Viscoelastic high-molecular-weight hyaluronic acid hydrogels support rapid glioblastoma cell invasion with leader-follower dynamics.

Hyaluronic acid (HA), the primary component of brain extracellular matrix, is increasingly used to model neuropathological processes, including glioblastoma (GBM) tumor invasion. While elastic hydrogels based on crosslinked low-molecular-weight (LMW) HA are widely exploited for this purpose and have proven valuable for discovery and screening, brain tissue is both viscoelastic and rich in high-MW (HMW) HA, and it remains unclear how these differences influence invasion. To address this question, hydrogels comprised of either HMW (1.5 MDa) or LMW (60 kDa) HA are introduced, characterized, and applied in GBM invasion studies. Unlike LMW HA hydrogels, HMW HA hydrogels relax stresses quickly, to a similar extent as brain tissue, and to a greater extent than many conventional HA-based scaffolds. GBM cells implanted within HMW HA hydrogels invade much more rapidly than in their LMW HA counterparts and exhibit distinct leader-follower dynamics. Leader cells adopt dendritic morphologies, similar to invasive GBM cells observed in vivo. Transcriptomic, pharmacologic, and imaging studies suggest that leader cells exploit hyaluronidase, an enzyme strongly enriched in human GBMs, to prime a path for followers. This study offers new insight into how HA viscoelastic properties drive invasion and argues for the use of highly stress-relaxing materials to model GBM.

Socioeconomic differences between medically and surgically treated prolactinomas: a retrospective review of 598 patients.

OBJECTIVE: Socioeconomic status (SES) is known to affect presentations and outcomes in pituitary neuroendocrine tumor resections, but there is a paucity of literature examining its impact specifically on patients with prolactinomas, who may be treated medically or surgically. The authors sought to determine whether SES was associated with differences in treatment choice or outcomes for prolactinoma patients. METHODS: The authors retrospectively reviewed patient records at a high-volume academic pituitary center for prolactinoma diagnoses. Patients were split into medically and surgically treated cohorts. Race, ethnicity, insurance status, primary care physician (PCP) status, and zip code-based income data were collected and examined as socioeconomic covariates. Outcomes of interest included pretreatment likelihood of surgical cure, medical versus surgical treatment allocation, and posttreatment remission rates. RESULTS: The authors analyzed 568 prolactinoma patients (351 medically treated and 217 surgically treated). Patients receiving surgery were more likely to have Medicaid or private insurance (p < 0.001) and have lower incomes (p < 0.001) than medically treated patients. Lower-income surgical patients were more likely to require surgical intervention for an indication such as tumor decompression than higher-income patients (p = 0.023). Surgical patients with a PCP had a higher estimated likelihood of surgical cure (p = 0.008), while no SES-based differences in surgical remission likelihood existed in the medical cohort. After surgery, surgical patients who achieved remission had significantly higher income than those who did not (p < 0.001). Other SES factors were not associated with surgical remission, and among medically treated patients, remission rates were not affected by any SES factor. Income was inversely related to prolactinoma size in both cohorts (surgical, p < 0.001; medical, p = 0.005) but was associated more prominently in surgical patients (surgical, -0.65 mm per $10,000; medical, -0.37 mm per $10,000). CONCLUSIONS: While surgical prolactinoma patients were prone to income and PCP-related disparities, no SES disparities were found among medically treated patients. Income had a more pronounced association with tumor size in the surgical cohort and likely contributed to the increased need for surgical intervention seen in low-income surgical patients. Addressing socioeconomic healthcare disparities is needed among surgical prolactinoma patients to increase rates of early presentation and improve the outcomes of low-SES populations.

Correlation of Brain Metastasis Genomic Alterations with Preoperative Imaging Features.

BACKGROUND: The aim of this study was to examine associations between genomic alterations in brain metastases and common preoperative imaging findings including overt intratumoral hemorrhage, cystic features, and edema. METHODS: A single-center, retrospective study was performed including patients who underwent surgical resection of brain metastasis with available preoperative magnetic resonance imaging (MRI). Next-generation sequencing of more than 500 coding genes was performed on the resected brain metastases. Preoperative MRI was reviewed to identify the presence of intratumoral hemorrhage, cystic features, and edema in the resected brain metastasis. Genomic data were then correlated with the imaging features using univariate and multivariate nominal logistic regression analyses. RESULTS: We included 144 brain metastases from 141 patients in the study cohort. Half (72) of the metastases had an intratumoral hemorrhage, 26 (18%) had cystic features, and 130 (90%) had edema. Mutations in TP53 were associated with a reduced risk of intratumoral hemorrhage (odds ratio [OR] 0.2, 95% confidence interval [CI] 0.07-0.5, P < 0.001). Mutations in RB1 and CCND1 were associated with elevated risk of the metastasis having cystic features (OR 10.3, 95% CI 2.0-52.6, P = 0.005, OR 18.4, 95% CI 2.2-155.3, P = 0.008, respectively). PIK3CA mutations were associated with a reduced risk of peritumoral edema (OR 0.2, 95% CI 0.04-0.8, P = 0.03). CONCLUSIONS: Several genomic alterations in brain metastases are associated with MRI features including hemorrhage, cystic features, and edema. These results provide insight into tumor biology and patients at risk of developing these imaging features.

Does waiting for surgery matter? How time from diagnostic MRI to resection affects outcomes in newly diagnosed glioblastoma.

OBJECTIVE: Maximal safe resection is the standard of care for patients presenting with lesions concerning for glioblastoma (GBM) on magnetic resonance imaging (MRI). Currently, there is no consensus on surgical urgency for patients with an excellent performance status, which complicates patient counseling and may increase patient anxiety. This study aims to assess the impact of time to surgery (TTS) on clinical and survival outcomes in patients with GBM. METHODS: This is a retrospective study of 145 consecutive patients with newly diagnosed IDH-wild-type GBM who underwent initial resection at the University of California, San Francisco, between 2014 and 2016. Patients were grouped according to the time from diagnostic MRI to surgery (i.e., TTS): ≤ 7, > 7-21, and > 21 days. Contrast-enhancing tumor volumes (CETVs) were measured using software. Initial CETV (CETV1) and preoperative CETV (CETV2) were used to evaluate tumor growth represented as percent change (ΔCETV) and specific growth rate (SPGR; % growth/day). Overall survival (OS) and progression-free survival (PFS) were measured from the date of resection and were analyzed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Of the 145 patients (median TTS 10 days), 56 (39%), 53 (37%), and 36 (25%) underwent surgery ≤ 7, > 7-21, and > 21 days from initial imaging, respectively. Median OS and PFS among the study cohort were 15.5 and 10.3 months, respectively, and did not differ among the TTS groups (p = 0.81 and 0.17, respectively). Median CETV1 was 35.9, 15.7, and 10.2 cm3 across the TTS groups, respectively (p < 0.001). Preoperative biopsy and presenting to an outside hospital emergency department were associated with an average 12.79-day increase and 9.09-day decrease in TTS, respectively. Distance from the treating facility (median 57.19 miles) did not affect TTS. In the growth cohort, TTS was associated with an average 2.21% increase in ΔCETV per day; however, there was no effect of TTS on SPGR, Karnofsky Performance Status (KPS), postoperative deficits, survival, discharge location, or hospital length of stay. Subgroup analyses did not identify any high-risk groups for which a shorter TTS may be beneficial. CONCLUSIONS: An increased TTS for patients with imaging concerning for GBM did not impact clinical outcomes, and while there was a significant association with ΔCETV, SPGR remained unaffected. However, SPGR was associated with a worse preoperative KPS, which highlights the importance of tumor growth speed over TTS. Therefore, while it is ill advised to wait an unnecessarily long time after initial imaging studies, these patients do not require urgent/emergency surgery and can seek tertiary care opinions and/or arrange for additional preoperative support/resources. Future studies are needed to explore subgroups for whom TTS may impact clinical outcomes.

Analysis of upfront resection or stereotactic radiosurgery for local control of solid and cystic cerebellar hemangioblastomas.

OBJECTIVE: The purpose of this study was to identify rates of and risk factors for local tumor progression in patients who had undergone surgery or radiosurgery for the management of cerebellar hemangioblastoma and to describe treatments pursued following tumor progression. METHODS: The authors conducted a retrospective single-center review of patients who had undergone treatment of a cerebellar hemangioblastoma with either surgery or stereotactic radiosurgery (SRS) between 1996 and 2019. Univariate and multivariate regression analyses were performed to examine factors associated with local tumor control. RESULTS: One hundred nine patients met the study inclusion criteria. Overall, these patients had a total of 577 hemangioblastomas, 229 of which were located in the cerebellum. The surgical and SRS cohorts consisted of 106 and 123 cerebellar hemangioblastomas, respectively. For patients undergoing surgery, tumors were treated with subtotal resection and gross-total resection in 5.7% and 94.3% of cases, respectively. For patients receiving SRS, the mean target volume was 0.71 cm3 and the mean margin dose was 18.0 Gy. Five-year freedom from lesion progression for the surgical and SRS groups was 99% and 82%, respectively. The surgical and SRS cohorts contained 32% versus 97% von Hippel-Lindau tumors, 78% versus 7% cystic hemangioblastomas, and 12.8- versus 0.56-cm3 mean tumor volumes, respectively. On multivariate analysis, factors associated with local tumor progression in the SRS group included older patient age (HR 1.06, 95% CI 1.03-1.09, p < 0.001) and a cystic component (HR 9.0, 95% CI 2.03-32.0, p = 0.001). Repeat SRS as salvage therapy was used more often for smaller tumor recurrences, and no tumor recurrences of < 1.0 cm3 required additional salvage surgery following repeat SRS. CONCLUSIONS: Both surgery and SRS achieve high rates of local control of hemangioblastomas. Age and cystic features are associated with local progression after SRS treatment for cerebellar hemangioblastomas. In cases of local tumor recurrence, salvage surgery and repeat SRS are valid forms of treatment to achieve local tumor control, although resection may be preferable for larger recurrences.

High-volume facilities are not always low risk: comparing risk-standardized mortality rates versus facility volume as quality measures in surgical neuro-oncology.

OBJECTIVE: Risk-standardized mortality rates (RSMRs) have recently been shown to outperform facility case volume as a proxy for surgical quality in lung and gastrointestinal cancer. The aim of this study was to investigate RSMR as a surgical quality metric in primary CNS cancer. METHODS: This retrospective observational cohort study used data from the National Cancer Database, a population-based oncology outcomes database sourced from more than 1500 institutions in the United States, and included adult patients 18 years of age and older who were diagnosed with glioblastoma, pituitary adenoma, or meningioma and were treated with surgery. For each group, RSMR quintiles and annual volume were calculated in a training set (2009-2013) and these thresholds were applied to the validation set (2014-2018). In this paper, the authors compared the effectiveness and efficiency of facility volume-based versus RSMR-based hospital centralization models and evaluated the overlap between the two systems. A patterns-of-care analysis was also performed to explore socioeconomic predictors of being treated at better-performing treating facilities. RESULTS: A total of 37,838 meningioma, 21,189 pituitary adenoma, and 30,788 glioblastoma patients were surgically treated from 2014 to 2018. There were substantial differences between RSMR and facility volume classification schemes among all tumor types. In an RSMR-based centralization model, an average of 36 patients undergoing glioblastoma surgery would need to relocate to a low-mortality hospital to prevent one 30-day mortality following surgery, whereas 46 would need to relocate to a high-volume hospital. For pituitary adenoma and meningioma, both metrics were inefficient in centralizing care to reduce surgical mortality. Additionally, overall survival for glioblastoma patients was better modeled in an RSMR classification scheme. Analyses to investigate the impact of care disparities found that Black and Hispanic patients, patients earning less than $38,000, and uninsured patients were more likely to be treated at high-mortality hospitals. CONCLUSIONS: RSMR is more effective and efficient than a traditional volume-based approach for preventing early postoperative death in glioblastoma surgery. These data have important implications for future quality-related studies in neurosurgical oncology and may be relevant for healthcare/insurance payments, hospital evaluation assessments, healthcare disparities, and the standardization of care across hospitals.

Genomic alterations associated with postoperative nodular leptomeningeal disease after resection of brain metastases.

OBJECTIVE: The relationship between brain metastasis resection and risk of nodular leptomeningeal disease (nLMD) is unclear. This study examined genomic alterations found in brain metastases with the aim of identifying alterations associated with postoperative nLMD in the context of clinical and treatment factors. METHODS: A retrospective, single-center study was conducted on patients who underwent resection of brain metastases between 2014 and 2022 and had clinical and genomic data available. Postoperative nLMD was the primary endpoint of interest. Targeted next-generation sequencing of > 500 oncogenes was performed in brain metastases. Cox proportional hazards analyses were performed to identify clinical features and genomic alterations associated with nLMD. RESULTS: The cohort comprised 101 patients with tumors originating from multiple cancer types. There were 15 patients with nLMD (14.9% of the cohort) with a median time from surgery to nLMD diagnosis of 8.2 months. Two supervised machine learning algorithms consistently identified CDKN2A/B codeletion and ERBB2 amplification as the top predictors associated with postoperative nLMD across all cancer types. In a multivariate Cox proportional hazards analysis including clinical factors and genomic alterations observed in the cohort, tumor volume (× 10 cm3; HR 1.2, 95% CI 1.01-1.5; p = 0.04), CDKN2A/B codeletion (HR 5.3, 95% CI 1.7-16.9; p = 0.004), and ERBB2 amplification (HR 3.9, 95% CI 1.1-14.4; p = 0.04) were associated with a decreased time to postoperative nLMD. CONCLUSIONS: In addition to increased resected tumor volume, ERBB2 amplification and CDKN2A/B deletion were independently associated with an increased risk of postoperative nLMD across multiple cancer types. Additional work is needed to determine if targeted therapy decreases this risk in the postoperative setting.

Survival outcomes and prognostic factors of infratentorial glioblastoma in the elderly.

INTRODUCTION: Infratentorial glioblastoma(itGBM) is a rare and rapidly progressive form of GBM with poor prognosis. However, no studies have adequately examined itGBM outcomes in elderly patients (>65 years). Here, we used a national database to fill this knowledge gap. METHODS: SEER 18 registries were utilized to identify adult itGBM patients diagnosed between 2000-2016. itGBM cases were further divided into cerebellar and brainstem GBM as cGBM and bGBM, respectively. Kaplan-Meier analysis and Cox hazards proportional regression models were performed to assess factors associated with overall survival (OS). RESULTS: Among 137 (33%) elderly patients from the study cohort (N = 420), median age was 74 years, 38% were female, and 85% were white. Median OS in elderly itGBM patients was shorter than younger adults (10 vs. 5-months, p < 0.001). Multivariate analysis by tumor location revealed that older age was associated with poor survival for cGBM, but not for bGBM. Gross-total resection (GTR) was associated with better outcomes for both cGBM and bGBM. Radiotherapy had survival benefits for cGBM; meanwhile, chemotherapy prolonged OS in bGBM. In the elderly, advanced age (80 + years) was associated with poor outcomes, while GTR, CT and RT were all associated with improved survival. CONCLUSIONS: In our study, while elderly patients had worse survival compared to younger adults for both cGBM and bGBM, GTR improved OS in elderly itGBM, with CT and RT exhibiting a location-dependent survival benefit. Thus, elderly itGBM patients should undergo a combination of maximal resection and adjuvant treatment guided by infratentorial tumor location for maximal survival benefit.

"De novo replication repair deficient glioblastoma, IDH-wildtype" is a distinct glioblastoma subtype in adults that may benefit from immune checkpoint blockade.

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53, NF1, PTEN, ATRX, and SETD2 and recurrent activating mutations in PDGFRA. DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as "Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A". Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients (p < 0.001). We conclude that "De novo replication repair deficient glioblastoma, IDH-wildtype" represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

Multiomic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations.

While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multiomics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Among oncologic ROS, H2O2 specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine γ-lyase (CTH), which converts cystathionine to the nonessential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.

An engineered glioblastoma model yields novel macrophage-secreted drivers of invasion.

Glioblastomas (GBMs) are highly invasive brain tumors replete with brain- and blood-derived macrophages, collectively known as tumor-associated macrophages (TAMs). Targeting TAMs has been proposed as a therapeutic strategy but has thus far yielded limited clinical success in slowing GBM progression, due in part to an incomplete understanding of TAM function in GBM. Here, by using an engineered hyaluronic acid-based 3D invasion platform, patient-derived GBM cells, and multi-omics analysis of GBM tumor microenvironments, we show that M2-polarized macrophages stimulate GBM stem cell (GSC) mesenchymal transition and invasion. We identify TAM-derived transforming growth factor beta induced (TGFßI/BIGH3) as a pro-tumorigenic factor in the GBM microenvironment. In GBM patients, BIGH3 mRNA expression correlates with poor patient prognosis and is highest in the most aggressive GBM molecular subtype. Inhibiting TAM-derived BIGH3 signaling with a blocking antibody or small molecule inhibitor suppresses GSC invasion. Our work highlights the utility of 3D in vitro tumor microenvironment platforms to investigate TAM-cancer cell crosstalk and offers new insights into TAM function to guide novel TAM-targeting therapies.

Intraventricular meningioma resection and visual outcomes.

OBJECTIVE: Intraventricular meningiomas (IVMs) of the lateral ventricle are rare tumors that present surgical challenges because of their deep location. Visual field deficits (VFDs) are one risk associated with these tumors and their treatment. VFDs may be present preoperatively due to the tumor and mass effect (tumor VFDs) or may develop postoperatively due to the surgical approach (surgical VFDs). This institutional series aimed to review surgical outcomes following resection of IVMs, with a focus on VFDs. METHODS: Patients who received IVM resection at one academic institution between the years 1996 and 2021 were retrospectively reviewed. Diffusion tensor imaging (DTI) reconstructions of the optic radiations around the tumor were performed from preoperative IVM imaging. The VFD course and resolution were documented. RESULTS: Thirty-two adult patients underwent IVM resection, with gross-total resection in 30 patients (93.8%). Preoperatively, tumor VFDs were present in 6 patients, resolving after surgery in 5 patients. Five other patients (without preoperative VFD) had new persistent surgical VFDs postoperatively (5/32, 15.6%) that persisted to the most recent follow-up. Of the 5 patients with persistent surgical VFDs, 4 received a transtemporal approach and 1 received a transparietal approach, and all these deficits occurred prior to regular use of DTI in preoperative imaging. CONCLUSIONS: New surgical VFDs are a common neurological deficit after IVM resection. Preoperative DTI may demonstrate distortion of the optic radiations around the tumor, thus revealing safe operative corridors to prevent surgical VFDs.

Pituitary adenoma or neuroendocrine tumour: the need for an integrated prognostic classification.

In the 2022 fifth edition of the WHO Classification of Endocrine Tumours and of Central Nervous System Tumours, pituitary adenomas are reclassified as neuroendocrine tumours (NETs). This change confers an oncology label to neoplasms that are overwhelmingly benign. A comprehensive clinical classification schema is required to guide prognosis, therapy and outcomes for all patients with pituitary adenomas. Pituitary adenomas and NETs exhibit some morphological and ultrastructural similarities. However, unlike NETs, pituitary adenomas are highly prevalent, yet indolent and rarely become malignant. This Perspective presents the outcomes of an interdisciplinary international workshop that addressed the merit and clinical implications of the classification change of pituitary adenoma to NET. Many non-histological factors provide mechanistic insight and influence the prognosis and treatment of pituitary adenoma. We recommend the development of a comprehensive classification that integrates clinical, genetic, biochemical, radiological, pathological and molecular information for all anterior pituitary neoplasms.

Molecular Features of Resected Melanoma Brain Metastases, Clinical Outcomes, and Responses to Immunotherapy.

Importance: Central nervous system (CNS)-penetrant systemic therapies have significantly advanced care for patients with melanoma brain metastases. However, improved understanding of the molecular landscape and microenvironment of these lesions is needed to both optimize patient selection and advance treatment approaches. Objective: To evaluate how bulk and single-cell genomic features of melanoma brain metastases are associated with clinical outcome and treatment response. Design, Setting, and Participants: This cohort study analyzed bulk DNA sequencing and single nuclear RNA-sequencing data from resected melanoma brain metastases and included 94 consecutive patients with a histopathologically confirmed diagnosis of melanoma brain metastasis who underwent surgical resection at a single National Comprehensive Cancer Network cancer center in San Francisco, California, from January 1, 2009, to December 31, 2022. Exposure: A Clinical Laboratory Improvement Amendments-certified targeted sequencing assay was used to analyze tumor resection specimens, with a focus on BRAF V600E alteration. For frozen pathologic specimens from CNS treatment-naive patients undergoing surgical resection, commercial single nuclear RNA sequencing approaches were used. Main Outcomes and Measures: The primary outcome was overall survival (OS). Secondary outcomes included CNS progression-free survival (PFS), microenvironmental composition with decreased T-cell and macrophage populations, and responses to immunotherapy. Results: To correlate molecular status with clinical outcome, Kaplan-Meier survival analysis of 94 consecutive patients (median age, 64 years [range, 24-82 years]; 70 men [74%]) with targeted BRAF alteration testing showed worse median intracranial PFS (BRAF variant: 3.6 months [IQR, 0.1-30.6 months]; BRAF wildtype: 11.0 months [IQR, 0.8-81.5 months]; P < .001) and OS (BRAF variant: 9.8 months [IQR, 2.5-69.4 months]; BRAF wildtype: 23.2 months [IQR, 1.1-102.5 months]; P = .005; log-rank test) in BRAF V600E variant tumors. Multivariable Cox proportional hazards regression analysis revealed that BRAF V600E status was an independent variable significantly associated with both PFS (hazard ratio [HR], 2.65; 95% CI, 1.54-4.57; P < .001) and OS (HR, 1.96; 95% CI, 1.08-3.55; P = .03). For the 45 patients with resected melanoma brain metastases undergoing targeted DNA sequencing, molecular classification recapitulated The Cancer Genome Atlas groups (NRAS variant, BRAF variant, NF1 variant, and triple wildtype) with no subtype enrichment within the brain metastasis cohort. On a molecular level, BRAF V600E variant lesions were found to have a significantly decreased tumor mutation burden. Moreover, single nuclear RNA sequencing of treatment-naive BRAF V600E variant (n = 3) brain metastases compared with BRAF wildtype (n = 3) brain metastases revealed increased immune cell populations in BRAF wildtype tumors (mean [SD], 11% [4.1%] vs 3% [1.6%] CD45-positive cells; P = .04). Survival analysis of postoperative immunotherapy responses by BRAF status revealed that BRAF wildtype lesions were associated with a response to checkpoint inhibition (median OS: with immunotherapy, undefined; without immunotherapy, 13.0 months [range, 1.1-61.7 months]; P = .001; log-rank test) while BRAF variant lesions (median OS: with immunotherapy, 9.8 months [range, 2.9-39.8 months]; without immunotherapy, 9.5 months [range, 2.5-67.2 months]; P = .81; log-rank test) were not. Conclusions and Relevance: This molecular analysis of patients with resected melanoma brain metastases found that BRAF V600E alteration is an important translational biomarker associated with worse clinical outcomes, differential microenvironmental composition, and benefit from immunotherapy. Patients with BRAF V600E variant melanoma brain metastases may thus benefit from alternative CNS-penetrant systemic regimens.

Association of CDKN2A alterations with increased postoperative seizure risk after resection of brain metastases.

OBJECTIVE: Seizures are common and significantly disabling for patients with brain metastases (BMs). Although resection can provide seizure control, a subset of patients with BMs may continue to suffer seizures postoperatively. Genomic BM characteristics may influence which patients are at risk for postoperative seizures. This work explores correlations between genomic alterations and risk of postoperative seizures following BM resection. METHODS: All patients underwent BM resection at a single institution, with available clinical and sequencing data on more than 500 oncogenes. Clinical seizures were documented pre- and postoperatively. A random forest machine learning classification was used to determine candidate genomic alterations associated with postoperative seizures, and clinical and top genomic variables were correlated with postoperative seizures by using Cox proportional hazards models. RESULTS: There were 112 patients with BMs who underwent 114 surgeries and had at least 1 month of postoperative follow-up. Seizures occurred preoperatively in 26 (22.8%) patients and postoperatively in 25 (21.9%). The Engel classification achieved at 6 months for those with preoperative seizures was class I in 13 (50%); class II in 6 (23.1%); class III in 5 (19.2%), and class IV in 2 (7.7%). In those with postoperative seizures, only 8 (32.0%) had seizures preoperatively, and preoperative seizures were not a significant predictor of postoperative seizures (HR 1.84; 95% CI 0.79-4.37; p = 0.156). On random forest classification and multivariate Cox analysis controlling for factors including recurrence, extent of resection, and number of BMs, CDKN2A alterations were associated with postoperative seizures (HR 3.22; 95% CI 1.27-8.16; p = 0.014). Melanoma BMs were associated with higher risk of postoperative seizures compared with all other primary malignancies (HR 5.23; 95% CI 1.37-19.98; p = 0.016). Of 39 BMs with CDKN2A alteration, 35.9% (14/39) had postoperative seizures, compared to 14.7% (11/75) without CDKN2A alteration. The overall rate of postoperative seizures in melanoma BMs was 42.9% (15/35), compared with 12.7% (10/79) for all other primary malignancies. CONCLUSIONS: CDKN2A alterations and melanoma primary malignancy are associated with increased postoperative seizure risk following resection of BMs. These results may help guide postoperative seizure prophylaxis in patients undergoing resection of BMs.

Genomic alterations associated with rapid progression of brain metastases.

OBJECTIVE: The aim of this study was to investigate associations between genomic alterations in resected brain metastases and rapid local and distant CNS recurrence identified at the time of postoperative adjuvant radiosurgery. METHODS: This was a retrospective study on patients who underwent resection of intracranial brain metastases. Next-generation sequencing of more than 500 coding genes was performed on brain metastasis specimens. Postoperative and preradiosurgery MR images were compared to identify rapid recurrence. Genomic data were associated with rapid local and distant CNS recurrence of brain metastases using nominal regression analyses. RESULTS: The cohort contained 92 patients with 92 brain metastases. Thirteen (14.1%) patients had a rapid local recurrence, and 64 (69.6%) patients had rapid distant CNS progression by the time of postoperative adjuvant radiosurgery, which occurred in a median time of 25 days (range 3-85 days) from surgery. RB1 and CTNNB1 mutations were seen in 8.7% and 9.8% of the cohort, respectively, and were associated with a significantly higher risk of rapid local recurrence (RB1: OR 13.6, 95% CI 2.0-92.39, p = 0.008; and CTNNB1: OR 11.97, 95% CI 2.25-63.78, p = 0.004) on multivariate analysis. No genes were found to be associated with rapid distant CNS progression. However, the presence of extracranial disease was significantly associated with a higher risk of rapid distant recurrence on multivariate analysis (OR 4.06, 95% CI 1.08-15.34, p = 0.039). CONCLUSIONS: Genomic alterations in RB1 or CTNNB1 were associated with a significantly higher risk of rapid recurrence at the resection site. Although no genomic alterations were associated with rapid distant recurrence, having active extracranial disease was a risk factor for new lesions by the time of adjuvant radiotherapy after resection.

Gender-Based Disparities in Academic Productivity Arise During Neurosurgery Residency: A Systematic Review.

BACKGROUND: Although female neurosurgery residents are increasing, women remain underrepresented in academic leadership. OBJECTIVES: To assess academic productivity differences between male and female neurosurgery residents. METHODS: We used the Accreditation Council for Graduate Medical Education records to obtain 2021-2022 recognized neurosurgery residency programs. Gender was dichotomized into male/female by male-presenting/female-presenting status. Extracted variables included degrees/fellowships from institutional websites, number of preresidency and total publications from PubMed, and h -indices from Scopus. Extraction occurred from March to July 2022. Residency publication number and h- indices were normalized by postgraduate year. Linear regression analyses were conducted to assess factors associated with numbers of in-residency publications. P < .05 was considered statistically significant. RESULTS: Of 117 accredited programs, 99 had extractable data. Information from 1406 residents (21.6% female) was successfully collected. 19 687 and 3261 publications were evaluated for male residents and female residents, respectively. Male and female residents' median preresidency publication numbers did not significantly differ (M:3.00 [IQR 1.00-8.50] vs F:3.00 [IQR 1.00-7.00], P = .09), nor did their h -indices. However, male residents had significantly higher median residency publications than female residents (M:1.40 [IQR 0.57-3.00] vs F:1.00 [IQR 0.50-2.00], P < .001). On multivariable linear regression, male residents (odds ratio [OR] 2.05, 95% CI 1.68-2.50, P < .001) and residents with more preresidency publications (OR 1.17, 95% CI 1.16-1.18, P < .001) had higher likelihood of publishing more during residency, controlling for other covariates. CONCLUSION: Without publicly available, self-identified gender designation for each resident, we were limited to review/designate gender based on male-presenting/female-presenting status from gender conventions of names/appearance. Although not an ideal measurement, this helped show that during neurosurgical residency, male residents publish significantly more than female counterparts. Given similar preresidency h- indices and publication records, this is unlikely explained by differences in academic aptitude. In-residency gender barriers to academic productivity must be acknowledged and addressed to improve female representation within academic neurosurgery.