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A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification., Competing Interests: Declaration of interests M.L.S. is equity holders, scientific co-founder and advisory board member of Immunitas Therapeutics. I.T. is advisory board member of Immunitas Therapeutics. D.P.C. has consulted for Lilly, Incephalo, Boston Pharmaceuticals, Servier, Boston Scientific and Pyramid Biosciences (equity interest), and has received honoraria and travel reimbursement from Merck for invited lectures. J.J.M. received consulting fees from Servier. The authors declare that such activities have no relationship to the present study. M.T. reports consulting or advisory role for Servier, Novocure, Resilience, Agios Pharmaceutical, Integragen, and Taiho Oncology, honoraria for Ono, and research funding from Sanofi. P.Y.W. reports research support from Astra Zeneca, Black Diamond, Bristol Meyers Squibb, Chimerix, Eli Lily, Erasca, Global Coalition For Adaptive Research, Kazia, MediciNova, Merck, Novartis, Quadriga, Servier, VBI Vaccines and consulting or advisory role for Anheart, Astra Zeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, Glaxo Smith Kline, Kintara, Merck, Mundipharma, Novartis, Novocure, Prelude Therapeutics, Sagimet, Sapience, Servier, Symbio, Tango, Telix, VBI Vaccines. K.L.L is equity holder, consultant, and co-founder of Travera, is a consultant for BMS, Blaze Biosciences and Integragen, and has grant research funding through DFCI from BMS and Lilly. L.N.G.C. has received research support from Merck & Co, and consulting fees from BMJ Best Practice and Oakstone Publishing., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer., Competing Interests: Declaration of interests I.T. is an advisory board member of Immunitas Therapeutics. M.L.S. is an equity holder, scientific co-founder, and advisory board member of Immunitas Therapeutics. Abcam provided carrier-free antibodies for CODEX experiments (to R.H.)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Artificial intelligence (AI) describes the application of computer algorithms to the solution of problems that have traditionally required human intelligence. Although formal work in AI has been slowly advancing for almost 70 years, developments in the last decade, and particularly in the last year, have led to an explosion of AI applications in multiple fields. Neuro-oncology has not escaped this trend. Given the expected integration of AI-based methods to neuro-oncology practice over the coming years, we set to provide an overview of existing technologies as they are applied to the neuropathology and neuroradiology of brain tumors. We highlight current benefits and limitations of these technologies and offer recommendations on how to appraise novel AI-tools as they undergo consideration for integration into clinical workflows., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nakhate and Gonzalez Castro.)

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM) 1,2 . Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV) 3 . In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue 4 . These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 )., (© 2023. The Author(s).)

Diffusely infiltrating gliomas - including glioblastoma (GBM), isocitrate dehydrogenase (IDH) mutant gliomas, and histone 3 (H3) altered gliomas - are primary brain tumors with an invariably fatal outcome. Despite advances in the understanding of their biology, standard, targeted and immune checkpoint inhibitor immunotherapies have proven ineffective in arresting their inexorable progression and associated morbidity and mortality. Recognizing the unique aspects of the immunogenicity of cancer cells, the last decade has seen the development and evaluation of vaccine-based therapies for the treatment of solid tumors, including gliomas. Here we review the current vaccine strategies for the treatment of GBM, IDH-mutant gliomas and diffuse midline glioma H3 K27M-altered. We discuss potential benefits and challenges of vaccine therapies in these specific patient populations., (© The Author(s), 2023.)

Paraneoplastic antibody syndromes result from the anti-tumor antibody response against normal antigens ectopically expressed by tumor cells. Although this antibody response plays an important role in helping clear a nascent or established tumor, the engagement of antigens expressed in healthy tissues can lead to complex clinical syndromes with challenging diagnosis and management. The majority of known paraneoplastic antibody syndromes have been found to affect the central and peripheral nervous system. The present review provides an update on the pathophysiology of paraneoplastic neurologic syndromes, as well as recommendations for their diagnosis and treatment.

Purpose: The Response Assessment in Neuro-Oncology (RANO) criteria are widely used in high-grade glioma clinical trials. We compared the RANO criteria with updated modifications (modified RANO [mRANO] and immunotherapy RANO [iRANO] criteria) in patients with newly diagnosed glioblastoma (nGBM) and recurrent GBM (rGBM) to evaluate the performance of each set of criteria and inform the development of the planned RANO 2.0 update., Materials and Methods: Evaluation of tumor measurements and fluid-attenuated inversion recovery (FLAIR) sequences were performed by blinded readers to determine disease progression using RANO, mRANO, iRANO, and other response assessment criteria. Spearman's correlations between progression-free survival (PFS) and overall survival (OS) were calculated., Results: Five hundred twenty-six nGBM and 580 rGBM cases were included. Spearman's correlations were similar between RANO and mRANO (0.69 [95% CI, 0.62 to 0.75] v 0.67 [95% CI, 0.60 to 0.73]) in nGBM and rGBM (0.48 [95% CI, 0.40 to 0.55] v 0.50 [95% CI, 0.42 to 0.57]). In nGBM, requirement of a confirmation scan within 12 weeks of completion of radiotherapy to determine progression was associated with improved correlations. Use of the postradiation magnetic resonance imaging (MRI) as baseline scan was associated with improved correlation compared with use of the pre-radiation MRI (0.67 [95% CI, 0.60 to 0.73] v 0.53 [95% CI, 0.42 to 0.62]). Evaluation of FLAIR sequences did not improve the correlation. Among patients who received immunotherapy, Spearman's correlations were similar among RANO, mRANO, and iRANO., Conclusion: RANO and mRANO demonstrated similar correlations between PFS and OS. Confirmation scans were only beneficial in nGBM within 12 weeks of completion of radiotherapy, and there was a trend in favor of the use of postradiation MRI as the baseline scan in nGBM. Evaluation of FLAIR can be omitted. The iRANO criteria did not add significant benefit in patients who received immune checkpoint inhibitors.

Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics 1 . Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH 2 . Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell-cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Antibodies against immune checkpoint inhibitors (ICIs) have revolutionized the treatment of multiple aggressive malignancies, including melanoma and non-small cell lung cancer. ICIs for the treatment of primary and metastatic brain tumors have been used with varying degrees of success. Here, we discuss the available evidence for the use of ICIs in the treatment of primary and metastatic brain tumors, highlighting challenges and opportunities for furthering this type of cancer immunotherapy in neuro-oncology.

Genomic and transcriptional heterogeneity is prevalent among the most common and aggressive primary brain tumors in children and adults. Over the past 20 years, advances in bioengineering, biochemistry and bioinformatics have enabled the development of an array of techniques to study tumor biology at single-cell resolution. The application of these techniques to study primary brain tumors has helped advance our understanding of their intra-tumoral heterogeneity and uncover new insights regarding their co-option of developmental programs and signaling from their microenvironment to promote tumor proliferation and invasion. These insights are currently being harnessed to develop new therapeutic approaches. Here we provide an overview of current single-cell techniques and discuss relevant biology and therapeutic insights uncovered by their application to primary brain tumors in children and adults., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although rare, the co-occurrence of multiple sclerosis (MS) and glioma poses unique challenges in terms of diagnosis and management for both neurologists and neuro-oncologists., Methods: Here we report on a single-center cohort of four patients with a diagnosis of multiple sclerosis who developed gliomas., Results: Our cohort reflects the epidemiology of glioma in terms of the relative frequency of IDH-wildtype and IDH-mutant cases. The patients in 3 out of the 4 cases presented did not develop their tumors in areas of pre-existing demyelinating lesions., Conclusions: We did not find evidence to support the hypothesis that chronic gliosis from demyelinating plaques may serve as a substrate for secondary induction of a glial neoplasm. In our Discussion, we provide recommendations for distinguishing neoplastic from demyelinating lesions, review the evidence for demyelination as a risk factor for gliomagenesis, and highlight important considerations for the concurrent management of glioma and MS., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

We discuss a case of a middle-aged woman with a history of urothelial carcinoma, who presented with subacute progression of double vision, right facial numbness, and back pain. Her MRI brain and spine demonstrated multifocal enhancing lesions at the skull base and throughout the spine. Since her initial serum and cerebrospinal fluid (CSF) studies were unrevealing, she underwent a biopsy of her skull base lesion, which was initially concerning for infection. However, her symptoms worsened despite appropriate antibiotic therapy, necessitating a spinal root biopsy that was consistent with leptomeningeal urothelial carcinoma. Her case illustrates the challenge of accurately diagnosing isolated leptomeningeal metastatic disease, which can be difficult to diagnose from CSF analysis and often requires multiple lumbar punctures to improve sensitivity. While genitourinary cancers rarely metastasize to the CNS, clinicians should retain high suspicion for neoplastic etiologies of leptomeningeal disease in patients with a history of cancer and new neurologic deficits., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Immunotherapy has revolutionized the care of cancer patients. A diverse set of strategies to overcome cancer immunosuppression and enhance the tumor-directed immune response are in clinical use, but have not achieved transformative benefits for brain tumor patients. Adoptive cell therapies, which employ a patient's own immune cells to generate directed anti-tumor activity, are emerging technologies that hold promise to improve the treatment of primary brain tumors in children and adults. Here, we review recent advances in chimeric antigen receptor (CAR) T-cell therapies for the treatment of aggressive primary brain tumors, including glioblastoma and diffuse midline glioma, H3 K27M-mutant. We highlight current approaches, discuss encouraging investigational data, and describe key challenges in the development and implementation of these types of therapies in the neuro-oncology setting.

The differential diagnosis of rapidly progressive dementia includes neurodegenerative, toxic/metabolic, infectious, inflammatory, vascular, and malignant etiologies. This case highlights a patient with rapidly progressive cognitive decline that remained a diagnostic dilemma due to nonspecific symptoms of disorientation that progressed to persistent alteration in mental status over the span of three months. Routine laboratory testing did not help clarify the diagnosis and initial brain imaging showed only subtle abnormalities that were not commensurate with the patient's neurologic examination. As imaging findings evolved over time to reveal a multifocal process, a biopsy was pursued, with histology consistent with infiltrating glioma and molecular testing consistent with glioblastoma. Glioblastoma with gliomatosis cerebri growth pattern should be considered on the differential diagnosis of rapidly progressive dementia in patients with multifocal imaging findings., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Introduction: Co-administration of direct oral anticoagulants (DOACs) with antiepileptic drugs (AEDs) is increasingly common in brain tumor patients. We therefore performed a systematic review of the current evidence for potential drug interactions between DOACs and AEDs in this patient population., Methods: We conducted a systematic review of the literature via PubMed according to PRISMA guidelines (last accessed December 15, 2021). Included were clinical studies and case reports, written in English language and published between 2010 and 2021, that investigated concurrent clinical use of AEDs with DOACs for any indication. Non-English articles, articles not related to our research question, review articles and commentaries were excluded. Full-text articles were evaluated for possible confounding factors and results were summarized using a data table highlighting the key characteristics of each article., Results: We identified a total of 122 unique articles, of which 27 were deemed relevant to our research question. Of these, 8 articles were clinical studies (n = 295,415 patients) and 19 were case reports (n = 25 patients). Only 3 clinical studies and 2 case reports reported interactions between AEDs and DOACs in patients with active cancer and none reported interactions in patients with brain tumors., Conclusion: We have identified low (class IV) level evidence of potential drug interactions between DOACs and AEDs. Even though there is no current report of interactions in brain tumor patients, neuro-oncology providers should be aware of the emerging evidence regarding drug interactions between DOACs and AEDs and take this into consideration when concurrently prescribing these to patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuro-oncology is a growing, interdisciplinary field at the intersection of neurology and oncology, devoted to the care of patients with central nervous system tumors and neurologic complications of cancer, and collaboratively interfacing with neurosurgery, neuropathology, medical oncology and radiation oncology. There is increasing trainee interest in the field of neuro-oncology and an increasing number of fellowship training programs, attracting applicants with backgrounds in neurology, neurosurgery and medical oncology. The present guide aims to provide some general recommendations for residents and fellows to help them make the most out of their neuro-oncology fellowship and enable them to start their careers as a neuro-oncologists on firm footing., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The 2016 revised fourth edition of the World Health Organization (WHO) classification of central nervous system (CNS) tumors incorporated molecular features with histologic grading, revolutionizing how oncologists conceptualize primary brain and spinal cord tumors as well as providing new insights into their management and prognosis. The 2021 revised fifth edition of the WHO classification further integrates molecular alterations for CNS tumor categorization, updating current understanding of the pathophysiology of many of these disease entities. Here, the authors review changes in the new classification for the most common primary adult tumors-gliomas (including astrocytomas, oligodendrogliomas, and ependymomas) and meningiomas-highlighting the key genomic alterations for each group classification to help clinicians interpret them as they consider therapeutic options-including clinical trials and targeted therapies-and discuss the prognosis of these tumors with their patients. The revised, updated 2021 WHO classification also further integrates molecular alterations in the classification of pediatric CNS tumors, but those are not covered in the current review., (© 2021 American Cancer Society.)