Neuro-oncology最新文献

Background: Adolescent and young adult (AYA) patients remain underrepresented in neuro-oncology research. Despite being the second most common primary brain tumor in this population, meningiomas have not been studied using age-specific molecular analyses. DNA methylation-based classification and prognostic tools have transformed meningioma care. This study aimed to evaluate the performance of these tools across age groups.

Methods: We analyzed 1,568 meningiomas with DNA methylation and clinical data, including 18 pediatric patients (<15 years), 195 AYA patients (15-39 years), and 1,355 adult patients (>39 years). Pediatric and AYA (P/AYA) tumors were combined and compared with adult tumors. The performance of established molecular classifiers and recurrence predictors, as well as differences in chromosomal copy number alterations were compared across age groups.

Results: While histologic grading was comparable between cohorts, P/AYA tumors displayed significantly fewer aggressive molecular groups and lower frequencies of chromosomal arm losses, including 1p, 6q, and 14q. The adult-trained recurrence predictor failed in the P/AYA population (AUC 0.57), despite similar score distributions. Retraining the model on an age-specific cohort using an identical analytic framework improved performance (AUC 0.79) and enabled effective stratification of progression-free survival (p = 0.00054). Importantly, 1p loss retained prognostic significance within the P/AYA group, supporting its clinical utility.

Conclusions: Molecular tools developed in adult-dominant cohorts do not generalize to younger patients due to both biological divergence and exclusion from model development. These findings underscore the need for age-specific molecular frameworks and highlight the imperative of including P/AYA populations in precision neuro-oncology research to ensure lifespan-equitable care.

Background: Gliomas are primary brain tumors arising from glial cells. WHO grade 2 gliomas are initially managed with surgery for diagnosis and tumor reduction. However, complete resection is difficult due to their infiltrative growth into the normal brain and the need to preserve brain function. Current treatment options for WHO grade 2 gliomas are limited. Isocitrate dehydrogenase 1 (IDH1) mutations are frequently observed in WHO grade 2 gliomas. Safusidenib erbumine is a selective inhibitor of mutant IDH1 with substantial blood-brain barrier penetration. This study aimed to investigate the efficacy and safety of safusidenib erbumine in patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 gliomas.

Methods: This phase II study implemented a multicenter, open-label, single-arm design and evaluated the efficacy and safety of safusidenib erbumine in 27 patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 gliomas (NCT04458272).

Results: The confirmed objective response rate according to the Response Assessment in Neuro-Oncology criteria for WHO grade 2 gliomas was 44.4%. Median progression-free survival was not reached, with an event-free probability of 87.9% at 24 months. The frequently reported treatment-emergent adverse events (TEAEs) by Medical Dictionary for Regulatory Activities Preferred Terms (reported in ≥ 40%) were alopecia (59.3%), arthralgia (55.6%), skin hyperpigmentation (48.1%), and alanine aminotransferase increased (40.7%). TEAEs were characterized as mostly grade 1 or 2. The incidence of treatment-related grade ≥3 TEAEs was 18.5%.

Conclusions: Safusidenib erbumine is a potential treatment option for patients with chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 gliomas.

Background: Outcomes for adult patients with high-grade glioma (HGG) remain poor, necessitating new treatment strategies. Key challenges include poor drug penetration in the brain and malignant cell state plasticity. Phase 0 studies identify agents that achieve target modulation through pharmacologically relevant brain concentrations.

Methods: A Phase 0/1 clinical trial combined the two targeted inhibitors ribociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) in recurrent HGG patients, aiming to identify brain-penetrant combinations and assess their impact on malignant cell states. We enrolled 24 patients with recurrent HGG, characterized by CDKN2A/B deletion or CDK4/6 amplification, PTEN loss or PIK3CA mutations, and wildtype retinoblastoma protein (Rb). Tumors were evaluated for pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics.

Results: Median unbound ribociclib concentrations in Gadolinium non-enhancing tumor regions were significantly above the biochemical IC50 for CDK4/6 inhibition at 400 and 600 mg QD doses. Unbound everolimus concentrations were undetectable (< 0.1 nM) in tumor regions across all dose levels. Ribociclib treatment was associated with significantly decreased Ki-67 positive cells. Single nucleus RNA sequencing of 17 on-trial IDH-wildtype recurrences and 88 standard-of-care treated recurrences showed a significantly lower fraction of cycling and neural progenitor-like malignant cell populations in ribociclib-everolimus treated tumors. CDK4/6 inhibitor-directed malignant cell state shifts were validated using three patient-derived cell lines.

Conclusions: This trial underscores the value of integrating pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics in Phase 0/1 surgical studies to assess treatment effects, including malignant cell state shifts. ClinicalTrials.gov identifier: NCT03834740.

The Society for Neuro-Oncology (SNO) marks its 30th anniversary in 2025, providing an opportunity to reflect on scientific advances and future directions on the field. Over three decades, SNO has catalyzed scientific innovation, education, mentorship, and global collaboration, advancing the care of patients with primary and metastatic brain tumors. Through its annual meeting and subspecialty conferences in pediatric neuro-oncology and brain metastases, as well as its journals, including Neuro-Oncology, Neuro-Oncology Practice, Neuro-Oncology Advances, and the recently launched Neuro-Oncology Pediatrics, SNO has established leading platforms for disseminating knowledge, sharing best practices, and shaping clinical, translational, and basic research worldwide. Scientific milestones during this period include the integration of molecular profiling into CNS tumor classification, advances in neuroimaging for diagnosis and treatment monitoring, targeted therapies for selected glioma patients and the evolution of brain metastases management from whole-brain radiotherapy to multimodal strategies that incorporate targeted and immune-based therapies. Pediatric neuro-oncology has similarly advanced with the use of histomolecular diagnostics, refined risk stratification, and the development of novel targeted agents, alongside an increased emphasis on survivorship. Looking forward, emerging insights into the tumor microenvironment and novel immunotherapeutic approaches offer promising directions for future discovery and translation.

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 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 = 0.007; 95% CI: 0.26 to 0.87). The 2-year PFS was 78.7% vs 54%, respectively. Differences in OS did not reach statistical significance (HR 0.71; p = 0.33). 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: With the growing adoption of stereotactic spine radiosurgery (SSRS), precise target delineation is essential. The International Spine Radiosurgery Consortium (ISRC) has proposed contouring guidelines covering both the tumor and adjacent structures, termed the elective field (EF). We designed this randomized trial comparing EF and involved field (IF)-contouring strategy to determine which yielded the lowest protocol-specified failure rate.

Methods: Patients with spinal metastases not requiring surgery were randomized 1:1 to receive 16 Gy in a single fraction via EF or IF SSRS. EF followed ISRC recommendations. IF comprised the gross tumor volume with an 8-mm isotropic intraosseous margin. We aimed to reject failure rates >10% at 6 months. Treatment failure was defined as grade ≥3 treatment-related toxicity or local progression.

Results: Between August 2019 and May 2024, 106 patients (164 segments) were analyzed. Fifty-two and 54 patients were randomized to EF and IF, respectively. The median follow-up was 41.6 months. At 6 months, the cumulative incidence of treatment failure (CIF) met the acceptability criteria (per-patient: EF 3.8% vs. IF 7.5%, p=0.42). By 12 months, EF group showed low CIF, both per-patient (3.8% vs 13.5%) and per-segment (2.6% vs 11.8%). CIF curves differed significantly between groups (Gray's test, per-patient: p=0.03, per-segment: p=0.02). In the IF group, two-thirds of the out-of-field or marginal recurrences could be enclosed by the EF contouring strategy.

Conclusions: EF and IF SSRS met the criteria for acceptable CIF at 6 months. With longer follow-up, EF demonstrated lower failure rates. ISRC contouring guidelines should be the standard practice.

Background: Despite advances in small-molecule inhibitors (SMIs), the clinical outcomes for glioblastoma (GBM) remain bleak. Recently, polymerase I and transcript release factor (PTRF/Cavin1) has emerged as a promising therapeutic target, with its inhibitor EPIC-1042 demonstrating preclinical anti-tumor activity. However, the therapeutic limitations of SMIs necessitate alternative strategies to achieve enduring target suppression.

Methods: EPIC-0726, a proteolysis-targeting chimera (PROTAC) degrader of PTRF, was developed through computer-aided drug design (CADD). Target engagement and degradation specificity were validated by Western blot. Quantitative proteomics identified downstream effectors, while mechanistic insights were elucidated through co-immunoprecipitation, immunofluorescence, and ubiquitination profiling. Orthotopic GBM models were used to assess therapeutic efficacy and temozolomide (TMZ) sensitization.

Results: EPIC-0726 induced dose-dependent PTRF degradation via the ubiquitin-proteasome system (UPS), requiring ternary complex formation. Proteomic analysis revealed RBX1, a core component of E3 ligase complexes, as a key downstream target. PTRF degradation by EPIC-0726 destabilized RBX1, concurrently suppressing K63-linked ubiquitination-mediated ERK1/2/AKT activation and stabilizing p21 via impaired K48-dependent proteasomal degradation. In vivo, EPIC-0726 monotherapy inhibited GBM growth and synergized with TMZ, with effects more potent than that of EPIC-1042.

Conclusion: This study establishes PROTAC-mediated PTRF degradation as a mechanistically distinct manner to activate proteolysis strategy-enhanced temozolomide efficacy by ERK1/2/AKT kinase suppression and p21 stabilization (PEAKS) through the PTRF-RBX1 regulatory axis. The superior efficacy of EPIC-0726 over EPIC-1042, particularly in overcoming TMZ resistance, provides a paradigm-shifting therapeutic approach for GBM. Our findings warrant the clinical translation of EPIC-0726 as both a monotherapy and a backbone for combination regimens.

Background: Recurrence invariably occurs in patients with high-grade glioma (HGG) despite maximal definitive therapy. Currently, there is no standard-of-care salvage treatment approach and re-irradiation is considered an option for select patients. Various radiotherapy fractionation schedules have been investigated, including the use of stereotactic radiosurgery (SRS). The aim of this study was to provide clinical practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS) specific to salvage SRS for recurrent-HGG. We define SRS as focal radiation in a single fraction and hypofractionated radiosurgery(HFSRS) as focal radiation delivered over 2-5 fractions.

Methods: A literature review and meta-analysis were performed according to PRISMA guidelines. Recommendations were formulated according to DELPHI methodology.

Results: Sixty-two studies met the eligibility criteria for analyses, resulting in 2640 recurrent HGG patients. SRS to a median total dose of 16 Gy was performed in 75% of patients, and HFSRS to the remaining 25% with a median total dose and number of fractions of 25 Gy and 5 fractions, respectively. The median overall survival from re-irradiation was 10.2 months. The pooled neurological toxicity rates were lower with HFSRS compared to SRS (4% vs. 7%,p=0.001). A cumulative EQD2 greater than 120-130 Gy was significantly associated with a greater risk of radiation necrosis (p = 0.003).

Conclusions: Focal re-irradiation with 16 Gy in single fraction or 24-25 Gy in 3-5 fractions, is safe and appears to be effective for recurrent-HGG. We also present clinical practice recommendations on behalf of the ISRS. Given the limited prospective data, no definitive conclusions can be drawn.

Background: In vivo stable isotope tracing is useful for natively surveying glioma metabolism but can be difficult to implement. Stable isotope tracing is tractable using in vitro glioma models, but most models lack nutrient conditions and cell populations relevant to human gliomas. This limits our ability to study glioma metabolism in the presence of an intact tumor microenvironment (TME) and immune-metabolic crosstalk.

Methods: We optimized an in vitro stable isotope tracing approach for human glioma explants and glioma stem-like cell (GSC) lines that integrates human plasma-like medium (HPLM). We performed 15N2-glutamine tracing in GSC monocultures and human IDH-wildtype glioblastoma explants and developed an analytical framework to evaluate microenvironment-dependent metabolic features that distinguish them. We also conducted spatial transcriptomics to assess transcriptional correlates to metabolic activities.

Results: HPLM culture preserved glioma explant viability and stemness while unmasking metabolic and immune programs suppressed by conventional culture conditions. Stable isotope tracing in HPLM revealed TME-dependent and TME-independent features of tumor metabolism. Tissue explants recapitulated tumor cell-intrinsic metabolic activities, such as synthesis of immunomodulatory purines. Unlike GSC monocultures, tissue explants captured tumor cell-extrinsic activities associated with stromal cell metabolism, as exemplified by astrocytic GDP-mannose production in heterocellular explants. Finally, glioma explants displayed tumor subtype-specific metabolic reprogramming, including robust pyrimidine degradation in mesenchymal cells.

Conclusions: We present a tractable approach to assess glioma metabolism in vitro under physiologic nutrient levels and in the presence of an intact TME. This platform opens new avenues to interrogate glioma metabolism and its interplay with the immune microenvironment.