Background:Immunotherapy, while effective for many extra-cranial solid tumors, has not shown benefits against glioblastoma. Limited T cell infiltration and an immunosuppressive tumor microenvironment (TME) are among the main barriers to successful immunotherapy. We hypothesized that blocking the chemokine CXCL12 would modulate the TME composition and reverse GBM resistance to immunotherapy. Methods:We used a syngeneic murine SB28 GBM model resistant to immune checkpoint inhibitor (ICI) and compared orthotopic and subcutaneous tumors to differentiate tumor-intrinsic factors from CNS-related barriers. We treated SB28 tumor-bearing mice with vehicle, ICI, CXCL12 inhibitor (NOX-A12), or a combination of NOX-A12 with ICI. We assessed treatment effects on immune cell populations in the blood and the TME, and on tumor growth and mouse survival. Results:ICI alone increased effector CD8+T cells in subcutaneous tumors but did not alter immune subsets in intracranial tumors. The combination of NOX-A12 and ICI increased effector CD8+ and CD4+ T cells in both models. In subcutaneous tumors, combination treatment also reduced MHC-IIlow tumor-associated macrophages (TAM) and slowed tumor growth. However, in orthotopic tumors, TAM populations remained unaffected, and survival was not extended, despite similar T-cell modulation, supporting the role of TAM in mediating GBM resistance to ICI. Conclusion:CXCL12 inhibition demonstrates therapeutic potential in facilitating anti-tumor immune response by dual mechanism, including T cell expansion and TAM reduction. The inability to deplete TAMs and improve survival in intracranial GBM underscores the need to address brain-specific mechanisms underlying TAM persistence to advance immunotherapy in GBM.

Background:Salvage therapies for adults with recurrent ependymoma are limited. A prior retrospective review of patients with recurrent ependymomas treated with bevacizumab and carboplatin reported a 75% radiographic response rate. This prospective single-arm, open-label Phase 2 study was designed to assess clinical efficacy of this regimen. Methods:Twenty-two patients were evaluated in this CERN Adult Clinical Trials network study. Adult patients (age ≥18) with recurrent ependymomas received carboplatin (AUC = 5-6) every 4 weeks and bevacizumab 10mg/kg every 2 weeks for 6 cycles, after which carboplatin was discontinued, while bevacizumab could be continued at physician's discretion. Imaging of areas involved and patient-reported outcomes (PRO) with the MD Anderson Symptom Inventory (brain and/or spine modules) were assessed at baseline and every 2 cycles. Results:With a median follow-up time of 25.9 months (mo), the primary endpoint of 12-mo progression-free survival rate (PFS-12) greater than 50% was reached, with a rate of 76.4% (95% CI, 52.2, 89.4). The median PFS of this cohort was 18.0 mo. Two patients achieved objective partial responses (9.1%). There were no treatment-related grade ≥4 toxicities. Brain tumor responders (radiographic objective response or stable disease) experienced improved cognitive and neurological symptoms, while spine tumor patients reported worsening symptom outcomes regardless of response. Conclusions:Treatment with carboplatin and bevacizumab in adult recurrent ependymomas met the PFS-12 clinical efficacy endpoint. However, symptomatic worsening in spinal tumors suggests imaging stability and symptom improvement in brain disease may be related to bevacizumab pseudo-response.

PURPOSE:Integrating external control data into clinical trial designs and analyses has the potential to accelerate drug development processes. We reanalyzed the three experimental arms of the Individual Screening Trial of Innovative Glioblastoma Therapy (INSIGhT), a randomized phase II platform trial in newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma (ClinicalTrials.gov identifier: NCT02977780). To evaluate the validity of using external data sets, we compared treatment effect estimates based on internal INSIGhT control data and matched external control data. METHODS:The three experimental arms of INSIGhT (abemaciclib [n = 72], neratinib [n = 80], and CC-115 [n = 12]) did not improve survival compared with internal controls (standard chemoradiation [n = 70]). We derived external control patient-level data from multiple real-world and clinical trial data sets. We applied propensity score matching and Cox proportional hazards models to estimate treatment effects with external controls. Additionally, using this glioblastoma (GBM) data collection, we specified simulation scenarios to evaluate trial designs that integrate external controls. RESULTS:After matching to external controls, no survival benefit was observed for patients receiving abemaciclib (hazard ratio [HR], 1.00 [95% CI, 0.75 to 1.34]), neratinib (HR, 0.93 [95% CI, 0.70 to 1.24]), or CC-115 (HR, 0.88 [95% CI, 0.41 to 1.88]). Simulations, together with the INSIGhT data and a collection of GBM data sets, allowed us to examine efficiencies and risks of clinical trial designs that leverage external control data. CONCLUSION:The use of carefully matched external controls, to replace or augment the internal controls of INSIGhT, produced treatment effect estimates that were similar to previously published analyses. Single-arm trial designs and hybrid randomized designs incorporating propensity score-matched external control data evaluated treatment effects in the early-phase testing of experimental therapies in newly diagnosed GBM. The validity of this approach and risks of bias depended on the availability of comprehensive and accurate data on all potential confounders, in the absence of unmeasured confounding.

2064 Background: Tumor mutational burden (TMB) is an emerging biomarker for the prediction of immune therapy success in solid tumors. Response to immune checkpoint inhibitor (ICI) treatment in rare gliomas with biallelic mismatch repair deficiencies has been attributed to their hypermutation phenotype (HMP). This has not been tested in other gliomas. We developed a phase II clinical trial using nivolumab in recurrent IDH-mutant gliomas evaluating response in tumors with HMP (approximately 10% of cases) and in tumors with non-HMP (NHMP). Here we report the results of the analysis of the NHMP cohort. Methods: Adults with recurrent IDH-mutant glioma, KPS ≥ 60, normal organ function, with known somatic TMB (analyzed at NIH) were enrolled in a phase II trial. Nivolumab was given at 480mg IV every 28-day cycle with a maximum of 16 cycles. The primary endpoint is PFS rate at 6 months (PFS6) in both HMP and NHMP cohorts. Responses to treatment were evaluated by MRI every 2 cycles using iRANO criteria. Simon’s two-stage design was used to independently evaluate the HMP/NHMP cohort. For the NHMP cohort, the null and alternative hypotheses for PFS6 are 0.2 and 0.4, respectively. A total of 30 were planned to be accrued across stages I and II. If ≥10 patients are progression-free at 6 months, the null hypothesis will be rejected, indicating that the treatment is promising for patients with NHMP IDH-mutant gliomas. The design controls the type I error at 0.05 and yields a power of 0.8. Tumor samples and peripheral blood were collected for correlative studies. Patient-reported outcomes (PRO) were evaluated by longitudinal symptom burden analysis using Brain Tumor Module of the MD Anderson Symptom Inventory. Results: As of January 2026, thirty patients were enrolled and treated on the NHMP cohort (TMB˂5 mut/Mb). Among 30 evaluable patients, 20 were male, median age 44 and KPS 90. Histological diagnosis included 22 astrocytoma (grade 3, n=10; grade 4, n=12) and 8 oligodendroglioma (grade 2, n=1; grade 3, n=7). Median number of prior recurrences is 2, ranging from 1 to 5. At the time of analysis, all 30 evaluable patients were off study treatment: 7 completed all 16 cycles, 17 had disease progression, 3 withdrew to start other management. Three patients were off treatment due to treatment related grade 3 colitis, pneumonitis and dry mouth. Eleven and 8 out of 30 patients were progression free at 6 and 12 months, respectively. PRO and correlative studies are ongoing. Conclusions: Nivolumab is well tolerated and has shown efficacy in a cohort of patients with recurrent IDH-mutant gliomas with low TMB. Clinical benefit measured by objective response, PFS, OS and PRO, along with longitudinal immune monitoring, will help determine whether tumor TMB correlates with immunologic and clinical response to ICI therapy in IDH-mutant gliomas. Clinical trial information: NCT03718767 .

Background:Primary central nervous system (CNS) tumors affect patients' psychological well-being and quality of life. Individualized approaches, such as Managing Cancer and Living Meaningfully (CALM), have shown potential in advanced cancers for improving these outcomes. Aims:This study assessed the effects and feasibility of CALM delivered remotely to a diverse cohort of patients with a primary CNS tumor. Methods:Patients completed 3-6 remote CALM sessions focusing on 4 interrelated domains. Depression, death anxiety, attachment style, and quality of life were assessed at study enrollment, 3-months, and 6-months into the intervention. Results:Of the 19 patients enrolled, 15 (79% retention rate) completed the study. Most patients had a high-grade (47%) tumor, mainly diagnosed in the brain (60%). The median age was 44 years (range, 24-70). Feasibility was demonstrated through adherence to completing outcome questionnaires and a high level of patient satisfaction (100% found it worthwhile). Although no statistically significant changes were seen in depression, death anxiety, attachment anxiety, or quality of life (p > 0.05; g = -0.09 to 0.78) at any measured time, a clinically meaningful decrease in depression was observed at the 6-month point (mean difference = -3.36, p = 0.13) among spine tumor patients. Conclusions:This study demonstrated that delivering CALM via telehealth is feasible, as evidenced by high compliance, low attrition, and acceptability among patients diagnosed with CNS tumors. The findings indicated meaningful reductions in depressive symptoms among patients with spinal cord tumors. These preliminary positive findings justify further evaluation of the feasibility and effectiveness of CALM in a larger sample. Trial registration:ClinicalTrials.gov ID NCT04852302.

Background:This multi-institutional phase I trial aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities, pharmacokinetics, and preliminary antitumor activity of berubicin (WP744 or RTA744), designed to cross the blood-brain barrier, in patients with primary brain cancers. Methods:Thirty-five patients with recurrent or refractory primary brain cancers, including glioblastoma multiforme, received berubicin infusions over 2 h for 3 consecutive days (one course) every 21 days. Daily doses escalated from 1.2 to 9.6 mg/m2 using an accelerated titration design. Plasma levels of berubicin were measured via high-performance liquid chromatography-tandem mass spectrometry to estimate pharmacokinetic parameters. Results:The daily MTD was determined to be 7.5 mg/m2. Nonhematological toxicities were minimal; no cardiotoxicity was observed. In the intention-to-treat population (n = 35), 1 patient had a durable complete response, 1 had a partial response, and 9 had stable disease, corresponding to an objective response rate of 5.7% and a disease control rate of 31.4%. In the response-evaluable subset (n = 25), the corresponding rates were 8% and 44%, respectively; these secondary estimates should be interpreted with caution as patients who discontinued early were excluded. Pharmacokinetic analysis determined a mean half-life of 32.8 h. The area under the curve increased proportionally with dose. Conclusions:The tolerability and efficacy of berubicin, including one durable complete response, warrant continued development of the molecule. Berubicin shows activity over a range of doses, including a durable response at 2.4 mg/m2. The recommended phase II dose is 7.5 mg/m2 infusions over 2 h for 3 days every 3 weeks. Trial registration:NCT00526812.

Background:Glioblastoma (GBM) has limited effective salvage therapy options. The combination of the Type 1B topoisomerase/HIF1α inhibitor topotecan and the tyrosine kinase inhibitor pazopanib has shown promise in solid tumors and may be effective in recurrent GBM. Methods:Patients with recurrent GBM who were bevacizumab-naïve (Group A, 9 patients) or had previous bevacizumab (BEV) (Group B, 22 patients) started daily oral pazopanib (600 mg) and topotecan (0.25 mg). The primary objective was progression-free survival (PFS) at 6 months for Group A and 3 months for Group B patients. Secondary objectives included median progression-free and overall survival (OS), safety, tolerability, and toxicity as measured by patient-reported outcomes (PROs) and adverse event documentation. Results:Group A enrolled 9 evaluable patients and closed to accrual early when interim primary objectives were not met (PFS-6 11%). Group B enrolled 22 evaluable patients and narrowly met its primary objective (PFS-3 18%). Median PFS and OS endpoints demonstrated equivalent to slight improvement upon historical metrics, respectively. The regimen was tolerable and safe save for high frequency of hypertension, with PROs data showing stability or worsening in parallel with tumor stability or progression, respectively. Conclusions:These findings suggest the regimen is safe and tolerable to GBM patients. The regimen was ineffective in bevacizumab-naïve patients and only narrowly met its predetermined endpoint in patients with prior BEV. These results do not support the combination regimen as tested in this protocol for further investigation in GBM.

Background:Primary central nervous system tumors (PCNST) are rare, understudied tumors for which knowledge of their clinical course, biology, physical, and psychological impact is limited. The National Cancer Institute's Neuro-Oncology Branch Natural History Study was developed to better understand the long-term disease course and outcomes experienced by these patients. Methods:Past medical histories, tumor tissue (if available), and patient-reported outcomes assessing symptom burden, general health status, anxiety, depression, and perceived cognitive deficits were collected at study enrollment. Sociodemographic, clinical, molecular, and patient-reported outcome data were analyzed descriptively. Results:Among the first 1000 participants, 796 had primary brain tumors (PBT) and 92 had primary spine tumors (PST); 88 were excluded. The cohort was predominantly male (56%), White (81%), and non-Hispanic (89%). Based on advanced molecular testing at enrollment, 190 (21%) patients had a change in diagnosis or subclassification since their initial diagnosis. Meningioma cases reported family brain tumor history more frequently than others. Most PBTs were diagnosed within 6 months of symptoms, while most PSTs were diagnosed ≥1 year after. Patients with PBT and PST reported an average of 10 symptoms, with 4 and 5 symptoms rated as moderate/severe, respectively. Nearly half of PBT participants reported anxiety or depression (46%) and difficulty with usual activities (48%). PST participants reported higher functional impairment and worse general health status. Conclusion:These findings underscore the substantial burden of PCNSTs and highlight the value of longitudinal, tumor-agnostic data in generating real-world insights into the disease trajectories of these rare and heterogeneous tumors to inform clinical research.

Background:Ependymoma is a malignancy of the neuroepithelium-derived ependyma that lines the spinal cord and ventricles of the brain, occurring most frequently in young children and older adults. Genetic susceptibility to ependymoma has proven difficult to assess due to disease rarity. Methods:We performed genome-wide association studies (GWAS) of 478 ependymoma patients and 4,841 disease-free controls of European ancestry. Ependymoma patients consisted of 117 children (<18 years old) with whole-genome sequencing (WGS), 142 children with genotyping, and 219 adults (≥18 years old) with genotyping. Genotyped samples were imputed using the 1,000 Genomes Project as the reference panel and underwent quality control filtering. The GWAS was performed separately by age group and technology (genotyped or WGS). GWAS variants were considered significant at P < 5 × 10-8. Results:Among pediatric subjects with WGS data, we identified a significant intronic variant in EDIL3 (rs149378, P = 1.9 × 10-8) and a nearly significant intronic variant in LHX4 (rs79008224, P = 7.2 × 10-8). In pediatric subjects with genotyped data, two significant intronic variants were detected: FAM149A (rs6852180, P = 1.8 × 10-8) and CYS1 (rs61052588, P = 3.0 × 10-8). Additionally, an intergenic variant near C1orf94 (rs1404350, P = 1.2 × 10-14) was highly significant. In genotyped adult subjects, a single variant was observed in KCNQ3 (rs79089725, P = 2.0 × 10-8). Conclusion:Our analysis represents one of the most extensive ependymoma-specific GWAS conducted to date. Several significant intronic variants were harbored in genes associated with cancer and neurological disease. Future studies are needed to investigate the role of these age-specific alterations in ependymoma pathogenesis.

Background:GBM is one of the most common and most aggressive brain tumors in adults, and upfront standard of care treatment has limited efficacy. Immune checkpoint inhibitor strategies have significantly improved outcomes in various solid tumors but have not proven effective in GBM, suggesting other strategies may be needed to realize their full potential. Methods:GBM patients were treated with upfront standard of care chemoradiation with temozolomide and pembrolizumab, followed by adjuvant temozolomide and pembrolizumab for six nine-week cycles. Depending on production of sufficient vaccine, patients were randomized into HSPPC-96 vaccine or placebo group (q4 weeks) while those with failed vaccine production continued on study unblinded as an ancillary group. The primary objective was overall survival at one year, and secondary endpoints were progression-free survival at six months, overall and progression-free survival, radiographic response, and tolerability by patient-reported outcomes and adverse event documentation. Results:90 patients were screened, 32 were treated (8 vaccine, 9 placebo, 15 ancillary), and 26 were evaluable for radiographic responses prior to accrual termination. The study did not meet its primary endpoint of overall survival at one year (65.5% in vaccine group, 75% in placebo). Progression-free endpoints were mildly improved in the vaccine group but were not significant, and response rates were not significantly different. The regimen was well-tolerated and safe. Conclusions:Though limited by early discontinuation, these findings do not support the combination of pembrolizumab and HSPPC-96 vaccine with standard of care therapy. Trials Registration:ClinicalTrials.gov identifier: NCT03018288.

Background:Glioblastoma (GBM) lacks effective therapies for recurrent disease. Unlike cancers with successful fusion-targeted treatments (eg BCR-ABL1 in CML), the incidence and therapeutic potential of gene fusions in GBM remain unclear. We analyzed a large genomic database to define fusion frequency and molecular associations. Methods:4800 IDH-wildtype GBM samples (WHO 2021) underwent NextGen DNA sequencing (592-gene panel/whole exome) and Whole Transcriptome Sequencing for fusions at Caris Life Sciences. Fisher-Exact/Chi-Square tests, adjusted by Benjamini-Hochberg (q < 0.05), assessed significance. Results:Pathogenic fusions occurred in 428 (8.9%) samples, primarily FGFR3 (37%, n = 159; FGFR3: TACC3, n = 134), MET (21%, n = 92), and EGFR (20%, n = 87). Pathogenic or likely pathogenic fusions included NTRK2 (n = 27), PDGFRA (n = 23), ROS1 (n = 14), and BRAF (n = 10). Fusion-positive tumors had higher MET (7.5% vs. 0.7%), FGFR3 (5% vs. 0.2%), CDK4 (17% vs. 11%), and MDM2 (12% vs. 7.5%) amplifications, but lower EGFR mutations (6.1% vs. 18%), amplifications (6.1% vs. 18%), and EGFRvIII (11.9% vs. 22.5%) (all q < 0.05). Median survival was 16.6 months (fusion-positive) vs. 15.5 months (fusion-negative) (P = 0.043). Tyrosine kinase inhibitor (TKI)-treated fusion-positive patients (n = 37) showed no significant survival benefit (18.4 vs. 16.5 months, P = .971). Conclusions:Approximately 9% of GBMs harbor targetable fusions, with five genes (FGFR3, MET, EGFR, NTRK2, PDGFRA) comprising 8%. These findings support multi-arm clinical trials to evaluate targeted therapies, potentially improving outcomes for molecularly defined GBM subgroups.

Glioblastoma is the most common type of malignant primary brain tumor and a major cause of morbidity and mortality. In 2021, the World Health Organization updated the classification of Central Nervous System (CNS) tumors to restrict glioblastomas to isocitrate dehydrogenase-wildtype (IDHwt) tumors, improving understanding of the prognosis and optimal therapy for these tumors. This revision also enables more homogeneous populations of patients to be enrolled in clinical trials, facilitating the evaluation of novel therapies. In this updated consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of patients with glioblastoma is discussed. In addition, novel therapies such as immunotherapies, viral therapies, targeted molecular therapies, theranostics, and antibody-drug conjugates will be reviewed, as well as the current challenges and future directions for research.

Background Incorporating Clinical Outcome Assessments (COAs) in oncology trials is essential for evaluating therapeutic benefits and balancing survival with quality of life and symptom management. Understanding COA adoption trends and gaps is especially critical in neuro-oncology due to the complex symptom profiles of neuro-oncology patients.Methods We reviewed neuro-oncology trials in ClinicalTrials.gov, identifying COA instruments using the PROQOLID database. We analyzed trends in COA usage, associations with trial characteristics, and the impact of key regulatory and advocacy efforts using correlation and regression analyses.Results Of 1,874 adult interventional neuro-oncology trials with sufficient data, 85% were early-phase, 91% treatment-focused, primarily studying glioblastomas (61%), and unspecified gliomas (42%); 16% used COAs, with 127 distinct instruments reported; of these trials, 71% used Patient Reported Outcomes, 46% used Clinician-Reported Outcomes, with other categories of COAs used by fewer than 12% of the trials. COA use was more likely in later-phase trials (OR = 1.38, P <.00001), supportive care trials (OR > 1, P <.01), studies on novel versus FDA-approved interventions (OR = 1.72, P <.00001), single- versus multi-arm trials (OR = 1.62, P =.027), and randomized versus nonrandomized trials (OR = 3.28, P <.00001). COA incorporation increased over time (R = 0.77, P <.00001), especially in treatment-focused trials (R = 0.88, P <.00001) and across all COA types except composite measures.Conclusions Our computational assessment highlights low but increasing COA adoption in neuro-oncology trials, mirroring broader oncology trends and reflecting a cumulative impact of regulatory and advocacy efforts. Priority areas for improvement include early-phase trials, FDA-approved interventions, and treatment-focused studies. Our findings emphasize the need for COA-specific reporting improvements and greater standardization in neuro-oncology research.

(A) Phase contrast images showed the cytotoxicity of TMZ (400 mM)/ipatasertib (Ipa, 2 mM) combination treatment in the brain tumor-initiating cells (BTICs). A ferroptosis inhibitor, Ferrstain-1 (Ferr-1, 5 mM), was used to rescue the ferroptotic cell death. Bar = 100 mM. (B) Representative flow cytometric analysis of live/dead staining in BTICs in response to TMZ/Ipa treatment. (C) Statistical analysis of dead/live cell ratio in BTICs. (D) The limiting dilution assay evaluated the frequency of generating spheres in GSC827 and TSC603 after receiving TMZ/Ipa treatment. **p < 0.01.

(A) Gene expression profiling showed the expression of GPX4 and SLC7A11 in IDH-mutated NHA cells (B) ROS-Glo assay measured the oxidative stress in IDH1WT and IDH1Mut NHA cells in response to ipatasertib (Ipa, 1 mM) treatment. (C) GSH, and GSSG level was measured in IDHWT and IDH1Mut NHA cells in response to Ipa (1 mM) treatment. GSH/GSSG ratio was calculated. (D) Immunoblotting analysis evaluated cleaved PARP in IDH1WT and IDH1Mut NHA cells with TMZ (200 mM) and/or Ipa (1mM) treatment. b-actin was used as an internal control. (E) Cell viability analysis on NHA IDHWT cells under TMZ (200 mM) and Ipa (1mM) treatment. **p < 0.01.

Meningiomas are the most frequent primary intracranial tumors. Hence, they constitute a major share of diagnostic specimens in neuropathology practice. The 2021 WHO Classification of Central Nervous System Tumors ("CNS5") has introduced the first molecular grading parameters for meningioma with oncogenic variants in the TERT promoter and homozygous deletion of CDKN2A/B as markers for CNS WHO grade 3. However, after the publication of the new classification volume, clarifications were requested, not only on novel but also on long-standing questions in meningioma grading that were beyond the scope of the WHO "blue book." In addition, more recent research into possible new molecular grading parameters could not yet be implemented in the 2021 classification but constitutes a compelling body of literature. Hence, the consortium to inform molecular and practical approaches to CNS tumor taxonomy-not official WHO (cIMPACT-NOW) Steering Committee convened a working group to provide such clarification and assess the evidence of possible novel molecular criteria. As a result, this cIMPACT-NOW update provides guidance for more standardized morphological evaluation and interpretation, most prominently pertaining to brain invasion, identifies scenarios in which advanced molecular testing is recommended, proposes to assign CNS WHO grade 2 for cases with CNS WHO grade 1 morphology but chromosomal arm 1p deletion in combination with 22q deletion and/or NF2 oncogenic variants, and discusses areas in which the current evidence is not yet sufficient to result in new recommendations.

Pathway enrichment analysis of carmustine-sensitive versus carmustine-resistant cell lines.

Evaluation of the combined contribution of MGMT promoter and body methylation to mRNA and protein expression and carmustine sensitivity.

Background Glioblastoma (GBM) is the most aggressive primary brain cancer in adults and remains incurable. Mucosal-associated invariant T (MAIT) cells are unconventional T cells with a semi-invariant T cell receptor and have been shown to regulate immune responses. However, the role of MAIT cells in glioblastoma (GBM) has not been well characterized. Methods We used flow cytometry, bulk RNA-seq and scRNA-seq, and multiplexed tissue imaging to investigate the role of MAIT cells in GBM. Results Flow cytometry analysis of peripheral blood samples of GBM patients showed a significant reduction of MAIT cell frequency and the ability to produce Th1 cytokines. In bulk RNA sequencing data analysis of GBM tissues, the MAIT cell gene signature significantly correlated with poor patient survival. A scRNA-seq of CD45+ cells from 20 GBM tissue samples showed 12 (60%) were positive for MAIT cells and the enrichment of RORC-expressing MAIT17. The MAIT cell signature significantly correlated with tumor-associated neutrophil (TAN) activities. Multiple immune suppressive genes known to be used by TANs were upregulated in MAIT-positive tumors. Spatial imaging analysis of GBM tissues showed that all specimens were positive for both MAIT cells and TANs, and localized enrichment of TANs. Conclusion These findings revealed an immunosuppressive role of MAIT cells in GBM and highlighted the MAIT-TAN axis as a potential novel therapeutic target to modulate GBM’s immunosuppressive tumor microenvironment.

BACKGROUND:Instruments to assess patient-reported outcomes (PRO) should generate high-quality evidence. Reliable PRO evidence is essential to policymakers, in conjunction with outcomes such as survival and radiological response, to understand the net clinical benefit of antitumor treatments. This study aimed to establish the content validity of 215 identified PRO measures used in patients with brain tumors. METHODS:A survey (n = 148 items) was developed reflecting aspects of the WHO International Classification of Functioning, Disability, and Health (ICF) framework. Patients with brain tumors, their proxies, and healthcare professionals (HCPs) were asked to rate each survey item on relevance. An item was considered a relevant issue if ≥25% of the patients or proxies or ≥50% of the HCPs considered that item to be an issue. Next, all items in the identified PRO measures were linked to ICF and relevant items in the survey, and the percentage of content coverage was calculated. RESULTS:In total, 114 patients, 71 proxies, and 65 HCPs from different countries completed the survey. Fifty-six of 148 (37.8%) items in the survey were considered relevant. The most important aspects mentioned by both patients and proxies were difficulty concentrating, difficulty remembering, multitasking, and handling stress. Depending on the definition, between 35% and 49% of PRO measures were considered to have sufficient content validity (≥80% coverage). CONCLUSION:The content validity was insufficient in more than half of the identified PRO measures, particularly multidimensional measures. Future research should investigate whether different approaches to PRO assessment better meet the needs of all stakeholders.