sequencing and found that it was likely mediated by Cre-recombination at the transgene insertion site. Both the tumor transcriptome and genetic dependencies are substantially shaped by this CNV.

Conclusions: Our work demonstrates the necessity of copy-number analysis when working with transgenic Cre-LoxP mouse models. Assessing CNVs should become a standard evaluation procedure when reporting new tumor models, preventing misleading conclusions that could dramatically impact the reliability of preclinical studies.

Background: Non-germinomatous germ cell tumors (NGGCTs) occur 3.5 times more frequently in Chinese children than in western populations. This study aimed to evaluate treatment outcomes, prognostic factors, and diagnostic challenges in a Chinese cooperative group, with particular focus on the roles of pathology and surgical intervention.

Methods: We retrospectively analyzed 62 consecutively diagnosed pediatric patients with NGGCT (September 2018-June 2023) from Shanghai Children's Medical Center and Huashan Hospital. NGGCT was diagnosed by histopathology with/without elevated tumor markers (n = 46) or by elevated markers alone (n = 16). All patients received standardized treatment according to Children's Oncology Group ACNS0122 protocol. Whole-exome sequencing was performed on 12 paired tumor-blood samples to characterize molecular alterations.

Results: The study cohort included 49 males and 13 females (median age, 9.8 year). Primary locations were mainly pineal (58%) and suprasellar (29%). Treatment delays (>6 mo) occurred in 21% of patients, particularly those with non-pineal locations and endocrine symptoms. The 3 years event-free survival and overall survival rates were 81.9 ± 5.4% and 91.3 ± 3.7%, respectively. Univariate analysis identified poor prognostic factors: elevated AFP >200 ng/mL, spinal metastases, and lack of complete/partial response after induction chemotherapy. Surgical resection of small residual tumors (<2 cm) provided no survival benefit. Molecular analysis revealed KRAS and KIT as the most frequent mutations, with chromosome 12p abnormalities in 50% of cases.

Conclusions: Standardized multidisciplinary treatment achieves favorable outcomes comparable to international benchmarks. Aggressive surgery does not improve survival when tumor markers normalize. Diagnostic delays remain common, emphasizing the need for improved awareness and referral systems in China.

The 2021 WHO classification of brain tumors emphasizes integrating molecular features with histopathology, notably redefining astrocytoma and glioblastoma entities. Recent research underscores the influence of sex hormones in glioblastoma development and therapy response. This review focuses on the 5-year updated understanding of the role of nuclear and membrane receptors in glioblastoma biology and therapy. Notably, androgen receptor expression is linked to worse outcomes, but recent studies suggest androgen signaling might sustain anti-tumor immunity. Estrogen receptor subtypes, as well as nuclear or membrane progesterone receptors, show divergent roles. Beyond classical nuclear receptors, attention is paid to membrane-bound and G protein-coupled receptors (GPCRs), which regulate key pathways in glioblastoma progression. Among them, G protein-coupled membrane estrogen receptor, the G protein-coupled estrogen receptor, is gaining attention for its ability to modulate cell proliferation and tumor behavior. CXCR4, a chemokine receptor, is now seen as a critical driver of tumor growth and immune evasion. Cannabinoid receptors are also implicated in glioblastoma proliferation and drug resistance. Dopamine receptors, particularly DRD2 and DRD3, are emerging as regulators of glioblastoma stem cell maintenance and therapy resistance. Targeting hormone and GPCR-related pathways, especially considering sex-specific factors, offers promising avenues for developing personalized glioblastoma treatments and enhancing current therapy outcomes.

Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid progression, extensive inter- and intra-tumoral heterogeneity, and resistance to standard-of-care, including radiotherapy. Radiotherapy remains a cornerstone of GBM management, but its efficacy is limited by complex tumor biology and mechanisms of radioresistance. This review explores the advances in radiotherapy for GBM, focusing on the interplay between tumor biology and emerging treatment strategies. Hallmarks of GBM biology, including hypoxia, the robust DNA repair mechanisms, the immunosuppressive tumor microenvironment (TME), and the extensive plasticity contribute to therapeutic resistance. Innovative approaches in radiotherapy may allow to address these challenges. Charged particle therapies (CPTs), including proton and carbon ion therapy, offer superior precision and enhanced biological effectiveness by delivering lethal doses to tumor cells while sparing surrounding healthy tissue. FLASH therapy, using ultra-high dose rates, could reduce normal tissue toxicity without compromising tumor control. Furthermore, targeted radionuclide therapy harnesses tumor-specific targets to systemically deliver radiopharmaceuticals carrying therapeutic radionuclides directly to cancer cells, improving specificity and reducing off-target effects. This review highlights the promise of these novel radiotherapy modalities to address GBM's inherent heterogeneity and treatment resistance. By integrating advancements in technology with novel insights into GBM biology, these approaches may significantly improve patient outcomes.

Background: Sex differences in glioblastoma (GBM) are recognized, but their treatment implications remain unclear. Recent preclinical studies have characterized mechanisms of sex-biased anti-tumor immunity in GBM, and have found in murine models that males derive greater survival benefit from immune checkpoint inhibitor (ICI). We evaluated sex differences associated with ICI in GBM patients.

Methods: We retrospectively evaluated consecutive patients with newly diagnosed GBM (nGBM) or recurrent GBM (rGBM) treated with ICI on clinical trials at one institution from 2014 to 2022. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier analysis, univariate and multivariable regression models. Sex-by-treatment interactions were assessed relative to a concurrent reference group treated on non-ICI clinical trials.

Results: 296 patients with nGBM (58% male, 19% ICI) and 458 patients with rGBM (60% male, 40% ICI) were evaluated. In nGBM, ICI was not associated with sex difference in PFS (HR_male 1.35; 95% CI, 0.62-2.95; P = .446; P _interaction = .142) or OS (HR_male 1.15 [0.53-2.53], P = .722; P _interaction = .438) compared to non-ICI treatment. In rGBM, males receiving ICI had worse OS (HR_male 1.64 [1.09-2.47], P = .017) and trended towards worse PFS (HR_male 1.41 [0.94-2.11], P = .095), but sex differences with ICI were not significantly different compared to non-ICI treatment (PFS P _interaction = .610; OS P _interaction = .361). No sex differences were observed when all immunotherapies were analyzed collectively.

Conclusion: In nGBM and rGBM, ICI therapy was not associated with sex difference in PFS or OS. Clinically meaningful sex-based outcome differences may be better understood by prospective evaluation in clinical trials.

Background: Glioblastoma represents one of the most aggressive and fatal primary brain tumors in adults. Chemotherapeutic agents, while integral to management, frequently induce varying levels of myelotoxicity. The aim is to investigate the clinical impact of myelotoxicity in patients treated with the CeTeG versus the Stupp regimen which has not yet been systematically investigated under real-world conditions.

Methods: This retrospective study included patients with newly diagnosed glioblastoma who underwent radiochemotherapy. Peripheral blood counts were systematically assessed throughout first-line therapy, starting at the initiation of radiation and continuing until either first disease progression or death, whichever occurred earlier.

Results: Among 161 identified patients, 133 (83%) were assigned to the myelotoxicity cohort and 28 (17%) to the non-myelotoxicity cohort. Female sex was independently associated with a higher incidence of myelotoxicity (p = 0.007). In multivariate analysis leukopenia ≥ grade 2 was significantly associated with improved progression-free and overall survival in both the overall and CeTeG cohorts. Neutropenia ≥ grade 2 similarly correlated with improved survival outcomes in the overall cohort. Prophylaxis against pneumocystis jiroveci pneumonia was associated with a significant survival advantage in both the overall and Stupp cohorts, as was lymphopenia grade 3-4.

Conclusion: Myelotoxicity at the time of glioblastoma diagnosis does not seem to be detrimental to patient outcomes. Our findings highlight the importance of pneumocystis jiroveci prophylaxis in the Stupp regimen. This raises the intriguing question of whether future chemotherapy dosages could be tailored based on individual blood values, potentially exceeding current standard doses. Prospective studies are needed to explore these possibilities, including the feasibility of high-dose therapies similar to those used in leukemia treatment.

Background: Glioblastoma (GBM) prognosis remains poor, and although immune checkpoint inhibitors (ICI) have transformed the treatment of many tumors, they are ineffective in GBM. However, response to ICIs occurs in high-tumor-mutational-burden (TMB) GBMs. To address the immunological impact of high TMB in GBM, we created a high TMB syngeneic mouse model from the low TMB SB28 GBM cell line.

Methods: We used CRISPR-Cas9 to target murine Msh2, Mlh1, CXCL10, and CCL5. Single-cell-sorted clones were characterized by whole exome, bulk RNA-sequencing, and neoantigen prediction. Clones were injected subcutaneously or intracranially with or without anti-PD-1/anti-CTLA4 and dexamethasone.

Results: Loss of mismatch repair (MMR) proteins Msh2 or Mlh1 increased nonsynonymous mutations. A fraction of mice with intracranial Msh2KO but not Mlh1KO SB28 showed long-term survival with anti-PD-1/anti-CTLA4 treatment plus dexamethasone. Long-term surviving mice from Msh2 KO SB28 rejected rechallenged subcutaneous tumors. Subcutaneous tumors from clones with increased TMB grew more slowly. This was fully abrogated in Rag1 null mice for Msh2KO but only partially for Mlh1KO SB28. Hypermutant Msh2KO clones spontaneously secreted CXCL10, CCL5, and increased pro-inflammatory chemokines after IFN-γ stimulation. Knockout of CXCL10 or CCL5 in the highest TMB Msh2KO clone restored flank tumor growth, indicating loss of immune response despite elevated TMB.

Conclusion: Mismatch repair-deficient SB28 tumors were more immunogenic, but this was not completely correlated with TMB. Rather, rejection depended on increased secretion of pro-inflammatory chemokines. Msh2 and Mlh1 loss was not equivalent, suggesting that additional studies are needed to elucidate germline and somatic mismatch repair gene-specific immune alterations.