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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.)

Single-cell RNA sequencing has revealed extensive transcriptional cell state diversity in cancer, often observed independently of genetic heterogeneity, raising the central question of how malignant cell states are encoded epigenetically. To address this, here we performed multiomics single-cell profiling-integrating DNA methylation, transcriptome and genotype within the same cells-of diffuse gliomas, tumors characterized by defined transcriptional cell state diversity. Direct comparison of the epigenetic profiles of distinct cell states revealed key switches for state transitions recapitulating neurodevelopmental trajectories and highlighted dysregulated epigenetic mechanisms underlying gliomagenesis. We further developed a quantitative framework to directly measure cell state heritability and transition dynamics based on high-resolution lineage trees in human samples. We demonstrated heritability of malignant cell states, with key differences in hierarchal and plastic cell state architectures in IDH-mutant glioma versus IDH-wild-type glioblastoma, respectively. This work provides a framework anchoring transcriptional cancer cell states in their epigenetic encoding, inheritance and transition dynamics., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The mesenchymal subtype of glioblastoma is thought to be determined by both cancer cell-intrinsic alterations and extrinsic cellular interactions, but remains poorly understood. Here, we dissect glioblastoma-to-microenvironment interactions by single-cell RNA sequencing analysis of human tumors and model systems, combined with functional experiments. We demonstrate that macrophages induce a transition of glioblastoma cells into mesenchymal-like (MES-like) states. This effect is mediated, both in vitro and in vivo, by macrophage-derived oncostatin M (OSM) that interacts with its receptors (OSMR or LIFR) in complex with GP130 on glioblastoma cells and activates STAT3. We show that MES-like glioblastoma states are also associated with increased expression of a mesenchymal program in macrophages and with increased cytotoxicity of T cells, highlighting extensive alterations of the immune microenvironment with potential therapeutic implications., Competing Interests: Declaration of interests M.L.S. and K.W.W. are equity holders, scientific co-founders, and advisory board members of Immunitas Therapeutics. I.T. is advisory board member of Immunitas Therapeutics. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics, and until July 31, 2020, was an SAB member for Thermo Fisher Scientific, Syros Pharmaceuticals, Asimov and Neogene Therapeutics. O.R.R. and A.R. are employees of Genentech since October 19, 2020, and August 1, 2020, respectively. K.W.W. serves on the scientific advisory board of TCR2 Therapeutics, T-Scan Therapeutics, SQZ Biotech, and Nextechinvest, and receives sponsored research funding from Novartis. N.D.M. serves as a scientific advisor to Immunitas Therapeutics. X.Z. is a co-founder and consultant for Vizgen, Inc., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Human tumors are composed of diverse malignant and nonmalignant cells, generating a complex ecosystem that governs tumor biology and response to treatments. Recent technological advances have enabled the characterization of tumors at single-cell resolution, providing a compelling strategy to dissect their intricate biology. Here we describe recent developments in single-cell expression profiling and the studies applying them in clinical settings. We highlight some of the powerful insights gleaned from these studies for tumor classification, stem cell programs, tumor microenvironment, metastasis, and response to targeted and immune therapies. SIGNIFICANCE: Intratumor heterogeneity (ITH) has been a major barrier to our understanding of cancer. Single-cell genomics is leading a revolution in our ability to systematically dissect ITH. In this review, we focus on single-cell expression profiling and lessons learned in key aspects of human tumor biology., (©2021 American Association for Cancer Research.)

T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets., Competing Interests: Declaration of interests N.D.M., O.A., I.T., A.R., M.L.S., and K.W.W. are co-inventors of a patent application on the CLEC2D-CD161 pathway for the treatment of cancer. K.W.W., M.L.S., and A.R. are co-founders of Immunitas Therapeutics. K.W.W., M.L.S., and I.T. are advisory board members of Immunitas Therapeutics. K.W.W. serves on the scientific advisory board of TCR2 Therapeutics, T-Scan Therapeutics, SQZ Biotech, and Nextechinvest and received sponsored research funding from Bristol-Myers Squibb and Novartis. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics, and until August 31, 2020, was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and Thermo Fisher Scientific. From August 1, 2020, A.R. is an employee of Genentech. N.D.M. serves as a scientific advisor to Immunitas Therapeutics. A.M. is cofounder, member of the Boards of Directors, and member of Scientific Advisory Boards of Spotlight Therapeutics and Arsenal Biosciences. A.M. has served as an advisor to Juno Therapeutics, was a member of the scientific advisory board at PACT Pharma, and an advisor to Trizell. A.M. has received an honorarium from Merck and a consulting fee from AlphaSights and is an investor in and informal advisor to Offline Ventures. A.M. owns stock in Arsenal Biosciences, Spotlight Therapeutics, and PACT Pharma. The Marson lab has received research support from Juno Therapeutics, Epinomics, Sanofi, GlaxoSmithKline, Gilead, and Anthem. E.A.C. is currently an advisor to Advantagene Inc., Alcyone Biosciences, Insightec, Inc., Sigilon Therepeutics, and DNAtrix Inc. and has equity interest in DNAtrix; A.M. has advised Oncorus, Merck, Tocagen, Ziopharm, Stemgen, NanoTx., Ziopharm Oncology, Cerebral Therapeutics, Genenta, Merck, Janssen, Karcinolysis, and Shanaghai Biotech and has received research support from Advantagene, NewLink Genetics, and Amgen. A.M. is a named inventor on patents related to oncolytic HSV1. D.A.R. has received research support from Acerta Phamaceuticals, Agenus, Celldex, EMD Serono, Incyte, Inovio, Midatech, Omniox, and Tragara, and he has served as paid consultant for Abbvie, Advantagene, Agenus, Amgen, Bayer, Bristol-Myers Squibb, Celldex, DelMar, EMD Serono, Genentech/Roche, Inovio, Merck, Merck KGaA, Monteris, Novocure, Oncorus, Oxigene, Regeneron, Stemline, and Taiho Oncology, Inc. P.K.B., outside the scope of this work, has consulted for Angiochem, Genentech-Roche, Lilly, Tesaro, ElevateBio, Pfizer (Array), SK Life Sciences, and Dantari and is supported by the Breast Cancer Research Foundation, Damon Runyon Cancer Research Foundation, Ben and Catherine Ivy Foundation, and the National Cancer Institute (5R01CA244975-02, 5R21CA220253-02, and 5R01CA227156-03), BMS, Lilly, and honoraria from Merck, Genentech-Roche, and Lilly. D.P.C. has consulted for Lilly and Boston Pharmaceuticals and has received honoraria and travel reimbursement from Merck. O.R.-R. is an employee of Genentech since October 2020. O.R.-R. is a co-inventor on patent applications filed by the Broad Institute for inventions relating to work in single-cell genomics, such as in PCT/US2018/060860 and US provisional application 62/745,259. E.A.C. is currently an advisor to Advantagene Inc., Alcyone Biosciences, Insightec Inc., DNAtrix, Immunomic Therapeutics, Sangamo Therapeutics, and Seneca Therapeutics, has equity interest in DNAtrix, Immunomic Therapeutics, and Seneca Therapeutics, and has also advised Oncorus, Merck, Tocagen, Ziopharm, Stemgen, NanoTx., Ziopharm Oncology, Cerebral Therapeutics, Genenta. Merck, Janssen, Karcinolysis, and Shanghai Biotech. E.A.C. has received research support from NIH, US Department of Defense, American Brain Tumor Association, National Brain Tumor Society, Alliance for Cancer Gene Therapy, Neurosurgical Research Education Foundation, Advantagene, NewLink Genetics, and Amgen and also is a named inventor on patents related to oncolytic HSV1 and noncoding RNAs. X.S.L. is a cofounder, board member, and consultant of GV20 Oncotherapy and its subsidiaries, SAB of 3DMedCare, a consultant for Genentech, a stockholder of Bristol Myers Squibb (BMY), Thermo Fisher Scientific (TMO), Walgreens Boots Alliance (WBA), Abbott Laboratories (ABT), AbbVie Inc. (ABBV), and Johnson & Johnson (JNJ), and receives research funding from Takeda and Sanofi., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Adoptive cell therapies are a group of cancer immunotherapies that involve the infusion of engineered immune cells targeting specific tumor antigens, with chimeric antigen receptor (CAR) T cells at the vanguard of this revolution in cancer therapy. Several CAR T-cell products have been approved for the treatment of leukemia and lymphoma and many more are currently undergoing evaluation in clinical trials for the treatment of other liquid and solid malignancies. Despite their remarkable effectiveness, as with other immunotherapies, CAR T cells are frequently associated with systemic and neurologic toxicity. There has been a major effort by many institutions to develop specific protocols to guide the management of treatment-associated toxicities (eg, cytokine release syndrome [CRS]). However, neurotoxic effects of CAR T-cell therapies are more difficult to evaluate and treat, not easily lending themselves to an algorithmic approach to diagnosis and management. Given the steadily expanding use of CAR T-cell therapies for various malignancies, it is of critical importance for neuro-oncologists to be familiar with the clinical presentation and management principles of CAR T-cell-associated neurotoxicity. Here, we present key principles for the evaluation and management of patients affected by CAR T-cell-associated neurotoxicity based on the most recent evidence., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Over the past 4 years, advances in molecular pathology have enhanced our understanding of CNS tumors, providing new elements to refine their classification and improve the 2016 World Health Organization (WHO) Classification of CNS tumors. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) was formed in late 2016 by a group of neuropathology and neuro-oncology experts to provide practical recommendations (published as cIMPACT-NOW updates) to improve the diagnosis and classification of CNS tumors, in advance of the publication of a new WHO Classification of CNS tumors. Here we review the content of all the available cIMPACT-NOW updates and discuss the implications of each update for the diagnosis and management of patients with CNS tumors., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Seizures are common in patients with cancer and either result from brain lesions, paraneoplastic syndromes, and complications of cancer treatment or are provoked by systemic illness (metabolic derangements, infections). Evaluation should include a tailored history, neurologic examination, laboratory studies, neuroimaging, and electroencephalogram. In unprovoked seizures, antiepileptic drug (AED) treatment is required, and a nonenzyme-inducing AED is preferred. Treatment of the underlying cancer with surgery, chemotherapy, and radiation therapy also can help reduce seizures. Benzodiazepines are useful in the treatment of both provoked seizures and breakthrough epileptic seizures and as first-line treatment for status epilepticus. Counseling for safety is an important component in the care of a patient with cancer who has seizures. Good seizure management can be challenging but significantly improves the quality of life during all phases of care, including end-of-life care., (© 2020 American Cancer Society.)

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein-directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity ( P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) ( P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival ( P = .048). We did not find evidence that steroid use ≥7 days altered the patient's outcome when compared with <7 days of steroids. Management of CAR T cell-mediated neurotoxicity warrants evaluation in prospective clinical trials., (© 2019 by The American Society of Hematology.)

Background: Pre-operative administration of benzodiazepines can cause hypoventilation-a decrease in minute ventilation (MV)-commonly referred to as "respiratory compromise or respiratory depression." Respiratory depression can lead to hypercarbia and / or hypoxemia, and may heighten the risk of other respiratory complications. Current anesthesia practice often places patients at risk for respiratory complications even before surgery, as respiratory monitoring is generally postponed until the patient is in the operating room. In the present study we examined and quantified the onset of respiratory depression following the administration of a single dose of midazolam in pre-operative patients, using a non-invasive respiratory volume monitor that reports MV, tidal volume (TV), and respiratory rate (RR)., Methods: Impedance-based Respiratory Volume Monitor (RVM) data were collected and analyzed from 30 patients prior to undergoing orthopedic or general surgical procedures. All patients received 2.0 mg of midazolam intravenously at least 20 minutes prior to the induction of anesthesia and the effects of midazolam on the patient's respiratory function were analyzed., Results: Within 15 minutes of midazolam administration, we noted a significant decrease in both MV (average decrease of 14.3% ± 5.9%, p<0.05) and TV (22.3% ± 4.5%, p<0.001). Interestingly, the corresponding RR increased significantly by an average of 10.3% ± 4.7% (p<0.05). Further analysis revealed an age-dependent response, in which elderly patients (age≥65 years, n = 6) demonstrated greater reductions in MV and TV and a lack of compensatory RR increase. In fact, elderly patients experienced an average decrease in MV of 34% ± 6% (p<0.05) compared to an average decrease of 9% ± 6% (p<0.05) in younger patients., Conclusions: We were able to quantify the effects of pre-operative midazolam administration on clinically significant respiratory parameters (MV, TV and RR) using a non-invasive RVM, uncovering that the respiratory depressive effect of benzodiazepines affect primarily TV rather than RR. Such respiratory monitoring data provide the opportunity for individualizing dosing and adjustment of clinical interventions, especially important in elderly patients. With additional respiratory data, clinicians may be able to better identify and quantify respiratory depression, reduce adverse effects, and improve overall patient safety.

Delirium is a common and costly complication of hospitalization. Although medications are a known cause of delirium, antibiotics are an underrecognized class of medications associated with delirium. In this article, we comprehensively review the clinical, radiologic, and electrophysiologic features of antibiotic-associated encephalopathy (AAE). AAE can be divided into 3 unique clinical phenotypes: encephalopathy commonly accompanied by seizures or myoclonus arising within days after antibiotic administration (caused by cephalosporins and penicillin); encephalopathy characterized by psychosis arising within days of antibiotic administration (caused by quinolones, macrolides, and procaine penicillin); and encephalopathy accompanied by cerebellar signs and MRI abnormalities emerging weeks after initiation of antibiotics (caused by metronidazole). We correlate these 3 clinical phenotypes with underlying pathophysiologic mechanisms of antibiotic neurotoxicity. Familiarity with these types of antibiotic toxicity can improve timely diagnosis of AAE and prompt antibiotic discontinuation, reducing the time patients spend in the delirious state., (© 2016 American Academy of Neurology.)

Background: The motor system has the remarkable ability not only to learn but also to learn how fast it should learn. However, the mechanisms behind this ability are not well understood. Previous studies have posited that the rate of adaptation in a given environment is determined by Bayesian sensorimotor integration based on the amount of variability in the state of the environment. However, experimental results have failed to support several predictions of this theory., Results: We show that the rate at which the motor system adapts to changes in the environment is primarily determined not by the degree to which environmental change occurs but by the degree to which the changes that do occur persist from one movement to the next, i.e., the consistency of the environment. We demonstrate a striking double dissociation whereby feedback response strength is predicted by environmental variability rather than consistency, whereas adaptation rate is predicted by environmental consistency rather than variability. We proceed to elucidate the role of stimulus repetition in speeding up adaptation and find that repetition can greatly potentiate the effect of consistency, although unlike consistency, repetition alone does not increase adaptation rate. By leveraging this understanding, we demonstrate that the rate of motor adaptation can be modulated over a range that encompasses a 20-fold increase from lowest to highest., Conclusions: Understanding the mechanisms that determine the rate of motor adaptation could lead to the principled design of improved procedures for motor training and rehabilitation. Regimens designed to control environmental consistency and repetition during training might yield faster, more robust motor learning., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Individual differences in motor learning ability are widely acknowledged, yet little is known about the factors that underlie them. Here we explore whether movement-to-movement variability in motor output, a ubiquitous if often unwanted characteristic of motor performance, predicts motor learning ability. Surprisingly, we found that higher levels of task-relevant motor variability predicted faster learning both across individuals and across tasks in two different paradigms, one relying on reward-based learning to shape specific arm movement trajectories and the other relying on error-based learning to adapt movements in novel physical environments. We proceeded to show that training can reshape the temporal structure of motor variability, aligning it with the trained task to improve learning. These results provide experimental support for the importance of action exploration, a key idea from reinforcement learning theory, showing that motor variability facilitates motor learning in humans and that our nervous systems actively regulate it to improve learning.

In motor tasks, errors between planned and actual movements generally result in adaptive changes which reduce the occurrence of similar errors in the future. It has commonly been assumed that the motor adaptation arising from an error occurring on a particular movement is specifically associated with the motion that was planned. Here we show that this is not the case. Instead, we demonstrate the binding of the adaptation arising from an error on a particular trial to the motion experienced on that same trial. The formation of this association means that future movements planned to resemble the motion experienced on a given trial benefit maximally from the adaptation arising from it. This reflects the idea that actual rather than planned motions are assigned 'credit' for motor errors because, in a computational sense, the maximal adaptive response would be associated with the condition credited with the error. We studied this process by examining the patterns of generalization associated with motor adaptation to novel dynamic environments during reaching arm movements in humans. We found that these patterns consistently matched those predicted by adaptation associated with the actual rather than the planned motion, with maximal generalization observed where actual motions were clustered. We followed up these findings by showing that a novel training procedure designed to leverage this newfound understanding of the binding of learning to action, can improve adaptation rates by greater than 50%. Our results provide a mechanistic framework for understanding the effects of partial assistance and error augmentation during neurologic rehabilitation, and they suggest ways to optimize their use.

The shape of the directional generalization function for adaptation to a viscous force-field environment has been controversial. Some studies have suggested wide, essentially global generalization and others have suggested narrow, local generalization. Here, we show definitively that motor adaptation displays narrow generalization with a minimal global component and a peak at the trained movement direction for both single-trial and asymptotic adaptation. Furthermore, we find that reaching movements in opposite directions do not interfere with one another during force-field learning.