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STUDY DESIGN.: A prospective clinical research article. OBJECTIVE.: The primary goals were to determine (1) radiation exposure to the spine surgeon with the use of an intraoperative 3-dimensional imaging system and (2) to define the safe distance from the computed tomographic scanner. SUMMARY OF BACKGROUND.: Intraoperative radiation exposure to the spinal surgeon has been assessed during 2-dimensional fluoroscopy but has not been investigated during intraoperative 3-dimensional imaging. METHODS.: Ten patients undergoing lumbar or thoracolumbar fusion were enrolled in a prospective trial to determine the radiation exposure to a spine surgeon standing in the substerile room, with the use of the O-ARM Imaging System (Medtronic, Memphis, TN). A thermolucent digital dosimeter was worn at chest level without a lead apron. Dosimeter readings and distance from the spine surgeon were recorded. RESULTS.: Average surgeon exposure was 44.22 ± 17.4 [mu]rem (range: 17.71-70.76 [mu]rem). The mean distance from the O-ARM was 4.56 ± .32 m, and the surgeon was exposed for an average of 19.6 ± 5.7 seconds (range: 8.05-28.7 s). The annual number of necessary procedures required to surpass the exposure limit, according to the data presented here, would be 113,071 operations using O-ARM. Hence, the number of necessary procedures for O-ARM use is predicted to be 1,130,710 annual procedures to reach the occupational exposure limits for extremity, skin, and all other organs and 339,213 procedures to reach the limits for the lens of eye. CONCLUSION.: Radiation exposure is minimal to the surgical team during routine use of the O-ARM imaging system. The number of procedures required to surpass occupational exposure limits is high if using appropriate distance from the O-ARM. [ABSTRACT FROM AUTHOR]

Study Design: Morphometric and volumetric analyses and virtual screw placement. Objective: The aim of the study was to (1) define the morphometric and volumetric dimensions of the laminae of C3-C7 and (2) analyze the feasibility of unilateral and bilateral translaminar screw placement at C3-C7. Summary Of Background Data: Previous studies on translaminar screw fixation have primarily focused on upper cervical and thoracic fixation. Most studies have been conducted on the subaxial cervical vertebrae in the pediatric population and a few in the adult population. In this study, we used computed tomographic (CT) scans to calculate the spatial anatomical environment for translaminar screws at C3-C7. We also determined the feasibility of translaminar screw placement at C3-C7 for clinical applicability. Methods: Morphometric and volumetric analyses were performed on CT scans of the C3-C7 laminae in 25 male and 25 female patients. A total of 2000 morphometric and 1000 volumetric measurements were performed. The feasibility analysis was performed using unilateral and bilateral virtual screw placement via BrainLAB software (BrainLAB AG, Heimstetten, Germany) on the same CT scans. Results: Male patients had significantly (P < 0.05) longer translaminar lengths (C5-C7), sagittal-diagonal measurements (C3-C7), and larger volumes (C6-C7) than female patients. Unilaterally, C7 showed 3.5-mm translaminar screw acceptance rates of 100%, C6 showed high acceptance rates (>64%), and C3-C5 showed lower acceptance rates (<52%). C7 accepted bilateral placement at a high rate (96% men, 84% women). C3 and C6 accepted bilateral screws at low placement rates (8%-24%). C4 and C5 never accepted bilateral translaminar screw placement. Conclusion: Subaxial cervical unilateral translaminar screw placement is a potentially safe and effective technique to use in conjunction with preoperative CT scanning for all vertebral levels. The same is true for bilateral placement at C7 but not at C3-C6. A prospective study to evaluate the long-term outcomes of translaminar fixation at all vertebral levels is currently underway. [ABSTRACT FROM AUTHOR]

STUDY DESIGN.: Review of literature. OBJECTIVE.: To evaluate the available literature supporting the use of lumbar fusion extenders in clinical practice. SUMMARY OF BACKGROUND DATA.: Because of the morbidity associated with the harvest of autologous iliac crest bone grafts, the search for lumber fusion extenders and replacements has accelerated. Many formulations of lumbar fusion extenders have been developed, and it is essential to evaluate clinical literature and available outcome metrics of these extenders. METHODS.: A review of English-language literature was performed between 1990 and January of 2010 for all literature presenting clinical outcomes of lumbar fusion extenders. After controlling for inclusion and exclusion criteria and assigning levels of evidence, 19 clinical studies were fully reviewed including those for demineralized bone matrix, recombinant human bone morphogenetic protein 2 (rhBMP-2), [beta]-tricalcium phosphate, and calcium sulfate. RESULTS.: The most extensively studied of the lumbar fusion extenders is [beta]-tricalcium phosphate, especially with regard to its use in adolescent scoliosis correction. The use of rhBMP-2 and demineralized bone matrix is supported only by two and three clinical studies, respectively. Calcium sulfate and other miscellaneous extenders are not conclusively or consistently supported by available clinical studies. CONCLUSION.: Calcium phosphate is the most supported of the lumbar fusion extenders. rhBMP-2 and demineralized bone matrix are supported by smaller bodies of evidence. These formulations are supported by these initial studies but in some cases need to be better examined with regard to side effect profiles. [ABSTRACT FROM AUTHOR]

Histone lysine lactylation is a physiologically and pathologically relevant epigenetic pathway that can be stimulated by the Warburg effect-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-coenzyme A (CoA) and how this process is regulated remains unknown. Here, we report the identification of guanosine triphosphate (GTP)-specific SCS (GTPSCS) as a lactyl-CoA synthetase in the nucleus. The mechanism was elucidated through the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to elevate histone lactylation but not succinylation. This process depends on a nuclear localization signal in the GTPSCS G1 subunit and acetylation at G2 subunit residue K73, which mediates the interaction with p300. GTPSCS/p300 collaboration synergistically regulates histone H3K18la and GDF15 expression, promoting glioma proliferation and radioresistance. GTPSCS represents the inaugural enzyme to catalyze lactyl-CoA synthesis for epigenetic histone lactylation and regulate oncogenic gene expression in glioma., Competing Interests: Declaration of interests Y. Zhao is a founder, board member, advisor to, and inventor on patents licensed to PTM Bio Inc. (Hangzhou, China and Chicago, IL) and Maponos Therapeutics Inc. (Chicago, IL)., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Despite advances in the treatment paradigm for patients with metastatic melanoma, melanoma brain metastasis (MBM) continues to represent a significant treatment challenge. The study of MBM is limited, in part, by shortcomings in existing preclinical models. Surgically eXplanted Organoids (SXOs) are ex vivo, three-dimensional cultures prepared from primary tissue samples with minimal processing that recapitulate genotypic and phenotypic features of parent tumors without an artificial extracellular scaffold. MBM SXOs were created by a novel protocol incorporating techniques for establishing glioma and cutaneous melanoma organoids. A BRAF V600K -mutant and BRAF-wildtype MBM sample were collected directly from the operating room. Organoids were cultured in an optimized culture medium without an artificial extracellular scaffold. Concurrently, matched patient-derived cell lines were created. Organoid growth was observed within 3-4 weeks, and MBM SXOs retained histological features of the parent tissue, including pleomorphic epithelioid cells with abundant cytoplasm, large nuclei, focal melanin accumulation, and strong SOX10 positivity. After sufficient growth, organoids could be manually parcellated to increase the number of replicates. Matched SXOs and cell lines demonstrated sensitivity to BRAF and MEK inhibitors. Further study using SXOs may improve the translational relevance of preclinical studies and enable the study of the metastatic melanoma tumor microenvironment., (© 2024. The Author(s).)

Gliomas are the most common primary brain tumor and are uniformly lethal. Despite significant advancements in understanding the genetic landscape of gliomas, standard-of-care has remained largely unchanged. Subsets of gliomas are defined by gain-of-function mutations in the metabolic genes encoding isocitrate dehydrogenase (IDH). Efforts to exploit mutant IDH activity and/or directly inhibit it with mutant IDH inhibitors have been the focus of over a decade of research. The recently published INDIGO trial, demonstrating the benefit of the mutant IDH inhibitor vorasidenib in patients with low-grade IDH-mutant gliomas, introduces a new era of precision medicine in brain tumors that is poised to change standard-of-care. In this review, we highlight and contextualize the results of the INDIGO trial and introduce key questions whose answers will guide how mutant IDH inhibitors may be used in the clinic. We discuss possible combination therapies with mutant IDH inhibition and future directions for clinical and translational research., (© 2024. The Author(s).)

In recent years, the classification of adult-type diffuse gliomas has undergone a revolution, wherein specific molecular features now represent defining diagnostic criteria of IDH-wild-type glioblastomas, IDH-mutant astrocytomas, and IDH-mutant 1p/19q-codeleted oligodendrogliomas. With the introduction of the 2021 WHO CNS classification, additional molecular alterations are now integrated into the grading of these tumors, given equal weight to traditional histologic features. However, there remains a great deal of heterogeneity in patient outcome even within these established tumor subclassifications that is unexplained by currently codified molecular alterations, particularly in the IDH-mutant astrocytoma category. There is also significant intercellular genetic and epigenetic heterogeneity and plasticity with resulting phenotypic heterogeneity, making these tumors remarkably adaptable and robust, and presenting a significant barrier to the design of effective therapeutics. Herein, we review the mechanisms and consequences of genetic and epigenetic instability, including chromosomal instability (CIN), microsatellite instability (MSI)/mismatch repair (MMR) deficits, and epigenetic instability, in the underlying biology, tumorigenesis, and progression of IDH-mutant astrocytomas. We also discuss the contribution of recent high-resolution transcriptomics studies toward defining tumor heterogeneity with single-cell resolution. While intratumoral heterogeneity is a well-known feature of diffuse gliomas, the contribution of these various processes has only recently been considered as a potential driver of tumor aggressiveness. CIN has an independent, adverse effect on patient survival, similar to the effect of histologic grade and homozygous CDKN2A deletion, while MMR mutation is only associated with poor overall survival in univariate analysis but is highly correlated with higher histologic/molecular grade and other aggressive features. These forms of genomic instability, which may significantly affect the natural progression of these tumors, response to therapy, and ultimately clinical outcome for patients, are potentially measurable features which could aid in diagnosis, grading, prognosis, and development of personalized therapeutics., (© 2024. The Author(s).)

The diagnosis and classification of glioma by liquid biopsy represent a critical unmet need in neuro-oncology. A recent study demonstrates targeted next-generation sequencing of cell-free DNA from cerebrospinal fluid as an evolving option for liquid biopsy in patients with glioma. See related article by Iser et al., p. 2974., (©2024 American Association for Cancer Research.)

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma., Competing Interests: Declaration of interests I.F.P. and S.A. have a utility use patent on ERK5 inhibitors for use in pediatric brain tumors., (Copyright © 2023. Published by Elsevier Inc.)

Nucleotides are substrates for multiple anabolic pathways, most notably DNA and RNA synthesis. Since nucleotide synthesis inhibitors began to be used for cancer therapy in the 1950s, our understanding of how nucleotides function in tumor cells has evolved, prompting a resurgence of interest in targeting nucleotide metabolism for cancer therapy. In this review, we discuss recent advances that challenge the idea that nucleotides are mere building blocks for the genome and transcriptome and highlight ways that these metabolites support oncogenic signaling, stress resistance, and energy homeostasis in tumor cells. These findings point to a rich network of processes sustained by aberrant nucleotide metabolism in cancer and reveal new therapeutic opportunities., Competing Interests: Declaration of interests None are declared by the authors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Mutations in mismatch repair (MMR) genes ( MSH2 , MSH6 , MLH1 , and PMS2) are associated with microsatellite instability and a hypermutator phenotype in numerous systemic cancers, and germline MMR mutations have been implicated in multi-organ tumor syndromes. In gliomas, MMR mutations can function as an adaptive response to alkylating chemotherapy, although there are well-documented cases of germline and sporadic mutations, with detrimental effects on patient survival., Methods: The clinical, pathologic, and molecular features of 18 IDH-mutant astrocytomas and 20 IDH-wild-type glioblastomas with MMR mutations in the primary tumor were analyzed in comparison to 361 IDH-mutant and 906 IDH-wild-type tumors without MMR mutations. In addition, 12 IDH-mutant astrocytomas and 18 IDH-wild-type glioblastomas that developed MMR mutations between initial presentation and tumor recurrence were analyzed in comparison to 50 IDH-mutant and 104 IDH-wild-type cases that remained MMR-wild-type at recurrence., Results: In both IDH-mutant astrocytoma and IDH-wild-type glioblastoma cohorts, the presence of MMR mutation in primary tumors was associated with significantly higher tumor mutation burden (TMB) ( P  < .0001); however, MMR mutations only resulted in worse overall survival in the IDH-mutant astrocytomas ( P  = .0069). In addition, gain of MMR mutation between the primary and recurrent surgical specimen occurred more frequently with temozolomide therapy ( P  = .0073), and resulted in a substantial increase in TMB ( P  < .0001), higher grade ( P  = .0119), and worse post-recurrence survival ( P  = .0022) in the IDH-mutant astrocytoma cohort., Conclusions: These results suggest that whether present initially or in response to therapy, MMR mutations significantly affect TMB but appear to only influence the clinical outcome in IDH-mutant astrocytoma subsets., Competing Interests: The authors have no conflict of interest to report. Competing interests: The results presented in this paper have not been published previously in whole or part. The authors declare that they have no competing interests., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose: Metabolism within the tumor microenvironment (TME) represents an increasing area of interest to understand glioma initiation and progression. Stable isotope tracing is a technique critical to the study of tumor metabolism. Cell culture models of this disease are not routinely cultured under physiologically relevant nutrient conditions and do not retain cellular heterogeneity present in the parental TME. Moreover, in vivo, stable isotope tracing in intracranial glioma xenografts, the gold standard for metabolic investigation, is time consuming and technically challenging. To provide insights into glioma metabolism in the presence of an intact TME, we performed stable isotope tracing analysis of patient-derived, heterocellular Surgically eXplanted Organoid (SXO) glioma models in human plasma-like medium (HPLM)., Methods: Glioma SXOs were established and cultured in conventional media or transitioned to HPLM. We evaluated SXO cytoarchitecture and histology, then performed spatial transcriptomic profiling to identify cellular populations and differential gene expression patterns. We performed stable isotope tracing with 15 N 2 -glutamine to evaluate intracellular metabolite labeling patterns., Results: Glioma SXOs cultured in HPLM retain cytoarchitecture and cellular constituents. Immune cells in HPLM-cultured SXOs demonstrated increased transcription of immune-related signatures, including innate immune, adaptive immune, and cytokine signaling programs. 15 N isotope enrichment from glutamine was observed in metabolites from diverse pathways, and labeling patterns were stable over time., Conclusion: To enable ex vivo, tractable investigations of whole tumor metabolism, we developed an approach to conduct stable isotope tracing in glioma SXOs cultured under physiologically relevant nutrient conditions. Under these conditions, SXOs maintained viability, composition, and metabolic activity while exhibiting increased immune-related transcriptional programs., Competing Interests: Competing Interests The authors declare no competing interests.

Isocitrate dehydrogenase (IDH) is a key enzyme in normal metabolism and homeostasis. However, mutant forms of IDH are also defining features of a subset of diffuse gliomas. In this review, we highlight current techniques targeting IDH-mutated gliomas and summarize current and completed clinical trials exploring these strategies. We discuss clinical data from peptide vaccines, mutant IDH (mIDH) inhibitors, and PARP inhibitors. Peptide vaccines have the unique advantage of targeting the specific epitope of a patient's tumor, inducing a highly tumor-specific CD4+ T-cell response. mIDH-inhibitors, on the other hand, specifically target mutant IDH proteins in cancer cell metabolism and thus help halt gliomagenesis. We also explore PARP inhibitors and their role in treating diffuse gliomas, which exploit IDH-mutant diffuse gliomas by allowing the persistence of unrepaired DNA complexes. We summarize various completed and current trials targeting IDH1 and IDH2 mutations in diffuse gliomas. Therapies targeting mutant IDH have significant promise in treating progressive or recurrent IDH-mutant gliomas and may significantly change treatment paradigms in the next decade., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment 1,2 . Lysine functions as a biosynthetic molecule, energy source and antioxidant 3-5 , but little is known about its pathological role in cancer. Here we show that glioblastoma stem cells (GSCs) reprogram lysine catabolism through the upregulation of lysine transporter SLC7A2 and crotonyl-coenzyme A (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase (GCDH) with downregulation of the crotonyl-CoA hydratase enoyl-CoA hydratase short chain 1 (ECHS1), leading to accumulation of intracellular crotonyl-CoA and histone H4 lysine crotonylation. A reduction in histone lysine crotonylation by either genetic manipulation or lysine restriction impaired tumour growth. In the nucleus, GCDH interacts with the crotonyltransferase CBP to promote histone lysine crotonylation. Loss of histone lysine crotonylation promotes immunogenic cytosolic double-stranded RNA (dsRNA) and dsDNA generation through enhanced H3K27ac, which stimulates the RNA sensor MDA5 and DNA sensor cyclic GMP-AMP synthase (cGAS) to boost type I interferon signalling, leading to compromised GSC tumorigenic potential and elevated CD8 + T cell infiltration. A lysine-restricted diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumour growth. Collectively, GSCs co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Since the discovery of IDH mutations in glioma over a decade ago, significant progress has been made in determining how these mutations affect epigenetic, transcriptomic, and metabolic programs in brain tumor cells. In this article, we summarize current understanding of how IDH mutations influence DNA damage in glioma and discuss clinical implications of these findings., Methods: We performed a thorough review of peer-reviewed publications and provide an overview of key mechanisms by which IDH mutations impact response to DNA damage in gliomas, with an emphasis on clinical implications., Results: The effects of mutant IDH on DNA damage largely fall into four overarching categories: Gene Expression, Sensitivity to Alkylating Agents, Homologous Recombination, and Oxidative Stress. From a mechanistic standpoint, we discuss how mutant IDH and the oncometabolite (R)-2HG affect each of these categories of DNA damage. We also contextualize these mechanisms with respect to ongoing clinical trials. Studies are underway that incorporate current standard-of-care therapies, including radiation and alkylating agents, in addition to novel therapeutic agents that exert genotoxic stress specifically in IDH-mutant gliomas. Lastly, we discuss key unanswered questions and emerging data in this field that have important implications for our understanding of glioma biology and for the development of new brain tumor therapies., Conclusion: Mounting preclinical and clinical data suggest that IDH mutations alter DNA damage sensing and repair pathways through distinct mechanisms. Future studies are needed to deepen our understanding of these processes and provide additional mechanistic insights that can be leveraged for therapeutic benefit., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Models for human gliomas prove critical not only to advancing our understanding of glioma biology but also to facilitate the development of therapeutic modalities. Specifically, creating lower-grade glioma (LGG) models has been challenging, contributing to few investigations and the minimal progress in standard treatment over the past decade. In order to reliably predict and validate the efficacies of novel treatments, however, LGG models need to adhere to specific standards that recapitulate tumor genetic aberrations and micro-environment. This underscores the need to revisit existing models of LGG and explore prospective models that may bridge the gap between preclinical insights and clinical translation. This review first outlines a set of criteria aimed to address the current challenges hindering model development. We then evaluate the strengths and weaknesses of existing preclinical models of LGG with respect to these established standards. To conclude, the review discusses potential future directions for integrating existing models to maximize the exploration of disease mechanisms and therapeutics development., 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 Tang, Mallela, Deng, Richardson, Hervey-Jumper, McBrayer and Abdullah.)

Glioblastoma (GBM) is an aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of MM0299, a tetracyclic dicarboximide with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a "shunt" pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant, and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications., Competing Interests: Declaration of interests A patent application related to this work has been filed by University of Texas Southwestern Medical Center., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation., Competing Interests: Declaration of interests R.J.D., W.G.K., and S.K.M. have served as paid advisors to Agios Pharmaceuticals. W.G.K. receives compensation for roles as an Eli Lilly and LifeMine Therapeutics Board Director, a founder of Tango Therapeutics and Cedilla Therapeutics, and a scientific advisor for Fibrogen, IconOVir Bio, Circle Pharma, Nextext Invest, and Casdin Capital. K.L.L. receives research support from Eli Lilly and Company via the DFCI. S.K.M. and W.G.K. received research funding from Bayer Pharmaceuticals. Bayer had no influence over the design, execution, or interpretation of studies. N.Y.R.A. is key opinion leader for Bruker Daltonics, scientific advisor to Invicro, and receives support from Thermo Finnegan and EMD Serono. S.G., A.S., M.S., A.J., and L.E. are employees at Bayer. S.G., A.S., and A.J. hold stock in Bayer. D.P.C. has consulted for Lilly, GlaxoSmithKline, and Boston Pharmaceuticals and serves on the advisory board of Pyramid Biosciences, which includes an equity interest. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chromosomal instability (CIN) is a fundamental property of cancer and a key underlying mechanism of tumorigenesis and malignant progression, and has been documented in a wide variety of cancers, including colorectal carcinoma with mutations in genes such as APC. Recent reports have demonstrated that CIN, driven in part by mutations in genes maintaining overall genomic stability, is found in subsets of adult-type diffusely infiltrating gliomas of all histologic and molecular grades, with resulting elevated overall copy number burden, chromothripsis, and poor clinical outcome. Still, relatively few studies have examined the effect of this process, due in part to the difficulty of routinely measuring CIN clinically. Herein, we review the underlying mechanisms of CIN, the relationship between chromosomal instability and malignancy, the prognostic significance and treatment potential in various cancers, systemic disease, and more specifically, in diffusely infiltrating glioma subtypes. While still in the early stages of discovery compared to other solid tumor types in which CIN is a known driver of malignancy, the presence of CIN as an early factor in gliomas may in part explain the ability of these tumors to develop resistance to standard therapy, while also providing a potential molecular target for future therapies., (© 2022. The Author(s).)

Intraosseous hemangiomas are rare, benign tumors that can arise from the calvarium. These lesions often invade the outer table of the skull, but typically spare the inner table and intracranial structures. En bloc surgical resection is the standard treatment for intraosseous hemangiomas. However, a piecemeal resection may be required to safely remove the tumor in cases involving the inner table to protect the underlying brain parenchyma and vascular structures. Proper reconstruction is critical to optimize the cosmetic outcome, and a staged procedure allowing implantation of a custom-made implant can be considered for large lesions involving the forehead. We present a case of a patient with a large frontal intraosseous hemangioma with intradural involvement to highlight the surgical nuances of resection and review the existing literature regarding optimal management of these patients., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

The creation of patient-derived cancer organoids represents a key advance in preclinical modeling and has recently been applied to a variety of human solid tumor types. However, conventional methods used to assess in vivo tumor tissue treatment response are poorly suited for the evaluation of cancer organoids because they are time-intensive and involve tissue destruction. To address this issue, we established a suite of 3-dimensional patient-derived glioma organoids, treated them with chemoradiotherapy, stained organoids with non-toxic cell dyes, and imaged them using a rapid laser scanning confocal microscopy method termed "Apex Imaging." We then developed and tested a fragmentation algorithm to quantify heterogeneity in the topography of the organoids as a potential surrogate marker of viability. This algorithm, SSDquant, provides a 3-dimensional visual representation of the organoid surface and a numerical measurement of the sum-squared distance (SSD) from the derived mass center of the organoid. We tested whether SSD scores correlate with traditional immunohistochemistry-derived cell viability markers (cellularity and cleaved caspase 3 expression) and observed statistically significant associations between them using linear regression analysis. Our work describes a quantitative, non-invasive approach for the serial measurement of patient-derived cancer organoid viability, thus opening new avenues for the application of these models to studies of cancer biology and therapy., 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.)

Background: Historically, creating patient-derived models of lower-grade glioma (LGG) has been challenging, contributing to few experimental platforms that support laboratory-based investigations of this disease. Although organoid modeling approaches have recently been employed to create in vitro models of high-grade glioma (HGG), it is unknown whether this approach can be successfully applied to LGG., Methods: In this study, we developed an optimized protocol for the establishment of organoids from LGG primary tissue samples by utilizing physiologic (5%) oxygenation conditions and employed it to produce the first known suite of these models. To assess their fidelity, we surveyed key biological features of patient-derived organoids using metabolic, genomic, histologic, and lineage marker gene expression assays., Results: Organoid models were created with a success rate of 91% (n = 20/22) from primary tumor samples across glioma histological subtypes and tumor grades (WHO Grades 1-4), and a success rate of 87% (13/15) for WHO Grade 1-3 tumors. Patient-derived organoids recapitulated stemness, proliferative, and tumor-stromal composition profiles of their respective parental tumor specimens. Cytoarchitectural, mutational, and metabolic traits of parental tumors were also conserved. Importantly, LGG organoids were maintained in vitro for weeks to months and reanimated after biobanking without loss of integrity., Conclusions: We report an efficient method for producing faithful in vitro models of LGG. New experimental platforms generated through this approach are well positioned to support preclinical studies of this disease, particularly those related to tumor immunology, tumor-stroma interactions, identification of novel drug targets, and personalized assessments of treatment response profiles., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Diffusely infiltrating gliomas are among the most common central nervous system tumors in adults. Over the past decade, the subcategorization of these tumors has changed to include both traditional histologic features and more recently identified molecular factors. However, one molecular feature that has yet to be integrated is the presence/absence of chromosomal instability (CIN). Herein, we use global methylation profiling to evaluate a reference cohort of IDH-mutant astrocytomas with and without prior evidence of CIN (n = 42), and apply the resulting methylation-based characteristics to a larger test cohort of publicly-available IDH-mutant astrocytomas (n = 245). We demonstrate that IDH-mutant astrocytomas with evidence of CIN cluster separately from their chromosomally-stable counterparts. CIN cases were associated with higher initial histologic grade, altered expression patterns of genes related to CIN in other cancers, elevated initial total copy number burden, and significantly worse progression-free and overall survival. In addition, in a grade-for-grade analysis, patients with CIN-positive WHO grade 2 and 3 tumors had significantly worse survival. These results suggest that global methylation profiling can be used to discriminate between chromosomally stable and unstable IDH-mutant astrocytomas, and may therefore provide a reliable and cost-effective method for identifying gliomas with chromosomal instability and resultant poor clinical outcome., (© 2022. The Author(s).)

Objective: Cortical mapping has been used as a tool to ensure maximal safe resection of intracranial tumors for several decades. Post-surgical motor and language deficits, including seizures, weakness, aphasia, and dysarthria have been well-documented in patients undergoing these operations, particularly on eloquent cortical regions. However, it is not known whether awake versus asleep cortical mapping contributes to differences in postoperative neurological deficits., Methods: A comprehensive review of the literature utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was completed for articles describing cortical mapping for tumor resection. We critically assessed all articles published in the last 20 years describing complications of patients who had undergone either awake or asleep motor mapping for eloquent brain tumor resection. Studies were analyzed for number of patients, follow-up duration, rates of transient and permanent motor and sensory deficits in the perioperative period, and outcomes at one-month follow-up., Results: Thirty-one studies met inclusion criteria, 24 of which reported long-term post-operative follow-up data. Follow-up among selected studies ranged from one month to four years. Nine of the 31 studies directly compared the postoperative outcomes of awake versus asleep mapping. The rate of transient deficits among patients who underwent awake and asleep mapping was 31.6% and 32.7%, respectively. The rate of permanent deficits was 10.8% in awake mapping patients and 12.7% in asleep mapping patients. Qualitative analysis showed that motor and sensory complications occurred at similar rates., Conclusions: Review of the current evidence suggests that the rates of transient and permanent postoperative neurologic deficits among awake versus asleep cortical mapping groups are similar. Thus, use of both techniques is reasonable to minimize perioperative morbidity., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Enhanced understanding of the molecular features of glioma has led to an expansion of murine glioma models and successful preclinical studies. However, clinical trials continue to have a high cost, extended production time, and low proportion of success. Studies in large-animal models of various cancer types have emerged to bridge the translational gap between in vitro and in vivo animal studies and human clinical trials. The anatomy and physiology of large animals are of more direct relevance to human disease, allowing for more rigorous testing of treatments such as surgical resection and adjuvant therapy in glioma. The recent generation of multiple porcine glioma models supports their use in high-throughput preclinical studies. The demonstration of spontaneous glioblastoma formation in canines further provides a unique avenue for the study of de novo glioma. The aim of this review was to outline the current status of large animal models of glioma and their value as a transitional step between rodent models and human clinical trials., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Previous studies have shown improved post-surgical outcomes in patients who travel farther for glioblastoma treatment. This study investigates socioeconomic and facility factors that may influence this relationship., Methods: Overall survival was calculated and compared by distance to treatment facility using univariate and multivariate survival models. The analysis was stratified by facility type, income quartile and insurance status and the association re-evaluated. Kaplan-Meier survival curves were created to analyze the relationship between overall survival and distance group., Results: Individuals who traveled less than 5 miles to treatment had the shortest overall survival (11.8 months), while those who traveled greater than 50 miles had the longest survival (12.9 months). Stratification by income quartile failed to demonstrate an association between distance traveled and survival for those making less than $63,000 (adjusted hazard ratio range: 0.94-1.01). There was no association between survival and distance traveled for patients treated at a community cancer center, comprehensive community cancer center or an integrated network cancer program (adjusted hazard ratio range: 0.86-1.04)., Conclusion: Financial strain, rather than distance traveled to treatment, may be associated with glioblastoma survival., (Copyright © 2021. Published by Elsevier B.V.)

Background: Primary peripheral T-cell central nervous system lymphoma (PCNSL) is a rare, aggressive tumor that arises in the craniospinal axis and has an increased risk in individuals who are immunocompromised. This lesion often mimics other benign and malignant processes on radiographic imaging, leading to misdiagnosis and delays in treatment. We present a case of a patient with a history of Sjögren's syndrome and progressive neurologic symptoms who underwent craniotomy for diagnosis., Case Description: A 61-year-old woman with a history of Sjögren's syndrome, progressive aphasia, left facial droop, and right-sided paresthesias for 4 months presented for evaluation and management. An enhancing, infiltrative lesion in the left frontal lobe with underlying vasogenic edema was appreciated and suggestive of a primary or metastatic neoplasm. The patient underwent an open biopsy for further evaluation of the lesion. Extensive histopathologic evaluation revealed a diagnosis of T-cell PCNSL. The patient was started on induction methotrexate and temozolomide followed by consolidative radiotherapy., Conclusion: Autoimmune conditions are a risk factor for T-cell PCNSL development. T-cell PCNSL has radiographic and gross histologic features that are consistent with a broad differential, including gliomas and inflammatory processes. Prompt diagnosis and extensive histopathological evaluation is essential to ensure appropriate treatment., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Surgical Neurology International.)

Purpose: Radiation necrosis (RN) represents a serious post-radiotherapy complication in patients with brain metastases. Bevacizumab and laser interstitial thermal therapy (LITT) are viable treatment options, but direct comparative data is scarce. We reviewed the literature to compare the two treatment strategies., Methods: PubMed, EMBASE, Scopus, and Cochrane databases were searched. All studies of patients with RN from brain metastases treated with bevacizumab or LITT were included. Treatment outcomes were analyzed using indirect meta-analysis with random-effect modeling., Results: Among the 18 studies included, 143 patients received bevacizumab and 148 underwent LITT. Both strategies were equally effective in providing post-treatment symptomatic improvement (P = 0.187, I 2  = 54.8%), weaning off steroids (P = 0.614, I 2  = 25.5%), and local lesion control (P = 0.5, I 2  = 0%). Mean number of lesions per patient was not statistically significant among groups (P = 0.624). Similarly, mean T1-contrast-enhancing pre-treatment volumes were not statistically different (P = 0.582). Patterns of radiological responses differed at 6-month follow-ups, with rates of partial regression significantly higher in the bevacizumab group (P = 0.001, I 2  = 88.9%), and stable disease significantly higher in the LITT group (P = 0.002, I 2  = 81.9%). Survival rates were superior in the LITT cohort, and statistical significance was reached at 18 months (P = 0.038, I 2  = 73.7%). Low rates of adverse events were reported in both groups (14.7% for bevacizumab and 12.2% for LITT)., Conclusion: Bevacizumab and LITT can be safe and effective treatments for RN from brain metastases. Clinical and radiological outcomes are mostly comparable, but LITT may relate with superior survival benefits in select patients. Further studies are required to identify the best patient candidates for each treatment group., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The emergence of three-dimensional human organoids has opened the door for the development of patient-derived cancer organoid (PDO) models, which closely recapitulate parental tumor tissue. The mainstays of preclinical cancer modeling include in vitro cell lines and patient-derived xenografts, but these models lack the cellular heterogeneity seen in human tumors. Moreover, xenograft establishment is resource and time intensive, rendering these models difficult to use to inform clinical trials and decisions. PDOs, however, can be created efficiently and retain tumor-specific properties such as cellular heterogeneity, cell-cell and cell-stroma interactions, the tumor microenvironment, and therapeutic responsiveness. PDO models and drug-screening protocols have been described for several solid tumors and, more recently, for gliomas. Since PDOs can be developed in clinically relevant time frames and share many characteristics of parent tumors, they may enhance the ability to provide precision oncologic care for patients. This review explores the current literature on cancer organoids, highlighting the history of PDO development, organoid models of glioma, and potential clinical applications of PDOs.

Despite advances in understanding of the molecular pathogenesis of glioma, outcomes remain dismal. Developing successful treatments for glioma requires faithful in vivo disease modeling and rigorous preclinical testing. Murine models, including xenograft, syngeneic, and genetically engineered models, are used to study glioma-genesis, identify methods of tumor progression, and test novel treatment strategies. Since the discovery of highly recurrent isocitrate dehydrogenase (IDH) mutations in lower-grade gliomas, there is increasing emphasis on effective modeling of IDH mutant brain tumors. Improvements in preclinical models that capture the phenotypic and molecular heterogeneity of gliomas are critical for the development of effective new therapies. Herein, we explore the current status, advancements, and challenges with contemporary murine glioma models.

Chromosomal instability due to mutations in genes guarding the stability of the genome is a well-known mechanism underlying tumorigenesis and malignant progression in numerous cancers. The effect of this process in gliomas is mostly unknown with relatively little research examining the effects of chromosomal instability on patient outcome and therapeutic efficacy, although studies have shown that overall/total copy number variation (CNV) is elevated in higher histologic grades and in cases with more rapid progression and shorter patient survival. Herein, we examine a 70-gene mRNA expression signature (CIN70), which has been previously shown to correlate tightly with chromosomal instability, in 2 independent cohorts of IDH-mutant astrocytomas (total n = 241), IDH-wildtype astrocytomas (n = 228), and oligodendrogliomas (n = 128). Our results show that CIN70 expression levels correlate with total CNV, as well as higher grade, progression-free survival, and overall survival in both IDH-mutant and IDH-wildtype astrocytomas. In oligodendrogliomas, these mRNA signatures correlate with total CNV but not consistently with clinical outcome. These data suggest that chromosomal instability is an underlying factor in aggressive behavior and progression of a subset of diffuse astrocytomas. In addition, chromosomal instability may in part explain the poor response of diffuse gliomas to treatment and may serve as a future therapeutic target., (© 2021 American Association of Neuropathologists, Inc. All rights reserved.)

5-aminolevulinic acid (5-ALA) is a porphyrin precursor in the heme synthesis pathway. When supplied exogenously, certain cancers consume 5-ALA and convert it to the fluorogenic metabolite protoporphyrin IX (PpIX), causing tumor-specific tissue fluorescence. Preoperative administration of 5-ALA is used to aid neurosurgical resection of high-grade gliomas such as glioblastoma, allowing for increased extent of resection and progression free survival for these patients. A subset of gliomas, especially low-grade tumors, do not accumulate PpIX intracellularly or readily fluoresce upon 5-ALA administration, making gross total resection difficult to achieve in diffuse lesions. We review existing literature on 5-ALA metabolism and PpIX accumulation to explore potential mechanisms of 5-ALA-induced glioma tissue fluorescence. Targeting the heme synthesis pathway and understanding its dysregulation in malignant tissues could aid the development of adjunct therapies to increase intraoperative fluorescence after 5-ALA treatment.

Objective: Patient demographics, comorbidities, and baseline quality of life (QOL) are major contributors to postoperative outcomes. The frequency and cost of lumbar spine surgery has been increasing, with controversy revolving around optimal management strategies and outcome predictors. The goal of this study was to generate predictive nomograms and a clinical calculator for postoperative clinical and QOL outcomes following lumbar spine surgery for degenerative disease., Methods: Patients undergoing lumbar spine surgery for degenerative disease at a single tertiary care institution between June 2009 and December 2012 were retrospectively reviewed. Nomograms and an online calculator were modeled based on patient demographics, comorbidities, presenting symptoms and duration of symptoms, indication for surgery, type and levels of surgery, and baseline preoperative QOL scores. Outcomes included postoperative emergency department (ED) visit or readmission within 30 days, reoperation within 90 days, and 1-year changes in the EuroQOL-5D (EQ-5D) score. Bootstrapping was used for internal validation., Results: A total of 2996 lumbar surgeries were identified. Thirty-day ED visits were seen in 7%, 30-day readmission in 12%, 90-day reoperation in 3%, and improvement in EQ-5D at 1 year that exceeded the minimum clinically important difference in 56%. Concordance indices for the models predicting ED visits, readmission, reoperation, and dichotomous 1-year improvement in EQ-5D were 0.63, 0.66, 0.73, and 0.84, respectively. Important predictors of clinical outcomes included age, body mass index, Charlson Comorbidity Index, indication for surgery, preoperative duration of symptoms, and the type (and number of levels) of surgery. A web-based calculator was created, which can be accessed here: https://riskcalc.org/PatientsEligibleForLumbarSpineSurgery/., Conclusions: The prediction tools derived from this study constitute important adjuncts to clinical decision-making that can offer patients undergoing lumbar spine surgery realistic and personalized expectations of postoperative outcome. They may also aid physicians in surgical planning, referrals, and counseling to ultimately lead to improved patient experience and outcomes.

Introduction: Glioblastoma is the most common primary brain tumor in adults. Standard of care includes maximal surgical resection of the tumor followed by concurrent chemotherapy and radiation. The treatment of glioblastoma must account for an increased disease severity and treatment intensity compared to other cancers which place a significant cost burden on the patient and health system. Cost assessments of glioblastoma treatment have been sparse in comparison to other solid cancer subtypes. This study evaluates all currently available cost literature with an emphasis on the modern treatment paradigm to properly assess the economic implications of this disease., Methods: A critical review of 21 studies from 13 different countries measuring direct costs related to glioblastoma management was performed. Evaluated data included itemized costs, total costs of treatment regimens from diagnosis until death, the cost of second-line care after recurrence, and the incremental costs and cost-effectiveness of emerging therapies., Results: The average cost of a craniotomy was $10,042 across studies. Imaging for the duration of glioblastoma care had a mean cost of $2,788 ± 3,719. Studies examined different combinations of treatment modalities. Utilization of the modern treatment paradigm led to survival of 16.3 months across studies and had a mean cost of $62,602. Surgery for the recurrent disease had an average cost of $27,442 ± 18,992., Limitations and Conclusions: Direct cost estimates for glioblastoma varied substantially between institutions and countries and often failed to uniformly describe direct cost estimates associated with care for glioblastoma. The limitations of these studies make a true economic assessment of standards of care, costs of recurrence, and incremental costs associated with adjunctive therapy uncertain.

Thirty-day readmission following glioblastoma (GBM) resection is not only correlated with decreased overall survival but also increasingly tied to quality metrics and reimbursement. This study aimed to determine factors linked with 30-day readmission to develop a simple risk stratification score. From 2005 to 2016, 666 unique resections (467 patients) of primary/recurrent tissue-confirmed glioblastoma were retrospectively identified. We recorded patient demographics and medical history, tumor characteristics, post-operative complications and 30-day readmission. Univariate and multivariate logistic regression, optimized using a genetic learning algorithm, were used to determine factors associated with readmission. The multivariate model was converted to a simple additive score. The 30-day readmission rate was 20.3% in our cohort of 666 unique resections (60.7% first resection). Lower pre/post-operative KPS, recurrent resection, surgical-site infection, post-operative VTE, post-operative VPS, and discharge to a rehabilitation facility were significantly associated with an increased readmission risk (p < 0.05). MGMT methylation and chemoradiation were associated with decreased readmission risk (p < 0.05). Medical co-morbidities and past medical history, location of tumor in eloquent areas of the brain, and length of ICU/hospital stay did not predict readmission. The Glioblastoma Readmission Risk Score, developed from the multivariate model, accounts for increased BMI, decreased pre-operative KPS, current smoking, post-operative complications, MGMT methylation, and post-operative radiation. This risk score can be routinely used to stratify risk and assist in clinical decision making and outcome analyses., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Intraoperative molecular imaging with tumor-targeting fluorophores offers real-time detection of neoplastic tissue. The second window indocyanine green (SWIG) technique relies on passive accumulation of indocyanine green (ICG), a near-infrared fluorophore, in neoplastic tissues. In this study, we explore the ability of SWIG to detect neoplastic tissue and to predict postoperative magnetic resonance imaging (MRI) findings intraoperatively., Procedures: Retrospective data were collected from 36 patients with primary high-grade gliomas (HGG) enrolled as part of a larger trial between October 2014 and October 2018. Patients received systemic ICG infusions at 2.5-5 mg/kg 24 h preoperatively. Near-infrared fluorescence was recorded throughout the case and from biopsy specimens. The presence/location of residual SWIG signal after resection was compared to the presence/location of residual gadolinium enhancement on postoperative MRI. The extent of resection was not changed based on near-infrared imaging., Results: All 36 lesions demonstrated strong near-infrared fluorescence (signal-to-background = 6.8 ± 2.2) and 100 % of tumors reaching the cortex were visualized before durotomy. In 78 biopsy specimens, near-infrared imaging demonstrated higher sensitivity and accuracy than white light for diagnosing neoplastic tissue intraoperatively. Furthermore, near-infrared imaging predicted gadolinium enhancement on postoperative MRI with 91 % accuracy, with visualization of residual enhancement as small as 0.3 cm 3 . Patients with no residual near-infrared signal after resection were significantly more likely to have complete resection on postoperative MRI (p value < 0.0001)., Conclusions: Intraoperative imaging with SWIG demonstrates highly sensitive detection of HGG tissue in real time. Furthermore, post-resection near-infrared imaging correlates with postoperative MRI. Overall, our findings suggest that SWIG can provide surgeons with MRI-like results in real time, potentially increasing resection rates.

This case video demonstrates the surgical technique for resection of a cavernous malformation in the right dorsal midbrain. This video was deemed exempt by the University of Pennsylvania Institutional Review Board (IRB), as it is considered a case report, which does not require IRB approval or patient consent. The patient was a 57-yr-old male with cerebral cavernous malformation syndrome with multiple intracranial cavernomas. He was noticed to have progressively slowed speech with worsening confusion and drowsiness. On exam, the patient exhibited worsening in swallowing and upward gaze paresis, secondary to Parinaud phenomena. The patient was treated with microsurgical resection, utilizing stereotactic navigation and intraoperative neurophysiologic monitoring. Intraoperative view provided in the video was captured using a Karl Storz Endoscope (Karl Storz SE & Co KG, Tuttlingen, Germany). Postoperatively, the patient had worsening double vision, which improved on follow-up, in addition to improvement in sensorium and swallowing., (Copyright © 2020 by the Congress of Neurological Surgeons.)

A recent study (Sulkowski et al., 2020) reveals that oncometabolites, which are produced by metabolic gene mutations in many cancers, sensitize cells to PARP inhibition by antagonizing histone demethylation and obscuring epigenetic marks that are necessary for efficient DNA repair., (Copyright © 2020 Elsevier Inc. All rights reserved.)

IDH-wildtype glioblastoma is a relatively common malignant brain tumor in adults. These patients generally have dismal prognoses, although outliers with long survival have been noted in the literature. Recently, it has been reported that many histologically lower-grade IDH-wildtype astrocytomas have a similar clinical outcome to grade IV tumors, suggesting they may represent early or undersampled glioblastomas. cIMPACT-NOW 3 guidelines now recommend upgrading IDH-wildtype astrocytomas with certain molecular criteria (EGFR amplifications, chromosome 7 gain/10 loss, and/or TERT promoter mutations), establishing the concept of a "molecular grade IV" astrocytoma. In this report, we apply these cIMPACT-NOW 3 criteria to 2 independent glioblastoma cohorts, totaling 393 public database and institutional glioblastoma cases: 89 cases without any of the cIMPACT-NOW 3 criteria (GBM-C0) and 304 cases with one or more criteria (GBM-C1-3). In the GBM-C0 groups, there was a trend toward longer recurrence-free survival (median 12-17 vs 6-10 months), significantly longer overall survival (median 32-41 vs 15-18 months), younger age at initial diagnosis, and lower overall mutation burden compared to the GBM-C1-3 cohorts. These data suggest that while histologic features may not be ideal indicators of patient survival in IDH-wildtype astrocytomas, these 3 molecular features may also be important prognostic factors in IDH-wildtype glioblastoma., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

Objective: We aim to examine the existing literature on, and identify knowledge gaps in, the study of adverse animal and human audiovestibular effects from exposure to acoustic or electromagnetic waves that are outside of conventional human hearing. Design/Setting/Participants: A review was performed, which included searches of relevant MeSH terms using PubMed, Embase, and Scopus. Primary outcomes included documented auditory and/or vestibular signs or symptoms in animals or humans exposed to infrasound, ultrasound, radiofrequency, and magnetic resonance imaging. The references of these articles were then reviewed in order to identify primary sources and literature not captured by electronic search databases. Results: Infrasound and ultrasound acoustic waves have been described in the literature to result in audiovestibular symptomology following exposure. Technology emitting infrasound such as wind turbines and rocket engines have produced isolated reports of vestibular symptoms, including dizziness and nausea and auditory complaints, such as tinnitus following exposure. Occupational exposure to both low frequency and high frequency ultrasound has resulted in reports of wide-ranging audiovestibular symptoms, with less robust evidence of symptomology following modern-day exposure via new technology such as remote controls, automated door openers, and wireless phone chargers. Radiofrequency exposure has been linked to both auditory and vestibular dysfunction in animal models, with additional historical evidence of human audiovestibular disturbance following unquantifiable exposure. While several theories, such as the cavitation theory, have been postulated as a cause for symptomology, there is extremely limited knowledge of the pathophysiology behind the adverse effects that particular exposure frequencies, intensities, and durations have on animals and humans. This has created a knowledge gap in which much of our understanding is derived from retrospective examination of patients who develop symptoms after postulated exposures. Conclusion and Relevance: Evidence for adverse human audiovestibular symptomology following exposure to acoustic waves and electromagnetic energy outside the spectrum of human hearing is largely rooted in case series or small cohort studies. Further research on the pathogenesis of audiovestibular dysfunction following acoustic exposure to these frequencies is critical to understand reported symptoms., (At least a portion of this work is authored by Philip D. Littlefield and Derek Rodgers behalf of the U.S. Government and, as regards Dr. Littlefield, Dr. Rodgers and the U.S. Government, is not subject to copyright protection in the United States. Foreign and other copyrights may apply.)

The ability of diffusion tensor MRI to detect the preferential diffusion of water in cerebral white matter tracts enables neurosurgeons to noninvasively visualize the relationship of lesions to functional neural pathways. Although viewed as a research tool in its infancy, diffusion tractography has evolved into a neurosurgical tool with applications in glioma surgery that are enhanced by evolutions in crossing fiber visualization, edema correction, and automated tract identification. In this paper the current literature supporting the use of tractography in brain tumor surgery is summarized, highlighting important clinical studies on the application of diffusion tensor imaging (DTI) for preoperative planning of glioma resection, and risk assessment to analyze postoperative outcomes. The key methods of tractography in current practice and crucial white matter fiber bundles are summarized. After a review of the physical basis of DTI and post-DTI tractography, the authors discuss the methodologies with which to adapt DT image processing for surgical planning, as well as the potential of connectomic imaging to facilitate a network approach to oncofunctional optimization in glioma surgery.

Purpose: Young adults with isocitrate-dehydrogenase wild-type (IDH-WT) glioblastoma (GBM) represent a rare, understudied population compared to pediatric high-grade glioma, IDH-mutant GBM, or IDH-WT GBM in older patients. We aimed to explore the prognostic impact of epidermal growth factor receptor copy number gain (EGFR CN gain), one of the most common genetic alterations in IDH-WT glioma, in young adults with IDH-WT GBM., Methods: We performed a retrospective cohort study of patients 18-45 years old with newly diagnosed, IDH-WT GBM whose tumors underwent next-generation sequencing at our institution between 2014 and 2018. The impact of EGFR CN gain on time to tumor progression (TTP) and overall survival (OS) was assessed. A validation cohort of patients 18-45 years old with IDH-WT GBM was analyzed from The Cancer Genome Atlas (TCGA)., Results: Ten of 28 patients (36%) from our institution had EGFR CN gain, which was associated with shorter TTP (median 6.5 vs. 11.9 months; p = 0.06) and OS (median 16.3 vs. 23.5 months; p = 0.047). The negative prognostic impact of EGFR CN gain on OS persisted in a multivariate model (HR 6.40, 95% CI 1.3-31.0, p = 0.02). In the TCGA cohort (N = 43), EGFR CN gain was associated with shorter TTP and worse OS, although these did not reach statistical significance (TTP, median 11.5 vs. 14.4 months, p = 0.18; OS, median 23.6 vs. 27.8 months; p = 0.18)., Conclusions: EGFR CN gain may be associated with inferior outcomes in young adults with newly diagnosed, IDH-WT GBM, suggesting a potential role for targeting EGFR in this population.

This case video demonstrates the surgical technique for resection of a cavernous malformation in the midleft cingulate gyrus using a contralateral transcingulate approach (Video 1). The indications for operating on a cavernoma such as this are seizures, recurrent hemorrhages, and a surgically resectable target. This video describes the operative steps, positioning, incision, and craniotomy for this approach. In addition, risks of air embolism, interhemispheric exposure, use of stereotactic navigation, and benefits of gravity retraction are highlighted. The contralateral transcingulate approach is indicated as it reduces the need for retraction by employing gravity retraction. Further, this approach is advantageous as it prevents injury to the left sided eloquent cortex, affords comfortable surgeon position and offers an improved trajectory. This case illustrates a well-described albeit unique surgical technique for cavernous malformation repair in an operative video format. In addition, this case shows that this technique results in a favorable patient outcome with minimal complication when appropriately used., (Copyright © 2019. Published by Elsevier Inc.)

Introduction:  Gliosarcoma (GS) is a rare, malignant mixed tumor of the central nervous system with a median survival of approximately 13 months across multiple studies. Although the value of the extent of resection (EOR) has been confirmed as a prognostic survival factor in glioblastoma, no such association has been defined for GS. The goal of this study was to establish an association between EOR and survival and to determine if a threshold of resection exists for which a survival benefit is conferred in GS., Methods: The authors identified 11 patients with histologically confirmed GS between January 2005 and January 2015, treated at the Hospital of the University of Pennsylvania. Clinical, radiographic, and outcome data were retrospectively reviewed. Volumetric analysis was completed using semi-automated segmentation to measure the change in contrast-enhancing material based on preoperative T1-contrast (T1c) and postoperative T1 & T1c magnetic resonance imaging (MRI) scans. A log-rank test was completed to confirm an association between EOR and survival, and a series of Kaplan-Meier curves were constructed to determine an EOR threshold. Univariate Cox proportional hazards model (CPHM) followed by multivariate CPHM was also completed to evaluate associations between the prognostic clinical and immunohistochemistry variables under consideration., Results:  Extent of resection categories were defined as gross total resection (GTR >95%), subtotal resection (STR 90%-95%), and partial resection (PR <90%). The median overall survival for the groups were as follows: GTR-17.3 months (n=4), STR-12.6 months (n=5), PR-4.3 months (n=2). A statistically significant association (p=05 level) was found between survival and the PR group with the GTR group as reference. Multivariate CPHM confirmed a statistically significant association between increased survival and age, preoperative Karnofsky Performance Status (KPS) scores, postoperative KPS scores, and KI-67 index. Serial Kaplan-Meier curves suggest a survival benefit with an EOR threshold of 94%., Conclusion:  This study agrees with previous correlations in glioblastoma EOR and prolonged survival. For patients undergoing surgical resection for GS, maximal surgical removal, when safely possible, should be attempted as it appears to translate to longer survival times., Competing Interests: The authors have declared that no competing interests exist.

Brain injuries are a significant cause of morbidity and mortality worldwide. Auditory and vestibular dysfunction may occur following trauma to the temporal bone (TB), including the lateral skull base. The porcine model is a commonly used large animal model for investigating brain injury. Reports detailing porcine TB anatomy based on high resolution computed tomography (HRCT) imaging, however, are limited. Herein, we employ HRCT to evaluate and describe the bony anatomy of the porcine TB and lateral skull base. High-resolution multi-detector and cone beam CT were used to image porcine TBs (n = 16). TBs were analyzed for major anatomical structures and compared to human species. Porcine temporal bone anatomy was readily identifiable by HRCT. Although some variability exists, the ossicular chain, vestibule, cochlea, course of the facial nerve, and skull base are similar to those of humans. Major differences included position of the external auditory canal and mastoid, as well as presence of the petrous carotid canal. Study findings may serve as an atlas to evaluate the porcine middle and inner ear, as well as lateral skull base injuries for future porcine brain injury models or other studies that require CT-based analysis.

Background and Context: The impact of underlying liver disease on surgical outcomes has been recognized in a wide variety of surgical disciplines. However, less empiric data are available about the importance of liver disease in spinal surgery., Purpose: To measure the independent impact of underlying liver disease on 30-day outcomes following surgery for the degenerative cervical spine., Study Design: Retrospective comparative study., Patient Sample: A cohort of 21,207 patients undergoing elective surgery for degenerative disease of the cervical spine from the American College of Surgeons National Surgical Quality Improvement Program., Outcome Measures: Outcome measures included mortality, hospital length of stay, and postoperative complications within 30 days of surgery., Methods: The NSQIP dataset was queried for patients undergoing surgery for degenerative disease of the cervical spine from 2006 to 2015. Assessment of underlying liver disease was based on aspartate aminotransferase-to-platelet ratio index and Model of End-Stage Liver Disease-Sodium scores, computed from preoperative laboratory data. The effect of liver disease on outcomes was assessed by bivariate and multivariate analyses, in comparison with 16 other preoperative and operative factors., Results: Liver disease could be assessed in 21,207 patients based on preoperative laboratory values. Mild liver disease was identified in 2.2% of patients, and advanced liver disease was identified in 1.6% of patients. The 30-day mortality rates were 1.7% and 5.1% in mild and advanced liver diseases, respectively, compared with 0.6% in patients with healthy livers. The 30-day complication rates were 11.8% and 31.5% in these patients, respectively, compared with 8.8% in patients with healthy livers. In multivariate analysis, the presence of any liver disease (mild or advanced) was independently associated with an increased risk of mortality (OR=2.00, 95% CI=1.12-3.55, p=.019), morbidity (OR=1.35, 95% CI=1.07-1.70, p=.012), and length of hospital stay longer than 7 days (OR=1.73, 95% CI=1.40-2.13, p<.001), when compared with 18 other preoperative and operative factors. Liver disease was also independently associated with perioperative respiratory failure (OR=1.80, 95% CI=1.21-2.68, p=.004), bleeding requiring transfusion (OR=1.43, 95% CI=1.01-2.02, p=.044), wound disruption (OR=2.82, 95% CI=1.04-7.66, p=.042), and unplanned reoperation (OR=1.49, 95% CI=1.05-2.11, p=.025)., Conclusions: Liver disease independently predicts poor perioperative outcome following surgery for degenerative disease of the cervical spine. Based on these findings, careful consideration of a patient's underlying liver function before surgery may prove valuable in surgical decision-making, preoperative patient counseling, and postoperative patient care., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Freehand bedside ventriculostomy placement can result in catheter malfunction requiring a revision procedure and cause significant patient morbidity. We performed a single-center retrospective review to assess factors related to this complication., Methods: Using an administrative database and chart review, we identified 101 first-time external ventricular drain placements performed at the bedside. We collected data regarding demographics, medical comorbidities, complications, and catheter tip location. We performed univariate and multivariate statistical analyses using MATLAB. We corrected for multiple comparisons using the false discovery rate (FDR) procedure., Results: Multivariate regression analyses revealed that revision procedures were more likely to occur after drain blockage (odds ratio [OR] 17.9) and hemorrhage (OR 10.3, FDR-corrected P values < 0.01, 0.05, respectively). Drain blockage was less frequent after placement in an "optimal location" (ipsilateral ventricle or near foramen of Monroe; OR 0.09, P = 0.009, FDR-corrected P < 0.03) but was more likely to occur after placement in third ventricle (post-hoc P values < 0.015). Primary diagnoses included subarachnoid hemorrhage (n = 30, 29.7%), intraparenchymal hemorrhage with intraventricular extravasation (n = 24, 23.7%), tumor (n = 20, 19.8%), and trauma (n = 17, 16.8%). Most common complications included drain blockage (n = 12, 11.8%) and hemorrhage (n = 8, 7.9%). In total, 16 patients underwent at least 1 revision procedure (15.8%)., Conclusions: Bedside external ventricular drain placement is associated with a 15% rate of revision, that typically occurred after drain blockage and postprocedure hemorrhage. Optimal placement within the ipsilateral frontal horn or foramen of Monroe was associated with a reduced rate of drain blockage., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Surgical-site infections (SSIs) are an important cause of morbidity and mortality in neurosurgical patients. Topical antibiotics are one potential method to reduce the incidence of these infections., Objective: To examine the efficacy of topical vancomycin applied within the wound during craniotomy in a large prospective cohort study at a major academic center., Methods: Three hundred fifty-five patients were studied prospectively in this cohort study; 205 patients received 1 g of topical vancomycin powder in the subgaleal space while 150 matched control patients did not. Patients otherwise received identical care. The primary outcome variable was SSI rate factored by cohort. Secondary analysis examined cost savings from vancomycin usage estimated from hospital costs associated with SSI in craniotomy patients., Results: The addition of topical vancomycin was associated with a significantly lower rate of SSI than standard of care alone (0.49% [1/205] vs 6% [9/150], P = .002). Based on the costs of revision surgery for infections, topical vancomycin usage was estimated to save $1367 446 per 1000 craniotomy patients. No adverse reactions occurred., Conclusion: Topical vancomycin is a safe, effective, and cost-saving measure to prevent SSIs following craniotomy. These results have broad implications for standard of care in craniotomy.

Objective: The objective of this study was to assess the independent effect of complications on 30-day mortality in 32,695 patients undergoing elective craniotomy., Methods: The American College of Surgeons National Surgical Quality Improvement Program was queried for patients undergoing elective craniotomy from 2006 to 2015. Multivariate logistic regression was used to examine the effect of complications on mortality independent of preoperative risk and other postoperative complications. This effect was further assessed in risk-stratified patient subgroups using the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator., Results: Of 13 complications analyzed, the 5 most strongly associated with mortality independent of preoperative risk factors were unplanned intubation (odds ratio [OR], 12.1; 95% confidence interval [CI], 9.5-15.4; P < 0.001), stroke (OR, 11.1; 95% CI, 8.3-14.9; P < 0.001), ventilator requirement >48 hours after surgery (OR, 9.9; 95% CI, 7.9-12.6; P < 0.001), and renal failure (OR, 8.5; 95% CI, 4.4-16.2; P < 0.001). These same complications were also the 5 most associated with mortality independent of other postoperative complications. They were also associated with mortality across all risk-stratified patient subgroups. On the contrary, venous thromboembolism (OR, 1.3; 95% CI, 0.98-1.7; P = 0.06), urinary tract infection (OR, 1.1; 95% CI, 0.76-1.6; P = 0.61), unplanned reoperation (OR, 1.1; 95% CI, 0.83-1.4; P = 0.55), and surgical site infection (OR, 0.35; 95% CI, 0.18-0.71; P = 0.004) showed no significant link with increased mortality independent of other complications., Conclusions: Of 13 complications analyzed, myocardial infarction, unplanned intubation, prolonged ventilator requirement, stroke, and renal failure showed the strongest association with mortality independent of preoperative risk, independent of other complications, and across all risk-stratified subgroups. These findings help identify causes of perioperative mortality after elective craniotomy. Dedicating additional resources toward preventing and treating these complications postoperatively may help reduce rates of failure-to-rescue in the neurosurgical population., (Copyright © 2018 Elsevier Inc. All rights reserved.)