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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.

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 with15N2-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.15N 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.

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 treating progressive or recurrent IDH-mutant gliomas and may significantly change treatment paradigms in the next decade.

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.

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. 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. 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, I2 = 54.8%), weaning off steroids (P = 0.614, I2 = 25.5%), and local lesion control (P = 0.5, I2 = 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, I2 = 88.9%), and stable disease significantly higher in the LITT group (P = 0.002, I2 = 81.9%). Survival rates were superior in the LITT cohort, and statistical significance was reached at 18 months (P = 0.038, I2 = 73.7%). Low rates of adverse events were reported in both groups (14.7% for bevacizumab and 12.2% for LITT). 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.

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.

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.

SUMMARYMutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they appear 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 vulnerability selectively applies to de novo pyrimidine, but not purine, synthesis because glioma cells engage disparate programs to produce these nucleotide species and because IDH oncogenes increase DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.

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 cellular viability in tissue specimens 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.

Creating in vitro models of lower grade glioma represents a major challenge in neuro-oncology research. There are few such models that are tractable and widely used, which has hindered understanding of the biology of these tumors. Recently, substantial progress has been made in generating patient-derived in vitro organoid models of high grade glioma, but modeling lower grade disease remains difficult. Based on our experience creating neurosphere cultures of lower grade astrocytomas from genetically engineered mice, we hypothesized that modifying patient-derived organoid generation protocols to incorporate physiological oxygen levels would allow establishment and propagation of lower grade glioma organoids. In this study, we show that this approach supports efficient organoid model generation from primary glioma specimens across all histological subtypes and tumor grades (WHO Grade I-IV, n = 20). These organoid models retain key characteristics of their respective parental tumors, including IDH mutations and other genetic alterations, metabolite profiles, intratumoral heterogeneity, cellular composition, and cytoarchitectural features. Importantly, lower grade glioma organoids can be cultured for months and reanimated after biobanking. Our high success rate ( >90%) in establishing organoid models from primary lower grade glioma tissue samples further highlighted opportunities for treatment response assessments. To perform longitudinal measurements of therapy-induced changes in glioma organoid viability, we designed a novel, non-invasive imaging assay (termed rapid apex imaging) to determine real-time treatment response in low and high grade gliomas. We evaluated longitudinal responses of glioblastoma and IDH1 R132H-positive Grade II astrocytoma organoids to temozolomide and olaparib with and without radiation treatment. We quantified topological changes in organoid structure by building a bioinformatics tool to translate imaging data into a cellularity metric as a biomarker of organoid response. Our work unveils an effective new method to create in vitro, personalized models of lower grade glioma that supports elucidation of treatment sensitivity profiles.

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.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.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.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.

Purpose: To investigate the therapeutic role of a novel telomere-directed inhibitor, 6-thio-2′-deoxyguanosine (THIO) in gliomas both in vitro and in vivo. Experimental Design: A panel of human and mouse glioma cell lines was used to test therapeutic efficacy of THIO using cell viability assays, flow cytometric analyses, and immunofluorescence. Integrated analyses of RNA sequencing and reverse-phase protein array data revealed the potential antitumor mechanisms of THIO. Four patient-derived xenografts (PDX), two patient-derived organoids (PDO), and two xenografts of human glioma cell lines were used to further investigate the therapeutic efficacy of THIO. Results: THIO was effective in the majority of human and mouse glioma cell lines with no obvious toxicity against normal astrocytes. THIO as a monotherapy demonstrated efficacy in three glioma cell lines that had acquired resistance to temozolomide. In addition, THIO showed efficacy in four human glioma cell lines grown as neurospheres by inducing apoptotic cell death. Mechanistically, THIO induced telomeric DNA damage not only in glioma cell lines but also in PDX tumor specimens. Integrated computational analyses of transcriptomic and proteomic data indicated that THIO significantly inhibited cell invasion, stem cell, and proliferation pathways while triggering DNA damage and apoptosis. Importantly, THIO significantly decreased tumor proliferation in two PDO models and reduced the tumor size of a glioblastoma xenograft and a PDX model. Conclusions: The current study established the therapeutic role of THIO in primary and recurrent gliomas and revealed the acute induction of telomeric DNA damage as a primary antitumor mechanism of THIO in gliomas.

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.

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.

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.

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. 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. 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. 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.

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.

Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors., Glioblastomas are generally resistant to treatment with immune checkpoint inhibitors. Here the authors show that IL6 blockade, in combination with a CD40 agonist, overcomes macrophage-mediated immunosuppression and sensitizes glioblastoma to immune checkpoint blockade in preclinical models.

Background Approximately 80,000 primary brain tumors are diagnosed annually. Social media provides a source of information and support for patients diagnosed with brain tumors; however, use of this forum for dissemination of information about brain tumors has not been evaluated. The objective of this study was to evaluate social media utilization and content related to brain tumors with an emphasis on patients’ trends in usage. Methods Social media platforms were systematically evaluated using two search methods: systematic manual inquiry and a keyword-based social media tracker. The search terms included brain tumor, glioblastoma, glioma, and glioblastoma multiforme. Social media content (which includes Facebook pages and groups, YouTube videos, and Twitter or Instagram accounts) and posts were assessed for activity (as quantified by views of posts) and analyzed using a categorization framework. Results The manual and keyword searches identified 946 sources of social media content, with a total count of 7,184,846 points of engagement. Social media platforms had significant variations in content type. YouTube was the largest social media platform for sharing content related to brain tumors overall, with an emphasis on surgical videos and documented patient experiences. Facebook accounted for the majority of patient-to-patient support, and Twitter was the most common platform for scientific dissemination. Overall social media content was mostly focused on treatment overviews and patient experience. When evaluated by search term, most social media posts by the “brain tumor” community shared illness narratives, and searches specific to “glioma” and “glioblastoma” demonstrated a higher proportion of educational and treatment posts. Conclusions This study presents novel observations of the characteristics of social media utilization for the online brain tumor community. A robust patient community exists online, with an emphasis on sharing personal narratives, treatment information, patient-to-patient support, treatment options, and fundraising events. This study provides a window to the role of social media utilization by patients, their families, and health professionals. These findings demonstrate the different roles of Facebook, YouTube, and Twitter in the rapidly changing era of social media and its relationship with neurosurgery and neuro-oncology.

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.

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. 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). 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). 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.

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.

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.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.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 values0.01, 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 P0.03) but was more likely to occur after placement in third ventricle (post-hoc P values0.015). 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%).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.

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.

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 gliomagenesis, 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.

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.

Simple Summary 5-aminolevulinic acid (5-ALA) is a medication that produces fluorescence in certain cancers, which enables surgeons to visualize tumor margins during surgery. Gliomas are brain tumors that can be difficult to fully resect due to their infiltrative nature. In this review we explored what is known about the mechanism of 5-ALA, recent discoveries that increase our understanding of that mechanism, and potential targets to increase fluorescence in lower grade gliomas. Abstract 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 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, I2=54.8%), weaning off steroids (P=0.614, I2=25.5%), and local lesion control (P=0.5, I2=0%). The 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, I2=88.9%), and stable disease significantly higher in the LITT group (P=0.002, I2=81.9%). Survival rates were superior in the LITT cohort, and statistical significance was reached at 18 months (P=0.038, I2=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 to superior survival benefits in select patients. Further studies are required to identify the best patient candidates for each treatment group.

Despite the high prevalence of IDH1-R132H mutations in lower grade gliomas, the ability to study this mutation in vivo has been hampered by a lack of faithful mouse models. Therefore, we used a CRISPR/Cas9- and AAV-based strategy to create a genetically engineered mouse model (GEMM) of astrocytoma driven by IDH1-R132H that recreates the genetic landscape of human IDH1 mutant astrocytoma. IDH1 mutations in astrocytomas often co-occur with mutations in TP53, ATRX, and either PIK3R1 or PIK3CA. Using human astrocytes immortalized via expression of telomerase (which phenocopies ATRX loss) and HPV E6 and E7 oncoproteins (which phenocopy p53 and pRb loss, respectively), we found that PIK3R1 and IDH1 oncogenes cooperate to promote anchorage-independent cell growth in vitro and orthotopic brain tumor formation in vivo. These data identified a combination of clinically relevant mutations that we hypothesized could be leveraged to cause spontaneous astrocytoma formation in mice. To simultaneously engineer Idh1, Pik3ca, Tp53, and Atrx mutations in mouse brain tissue, we intracranially injected adeno-associated virus (AAV) expressing Cre recombinase and sgRNAs targeting murine Atrx and Tp53 genes into four mouse strains with the following conditional alleles: 1) LSL-Cas9; 2) LSL-Cas9; LSL-Pik3caH1047R, 3) LSL-Cas9; LSL-Idh1R132H, and 4) LSL-Cas9; LSL-Idh1R132H; LSL-Pik3caH1047R. Grade III anaplastic astrocytomas preferentially formed 9-14 months after injecting the mice carrying both the Idh1 and Pik3ca conditional alleles. These astrocytomas harbored all intended mutations, expressed astrocytoma lineage markers, and displayed elevated (R)-2-hydroxyglutarate, the oncometabolite produced by mutant Idh1. To create an additional model with shorter tumor latency, we transplanted glioma stem-like cells derived from our GEMM into recipient mice to produce Idh1 mutant astrocytoma allografts. These allografts provide a tractable platform for preclinical therapeutic studies. Taken together, our findings show that IDH1 and PI3K oncoproteins cooperate to promote gliomagenesis and unveil new genetically faithful mouse models of mutant IDH1-driven astrocytoma.

The objective of this study was to assess the independent effect of complications on 30-day mortality in 32,695 patients undergoing elective craniotomy.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.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; P0.001), stroke (OR, 11.1; 95% CI, 8.3-14.9; P0.001), ventilator requirement48 hours after surgery (OR, 9.9; 95% CI, 7.9-12.6; P0.001), and renal failure (OR, 8.5; 95% CI, 4.4-16.2; P0.001). 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.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.

This was a retrospective cohort study.The main objectives of this study were: (1) to determine whether patient-reported allergies (PRAs) are associated with patient satisfaction scores, and (2) to clarify the association between PRAs and preoperative anxiety and depression in a lumbar spine surgery population.Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey is currently used to measure the patient experience and there is concern that psychosocial factors are unaccounted for. Interestingly, PRAs have been linked to concurrent mood and other psychiatric disorders, as well as poor clinical outcomes in the orthopedic surgery setting.HCAHPS survey data, patient demographics, surgical characteristics, and preoperative health status were obtained for each patient. Allergies were categorized as medical (ie, medications) and environmental (ie, food, animals). Univariable and multivariable logistic regression models were used to determine whether the number of medical and environmental PRAs are associated with HCAHPS scores. In addition, multivariable logistic regression was used to analyze the association between PRAs and psychological distress.In 421 patients included, PRAs were associated with lower HCAHPS scores under several dimensions of the patient experience of care, including: nursing communication, pain management, communication about medicines, and transition of care. Medical PRAs was an independent predictor of low satisfaction with communication about a medication's side effects [odds ratio (OR), 0.88; P=0.03] and understanding the purpose for new medications (OR, 0.90; P=0.03). Environmental PRAs was an independent predictor of low satisfaction with both communication about a medication's side effects (OR, 0.68; P=0.03), and pain control (OR, 0.67; P=0.01). Moreover, having a PRA (OR, 1.64; P=0.04) was associated with EuroQol-5 Dimensions anxiety/depression and having an environmental PRA (OR, 2.13; P=0.03) was associated with depression.These findings highlight the potential utility of PRAs to help identify patients with psychological distress who are at risk for a poor experience of lumbar spine surgery.

Objective Otogenic brain abscesses are one of the most significant life-threatening complications of otologic infections. Given their low prevalence, otogenic brain abscesses require a high index of suspicion for diagnosis. In this systematic review, we aim to provide an analysis of otogenic brain abscesses and describe common clinical signs and symptoms, bacteriology, location, treatment options, morbidity, and mortality. Data sources PubMed, Cochrane CENTRAL database, Google Scholar, and Scopus. Methods A systematic review of literature was performed using the Preferred Reporting Items for Systematic Reviews and Meta-analyses recommendations. Variables assessed included clinical signs and symptoms, bacteriology, location, treatment, morbidity, and mortality. Results Twenty-nine studies met inclusion and exclusion criteria, corresponding to a total of 1307 otogenic abscess cases for review. Fifty-five percent of abscesses were found in the temporal lobe and 28% in the cerebellum. Most patients (88.3%) had a history of suppurative chronic otitis media. The most common symptoms were headache, altered mental status, papilledema, and meningeal irritation. Fever, nausea, and vomiting affected about 40% of patients. The most commonly cultured bacterial species was Proteus mirabilis. In addition to antibiotics, most otogenic brain abscesses were treated by burr hole aspiration. Average mortality following advent of computed tomography was 8.11%. Conclusion Although rare, otogenic brain abscesses may occur as a complication of suppurative otitis media and require a high index of suspicion. Appropriate imaging studies and multidisciplinary expertise are crucial in the diagnosis and management. Level of evidence 4.