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OBJECTIVE Meningiomas are the most common primary intracranial tumor, and resection is a mainstay of treatment. It is unclear what duration of imaging follow-up is reasonable for WHO grade I meningiomas undergoing complete resection. This study examined recurrence rates, timing of recurrence, and risk factors for recurrence in patients undergoing a complete resection (as defined by both postoperative MRI and intraoperative impression) of WHO grade I meningiomas. METHODS The authors conducted a retrospective, single-center study examining recurrence risk for adult patients with a single intracranial meningioma that underwent complete resection. Uni- and multivariate nominal logistic regression and Cox proportional hazards analyses were performed to identify variables associated with recurrence and time to recurrence. Two supervised machine learning algorithms were then implemented to confirm factors within the cohort that were associated with recurrence. RESULTS The cohort consisted of 823 patients who met inclusion criteria, and 56 patients (6.8%) had recurrence on imaging follow-up. The median age of the cohort was 56 years, and 77.4% of patients were female. The median duration of head imaging follow-up for the entire cohort was 2.7 years, but for the subgroup of patients who had a recurrence, the median follow-up was 10.1 years. Estimated 1-, 5-, 10-, and 15-year recurrence-free survival rates were 99.8% (95% confidence interval [CI] 98.8%–99.9%), 91.0% (95% CI 87.7%–93.6%), 83.6% (95% CI 78.6%–87.6%), and 77.3% (95% CI 69.7%–83.4%), respectively, for the entire cohort. On multivariate analysis, MIB-1 index (odds ratio [OR] per 1% increase: 1.34, 95% CI 1.13–1.58, p = 0.0003) and follow-up duration (OR per year: 1.12, 95% CI 1.03–1.21, p = 0.012) were both associated with recurrence. Gradient-boosted decision tree and random forest analyses both identified MIB-1 index as the main factor associated with recurrence, aside from length of imaging follow-up. For tumors with an MIB-1 index < 8, recurrences were documented up to 8 years after surgery. For tumors with an MIB-1 index ≥ 8, recurrences were documented up to 12 years following surgery. CONCLUSIONS Long-term imaging follow-up is important even after a complete resection of a meningioma. Higher MIB-1 labeling index is associated with greater risk of recurrence. Imaging screening for at least 8 years in patients with an MIB-1 index < 8 and at least 12 years for those with an MIB-1 index ≥ 8 may be needed to detect long-term recurrences.

OBJECTIVE Resection of brain metastases (BMs) may be associated with increased risk of leptomeningeal disease (LMD). This study examined rates and predictors of LMD, including imaging subtypes, in patients who underwent resection of a BM followed by postoperative radiation. METHODS A retrospective, single-center study was conducted examining overall LMD, classic LMD (cLMD), and nodular LMD (nLMD) risk. Logistic regression, Cox proportional hazards, and random forest analyses were performed to identify risk factors associated with LMD. RESULTS Of the 217 patients in the cohort, 47 (21.7%) developed postoperative LMD, with 19 cases (8.8%) of cLMD and 28 cases (12.9%) of nLMD. Six-, 12-, and 24-month LMD-free survival rates were 92.3%, 85.6%, and 71.4%, respectively. Patients with cLMD had worse survival outcomes from the date of LMD diagnosis compared with nLMD (median 2.4 vs 6.9 months, p = 0.02, log-rank test). Cox proportional hazards analysis identified cerebellar/insular/occipital location (hazard ratio [HR] 3.25, 95% confidence interval [CI] 1.73–6.11, p = 0.0003), absence of extracranial disease (HR 2.49, 95% CI 1.27–4.88, p = 0.008), and ventricle contact (HR 2.82, 95% CI 1.5–5.3, p = 0.001) to be associated with postoperative LMD. A predictive model using random forest analysis with an area under the receiver operating characteristic curve of 0.87 in a test cohort identified tumor location, systemic disease status, and tumor volume as the most important factors associated with LMD. CONCLUSIONS Tumor location, absence of extracranial disease at the time of surgery, ventricle contact, and increased tumor volume were associated with LMD. Further work is needed to determine whether escalating therapies in patients at risk of LMD prevents disease dissemination.

To compare functional hearing and tinnitus outcomes in treated large (~ 3 cm) vestibular schwannoma (VS) and posterior fossa meningioma cohorts, and construct willingness-to-accept profiles for an experimental brain implant to treat unilateral hearing loss.A two-way MANOVA model with two independent variables (tumor type; time from treatment) and three dependent variables (hearing effort of tumor ear; abbreviated Speech, Spatial, and Qualities of Hearing scale (SSQ12); Tinnitus Functional Index (TFI)) was used to analyze data from VS (Tumor type was statistically significant on the combined dependent variables analysis (Hearing outcome is better for posterior fossa meningioma compared to VS. Most patients with hearing loss in the tumor ear would consider a brain implant if the benefit level would be comparable to a cochlear implant.2.

Interfacility transfers represent a large proportion of neurosurgical admissions to tertiary care centers each year. In this study, the authors examined the impact of the COVID-19 pandemic on the number of transfers, timing of transfers, demographic profile of transfer patients, and clinical outcomes including rates of surgical intervention.A retrospective review of neurosurgical transfer patients at a single tertiary center was performed. Patients transferred from April to November 2020 (the "COVID Era") were compared with an institutional database of transfer patients collected before the COVID-19 pandemic (the "Pre-COVID Era"). During the COVID Era, both emergent and nonemergent neurosurgical services had resumed. A comparison of demographic and clinical factors between the 2 cohorts was performed.A total of 674 patients were included in the study (331 Pre-COVID and 343 COVID-Era patients). Overall, there was no change in the average monthly number of transfers (P = 0.66) or in the catchment area of referral hospitals. However, COVID-Era patients were more likely to be uninsured (1% vs. 4%), had longer transfer times (COVID vs. Pre-COVID Era: 18 vs. 9 hours; P0.001), required higher rates of surgical intervention (63% vs. 50%, P = 0.001), had higher rates of spine pathology (17% vs. 10%), and less frequently were admitted to the intensive care unit (34% vs. 52%, P0.001). Overall, COVID-Era patients did not experience delays to surgical intervention (3.1 days vs. 3.6 days, P = 0.2). When analyzing the subgroup of COVID-Era patients, COVID infection status did not impact the time of transfer or rates of operation, although COVID-infected patients experienced a longer time to surgery after admission (14 vs. 2.9 days, P0.001).The COVID-19 pandemic did not reduce the number of monthly transfers, operation rates, or catchment area for transfer patients. Transfer rates of uninsured patients increased during the COVID Era, potentially reflecting changes in access to community neurosurgery care. Shorter time to surgery seen in COVID-Era patients possibly reflects institutional policies that improved operating room efficiency to compensate for surgical backlogs. COVID status affeted time to surgery, reflecting the preoperative care that these patients require before intervention.

Shunting is an established treatment for hydrocephalus, yet reports on shunt outcomes for nonbacterial infection (NBI) hydrocephalus are limited. Furthermore, comparison of mechanisms and rates of failure for shunted NBI hydrocephalus versus more typical etiologies remains undetermined.Patients who underwent shunting for hydrocephalus at 2 centers (1995-2020) were included. Indications for shunting were grouped as "typical" (congenital, posthemorrhagic, normal pressure hydrocephalus, malignancy-related, trauma, and idiopathic) and NBI hydrocephalus (coccidioidomycosis, cryptococcosis, and neurocysticercosis). Rates of shunt malfunction were compared.There were 261 patients shunted for typical hydrocephalus (48.7% male; age = 50.7 ± 21.7) and 93 patients for NBI hydrocephalus (72.0% male; age = 41.8 ± 13.2). For patients with typical hydrocephalus, 29.5% required ≥1 shunt revision, compared with 64.5% with NBI hydrocephalus (P 1E-5). Of those with malfunction, NBI shunts required more revision operations (median = 3.0; max = 21) than typical shunts (median = 2.0; max = 6; P0.05). The censored median time to shunt failure for NBI hydrocephalus was 26.9 months and was not reached for typical etiologies by 180 months. Multivariate analysis showed shunts for NBI hydrocephalus were significantly more likely to fail (hazard ratio = 2.25; 95% confidence interval = 1.58-3.19). A distal pseudocyst was implicated in 30.0% and 2.6% of shunt failures for NBI and typical hydrocephalus, respectively (P 1E-5). Sixteen (26.7%) NBI shunt failures required revision to lower-resistance systems compared to 6 (7.8%) typical failures (P0.05).Shunts placed for hydrocephalus secondary to nonbacterial infections are complicated by significantly higher rates of malfunction. These patients are prone to develop distal abdominal pseudocysts and often require revision to low-resistance systems.

OBJECTIVE The clinical outcomes for patients undergoing resection of diffuse glioma within the middle frontal gyrus (MFG) are understudied. Anatomically, the MFG is richly interconnected to known language areas, and nearby subcortical fibers are at risk during resection. The goal of this study was to determine the functional outcomes and intraoperative mapping results related to resection of MFG gliomas. Additionally, the study aimed to evaluate if subcortical tract disruption on imaging correlated with functional outcomes. METHODS The authors performed a retrospective review of 39 patients with WHO grade II–IV diffuse gliomas restricted to only the MFG and underlying subcortical region that were treated with resection and had no prior treatment. Intraoperative mapping results and postoperative neurological deficits by discharge and 90 days were assessed. Diffusion tensor imaging (DTI) tractography was used to assess subcortical tract integrity on pre- and postoperative imaging. RESULTS The mean age of the cohort was 37.9 years at surgery, and the median follow-up was 5.1 years. The mean extent of resection was 98.9% for the cohort. Of the 39 tumors, 24 were left sided (61.5%). Thirty-six patients (92.3%) underwent intraoperative mapping, with 59% of patients undergoing an awake craniotomy. No patients had positive cortical mapping sites overlying the tumor, and 12 patients (33.3%) had positive subcortical stimulation sites. By discharge, 8 patients had language dysfunction, and 5 patients had mild weakness. By 90 days, 2 patients (5.1%) had persistent mild hand weakness only. There were no persistent language deficits by 90 days. On univariate analysis, preoperative tumor size (p = 0.0001), positive subcortical mapping (p = 0.03), preoperative tumor invasion of neighboring subcortical tracts on DTI tractography (p = 0.0003), and resection cavity interruption of subcortical tracts on DTI tractography (p < 0.0001) were associated with an increased risk of having a postoperative deficit by discharge. There were no instances of complete subcortical tract transections in the cohort. CONCLUSIONS MFG diffuse gliomas may undergo extensive resection with minimal risk for long-term morbidity. Partial subcortical tract interruption may lead to transient but not permanent deficits. Subcortical mapping is essential to reduce permanent morbidity during resection of MFG tumors by avoiding complete transection of critical subcortical tracts.

Background Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit. Methods The international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected. Results We collected 1,008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC-26981/22981 (TMZ/RT→TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with “maximal CE resection” (class 2) had superior outcome compared to patients with “submaximal CE resection” (class 3) or “biopsy” (class 4). Extensive resection of non-CE tumor (≤5 cm3 residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 (“supramaximal CE resection”). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers. Conclusions The proposed “RANO categories for extent of resection in glioblastoma” are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such “supramaximal CE resection.”

Full information pertaining to supplementary figure legends.

Morphology and proliferation of knockdown cells.

Primer sequence.

Brain metastases occur in about 10% to 30% of breast cancer patients, which culminates in a poor prognosis. It is, therefore, critical to understand the molecular mechanisms underlying brain metastatic processes to identify relevant targets. We hypothesized that breast cancer cells must express brain-associated markers that would enable their invasion and survival in the brain microenvironment. We assessed a panel of brain-predominant markers and found an elevation of several neuronal markers (βIII-tubulin, Nestin, and AchE) in brain metastatic breast cancer cells. Among these neuronal predominant markers, in silico analysis revealed overexpression of βIII-tubulin (TUBB3) in breast cancer brain metastases (BCBM) and its expression was significantly associated with distant metastases. TUBB3 knockdown studies were conducted in breast cancer models (MDA-Br, GLIM2, and MDA-MB-468), which revealed significant reduction in their invasive capabilities. MDA-Br cells with suppressed TUBB3 also demonstrated loss of key signaling molecules such as β3 integrin, pFAK, and pSrc in vitro. Furthermore, TUBB3 knockdown in a brain metastatic breast cancer cell line compromised its metastatic ability in vivo, and significantly improved survival in a brain metastasis model. These results implicate a critical role of TUBB3 in conferring brain metastatic potential to breast cancer cells. Mol Cancer Ther; 14(5); 1152–61. ©2015 AACR.

Generation of TUBB3 knockdown cells.

OBJECTIVE Pediatric brain arteriovenous malformations (AVMs) are the leading cause of spontaneous intracranial hemorrhage (SICH) in children. Although the incidence of SICH is low in pediatric populations, such events cause substantial morbidity. The recently created Ruptured Arteriovenous Malformation Grading Scale (RAGS) is proposed as a reliable and novel grading system to specifically serve as a predictor of clinical outcomes in patients following AVM rupture, similar to the Hunt and Hess (HH) grade for ruptured aneurysms. While these data are promising, pediatric patients were notably absent from the original study validating the RAGS. Therefore, correlation of the RAGS score with clinical outcomes following AVM rupture in individuals younger than 18 years of age using the RAGS score is needed. The objective of this study was to validate the RAGS in a cohort of pediatric patients with AVMs who presented with hemorrhage, thereby demonstrating the score’s generalizability, and expanding its external validity. METHODS A cohort of children with ruptured AVMs were retrospectively reviewed. Using disability, measured by the modified Rankin Scale (mRS), as the response variable, the area under the receiver operating characteristic curve (AUROC) was calculated for patients based on their RAGS scores for three time periods. The AUROC values were then compared with those generated by two commonly used clinical grading systems, the HH classification and Glasgow Coma Scale. RESULTS A total of 81 children who presented with ruptured AVMs were included in the study, with a mean follow-up duration of 4 years. The RAGS score outperformed other clinical grading scales in predicting mRS scores, with AUROC values of 0.81, 0.82, and 0.81 at three distinct follow-up periods. CONCLUSIONS The RAGS score correlated well with the clinical outcome after AVM rupture in pediatric patients. Additional validation studies across multiple treatment centers are needed to further demonstrate the generalizability of the scoring system.

Although overall survival (OS) has improved in patients with brain metastases (BMs), control of recurrent BMs remains a therapeutic challenge. Salvage surgery may achieve acceptable control rates in the setting of progression after previous stereotactic radiosurgery (SRS), yet it remains a question how additional adjuvant therapies may affect outcomes and how patient selection for salvage surgery may be optimized.Patients receiving salvage surgery for BM progression after previous SRS were retrospectively reviewed from a single center. Outcomes of interest included local tumor progression, leptomeningeal dissemination, and OS. Cox proportional hazard models and nominal logistic regression were applied to determine factors associated with outcomes of interest.A total of 43 patients with 50 BMs were included. After salvage surgery, local progression was observed for 17 BMs (34%), leptomeningeal dissemination was observed in 17 patients (39.5%), and censored median OS was 17.9 months. On multivariate analysis, use of brachytherapy was associated with improved local control (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04-0.6; P = 0.008). For patients treated with SRS ≥4.5 months before salvage surgery, both brachytherapy (HR, 0.07; 95% CI, 0.01-0.39; P = 0.002) and postoperative adjuvant SRS (HR, 0.14; 95% CI, 0.02-1.00; P = 0.05) were associated with improved local control compared with no adjuvant radiation therapy. Presence of extracranial malignancy (HR, 6.70; 95% CI, 2.58-17.42; P0.0001) was associated with shorter survival. Graded prognostic assessment underestimated survival in 79.1% of patients, with a mean difference of 18.9 months between graded prognostic assessment-estimated and actual OS.In properly selected patients, salvage surgery may be an appropriate therapy for BM progression after previous SRS. Adjuvant brachytherapy and repeat SRS can offer significant benefit for local control with salvage resection.

PURPOSE In patients with diffuse low-grade glioma (LGG), the extent of surgical tumor resection (EOR) has a controversial role, in part because a randomized clinical trial with different levels of EOR is not feasible. METHODS In a 20-year retrospective cohort of 392 patients with IDH-mutant grade 2 glioma, we analyzed the combined effects of volumetric EOR and molecular and clinical factors on overall survival (OS) and progression-free survival by recursive partitioning analysis. The OS results were validated in two external cohorts (n = 365). Propensity score analysis of the combined cohorts (n = 757) was used to mimic a randomized clinical trial with varying levels of EOR. RESULTS Recursive partitioning analysis identified three survival risk groups. Median OS was shortest in two subsets of patients with astrocytoma: those with postoperative tumor volume (TV) > 4.6 mL and those with preoperative TV > 43.1 mL and postoperative TV ≤ 4.6 mL. Intermediate OS was seen in patients with astrocytoma who had chemotherapy with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL in addition to oligodendroglioma patients with either preoperative TV > 43.1 mL and residual TV ≤ 4.6 mL or postoperative residual volume > 4.6 mL. Longest OS was seen in astrocytoma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL who received no chemotherapy and oligodendroglioma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL. EOR ≥ 75% improved survival outcomes, as shown by propensity score analysis. CONCLUSION Across both subtypes of LGG, EOR beginning at 75% improves OS while beginning at 80% improves progression-free survival. Nonetheless, maximal resection with preservation of neurological function remains the treatment goal. Our findings have implications for surgical strategies for LGGs, particularly oligodendroglioma.

BackgroundWhile genetic alterations in brain metastases (BMs) have been previously explored, there are limited data examining their association with recurrence after surgical resection. This study aimed to identify genetic alterations within BMs associated with CNS recurrence after surgery across multiple cancer types.MethodsA retrospective, single-center study was conducted with patients who underwent resection of a BM with available clinical and gene sequencing data available. Local and remote CNS recurrence were the primary study outcomes. Next-generation sequencing of the coding regions in over 500 oncogenes was performed in brain metastasis specimens. Cox proportional hazards analyses were performed to identify clinical features and genomic alterations associated with CNS recurrence.ResultsA total of 90 patients undergoing resection of 91 BMs composed the cohort. Genes most frequently mutated in the cohort included TP53 (64%), CDKN2A (37%), TERT (29%), CDKN2B (23%), NF1 (14%), KRAS (14%), and PTEN (13%), all of which occurred across multiple cancer types. CDKN2A/B co-deletion was seen in 21 (23.1%) brain metastases across multiple cancer types. In multivariate Cox proportional hazard analyses including patient, tumor, and treatment factors, CDKN2A/B co-deletion in the brain metastasis was associated with increased risk of local (HR 4.07, 95% CI 1.32-12.54, P = 0.014) and remote (HR 2.28, 95% CI 1.11-4.69, P = 0.025) CNS progression. Median survival and length of follow-up were not different based on CDKN2A/B mutation status.ConclusionsCDKN2A/B co-deletion detected in BMs is associated with increased CNS recurrence after surgical resection. Additional work is needed to determine whether more aggressive treatment in patients with this mutation may improve outcomes.

Background There is a concern that glioma patients undergoing repeat craniotomies are more prone to complications. The study’s goal was to assess if the complication profiles for initial and repeat craniotomies were similar, to determine predictors of complications, and to compare results with those in the literature. Methods A retrospective study was conducted of glioma patients (WHO grade II–IV) who underwent either an initial or repeat craniotomy performed by the senior author from 2012 until 2019. Complications were recorded by discharge, 30 days, and 90 days postoperatively. New neurologic deficits were recorded by 90 days postoperatively. Multivariate regression was performed to identify factors associated with complications. A meta-analysis was performed to identify rates of complications based on number of prior craniotomies. Results Within the cohort of 714 patients, 400 (56%) had no prior craniotomies, 218 (30.5%) had undergone 1 prior craniotomy, and 96 (13.5%) had undergone ≥ 2 prior craniotomies. There were 27 surgical and 10 medical complications in 30 patients (4.2%) and 19 reoperations for complications in 19 patients (2.7%) with no deaths by 90 days. Complications, reoperation rates, and new neurologic deficits did not differ based on number of prior craniotomies. On multivariate analysis, older age (OR1.5, 95%CI 1.0–2.2) and significant leukocytosis due to steroid use (OR12.6, 95%CI 2.5–62.9) were predictors of complications. Complication rates in the cohort were lower than rates reported in the literature. Conclusion Contrary to prior reports in the literature, repeat craniotomies can be as safe as initial operations if surgeons implement best practices.

OBJECTIVETumor proximity to the ventricle and ventricular entry (VE) during surgery have both been associated with worse prognoses; however, the interaction between these two factors is poorly understood. Given the benefit of maximal tumor resection, it is imperative for surgical planning and technique to know if VE has negative consequences for patient survival and tumor dissemination.METHODSThe University of California, San Francisco tumor registry was searched for patients with newly diagnosed and recurrent supratentorial glioblastoma (GBM) who underwent resection by the senior author between 2013 and 2018. Tumor location with respect to the subventricular zone (SVZ), size, and extent of resection were assessed using pre- and postoperative imaging. VE was determined by postoperative imaging and/or the operative report.RESULTSIn this 200-patient cohort of newly diagnosed and recurrent GBM, 26.5% of patients had VE during resection. Patients with VE were more likely to have preexisting subependymal disease (41.5% vs 15.0%, p < 0.001). Comparing patients with VE to those without VE, there was no difference in the rates of postoperative hydrocephalus (1.9% vs 4.8%, p = 0.36), ventriculoperitoneal shunting (0% vs 3.4%, p = 0.17), pseudomeningoceles (7.5% vs 5.4%, p = 0.58), or subdural hematomas (11.3% vs 3.4%, p = 0.07). Importantly, rates of subsequent leptomeningeal disease (7.5% vs 10.2%, p = 0.57) and distant parenchymal recurrence (17.0% vs 23.1%, p = 0.35) were not different between the groups. Newly diagnosed patients with tumors contacting the SVZ (type I or II) had worse survival than patients with tumors that did not contact the SVZ (type III or IV) (1.27 vs 1.84 years, p = 0.014, HR 1.8, 95% CI 1.08–3.03), but VE was not associated with worse survival in these patients with high-risk SVZ type I and II tumors (1.15 vs 1.68 years, p = 0.151, HR 0.59, 95% CI 0.26–1.34).CONCLUSIONSVE was well tolerated, with postoperative complications being rare events. There was no increase in leptomeningeal spread or distant parenchymal recurrence in patients with VE. Finally, although survival was worse for patients with preoperative subependymal disease, VE did not change survival for patients with tumors contacting the ventricle. Therefore, VE during GBM resection is not associated with adverse patient outcomes and should be used by surgeons to enhance extent of resection.■ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: retrospective cohort; evidence: class II.

Vestibular schwannomas are WHO grade I tumors of the eighth cranial nerve that lead to hearing loss, tinnitus, vestibular dysfunction, and facial nerve compromise. The management of vestibular schwannomas consists of observation, radiosurgery, or microsurgical resection. In this review, we discuss the various treatment modalities specifically targeting large vestibular schwannomas in addition to their treatment risk profiles. Although there has been a trend towards treatment with radiosurgery for smaller lesions, consensus reports still advocate for surgical debulking in patients with large vestibular schwannomas. There has been a shift in management philosophy towards functional preservation at the cost of more extensive resection, yet subtotal resection of vestibular schwannomas is associated with higher rates of recurrence on follow-up. Some groups have demonstrated new promise for the management of large vestibular schwannomas with stereotactic radiosurgery alone and multimodality therapy involving subtotal surgical resection with planned postoperative radiosurgery to residual tumor. Although most groups would still advocate for microsurgical debulking of large vestibular schwannomas with evidence of brainstem compression, hybrid treatment strategies have become preferable. More work is required to determine which patients are at risk of progression after a subtotal resection to stratify those who should or should not receive postoperative stereotactic radiosurgery.

Intraoperative functional mapping of tumor and peri-tumor tissue is a well-established technique for avoiding permanent neurologic deficits and maximizing extent of resection. Motor, language, and other cognitive domains may be assessed with intraoperative tasks. This article describes techniques used for motor and language mapping including awake mapping considerations in addition to less traditional intraoperative testing paradigms for cognition. It also discusses complications associated with mapping and insights into complication avoidance.

Understanding the molecular landscape and microenvironment of melanoma brain metastases is critical to devise improved treatments. Here, we perform bulk and single cell genomic analysis of melanoma brain metastases to identify molecular correlates of clinical outcome. 84 consecutive patients who underwent surgical resection at a single institution with a histo-pathologically confirmed diagnosis of melanoma brain metastasis were retrospectively identified. In 60 patients (71%) with sufficient brain metastasis tissue for targeted next generation sequencing, DNA mutations were assessed with a CLIA certified sequencing assay. Single nuclear RNA sequencing using the 10x platform was performed on n=6 samples from treatment naïve patients. Overall survival (OS) and CNS progression free survival (CNS PFS) from time of brain metastasis diagnosis were estimated using the Kaplan-Meier method. The median patient age was 62 years old (range: 25-78 years), and the median clinical follow up was 17 months. A total of 33 patients (39%) had BRAFV600E melanoma brain metastases. Multivariate analysis incorporating age, performance status, and extracranial disease revealed BRAF status was an independent prognostic factor for OS (p< 0.05). In patients undergoing targeted next generation sequencing, the most common pathogenic variant was TERT promoter mutation (n=44; 73%). With regard to TCGA molecular melanoma subgroups, NRAS mutant (n=22; 37%) brain metastases were most common followed by BRAF mutant (n=20; 33%), NF1 mutant (n=11; 18%), and triple wildtype (n=7; 12%). Evaluation of clinical outcomes in the context of next generation sequencing results revealed no differences by TERT status but demonstrated worse overall survival in the BRAF mutant molecular group (p< 0.01, log-rank test). Single nuclear sequencing of 36,115 nuclei across 6 samples revealed BRAF wildtype tumors exhibit greater infiltrating immune cell populations including microglia and T cell subtypes. Future work will require integration of these findings with different systemic therapy regimens and across larger, prospective, multi-institutional cohorts.

INTRODUCTION Predictors of postoperative leptomeningeal disease (LMD) after resection of brain metastases (BMs) are not well defined. OBJECTIVE This study examined rates and predictors of LMD, including subtypes, in patients who underwent resection of a BM followed by postoperative radiation.Method: A retrospective, single-center study was conducted examining overall LMD, classical LMD (cLMD), and nodular LMD (nLMD) risk. Logistic regression and a Cox proportional hazards analyses were performed to identify risk factors associated with LMD. Random forest models were constructed to predict LMD and differentiate cLMD versus nLMD. Accuracy and the area under the receiver operating characteristic curve (AUROC) were calculated to evaluate the models.Result: Of the 217 patients in the cohort, 47 (21.7%) developed postoperative LMD with 19(8.8%) cLMD cases and 28(12.9%) nLMD cases . Six-, 12-, and 24-month LMD-free survival rates were 92.3%, 85.6%, and 71.4%, respectively. Patients with cLMD had worse survival outcomes from LMD diagnosis compared to nLMD (2.4 vs 6.9 mo, Log-rank p=0.02), and treatment of LMD was associated with improved survival for both cLMD and nLMD subtypes. Multivariate Cox hazard analysis identified cerebellar/insular/occipital location (HR 3.25, 95% CI 1.73-6.11, p=0.0003), absence of extracranial disease (HR 2.49, 95% CI 1.27-4.88, p=0.008), and ventricle contact (HR 2.82, 95% CI 1.5-5.3, p=0.001) to be associated with postoperative LMD. A predictive model using random forest analysis with an AUROC of 0.87 in a test cohort identified tumor location, systemic disease status, and tumor volume as the most important factors associated with LMD. Both regression analysis and random forest analysis identified postoperative systemic therapy exposure as the main factor differentiating cLMD from nLMD development. CONCLUSION Tumor location, absence of extracranial disease at the time of surgery, contact with a ventricle, and increased tumor volume are associated with LMD. Classical LMD is associated with worse prognosis compared to nLMD.

Background Genomic profiling studies of diffuse gliomas have led to new improved classification schemes that better predict patient outcomes compared to conventional histomorphology alone. One example is the recognition that patients with IDH-wildtype diffuse astrocytic gliomas demonstrating lower-grade histologic features but genomic and/or epigenomic profile characteristic of glioblastoma typically have poor outcomes similar to patients with histologically diagnosed glioblastoma. Here we sought to determine the clinical impact of prospective genomic profiling for these IDH-wildtype diffuse astrocytic gliomas lacking high-grade histologic features but with molecular profile of glioblastoma. Methods Clinical management and outcomes were analyzed for 38 consecutive adult patients with IDH-wildtype diffuse astrocytic gliomas lacking necrosis or microvascular proliferation on histologic examination that were genomically profiled on a prospective clinical basis revealing criteria for an integrated diagnosis of “diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV” per cIMPACT-NOW criteria. Results We identified that this diagnosis consists of two divergent clinical scenarios based on integration of radiologic, histologic, and genomic features that we term “early/evolving” and “undersampled” glioblastoma, IDH-wildtype. We found that prospective genomically guided identification of early/evolving and undersampled IDH-wildtype glioblastoma resulted in more aggressive patient management and improved clinical outcomes compared to a biologically matched historical control patient cohort receiving standard-of-care therapy based on histomorphologic diagnosis alone. Conclusions These results support routine use of genomic and/or epigenomic profiling to accurately classify glial neoplasms, as these assays not only improve diagnostic classification but critically lead to more appropriate patient management that can improve clinical outcomes.

BACKGROUND Acute intratumoral hemorrhage within a vestibular schwannoma, or vestibular apoplexy, is a rare condition. Unlike the typical insidious vestibulopathy typically caused by vestibular schwannoma growth, patients with vestibular apoplexy have an acute and severe presentation with nausea and emesis in addition to severe vertigo and hearing loss. Here, the authors present an illustrative case demonstrating this rare clinical condition and an operative video detailing the surgical management. OBSERVATIONS A 76-year-old man presented to the emergency department with acute-onset dizziness, left-ear fullness, double vision, gait ataxia, emesis, and facial numbness. Imaging revealed a 2.8-cm hemorrhagic left cerebellopontine angle lesion extending into the left internal auditory canal, consistent with hemorrhagic vestibular schwannoma. The patient subsequently underwent a retrosigmoid craniotomy for resection of the hemorrhagic mass, and by 1 month after surgery, all his presenting symptoms had resolved, allowing his return to daily activities. LESSONS Vestibular schwannomas typically present with decreased hearing and chronic vestibulopathy. Acute presentation should raise the suspicion for an apoplectic event, and surgical debulking may lead to improvement in most vestibular symptoms.

OBJECTIVEAlthough most patients with low-grade glioma (LGG) present after a seizure, a small proportion is diagnosed after neuroimaging is performed for a sign or symptom unrelated to the tumor. While these tumors invariably grow, some surgeons argue for a watchful waiting approach. Here, the authors report on their experience in the surgical treatment of patients with incidental LGG (iLGG) and describe the neurological outcomes, survival, and complications.METHODSRelevant cases were identified from a prospective registry of patients undergoing glioma resection at the University of California, San Francisco, between 1997 and 2019. Cases were considered iLGG when the lesion was noted on imaging performed for a reason unrelated to the tumor. Demographic, clinical, pathological, and imaging data were extracted from the electronic medical record. Tumor volumes, growth, and extent of resection were calculated from pre- and postoperative volumetric FLAIR sequences.RESULTSOne hundred thirteen of 657 (17.2%) first-time resections for LGG were for incidental lesions. The most common reasons for the discovery of an iLGG were headaches (without mass effect, 34.5%) or trauma (16.8%). Incidental tumors were no different from symptomatic lesions in terms of laterality or location, but they were significantly smaller (22.5 vs 57.5 cm3, p < 0.0001). There was no difference in diagnosis between patients with iLGG and those with symptomatic LGG (sLGG), incorporating both molecular and pathological data. The median preoperative observation time for iLGG was 3.1 months (range 1 month–12 years), and there was a median growth rate of 3.9 cm3/year. Complete resection of the FLAIR abnormality was achieved in 57% of patients with incidental lesions but only 23.8% of symptomatic lesions (p < 0.001), and the residual volumes were smaller for iLGGs (2.9 vs 13.5 cm3, p < 0.0001). Overall survival was significantly longer for patients with incidental tumors (median survival not reached for patients with iLGG vs 14.6 years for those with sLGG, p < 0.0001). There was a 4.4% rate of neurological deficits at 6 months.CONCLUSIONSThe authors present the largest cohort of iLGGs. Patient age, tumor location, and molecular genetics were not different between iLGGs and sLGGs. Incidental tumors were smaller, a greater extent of resection could be achieved, and overall survival was improved compared to those for patients with sLGG. Operative morbidity and rates of neurological deficit were acceptably low; thus, the authors advocate upfront surgical intervention aimed at maximal safe resection for these incidentally discovered lesions.

Moyamoya is a progressive cerebrovascular arteriopathy that affects children of any age. The goal of this study was to determine imaging and clinical outcomes as well as complication rates in a pediatric cohort undergoing either a combined direct/indirect or indirect-only revascularization approach. Patients with moyamoya disease or syndrome≤18years of age at the time of initial surgery were identified, and clinical data were collected retrospectively. Over a 12-year period, 26 patients underwent revascularization procedures on 49 hemispheres with a median follow-up of 2.6years from surgery. Median age at surgery was 7.3years (range 1.4-18.0years). Thirty-three hemispheres (67.3%) underwent combined revascularization with a direct bypass and encephalomyosynangiosis, and sixteen hemispheres (32.7%) underwent indirect-only revascularization. The rate of 30-day perioperative complication was 10.2%, and the rate of postoperative clinical stroke by end of follow-up was 10.2% by hemisphere. There was a 5.7% rate of intraoperative bypass failure requiring conversion to an indirect revascularization approach. On follow-up imaging, 96.9% of direct bypasses remained patent. On multivariate analysis, higher preoperative Pediatric Stroke Outcome Measure (PSOM) scores were associated with lower rates of good clinical outcome on follow-up (unit OR 0.03; p=0.03). Patients with age&nbsp

The importance of genomic information in intrinsic brain tumors is highlighted in the World Health Organization (WHO) 2016 classification of gliomas, which now incorporates both phenotype and genotype data to assign a diagnosis. By using genetic markers to both categorize tumors and advise patients on prognosis, this classification system has minimized the risk of tissue sampling error, improved diagnostic accuracy, and reduced inter-rater variability. In the neurosurgical community, it is critical to understand the role genetics plays in tumor biology, what certain mutations mean for the patient's prognosis and adjuvant treatment, and how to interpret the results of sequencing data that are generated following tumor resection. In this review, we examine the critical role of genetics for diagnosis and prognosis and highlight the importance of tumor genetics for neurosurgeons caring for patients with diffuse lower grade gliomas.

Under-enrollment in clinical trials significantly limits valid analyses of clinical interventions and generalizability of findings. Often it results in premature study termination, with estimates of 22% to 50% of clinical trials terminated due to poor accrual. Currently, there are limited reports addressing the influence of race/ethnicity and socioeconomic status on clinical trial enrollment in adult glioma patients. The goal of this study was to test the hypothesis that race and socioeconomic status negatively impact therapeutic clinical trial enrollment. 988 adult patients were identified from the UCSF Tumor Board Registry and analyzed to determine the rate of therapeutic clinical trial screening and study enrollment. At initial diagnosis, 43.6% and 17.5% of glioma patients were screened and enrolled in a therapeutic clinical trial, respectively. At recurrence, 49.8% and 26.3% of patients were screened and enrolled in a clinical trial, respectively. Thirty-three percent of the study population belonged to a NIH-designated underrepresented minority group; Asian/Pacific-Islander comprised 19.6% of the overall cohort. On univariate analysis, only in-state location, distance to the hospital, and WHO grade were associated with enrollment at initial diagnosis and recurrence. Minority status, insurance type, median household income, and percent below poverty were not associated with clinical trial enrollment. Minority and socioeconomic status did not impact adult glioma clinical trial enrollment. Proximity to the tertiary care cancer center may be an important consideration for minority patients. Patient screening should be carefully considered in order to avoid bias based on minority and socioeconomic status.

Background The frontal aslant tract (FAT) is a white matter fiber pathway connecting the superior frontal gyrus to the Broca area. This tract in the dominant hemisphere has been shown to play a role in speech initiation and production, and direct subcortical stimulation can induce stuttering and speech arrest in a patient. However, controversy remains as to whether disruption of this pathway will lead to a permanent language deficit and if it is even necessary to map this tract during tumor resections of the dominant frontal lobe. Case Description Here, we report a case of a patient with a lower-grade diffuse glioma invading the dominant FAT that was removed with an asleep craniotomy. In the immediate postoperative state, the patient had a transcortical motor dysphasia and was unable to initiate speech. These immediate language deficits quickly recovered, and the patient was neurologically intact at the time of discharge a few days after surgery. Conclusions Given the high likelihood for a complete neurologic recovery including transient aphasia, we propose that awake mapping for the purpose of identifying the dominant FAT is unnecessary during tumor resection and that disruption of this tract is not associated with any long-term language deficits.

BACKGROUNDThe NIH Revitalization Act, implemented 29 years ago, set to improve the representation of women and minorities in clinical trials. In this study, we investigate progress made in all phase therapeutic clinical trials for neuro-epithelial CNS tumors stratified by demographic-specific age-adjusted disease incidence and mortality. Additionally, we identify workforce characteristics associated with clinical trials meeting established accrual benchmarks.METHODSRegistry study of published clinical trials for World Health Organization defined neuro-epithelial CNS tumors between January 2000 and December 2019. Study participants were obtained from PubMed and ClinicalTrials.gov. Population-based data originated from the CBTRUS for incidence analyses. SEER-18 Incidence-Based Mortality data was used for mortality analysis. Descriptive statistics, Fisher exact, and χ2 tests were used for data analysis.RESULTSAmong 662 published clinical trials representing 49,907 participants, 62.5% of study participants were men and 37.5% were women (PCONCLUSIONSFollowing the Revitalization Act, minorities and women remain underrepresented when compared with their demographic-specific incidence and mortality in therapeutic clinical trials for neuroepithelial tumors. This study provides a framework for clinical trial accrual efforts and offers guidance regarding workforce considerations associated with enrollment of vulnerable patients.Key PointsMinorities and women with brain tumor diagnosis remain significantly under-accrued for neuro-oncology clinical trials compared to Caucasians and men based on proportional disease burden and demographic-specific mortality.Importance of the StudyThe current state of clinical trial accrual in the U.S. for adult patients with gliomas across different demographic groups has not been comprehensively studied. This study aims to quantify clinical trial accrual by age-adjusted disease incidence and mortality for gender and race during a 20-year period following the NIH Revitalization Act, and to identify workforce characteristics associated with clinical trials meeting established race and gender accrual benchmarks. Minorities and women with brain tumor diagnosis remain significantly under-accrued for neuro-oncology clinical trials compared to Caucasians and men based on proportional disease burden and demographic-specific mortality. Despite the enactment of the NIH Revitalization Act to improve the representation of women and minorities in clinical trials nearly 30 years ago, this goal remains unmet in the field of neuro-oncology. Significant work is required to continue to implement and improve interventions to increase accrual of diverse patient populations.

OBJECTIVE Decision-making in how to manage pituitary adenomas (PAs) in the elderly (age ≥ 65 years) can be challenging given the benign nature of these tumors and concerns about surgical morbidity in these patients. In this study involving a large multicenter national registry, the authors examined treatment trends and surgical outcomes in elderly compared to nonelderly patients. METHODS The National Cancer Data Base (NCDB) was queried for adults aged ≥ 18 years with PA diagnosed by MRI (in observed cases) or pathology (in surgical cases) from 2004 to 2016. Univariate and multivariate logistic regressions were used to evaluate the prognostic impact of age and other covariates on 30- and 90-day postsurgical mortality (30M/90M), prolonged (≥ 5 days) length of inpatient hospital stay (LOS), and extent of resection. RESULTS A total of 96,399 cases met the study inclusion criteria, 27% of which were microadenomas and 73% of which were macroadenomas. Among these cases were 25,464 elderly patients with PA. Fifty-three percent of these elderly patients were treated with surgery, 1.9% underwent upfront radiotherapy, and 44.9% were observed without treatment. Factors associated with surgical treatment compared to observation included younger age, higher income, private insurance, higher Charlson-Deyo comorbidity (CD) score, larger tumor size, and receiving treatment at an academic hospital (each p ≤ 0.01). Elderly patients undergoing surgery had increased rates of 30M (1.4% vs 0.6%), 90M (2.8% vs 0.9%), prolonged LOS (26.1% vs 23.0%), and subtotal resection (27.2% vs 24.5%; each p ≤ 0.01) compared to those in nonelderly PA patients. On multivariate analysis, age, tumor size, and CD score were independently associated with worse postsurgical mortality. High-volume facilities (HVFs) had significantly better outcomes than low-volume facilities: 30M (0.9% vs 1.8%, p < 0.001), 90M (2.0% vs 3.5%, p < 0.001), and prolonged LOS (21.8% vs 30.3%, p < 0.001). A systematic literature review composed of 22 studies demonstrated an elderly PA patient mortality rate of 0.7%, which is dramatically lower than real-world NCDB outcomes and speaks to substantial selection bias in the previously published literature. CONCLUSIONS The study findings confirm that elderly patients with PA are at higher risk for postoperative mortality than younger patients. Surgical risk in this age group may have been previously underreported in the literature. Resection at HVFs better reflects these historical rates, which has important implications in elderly patients for whom surgery is being considered.

In IDH-wildtype glioblastomas which meet the histopathological or molecular diagnosis criteria, it remains unclear whether the presence of TERT promotor mutations provides additional prognostic information. Based on a multicenter cohort of 466 IDH-wildtype glioblastomas (including 396 with and 70 patients without TERT promotor mutations), we found that TERT promotor mutations were neither associated with progression-free survival nor overall survival. This held true in various treatment-based or molecular subgroups. This argues against standardized analysis for TERT promotor mutation status for the purpose of prognostic or therapeutic relevance in newly diagnosed IDH-wildtype glioblastoma that otherwise meets the histopathological and molecular diagnosis criteria.

BACKGROUND Acute postoperative sialadenitis is a rare and potentially morbid complication of cranial neurosurgery. This rapidly progressive, unilateral neck swelling often presents within hours of extubation. Diagnosis is made by imaging and exclusion of other causes of etiologies, such as neck hematoma, sialolithiasis, and dependent soft tissue edema. OBSERVATIONS The authors presented a case of acute postoperative sialadenitis after suboccipital resection of a right cerebellar metastasis. Shortly after extubation, extensive left-sided neck swelling was apparent in the postanesthesia care unit. No central lines were placed during the procedure. Imaging revealed submandibular gland edema and fluid accumulation in the surrounding tissue. The patient was managed conservatively with steroids, antibiotics, and warm compresses, with complete resolution of symptoms 2 weeks after the procedure. LESSONS This case emphasizes the broad differential of acute neck swelling after cranial surgery. Physical examination of the neck and airway protection should guide initial treatment. If a patient is stable, bedside ultrasound and computed tomography can be helpful with the differential diagnosis. Here the authors proposed an algorithm for diagnosis and treatment of acute neck swelling after cranial surgery.