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Background: Ethnic diversity in cancer clinical trials is essential to ensure that therapeutic advances are equitable and broadly applicable in multicultural societies. Yet, missing consensus on the documentation of ethnic origin, partially based on the complexity of the terminology and fear of discrimination, leads to suboptimal patient management of minority populations. Additionally, eligibility criteria, such as stringent laboratory cut-offs, often fail to account for variations across ethnic groups, potentially excluding patients without evidence-based justification., Patients and Methods: This analysis addresses this issue by investigating ethnic diversity in clinical trials that led to European Medicines Agency (EMA) and Food and Drug Administration (FDA) approvals between 2020 and 2022. Trials were identified from FDA and EMA databases, and available protocols and full-text publications were reviewed for documentation of ethnic background and eligibility criteria for organ function (bone marrow, liver, and renal). Descriptive statistics were applied to summarize the findings., Results: Of the 56 trials analyzed, only two-thirds of primary result publications included information on ethnic origin. Caucasian and Asian groups were documented in most of those trials and also had the highest percentages of participants across trials, while other ethnic subgroups were less frequently documented and only made up a small proportion of trial participants. Eligibility criteria often set strict organ function cut-offs that did not consider variations among ethnic groups, potentially excluding minorities. The Cockcroft-Gault formula was frequently used to assess kidney function, despite its known limitations for multiethnic cohorts., Conclusions: Ethnic homogenous participants and eligibility criteria that favor majority groups limit the applicability of findings in diverse populations, leading to inadequate patient management. While United States guidelines encourage inclusivity, similar recommendations are lacking in Europe. Thus European regulatory authorities, research organizations, and patient advocates should establish guidelines to improve ethnic diversity in cancer clinical trials, aligning research practices with the increasingly multicultural composition of European societies., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Brain metastases (BMs) are common in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer, increasing morbidity and mortality. Systemic therapy for BMs can be effective, with the triple combination of trastuzumab, capecitabine, and tucatinib being a potential standard. More recently, intracranial activity of antibody-drug conjugates has been reported, but the size of individual studies has been small. Therefore, this patient-level pooled analysis was conducted., Patients and Methods: This is a patient-level pooled analysis of the prospective phase II DEBBRAH and TUXEDO-1 trials and the retrospective DFCI/Duke/MDACC cohort. Patients with evaluable active BMs (defined as newly diagnosed and untreated or progressing with measurable tumor-related size after previous local therapy) from HER2-positive breast cancer (BC) and treated with trastuzumab deruxtecan (T-DXd) included in these studies were eligible. The primary endpoint was intracranial objective response rate (ORR-IC) by Response Assessment in Neuro-Oncology (RANO)-BM criteria., Results: Overall, 37 patients were assessable for intracranial response assessment. BMs progressing after prior local therapy were present in 64.9% of patients. The median patient age was 49.1 years. All patients had received prior trastuzumab and the median number of prior systemic treatment lines was 3 (0-13). The pooled ORR-IC by RANO-BM criteria was 64.9% [95% confidence interval (CI) 47.5% to 79.8%] with low heterogeneity observed between the studies included. The clinical benefit rate by RANO-BM was 81.1% (95% CI 64.8% to 92.0%). The median progression-free survival was 13.3 months (95% CI 8.4-22.6 months) and the median overall survival was 22.5 months (95% CI 14.9 months-not achieved) with high heterogeneity between studies and numerically longer in patients with few prior treatment lines. Quality of life remained stable throughout treatment, with no new safety concerns., Conclusions: This patient-level pooled analysis of DEBBRAH, TUXEDO-1, and the DFCI/Duke/MDACC cohort indicates clinically relevant intracranial activity of T-DXd in patients with active HER2-positive BC, BMs, and extensive systemic pretreatment. The results therefore support the use of T-DXd when clinically indicated irrespective of BMs., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Gliomas are the most common brain tumor type in children and adolescents. To date, diagnosis and therapy monitoring for these tumors rely on magnetic resonance imaging (MRI) and histopathological as well as molecular analyses of tumor tissue. Recently, liquid biopsies (LB) have emerged as promising tool for diagnosis and longitudinal tumor assessment potentially allowing for a more precise therapeutic management. However, the optimal strategy for monitoring gliomas by LB remains to be determined. In this study, we analyzed circulating tumor DNA (ctDNA) from 78 liquid biopsies (plasma n = 44, cerebrospinal fluid n = 34 (CSF)) of 35 glioma patients, determining H3F3A K28M (K27M) and BRAF V600E mutation allele frequency using droplet digital PCR (ddPCR). All results were correlated to clinically relevant parameters including diagnostic imaging and CSF aspiration site (ventricular vs lumbar) with respect to tumor localization. Regarding diagnostic accuracy, the calculated sensitivity score in the H3F3A K27M cohort was 84.61% for CSF and 73.68% for plasma. In the BRAF V600E cohort, we determined a sensitivity of 83.3% in plasma and 80% in CSF. The overall specificity was 100%. With respect to the CSF aspiration, the intra-operatively obtained CSF demonstrated 100% detection rate, followed by ventricular CSF obtained via Ommaya Reservoir/shunt puncture (93%) and CSF obtained via lumbar puncture (66%). Notably, this further correlated with the proximity of the CSF site to tumor localization. Longitudinal CSF monitoring demonstrated a good correlation to clinical and radiological disease evolution. Importantly, we show for the first time that monitoring BRAF V600E by ddPCR could serve as treatment response assessment in gliomas. In summary, our observation may inform recommendations with regard to location of CSF aspiration when incorporating LB into future treatment protocols., Competing Interests: Declarations. Conflict of interest: MP has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp and Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, Medscape, OncLive. All the other authors declare no conflicts of interests. JG has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Novartis, Roche. A.A. has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Novartis, Alexion. All the other authors declare no conflicts of interests. Ethical approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of the Medical University of Vienna (EK 1244/2016)., (© 2024. The Author(s).)

Isocitrate dehydrogenase (IDH)-mutant gliomas are the most common malignant primary brain tumors in young adults. This condition imposes a substantial burden on patients and their caregivers, marked by neurocognitive deficits and high mortality rates due to tumor progression, coupled with significant morbidity from current treatment modalities. Although surgery, radiation therapy, and chemotherapy improve survival, these treatments can adversely affect cognitive function, quality of life, finances, employment status, and overall independence. Consequently, there is an urgent need for innovative strategies that delay progression and the use of radiation therapy and chemotherapy. The recent Federal Drug Administration (FDA) approval of vorasidenib, a brain-penetrant small molecule targeting mutant IDH1/2 proteins, heralds a shift in the therapeutic landscape for IDH-mutant gliomas. In this review, we address the role of vorasidenib in the treatment of IDH-mutant gliomas, providing a roadmap for its incorporation into daily practice. We discuss ongoing clinical trials with vorasidenib and other IDH inhibitors, as single-agent or in combination with other therapies, as well as current challenges and future directions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The Brain Tumor Group (BTG) of the European Organization for Research and Treatment of Cancer (EORTC) conducts academic clinical trials and translational research to improve clinical management of patients with primary and secondary brain tumors. The EORTC BTG has traditionally played an important role in providing evidence and thus advancing the field, albeit with a main focus on radiotherapy and pharmacotherapy in gliomas. Although examples of well-designed neuro-oncological surgical trials can be found, evidence in surgical neuro-oncology predominantly includes data from uncontrolled prospective series or retrospective cohorts. By means of a thorough literature and EORTC database review, we demonstrate, firstly, that while the pathway of the neuro-oncology patient most often starts with neurosurgery, its several aspects have traditionally been poorly acknowledged in clinical trials in neuro-oncology. We also show that the definitions and methods of assessment vary greatly between studies, limiting generalizability. The newly established Neurosurgery Committee of the EORTC BTG aims to address this gap by increasing the number of prospective surgical trials, but also the involvement of neurosurgeons in clinical trial design, promoting standardized terminology for description of the surgical aspects, including extent of resection. We will also explore alternative trial designs when randomization is deemed difficult, as well as focus on defining surgical quality indicators that influence outcome. By addressing these challenges, the committee aims to enhance the quality of neurosurgical evidence in neuro-oncology and define optimal surgical methods and standards of care. This should ultimately improve outcomes and quality of life for patients with brain tumors through evidence-based surgical interventions., Competing Interests: Declaration of Competing Interest PK, MB, JG, GP, AJ, RG, RG, MJ, GW, MN, TP, CQ, TG, GM report no COI JD is editorial board member of Neuro-Oncology practice and was not involved in the editorial review or the decision to publish this article. TP is member of the editorial board of Neurosurgical Review (advisory board) and was not involved in the editorial review or the decision to publish this article. MB is in the editorial board of Acta Neurochirurgica and Brain and Spine and was not involved in the editorial review or the decision to publish this article. MJ is editorial board member of Neuro-Oncology and was not involved in the editorial review or the decision to publish this article. GM is an Editorial Board Member of Neuro-Oncology, Radiotherapy and Oncology, Journal of Neuro-Oncology; Associate Editor of Neuro-Oncology Practice, Neuro-oncology Advance and was not involved in the editorial review or the decision to publish this article. MP is executive editor of Neuro-Oncology and was not involved in the editorial review or the decision to publish this article. JD has received honoraria for advisory board participation from Miltenyi, Servier E.L.R. has received research grants from Bristol Meyers Squibb (BMS), and honoraria for lectures or advisory board participation or consulting from Bayer, Biodexa / Sitoxi, Janssen, Leo Pharma, Pierre Fabre, Roche, Seattle Genetics, and Servier. MP has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, Medscape, OncLive. MW has received research grants from Novartis, Quercis and Versameb, and honoraria for lectures or advisory board participation or consulting from Anheart, Bayer, Curevac, Medac, Neurosense, Novartis, Novocure, Orbus, Pfizer, Philogen, Roche and Servier., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Theranostics is a new treatment modality integrating molecular imaging with targeted radionuclide therapy. Theranostic agents have received regulatory approval for some systemic cancers and have therapeutic potential in neuro-oncology. As clinical trials are developed to evaluate the efficacy of theranostic agents in brain tumors, specific considerations will have to be considered, taking into account lessons learned from previous studies examining other treatment modalities in neuro-oncology. These include the need for molecular imaging or surgical window-of-opportunity studies to confirm adequate passage across the blood-brain barrier, optimize eligibility criteria, and selection of the most appropriate response criteria and endpoints to address issues such as pseudoprogression. This review will discuss some of the issues that should be considered when designing clinical trials for theranostic agents., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Targeted radionuclide therapy is an emerging therapeutic concept for metastatic cancer that can be considered if a tumor can be delineated by nuclear medicine imaging and also targeted based on the expression of a particular target (thera-nostics). This mode of treatment can also compete with or supplement conventional radiotherapy, for example, if MRI does not fully capture the extent of the disease, including microscopic metastases. Targeted radionuclide therapy for patients with thyroid cancer, with certain somatostatin receptor 2-expressing tumors and with prostate-specific membrane antigen-expressing prostate cancer is approved, and numerous approaches of targeted radionuclide therapy for patients with metastatic cancer are in development (eg, using fibroblast activation protein as a target). Although brain metastases are rare in cancers with approved targeted radionuclide therapies, there is no a priori reason to assume that such treatments would not be effective against brain metastases if the targets are expressed and not shielded by the blood-brain barrier. Here, we discuss the current state of the art and opportunities of targeted radionuclide therapies for patients with brain and leptomeningeal metastases., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Meningiomas are the most common intracranial neoplasms in adults. While most meningiomas are cured by resection, further treatment by radiotherapy may be needed, particularly in WHO grades 2 and 3 tumors which have an increased risk of recurrence, even after conventional therapies. Still, there is an urgent need for novel therapeutic strategies after the exhaustion of local treatment approaches. Radionuclide therapies combine the specificity of tumor-specific antibodies or ligands with the cytotoxic activity of radioactive emitters. Alongside this, integrated molecular imaging allows for a noninvasive assessment of predictive biomarkers as treatment targets. Whereas the concept of "theranostics" has initially evolved in extracranial tumors such as thyroid diseases, neuroendocrine tumors, and prostate cancer, data from retrospective case series and early phase trials underscore the potential of this strategy in meningioma. This review aims to explore the available evidence of radionuclide treatments and ongoing clinical trial initiatives in meningioma. Moreover, we discuss optimal clinical trial design and future perspectives in the field, including compound- and host-specific determinants of the efficacy of "theranostic" treatment approaches., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

According to the new WHO classification of 2021, gliomas are a heterogeneous group of tumors with very different histology, molecular genetics, and prognoses. In addition to glioblastomas, the most common gliomas, there are also numerous less common gliomas, some of which have a very favorable prognosis. Targeted radionuclide therapy is a therapeutic option that can be attractive if a tumor can be targeted based on its molecular characteristics. It is particularly useful when tumors cannot be completely resected or when conventional imaging does not fully capture the extent of the tumor. Numerous approaches to radionuclide therapy for gliomas are in early development. The most advanced approaches for patients with gliomas in the clinic employ L-type amino acid transporter 1 as an uptake mechanism for radiolabeled amino acids or target somatostatin receptor 2 or gastrin-releasing peptide receptor. Here, we discuss the various target structures of radionuclide therapy in gliomas and provide an outlook for which glioma entities radionuclide therapy could most likely provide a therapeutic alternative., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Brain metastases (BM) are a devastating complication of HER2-positive metastatic breast cancer (BC) and treatment strategies providing optimized local and systemic disease control are urgently required. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) and overall survival (OS) over trastuzumab emtansine but data regarding intracranial activity is limited. In the primary outcome analysis of TUXEDO-1, a high intracranial response rate (RR) was reported with T-DXd. Here, we report the final PFS and OS results., Patients and Methods: TUXEDO-1 accrued adult patients with HER2-positive BC and active BM (newly diagnosed or progressing) without indication for immediate local therapy. The primary endpoint was intracranial RR; secondary endpoints included PFS, OS, safety, quality-of-life (QoL), and neurocognitive function. PFS and OS were estimated with the Kaplan-Meier method and analyzed in the per-protocol population., Results: At 26.5 months median follow-up, median PFS was 21 months (95% CI: 13.3-n.r.) and median OS was not reached (95% CI: 22.2-n.r.). With longer follow-ups, no new safety signals were observed. The most common grade 3 adverse event was fatigue (20%). Grade 2 interstitial lung disease and a grade 3 symptomatic drop of left-ventricular ejection fraction were observed in one patient each. QoL was maintained over the treatment period., Conclusions: T-DXd yielded prolonged intra- and extracranial disease control in patients with active HER2-positive BC BM in line with results from the pivotal trials. These results support the concept of antibody-drug-conjugates as systemic therapy for active BM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Gliomas are the most common primary malignant brain tumours in adults. Despite decades of research into novel therapeutic approaches, the prognosis remains poor. PARP1-2 are critical for DNA repair, cell survival and genomic stability and PARP inhibition (PARPi) may be a promising therapeutic approach for gliomas. Inhibition of PARP activity leads to homologous recombination deficiency (HRD), which, in combination with DNA damage, results in cell death. This review summarises the current knowledge and future perspectives of PARPi in glioma. The available literature was reviewed using PubMed, recent major international oncology congresses were consulted, and ongoing clinical trials were searched using ClinicalTrials.gov. In translational research, PARPi have demonstrated a strong scientific rationale for their use in the treatment of glioma. They have been evaluated both alone and in combination with radiotherapy, temozolomide, anti-angiogenic agents, immunotherapy and other new drugs in newly diagnosed or recurrent glioma. Most studies were open-label, non-randomised, dose-escalation phase I-II trials. Early results show promising anti-tumour activity, and key challenges include identifying predictive biomarkers, elucidating synergistic effects in combination therapies, addressing the development of resistance, and managing hematological toxicity. In conclusion, early phase studies have shown promising anti-tumour activity of PARPi that should be confirmed in larger prospective and randomised trials. In addition, the development of novel PARPi with improved blood brain barrier (BBB) penetration and PARP inhibitor activity with new synergistic treatment combinations seems promising and needs to be further explored., Competing Interests: Declaration of Competing Interest Ahmed Idbaih reports a relationship with Research grants from Carthera, Transgene, Sanofi, Air Liquide, Servier, Nutritheragene, advisory board for Leo Pharma, Novocure and Boehringer Ingelheim Int, travel funding from Novocure, Carthera and Leo Pharma. Michael Weller reports a relationship with research grants from Novartis, Quercis and Versameb, and honoraria for lectures or advisory board participation or consulting from Anheart, Bayer, Curevac, Medac, Neurosense, Novartis, Novocure, Orbus, Pfizer, Philogen, Roche and Servier. Matteo Simonelli reports a relationship with honoraria for lectures or advisory board participation or consulting from Incyte, Bristol Myers Squibb, Servier, GlaxoSmithKline, Sanofi and travel funding from Roche, Pfizer, Sanofi. Giuseppe Lombardi reports a relationship with consulting or advisory role funding from ABBVIE, Bayer, Novartis, Orbus Therapeutics, BrainFarm, Celgene, CureTeq, GlaxoSmithKline, Health4U, Braun, Janssen, BioRegio Stern, Servier, Novocure, and travel funding from Roche and Bayer, Servier. Matthias Preusser has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, Medscape, OncLive., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The phase-3 INDIGO trial demonstrated that the isocitrate dehydrogenase ( IDH ) inhibitor vorasidenib significantly prolonged progression-free survival and delayed intervention in patients with CNS WHO grade 2 gliomas. However, conventional MRI showed limited response, with only 11% of patients having objective responses. Studies suggest that serial PET imaging with radiolabeled amino acids, such as O -(2-[ 18 F]-fluoroethyl)-L-tyrosine (FET) PET, may provide earlier and more informative assessments of treatment response than MRI. In an initial experience with FET PET, 3 out of 5 patients showed metabolic response to vorasidenib. This highlights FET PET's potential to guide decision-making, though further trials are needed to confirm outcome benefits., Competing Interests: N.G. received honoraria for lectures from Blue Earth Diagnostics, for advisory board participation from Telix Pharmaceuticals and Servier, and for consultancy services from Telix Pharmaceuticals. H.C.P. received travel support from Eli Lilly, MSD, Novartis, Pfizer, and Roche, and received lecture honoraria from Eli Lilly. N.L.A. has received honoraria for lectures, consultation or advisory board participation from Novartis, Advanced Accelerator Applications, Telix Pharmaceuticals, OncLive, MEDSIR, and Servier, and research funding from Novocure and Telix Pharmaceuticals. K.-J.L. received honoraria for consultancy services from Telix Pharmaceuticals. P.L. received honoraria for lectures from Blue Earth Diagnostics, and for advisory board participation from Servier. M.P. received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer Ingelheim, Telix, Medscape, and OncLive. All other authors reported no potential conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Abstract: Hemostatic imbalances are frequent in patients with cancer. Although cancer-associated thrombotic complications have been well characterized, data on bleeding events in patients with cancer are sparse. Therefore, we aimed to investigate the incidence, risk factors, and impact on prognosis of bleeding events in patients with cancer initiating systemic anticancer therapies in a prospective cohort study, the Vienna Cancer, Thrombosis, and Bleeding Study. The primary study outcome was defined as clinically relevant bleeding (CRB), comprising major bleeding (MB) and clinically relevant nonmajor bleeding. In total, 791 patients (48% female), with median age of 63 years (interquartile range [IQR], 54-70), with various cancer types, 65.5% stage IV, were included. Over a median follow-up of 19 months (IQR, 8.7-24.0), we observed 194 CRB events in 139 (17.6%) patients, of which 42 (30.0%) were tumor related, 64 (46.0%) gastrointestinal, and 7 (5.0%) intracerebral. The 12-month cumulative incidence of first CRB and MB was 16.6% (95% confidence interval [CI], 13.7-19.6) and 9.1% (95% CI, 6.8-11.3), respectively, in the whole cohort, and 14.4% (95% CI, 11.2-17.5) and 7.0% (95% CI, 4.7-9.2), respectively, in those without anticoagulation. Patients with head and neck cancer had the highest risk of CRB. Lower baseline hemoglobin and albumin were associated with bleeding in patients without anticoagulation. Seven (5.0%) bleeding events were fatal, of which 6 occurred in patients without anticoagulation. Patients with CRB were at an increased risk of all-cause mortality (multivariable transition hazard ratio, 5.80; 95% CI, 4.53-7.43). In patients with cancer, bleeding events represent a frequent complication and are associated with increased mortality., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4, ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGFR, PDGFR, as well as homologous recombination deficiency (HRD), genomic copy number variations, DNA methylation classes and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence level criteria, no molecular target reached ESCAT I ("ready for clinical use") classification and only mTOR pathway activation and NF2 alterations reached ESCAT II ("investigational") classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Recently, criteria based on amino acid positron emission tomography (PET) have been proposed for response assessment in diffuse gliomas (PET RANO 1.0). In this study, we compare the prevalence of measurable disease according to PET RANO 1.0 with magnetic resonance imaging (MRI)-based Response Assessment in Neuro-Oncology (RANO) criteria in glioblastoma., Methods: We retrospectively identified patients with newly diagnosed IDH-wild-type glioblastoma who underwent [18F] Fluoroethyltyrosine (FET) PET and MRI after resection or biopsy and before radio-/radiochemotherapy. Two independent investigators analyzed measurable disease according to PET RANO 1.0 or MRI-RANO criteria. Additionally, lesion size, congruency patterns, and uptake intensity on [18F]FET PET images were assessed., Results: We evaluated 125 patients including 49 cases after primary resection and 76 cases after biopsy. Using PET criteria, 113 out of 125 patients (90.4%) had measurable disease, with a median PET-positive volume of 15.34 cm3 (8.83-38.03). With MRI, a significantly lower proportion of patients had measurable disease (57/125, 45.6%; P < .001) with a median sum of maximum cross-sectional diameters of 35.65 mm (26.18-45.98). None of the 12 patients without measurable disease on PET had measurable disease on MRI. Contrariwise, 56/68 patients (82.4%) without measurable disease on MRI exhibited measurable disease on PET. Clinical performance status correlated significantly with PET-positive volume and MRI-based sum of diameters (P < .0059, P < .0087, respectively)., Conclusions: [18F]FET PET identifies a higher number of patients with measurable disease compared to conventional MRI in newly diagnosed glioblastoma. PET-based assessment may serve as a novel baseline parameter for evaluating residual tumor burden and improving patient stratification in glioblastoma studies. Further validation in prospective trials is warranted., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The clinical efficacy of isocitrate dehydrogenase (IDH) inhibitors in the treatment of patients with grade 2 IDH-mutant (mIDH) gliomas is a significant therapeutic advancement in neuro-oncology. It expands treatment options beyond traditional radiation therapy and cytotoxic chemotherapy, which may lead to significant long-term neurotoxic effects while extending patient survival. The INDIGO study demonstrated that vorasidenib, a pan-mIDH inhibitor, improved progression-free survival for patients with grade 2 mIDH gliomas following surgical resection or biopsy compared to placebo and was well tolerated. However, these encouraging results leave a wake of unanswered questions: Will higher-grade mIDH glioma patients benefit? When is the appropriate timing to start and stop treatment? Where does this new treatment option fit in with other treatment modalities? In this study, we review the limited data available to start addressing these questions, provide a framework of how to discuss these gaps with current patients, and highlight what is needed from the neuro-oncology community for more definitive answers., Competing Interests: A.D. has received honoraria for advisory board participation from the following for-profit companies: Novocure and Servier Pharmaceuticals. M.P. has received honoraria for lectures, consultation, or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group, CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Böhringer-Ingelheim, Telix, and Medscape. S.L.H.-J. has no interest to disclose. H.A.S. received compensation from UpToDate (writer and section editor), MedLink Neurology (writer), Servier Pharmaceuticals (advisory board), and AbbVie (institutional research support). E.M. has no interest to disclose. J.W.T. has received research support from Servier Pharmaceuticals and Bristol-Myers Squibb and compensation from Servier Pharmaceuticals for advisory board participation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Meningiomas are the most common primary intracranial tumours in adults. Several studies proposed new stratification systems with a more accurate risk prediction than the WHO grading, e.g. based on methylation and copy number variations (CNVs). Yet, common shortcomings in these analyses are either a lack of stratification by sex of patients or excluding the gonososmes from CNV assessment., Methods: Within this study, DNA methylation array data from 7,424 meningioma samples as well as targeted sequencing, clinical annotations and morphology subtyping of 796 samples were examined for differences between females and males regarding mutations, methylation classes, copy number variations and histology., Results: Meningiomas from females accounted for about 53 % of the malignant tumours and present a loss of one X chromosome in 57 % of these malignant cases. In the group of benign tumours, females comprised about 75 % of the patients. Therein, a loss of one X chromosome was detected in only about 10 % of the cases but was associated with a significantly worse progression free survival., Conclusion: Although genomic instability is a common feature of malignant meningiomas, particularly loss of the X chromosome in tumours of female patients in otherwise histologically and molecularly low-risk tumours confers higher risk. Hence, the gonosomal copy number status can be leveraged for increased diagnostic accuracy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Radiation therapy, including conventionally fractionated external beam radiation therapy, stereotactic radiosurgery, and fractionated stereotactic radiation therapy, is a cornerstone in the interdisciplinary management of meningiomas. Recent advances in radiation oncology and also in other fields, such as neuropathology and imaging, have various implications for meningioma radiation therapy. This review aims to summarize current and anticipated developments, as well as active clinical trials related to the use of radiation therapy for meningiomas. In imaging, positron emission tomography has proven valuable for assessing the spatial extension of meningiomas and may enhance target delineation, treatment response monitoring, and recurrence assessment after radiation therapy. Particle therapy, including protons and carbon ions, as well as stereotactic radiosurgery and fractionated stereotactic radiation therapy, allow for conformal treatments that permit dose escalation in selected patients with high-grade meningiomas. Additionally, emerging integrated molecular and genetic classifications offer superior risk stratification and may refine patient selection for radiation therapy. However, there is a paucity of active meningioma trials directly investigating or refining the use of radiation therapy. In summary, significant advances in functional imaging, molecular and genetic diagnostics, and radiation treatment techniques hold the potential to improve patient outcomes and to avoid over- and undertreatment. Collaborative efforts and further clinical trials are essential to optimize meningioma radiation therapy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)