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The 2016 and 2021 World Health Organization 2021 Classification of central nervous system tumors have resulted in a major improvement in the classification of isocitrate dehydrogenase (IDH)-mutant gliomas. With more effective treatments many patients experience prolonged survival. However, treatment guidelines are often still based on information from historical series comprising both patients with IDH wild-type and IDH-mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological, and molecular factors associated with the outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with IDH-mutant grades 2 and 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize the overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment.

BACKGROUND: Resection of the contrast-enhancing (CE) tumor represents the standard of care in newly diagnosed glioblastoma. However, some tumors ultimately diagnosed as glioblastoma lack contrast enhancement and have a low-grade appearance on imaging (non-CE glioblastoma). We aimed to (a) volumetrically define the value of non-CE tumor resection in the absence of contrast enhancement, and to (b) delineate outcome differences between glioblastoma patients with and without contrast enhancement. METHODS: The RANO resect group retrospectively compiled a global, eight-center cohort of patients with newly diagnosed glioblastoma per WHO 2021 classification. The associations between postoperative tumor volumes and outcome were analyzed. Propensity score-matched analyses were constructed to compare glioblastomas with and without contrast enhancement. RESULTS: Among 1323 newly diagnosed IDH-wildtype glioblastomas, we identified 98 patients (7.4%) without contrast enhancement. In such patients, smaller postoperative tumor volumes were associated with more favorable outcome. There was an exponential increase in risk for death with larger residual non-CE tumor. Accordingly, extensive resection was associated with improved survival compared to lesion biopsy. These findings were retained on a multivariable analysis adjusting for demographic and clinical markers. Compared to CE glioblastoma, patients with non-CE glioblastoma had a more favorable clinical profile and superior outcome as confirmed in propensity score analyses by matching the patients with non-CE glioblastoma to patients with CE glioblastoma using a large set of clinical variables. CONCLUSIONS: The absence of contrast enhancement characterizes a less aggressive clinical phenotype of IDH-wildtype glioblastomas. Maximal resection of non-CE tumors has prognostic implications and translates into favorable outcome.

Background: Following surgery, patients with newly diagnosed glioblastoma frequently enter clinical trials. Nuanced risk assessment is warranted to reduce imbalances between study arms. Here, we aimed (I) to analyze the interactive effects of residual tumor with clinical and molecular factors on outcome and (II) to define a postoperative risk assessment tool., Methods: The RANO resect group retrospectively compiled an international, seven-center training cohort of patients with newly diagnosed glioblastoma. The combined associations of residual tumor with molecular or clinical factors and survival were analyzed, and recursive partitioning analysis was performed for risk modeling. The resulting model was prognostically verified in a separate external validation cohort., Results: Our training cohort compromised 1003 patients with newly diagnosed isocitrate dehydrogenase-wildtype glioblastoma. Residual tumor, O6-methylguanine DNA methyltransferase (MGMT) promotor methylation status, age, and postoperative KPS were prognostic for survival and incorporated into regression tree analysis. By individually weighting the prognostic factors, an additive score (range, 0-9 points) integrating these four variables distinguished patients with low (0-2 points), intermediate (3-5 points), and high risk (6-9 points) for inferior survival. The prognostic value of our risk model was retained in treatment-based subgroups and confirmed in an external validation cohort of 258 patients with glioblastoma. Compared to previously postulated models, goodness-of-fit measurements were superior for our model., Conclusions: The novel RANO risk model serves as an easy-to-use, yet highly prognostic tool for postoperative patient stratification prior to further therapy. The model may serve to guide patient management and reduce imbalances between study arms in prospective trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

As cancer patients with intracranial metastatic disease experience increasingly prolonged survival, the diagnosis and management of recurrent brain metastasis pose significant challenges in clinical practice. Prior to deciding upon a management strategy, it is necessary to ascertain whether patients have recurrent/progressive disease vs adverse radiation effect, classify the recurrence as local or distant in the brain, evaluate the extent of intracranial disease (size, number and location of lesions, and brain metastasis velocity), the status of extracranial disease, and enumerate the interval from the last intracranially directed intervention to disease recurrence. A spectrum of salvage local treatment options includes surgery (resection and laser interstitial thermal therapy [LITT]) with or without adjuvant radiotherapy in the forms of external beam radiotherapy, intraoperative radiotherapy, or brachytherapy. Nonoperative salvage local treatments also range from single fraction and fractionated stereotactic radiosurgery (SRS/FSRS) to whole brain radiation therapy (WBRT). Optimal integration of systemic therapies, preferably with central nervous system (CNS) activity, may also require reinterrogation of brain metastasis tissue to identify actionable molecular alterations specific to intracranial progressive disease. Ultimately, the selection of the appropriate management approach necessitates a sophisticated understanding of patient, tumor, and prior treatment-related factors and is often multimodal; hence, interdisciplinary evaluation for such patients is indispensable., (© 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.)

Supramaximal resection beyond the contrast-enhancing tumor borders represents an emerging surgical strategy for patients with newly diagnosed glioblastoma. A recent study provides evidence detailing the interactive effects of more aggressive surgery on other clinical predictors of outcome, supporting guidance for surgical decision-making and informing clinical trialists about the need to stratify for extent of resection. See related article by Park et al., p. 4866., (©2024 American Association for Cancer Research.)

Background: Lung cancer brain metastasis has a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cell show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy. This study aims to evaluate the impact of anti-PD-1 antibodies on CAR T-cell in treating lung cancer brain metastasis., Methods: We utilized a murine immunocompetent, syngeneic orthotopic cerebral metastasis model for repetitive intracerebral two-photon laser scanning microscopy, enabling in vivo characterization of red fluorescent tumor cells and CAR T-cell at a single-cell level over time. Red fluorescent EpCAM-transduced Lewis lung carcinoma cells ( EpCAM/tdt LL/2 cells) were implanted intracranially. Following the formation of brain metastasis, EpCAM-directed CAR T-cell were injected into adjacent brain tissue, and animals received either anti-PD-1 or an isotype control., Results: Compared to controls receiving T-cell lacking a CAR, mice receiving EpCAM-directed CAR T-cell showed higher intratumoral CAR T-cell densities in the beginning after intraparenchymal injection. This finding was accompanied with reduced tumor growth and translated into a survival benefit. Additional anti-PD-1 treatment, however, did not affect intratumoral CAR T-cell persistence nor tumor growth and thereby did not provide an additional therapeutic effect., Conclusion: CAR T-cell therapy for brain malignancies appears promising. However, additional anti-PD-1 treatment did not enhance intratumoral CAR T-cell persistence or effector function, highlighting the need for novel strategies to improve CAR T-cell therapy in solid tumors., (© 2024. The Author(s).)

Patients with brain tumours are motivated to participate in clinical trials involving repeat tissue sampling. Normalising the use of neoadjuvant and staged surgical trials necessitates collaboration among patients, regulatory agencies, and researchers. Initial and repetitive tissue sampling plays a crucial role in enhancing our understanding of resistance mechanisms and vulnerabilities in brain tumour therapy. Standardising biopsy techniques and ensuring technical uniformity across institutions are vital for effective interinstitutional collaboration. Although liquid biopsy technologies hold promise, they are not yet ready to replace tissue analysis. Clear communication about the risks and benefits of biopsies is essential, particularly regarding potential postoperative deficits. Changes in mindset and neurosurgical culture are imperative to achieve much needed breakthroughs in the development of new, effective therapies for brain tumours., Competing Interests: Declaration of interests MG declares research grant support from Evgen Pharm. KCS declares honoraria from Springworks Therapeutics and Novartis; declares research funding to her institution from Springworks Therapeutics; and serves on a data and safety monitoring board for Advarra. TFC is cofounder, major stock holder, consultant, and board member of Katmai Pharmaceuticals; holds stock for Erasca; is a member of the board and paid consultant for the 501c3 Global Coalition for Adaptive Research; holds stock in Chimerix and receives milestone payments and possible future royalties; is a member of the scientific advisory board for Break Through Cancer foundation and Cure Brain Cancer Foundation; has provided paid consulting services to Symbio, Mundipharma, Tango BlueRock, Vida Ventures, Lista Therapeutics, Stemline, Novartis, Roche, Sonalasense, Sagimet, Clinical Care Options, Ideology Health, Servier, Jubilant, Immvira, Gan & Lee, BrainStorm, Katmai, Sapience, Inovio, Vigeo Therapeutics, DNATrix, Tyme, SDP, Kintara, Bayer, Merck, Boehringer Ingelheim, VBL, Amgen, Kiyatec, AbbVie, VBI, Deciphera, Agios, Novocure, and Medscape; and has contracts with UCLA for the Brain Tumour Programme with Roche, VBI, Merck, Novartis, and Bristol Myers Squibb. The Regents of the University of California, TFC's employer, has licensed intellectual property co-invented by TFC to Katmai Pharmaceuticals. GL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics, IOBiotech, Immunocore, Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, PHMR, Pierre Fabre, and Regeneron. AC declares research funding and honoraria from AstraZeneca, Benevolent AI, Duke Street Bio, and Evgen Pharmaceuticals; and has received honoraria from Storm Therapeutics. MSA declares a grant from Seagen; declares consulting fees from Bayer, Kiyatec, Insightec, GSK, Xoft, Nuvation, SDP Oncology, Apollomics, Prelude, Janssen, Voyager Therapeutics, Viewray, Caris Lifesciences, Pyramid Biosciences, Varian Medical Systems, Cairn Therapeutics, Anheart Therapeutics, Theraguix, Menarini Ricerche, Sumitomo Pharma Oncology, Autem Therapeutics, GT Medical Technologies, Allovir, and Equillium Bio; is on the data and safety monitoring board for VBI Vaccines; is on the scientific advisory board of Modifi biosciences and Bugworks; and is a shareholder for Mimivax, Cytodyn, MedInnovate Advisors, and Trisalus Lifesciences. SB reports consulting fees from and is a member of the advisory boards of Telix, Servier, Bayer, and Novocure; and research grants from Incyte, GSK, Lilly, Kite, and Novocure. JdG reports being an advisory board member for Kintara Pharmaceuticals, Kazia, MundiPharma, Insightec, Monteris, Carthera, Samus, Sapience, DSP Pharma, Telix, Servier, Alpha Pharmaceuticals, Nervianos, and CapitalOne; is a data safety monitoring board member for Chimerix and VBI; and has consulted for MundiPharma, Insightec, Carthera, Kintara, Deciphera, Kazia, and Nervianos. IP reports research funding from Merck. TCB reports consulting roles for Predicine; has received financial support from AbbVie and Predicine, with consulting fees paid to Mayo Clinic; and has been a member of the advisory board for Neurametrix. MPr reports honoraria from the following for-profit companies: Bayer, Bristol Myers Squibb, Novartis, Gerson Lehrman Group, CMC Contrast, GSK, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dohme, Tocagen, Adastra, Gan & Lee Pharmaceuticals, Janssen, Servier, Miltenyi, Boehringer Ingelheim, Telix, and Medscape. JCT reports research grants from Novocure and Munich Surgical Imaging; being on the advisory board of Advanced Accelerator Applications, Novartis; and Servier; and has received royalties from Springer Publishing. MPl reports being a founder of Tcelltech; has received research support from Bayer, Roche, Pfizer, and Merck; and is an advisory board member of Bayer and Servier. SD is speaker for the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons; receives research funding from Alkermes; is a member of the Subcortical Surgery Group advisory board; has received royalties from Oxford University Press; and is provincial lead for CNS Oncology at Ontario Health. KT reports consulting fees from Oncohereos Biosciences; and advisory board roles for Advanced Accelerator Applications, Novartis; Sage Therapeutics; FYR Diagnostics; Cordance Medical; Telo Therapeutics; and Modifi Bio. MAV reports clinical trial funding to their institution from DeNovo Pharma, Infuseon, and Oncosynergy; and received honoraria fees from Biodexa and Servier Pharma. MW reports research grants from Novartis, Quercis, and Versameb; honoraria for advisory boards from Roche and Servier; and honoraria for consultation from Bayer, Curevac, Medac, Neurosense, Novartis, Novocure, Orbus, Philogen, and Servier. JRW reports research funding from AnHeart Therapeutics to their institution; received consulting fees from AnHeart Therapeutics and Servier; being on advisory boards for Roche and Merck; is a data safety monitoring member for Telix Pharmaceuticals; and is an employee of The Walter and Eliza Hall Institute and could be eligible for milestone and royalty payments related to Venetoclax. MK reports research grants from Bristol Myers Squibb, AbbVie, BioNTech, CNS Pharmaceuticals, Daiichi Sankyo, Immorna Therapeutics, Immvira Therapeutics, and Personalis; received consulting fees from The Jackson Lab for Genomic Research, AnHeart Therapeutics, Berg Pharma, George Clinical, Manarini Stemline, and Servier; received honoraria from GSK; and is on a data safety monitoring board for BPGbio. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

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 expression of a particular target (thera-nostics). This mode of treatment can also compete with or supplement conventional radiotherapy e.g., if MRI does not fully capture the extent of 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 (PSMA)-expressing prostate cancer are approved, and numerous approaches of targeted radionuclide therapy for patients with metastatic cancer are in development (e.g. using fibroblast activation protein (FAP) as a target). Although brain metastases are rare in the 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.)

Glioma resection is associated with prolonged survival, but neuro-oncological trials have frequently refrained from quantifying the extent of resection. The Response Assessment in Neuro-Oncology (RANO) resect group is an international, multidisciplinary group that aims to standardise research practice by delineating the oncological role of surgery in diffuse adult-type gliomas as defined per WHO 2021 classification. Favourable survival effects of more extensive resection unfold over months to decades depending on the molecular tumour profile. In tumours with a more aggressive natural history, supramaximal resection might correlate with additional survival benefit. Weighing the expected survival benefits of resection as dictated by molecular tumour profiles against clinical factors, including the introduction of neurological deficits, we propose an algorithm to estimate the oncological effects of surgery for newly diagnosed gliomas. The algorithm serves to select patients who might benefit most from extensive resection and to emphasise the relevance of quantifying the extent of resection in clinical trials., Competing Interests: Declaration of interests DPC serves on advisory boards for Lilly, GlaxoSmithKline, Incephalo, Boston Pharmaceuticals, Servier, Boston Scientific, and Pyramid Biosciences; receives consultant fees from the USA National Institutes of Health and Department of Defense; and fees from lectures for Merck. MvdB receives consultant fees from Celgene, Bristol Myers Squibb, Agios, Boehringer, AbbVie, Bayer, Carthera, Nerviano, and Genenta. MW receives fees for honoraria or advisory board participation and consulting from Bayer, CureVac, Medac, Novartis, Novocure, Orbus, and Philogen; and research grants from Quercis and Versameb. MMK receives consultant fees from Blue Earth Diagnostics, and research grants from EpicentRx and Blue Earth Diagnostics. J-CT receives research grants from Novocure and Munich Surgical Imaging; serves on an advisory board for AAA Novartis; and receives royalties from Springer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Central nervous system (CNS) injury following brain-directed radiotherapy remains a major challenge. Proton radiotherapy (PRT) minimizes radiation to healthy brain, potentially limiting sequelae. We characterized CNS radiotoxicity, including radiation-induced leukoencephalopathy (RIL), brain tissue necrosis (TN), and cerebral microbleeds (CMB), in glioma patients treated with PRT or photons (XRT)., Patients and Methods: Thirty-four patients (19 male; median age 39.6 years) with WHO grade 2-3 gliomas treated with partial cranial radiotherapy (XRT [n = 17] vs PRT[n = 17]) were identified and matched by demographic/clinical criteria. Radiotoxicity was assessed longitudinally for 3 years post-radiotherapy via serial analysis of T2/FLAIR- (for RIL), contrast-enhanced T1- (for TN), and susceptibility (for CMB)-weighted MRI sequences. RIL was rated at whole-brain and hemispheric levels using a novel Fazekas scale-informed scoring system., Results: The scoring system proved reliable (ICC > 0.85). Both groups developed moderate-to-severe RIL (62%[XRT]; 71%[PRT]) within 3 years; however, XRT was associated with persistent RIL increases in the contralesional hemisphere, whereas contralesional hemispheric RIL plateaued with PRT at 1-year post-radiotherapy (t = 2.180; P = .037). TN rates were greater with PRT (6%[XRT] vs 18%[PRT]; P = ns). CMB prevalence (76%[XRT]; 71%[PRT]) and burden (mean #CMB: 4.0[XRT]; 4.2[PRT]) were similar; however, XRT correlated with greater contralesional hemispheric CMB burden (27%[XRT]; 17%[PRT]; X2 = 4.986; P = .026), whereas PRT-specific CMB clustered at the radiation field margin (X2 = 14.7; P = .002)., Conclusions: CNS radiotoxicity is common and progressive in glioma patients. Injury patterns suggest radiation modality-specificity as RIL, TN, and CMB exhibit unique spatiotemporal differences following XRT vs PRT, likely reflecting underlying dosimetric and radiobiological differences. Familiarity with such injury patterns is essential to improve patient management. Prospective studies are needed to validate these findings and assess their impacts on neurocognitive function., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Patients with intracranial meningiomas frequently suffer from tumor-related seizures prior to resection, impacting patients' quality of life. We aimed to elaborate on incidence and predictors for seizures in a patient cohort with meningiomas WHO grade 2 and 3., Methods: We retrospectively searched for patients with meningioma WHO grade 2 and 3 according to the 2021 WHO classification undergoing tumor resection. Clinical, histopathological and imaging findings were collected and correlated with preoperative seizure development. Tumor and edema volumes were quantified., Results: Ninety-five patients with a mean age of 59.5 ± 16.0 years were included. Most tumors (86/95, 90.5%) were classified as atypical meningioma WHO grade 2. Nine of 95 tumors (9.5%) corresponded to anaplastic meningiomas WHO grade 3, including six patients harboring TERT promoter mutations. Meningiomas were most frequently located at the convexity in 38/95 patients (40.0%). Twenty-eight of 95 patients (29.5%) experienced preoperative seizures. Peritumoral edema was detected in 62/95 patients (65.3%) with a median volume of 9 cm 3 (IR: 0-54 cm 3 ). Presence of peritumoral edema but not age, tumor localization, TERT promoter mutation, brain invasion or WHO grading was associated with incidence of preoperative seizures, as confirmed in multivariate analysis (OR: 6.61, 95% CI: 1.18, 58.12, p = *0.049). Postoperative freedom of seizures was achieved in 91/95 patients (95.8%)., Conclusions: Preoperative seizures were frequently encountered in about every third patient with meningioma WHO grade 2 or 3. Patients presenting with peritumoral edema on preoperative imaging are at particular risk for developing tumor-related seizures. Tumor resection was highly effective in achieving seizure freedom., (© 2024. The Author(s).)

Tumors of astrocytic origin represent one of the most frequent entities among the overall rare group of spinal cord gliomas. Initial clinical symptoms are often unspecific, and sensorimotor signs localizing to the spinal cord occur with progressing tumor growth. On MRI, a hyperintense intrinsic spinal cord signal on T 2 -weighted sequences with varying degrees of contrast enhancement raises suspicion for an infiltrative neoplasm. Blood and CSF analysis serves to exclude an infectious process, nutritional deficits, or metabolic disorders. When such other differential diagnoses have been ruled out, a neuropathological tissue-based analysis is warranted to confirm the diagnosis of a spinal cord astrocytoma and guide further patient management. As such, maximal safe resection forms the basis of any treatment. Meticulous preoperative planning is necessary to weigh the potential improvement in survival against the risk of functional deterioration. Intraoperative neuromonitoring and ultrasound may aid in achieving a more extensive resection. Depending on the assigned WHO tumor grade spanning from grade 1 to grade 4, the use of radiotherapy and chemotherapy might be indicated but also wait-and-scan approaches appear reasonable in tumors of lower grade. Close imaging follow-up is necessary given that recurrence inevitably occurs in astrocytomas of grades 2-4. Prognosis is so far dictated by tumor grade and histopathological findings, but also by age and clinical performance of the patient. Targeted therapies resting upon an in-depth tissue analysis are emerging in recurrent tumors, but no prospective study is available so far given the rarity of spinal cord astrocytomas., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)