Despite best clinical management, patients with meningiomas frequently experience tumor recurrence. During recent decades, efforts have been made to improve the prognostic stratification of meningiomas by incorporating molecular data. A subgroup of tumors harboring a homozygous CDKN2A deletion was identified, and a higher risk of tumor progression was observed, suggesting the potential use of cyclin-dependent kinases as biomarkers. In this retrospective single-center study, the immunohistochemical staining for the cyclin-dependent kinases p16, phosphoRB1 (pRB1), CDK4 and CDK6 was analyzed in 1751 paraffin-embedded meningioma samples. For the assessment of p16, CDK4 and CDK6, a semi-quantitative score was applied, whereas an automated quantification tool was used for pRB1. The distribution and association with histopathological results, clinical data and progression-free survival (PFS)—defined by radiographic tumor recurrence—were assessed. Of all meningioma samples, 14.9

Malignant brain tumors inevitably recur, leading to progressive neurological decline. Palliative care is essential for optimizing patient outcomes, yet its integration into neuro-oncology remains inconsistent. We conducted a nationwide survey to evaluate palliative care practices among German neuro-oncologists and assessed the impact of physicians’ comfort on end-of-life discussions in patient care. A nationwide, anonymous survey was distributed to 481 neuro-oncologists who are members of the Neuro-oncology Working Group of the German Cancer Society. The questionnaire, developed in collaboration with board-certified palliative care specialists, evaluated physicians’ demographic characteristics, palliative care knowledge, and access to palliative care resources. Of 92 respondents, 81 (88%) reported comfort in discussing end-of-life issues, while 11 (12%) expressed discomfort. Physicians comfortable with these discussions more frequently addressed withholding of life-sustaining interventions (88% versus 55%, p=0.011), arranged home care (81% versus 64%, p=0.019), and facilitated hospice placement (68% versus 36%, p=0.021). They also initiated these conversations earlier and observed greater patient receptivity to palliative care (p=0.049). These associations remained significant in multivariable logistic regression. While most neuro-oncologists report comfort with end-of-life discussions, this comfort strongly influences timing and extent of palliative care integration. Our findings highlight the need for structured palliative care training to ensure timely and effective discussions, ultimately improving care for neuro-oncological patients.

Classification of tumors in neuro-oncology today relies on molecular patterns (mostly DNA methylation) and their machine learning-supported interpretation. Understanding the process of algorithmic interpretation is essential for safe application in clinical routine. This is paradigmatically true for the most common primary intracranial tumor in adults, meningioma. Here, by applying multiomic profiling and multiple lines of orthogonal computational evaluation in multiple independent datasets, we found that not only tumor cell characteristics but also incremental changes in the tumor microenvironment (TME) have impact on epigenetic meningioma classification and clinical outcome. Besides revealing the decisive role of non-neoplastic cells in the CNS methylation classifier, this challenges the model of distinct meningioma subgroups toward a TME-determined risk continuum. This refines current controversies in molecular meningioma subtyping. In addition, we apply these learnings to devise and validate a simple diagnostic approach for increased clinical prediction accuracy based on immunohistochemistry, which is also applicable in resource-limited settings.

Background:Dexamethasone (DEXA) is the routine therapy for tumor- or treatment-associated edema management in glioblastoma, whereas bevacizumab (BEV) is increasingly used as a steroid-sparing alternative. Although both reduce edema, their broader immunometabolic effects remain ill-defined. Here, we examine how DEXA and BEV differentially affect tumor metabolism and microenvironment in patient samples and experimental models. Methods:We integrated 1H-NMR-based metabolomics of human glioblastoma specimens with mechanistic in vitro studies to compare DEXA and BEV. Microenvironmental modulation by DEXA vs BEV was further investigated in vivo in a syngeneic, immunocompetent orthotopic glioma mouse model by flow cytometry and immunohistochemistry, followed by ex vivo co-culture models. Results:Tumors from DEXA-treated patients (n = 12) vs steroid-naive controls (n = 18) showed nine significantly altered metabolites, including increased lactate, cystathionine, and 2-hydroxybutyrate, indicating a metabolically accelerated, proliferation-associated state. In an immunocompetent orthotopic glioma model, DEXA reduced intratumoral T cell infiltration and induced cytokine conditions favoring regulatory T cells (Tregs) and myeloid recruitment. In contrast, BEV elicited a coordinated immunostimulatory phenotype: it increased chemotactic cytokines in vitro (eg CCL5), decreased intratumoral Tregs (CD4+FOXP3+), enhanced activated, Granzyme B (GzmB) expressing effector T cells (CD4+GzmB+) in vivo, and improved spleenocyte-mediated tumor cell killing ex vivo. Conclusions:Together, DEXA promotes an immunosuppressive, metabolically active tumor microenvironment, whereas BEV supports immune infiltration and activation. These data, combining tissue-derived metabolomics with functional and mechanistic studies in vitro, ex vivo, and in vivo, reveal fundamentally divergent immunometabolic effects of anti-edematous therapies with direct implications in clinical practice, particularly alongside immunotherapy in glioblastoma.

Leptomeningeal metastatic disease (LMD) of solid tumors represents a cancer stage with high unmet therapeutic need. Here we report results from the dose escalation part of a multicenter phase 1 trial investigating intraventricular nivolumab, now continuing in the expansion part. Eligible participants had LMD from tumors with an approval for intraveneous PD1/PDL1 therapy or high tumor mutational burden. The primary endpoint was safety across four dose levels (20, 30, 40 and 50 mg) with each cohort reviewed by an independent data safety monitoring board before escalation. The secondary endpoint was overall survival. Exploratory endpoints included participant-reported outcome measures. Of 30 enrolled participants, 24 received at least one dose (intention-to-treat population) and 18 completed predefined safety evaluations (per-protocol population). One dose-limiting toxicity occurred at 40 mg. The primary endpoint was met and the recommended fixed dose for the ongoing expansion part is 50 mg. Median overall survival (OS) was 6.6 months. The 6-month, 12-month and 18-month OS rates were 55.0% (95% confidence interval (CI): 37.5-80.6%), 33.3% (95% CI: 17.8-62.4%) and 16.7% (95% CI 6.03-46.1%), respectively. Participant-reported quality of life remained stable. Intraventricular nivolumab has demonstrated safety and feasibility (ClinicalTrials.gov: NCT05112549 ).

The isocitrate dehydrogenase (IDH) family of proteins comprises three important metabolic enzymes that convert isocitrate to alpha ketoglutarate (α-KG) via oxidative decarboxylation. The IDH enzymes play important roles in epigenetic regulation, DNA repair, and cellular metabolism and biosynthesis. In mutant IDH (mIDH) cells, α-KG is converted into the functional oncometabolite 2-hydroxyglutarate (2-HG) in a process that consumes the reduced form of nicotinamide adenine dinucleotide phosphate to generate its oxidised form. 2-HG competitively inhibits α-KG from binding to the active site of histone and DNA demethylases, leading to hypermethylation, which inhibits cellular differentiation and induces tumour cell proliferation. Increased 2-HG also has other effects on cellular biology, including altered metabolism, dysregulation of gene expression, alterations in the DNA damage repair pathway, inflammation, and cell death, therefore supporting and promoting tumorigenesis. mIDH genes are associated with a variety of cancers, including but not limited to, cholangiocarcinoma, acute myeloid leukaemia, glioma, and chondrosarcoma, and the incidences of mIDH in these cancers varies and is approximately 13%, 33%, 73%, and 56%, respectively. The biological effects of mIDH are distinct in different cancers, but the reason that mIDH promotes tumour development in some tissues and not others is not clear. mIDH has no definitive prognostic impact in these cancers, except glioma, in which it is a disease-defining marker due to its distinct prognostic significance. mIDH1/2 are actionable mutations that represent therapeutic targets, however available targeted therapies to treat mIDH cancers are lacking. This article discusses mIDH genes and their importance in each of these cancers.

Background:Primary central nervous system (CNS) tumors are rare malignancies with limited treatment options, resulting in high mortality. Unlike other solid tumors, CNS tumors present unique challenges that impact the health-related quality of life (HRQoL) of patients and caregivers. Effective management requires balancing oncologic treatment with the control of neurocognitive deficits, epilepsy, and other neurological symptoms. Methods:The European Society for Medical Oncology (ESMO) CNS Faculty conducted a consensus process to identify the most pressing educational priorities for physicians managing CNS malignancies. This process involved structured data collection and expert input to determine critical areas for disease-specific education and training. Results:The consensus process highlighted key educational gaps in managing CNS tumors, emphasizing the need for a multidisciplinary approach to optimize therapeutic strategies, improve survival outcomes, enhance HRQoL during treatment and survivorship, and facilitate access to emerging therapies. Physicians reported that comprehensive, disease-specific education is essential to address these challenges effectively. Conclusion:CNS tumors require targeted educational initiatives to equip healthcare providers with the knowledge and skills necessary for optimal patient care. The ESMO CNS Faculty consensus underscores the importance of structured, disease-specific training to improve outcomes, support HRQoL, and advance oncology education in the management of CNS malignancies.

Background The use of proton pump inhibitors with strong aldehyde dehydrogenase 1A1-activating properties (PA-PPI) has recently been associated with inferior outcomes in patients with newly diagnosed glioblastoma. While the mechanisms mediating such outcome associations remain incompletely understood, no such data have been generated for patients with recurrent glioblastoma. Materials and Methods We conducted a pooled analysis of four clinical trials in the setting of first recurrence of glioblastoma: DIRECTOR (NCT00941460), EORTC 1410 (NCT02343406), EORTC 1608 (arm C) (NCT03224104), and EORTC 26034 (NCT00086879). We assessed PA-PPI use at baseline and at two defined landmarks, week 8 and week 16. Cox models were used to identify associations of PA-PPI use with outcome. Results On univariate analysis, PA-PPI use was associated with inferior overall survival, but not progression-free survival, at baseline and at both landmarks. However, PA-PPI use was no longer prognostic in multivariable analyses controlling for major prognostic factors. Omission of distinct prognostic factors from the multivariate Cox models revealed that steroid use made PA-PPI use insignificant. Indeed, PA-PPI use was associated with steroid use. Discussion The present analysis of prognostic outcome associations of PA-PPI use in patients with recurrent glioblastoma provides no evidence that PA-PPI use may compromise outcome in this setting. The disconnect between clear outcome associations in the first-line setting, without a link to MGMT promoter methylation, versus no associations in the recurrent setting may be linked to changing prescriptions patterns, but requires further studies. Since alternative medications are available, the indications for PA-PPI prescription should probably be narrowed in patients with glioblastoma.

The clonal glioma driver mutation IDH1R132H gives rise to a major histocompatibility class II-restricted neoepitope. A multicenter, first-in-human phase 1 trial met its prespecified primary endpoints by demonstrating safety and immunogenicity of an IDH1-R132H peptide vaccine (IDH1-vac) integrated into standard of care in 33 participants with newly diagnosed grade III and IV (World Health Organization classification 2007) IDH1-R132H+ astrocytomas (NOA16). Here we report on the clinical and immunological long-term follow-up of this trial as secondary and translational endpoints. The 8-year progression-free and overall survival (OS) rates were 0.42 (confidence interval (CI): 0.24-0.59) and 0.66 (CI: 0.46-0.79), respectively. For participants with grade IV astrocytoma, median OS was 106.1 months (CI: 39.6-not estimable (NE)), comparing favorably to the published median OS in this population ranging from 31.6-56.4 months. Within the responder group, sustained antibody responses to IDH1-R132H were associated with a favorable long-term clinical course. IDH1-vac-induced T cell responses were detected in the inflamed brain lesion of an IDH1-vac-associated pseudoprogression, whereas no IDH1-vac-induced T cells were found in participants with early progressive disease. The favorable long-term outcome of the NOA16 cohort supports investigating IDH1-vac in persons with newly diagnosed grade 3 and 4 (World Health Organization classification 2021) IDH-mutant astrocytomas in a randomized phase 2 trial (ClinicalTrials.gov identifier: NCT02454634 ).

Abstract Rapid vascular recovery is a key feature preceding glioblastoma (GBM) recurrence after radiotherapy (RT). We performed spatial expression analyses, providing a rationale for dual inhibition of two non-redundant, spatially distinct acting factors, CXCL12 and VEGF. Subsequently, we expanded a multicentric phase 1/2 trial (NCT04121455), which initially combined RT and the CXCL12-neutralizing L-RNA-aptamer olaptesed pegol (NOX-A12) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT promoter methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose, recommended phase 2 dose, NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life, median progression-free survival (PFS), 6-months PFS and overall survival (OS). For the expansion arm, six patients were included that additionally received the VEGF-targeting antibody bevacizumab (BEV) to RT and NOX-A12. Combinatory treatment was well-tolerated and safe with no treatment-related deaths, resulting in abrogated tumor perfusion (rCBV, FTBhigh) and delayed tumor regrowth as per mRANO. Median progression-free (PFS) and overall survival (OS) after RT + BEV + NOX-A12 were 9.1 and 19.9 months, respectively, significantly outperforming RT + NOX-A12 (p = 0.009; p = 0.021) in a post-hoc comparative analysis, with two patients exceeding 2-year OS. These findings establish proof-of-principle for dual inhibition of CXCL12 and VEGF in patients with newly-diagnosed GBM following RT.

BACKGROUND:Glioblastoma harbors frequent alterations in the retinoblastoma pathway, providing a genetic rationale for therapeutic targeting with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. The NOA-20 trial did not reveal a progression-free survival benefit of CDK4/6 inhibition plus radiation therapy in newly diagnosed, O6-methylguanine DNA methyltransferase (MGMT)-unmethylated glioblastoma. In fact, CDK4/6 inhibitor monotherapy has not demonstrated efficacy in solid tumors. We aimed at discovering response modulators to CDK4/6 inhibition, paving the way for rational combination therapies. METHODS:We conducted genome-wide CRISPR-Cas9 screens in human glioma cell lines and stem-like cells (LN229, LN18, LNZ308, T98G, and GS-9) under CDK4/6 inhibition, employing knockout (Brunello library) and activation strategies (Calabrese library), followed by genetic and pharmacological validation of selected candidate genes in vitro and ex vivo (primary cultures) as well as the investigation of 1 functionally instructed combination therapy in vivo. RESULTS:Loss of AMBRA1 and gain of function of CCNE1 reduced sensitivity to CDK4/6 inhibition in glioma cells, whereas disruption of checkpoint kinase 1 (CHEK1) or FAM122A resulted in synthetic lethality in combination with CDK4/6 inhibition. AMBRA1-deficient glioma cells exhibited increased sensitivity to CHK1 inhibition, revealing a context-specific vulnerability. Combined inhibition of CHK1 and CDK4/6 led to synergistic antiglioma activity in vitro, ex vivo, and in vivo. CONCLUSIONS:Our data identify AMBRA1, CCNE1, CHEK1, and FAM122A as potential molecular modifiers of CDK4/6 inhibition response in experimental glioma and provide a biological rationale for combinatorial targeting with CDK4/6 inhibition in glioblastoma.

Meningioma is the most common primary brain tumour in adults. However, molecular drivers of progression occurring in a subset of meningiomas are poorly understood. We hypothesise that epigenomic variations are causal for the clinical heterogeneity of meningiomas and may be functionally relevant for disease progression. To test this hypothesis, we perform global DNA methylation profiling of a large cross-sectional cohort and a longitudinal cohort of human meningiomas. Our analysis identifies a DNA hypermethylation signature that is correlated with clinical outcomes and enables more accurate prognostication for meningiomas than previous classification systems. Analyses of longitudinal high-grade meningioma samples in comparison to clinically benign meningiomas and normal meningeal tissue show convergent contributions but differing plasticity of copy number variations and DNA hypermethylation along the trajectory of meningioma progression. Systematic analysis of DNA hypermethylation in high-grade meningiomas unravels a tumour suppressive role of clustered protocadherins by restricting β-catenin nuclear localisation, consistent with the association between nuclear β-catenin staining and meningioma progression. Together, our study provides fundamental insights into the molecular mechanisms underlying the heterogeneity of clinically benign and aggressive meningiomas and the microevolutionary adaptation during disease progression.

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:DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed. METHODS:We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade. RESULTS:We first demonstrated that all risk groups benefit from gross total resection. All "high-risk, RT sensitive" tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (P = .003); after subtotal resection (STR), from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (P = .004). "Low-risk, RT sensitive cases" (n = 1207, 61.8%) also benefited from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, P = .03), suggesting that RT be considered in these patients. Neither "low-risk RT resistant" (n = 84, 4.3%) nor "high-risk RT resistant" (n = 356, 18.2%) cases benefited from RT, and the latter group was associated with universally poor outcomes. CONCLUSIONS:We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

BACKGROUND:Tumor resection is a prerequisite in many studies of new glioblastoma therapeutics; however, no clear parameters for "resectability" exist. We evaluated inter-rater variability in assessing tumor resectability and potential associations between resectability and survival in a trial cohort of glioblastoma recurrence. METHODS:DIRECTOR (NCT00941460; 9/2009-6/2012) evaluated two dose-dense temozolomide regimens for first recurrent glioblastoma, yielding similar outcomes between arms. Re-resection was allowed before initiation of systemic therapy by institutional decision. Eleven surgical neuro-oncologists (blinded to final outcomes) rated whether a "meaningful resection" was achievable for each recurrent IDH-wildtype glioblastoma based on imaging and clinical data. RESULTS:MRI scans from 69 patients were available (median age: 58.2 ± 1.1 years, median survival: 10.0 months). Forty patients underwent re-resection (median age: 56.4 ± 1.7 years, median survival: 10.8 months). Surgical decision-making markedly varied between raters, ranging from 30 to 58 of 69 cases being classified as "resectable" (κ = 0.405). In patients who received re-resection, a "meaningful resection" was deemed feasible by >80% of raters in 30/40 cases (75.0%). For patients without re-resection, unanimous agreement on non-resectability occurred in only 3/29 cases (10.4%); and 5/29 tumors (17.2%) were considered resectable by >80% of raters. Knowledge of additional clinical factors virtually never changed MRI-based judgments. While patients who had a complete resection of contrast-enhancing tumor had favorable outcomes, a consensus on resectability by >80% of raters was not associated with prolonged overall survival. DISCUSSION:Feasibility assessment for re-resection is heterogeneous among neurosurgeons, challenging single-surgeon evaluation of "resectability." Those findings are limited by the number of surgical raters and the size of the DIRECTOR cohort.

The use of mutant isocitrate dehydrogenase (mIDH) inhibitors has been investigated and has shown significant improvement in survival outcomes in patients with a range of mIDH cancers, including acute myeloid leukaemia (AML), cholangiocarcinoma (CCA), glioma and conventional chondrosarcoma. In the phase 3 clinical trial ClarIDHy, patients with mIDH1 CCA treated with ivosidenib had improved overall survival (OS) compared to those treated with placebo (hazard ratio [HR]: 0.79 [95% confidence interval [CI]: 0.56-1.12]; P=0.09). In the phase 3 AGILE study, patients with mIDH1 AML treated with ivosidenib plus azacitidine showed improved OS compared to those treated with placebo plus azacitidine (HR: 0.42 [95% CI: 0.27-0.73]; P=0.001). In conventional chondrosarcoma, ivosidenib demonstrated efficacy in a phase 1 trial and the ongoing phase 3, placebo-controlled clinical trial CHONQUER will investigate the use of ivosidenib in patients with unresectable, progressive, conventional mIDH1 chondrosarcoma. The phase 3 clinical trial INDIGO explored the use of vorasidenib for the treatment of Central Nervous System World Health Organization grade 2 mIDH glioma and showed that vorasidenib had a progression-free survival benefit over placebo in previously untreated patients (HR: 0.39 [95% CI: 0.27-0.56]; P<0.0001). Across these studies, mIDH inhibitors were well-tolerated. Current efforts focus on further evaluating the efficacy and safety of mIDH inhibitors in different lines of therapy, in combination with other anti-neoplastic agents, and in other mIDH cancers.