BACKGROUND:Melanoma brain metastases (BM) carry high morbidity and mortality despite advances in systemic therapy. Combined immune checkpoint inhibition (ICI) with ipilimumab and nivolumab (ipi/nivo) demonstrates intracranial activity, but the influence of prior systemic therapy exposure is poorly defined. This is the first real-world study evaluating outcomes of melanoma BM treated with stereotactic radiosurgery (SRS) and concurrent ipi/nivo, focusing on the impact of prior ICI or targeted therapy. PATIENTS AND METHODS:We retrospectively analyzed 68 patients with 413 melanoma BM treated with concurrent SRS and ipi/nivo from 2015 to 2025. Primary endpoints were overall survival (OS) and intracranial progression-free survival (iPFS). Secondary endpoints included local and distant control, radionecrosis, and leptomeningeal disease. Univariable and multivariable Cox models identified predictors of outcome. RESULTS:Median OS was 24.0 months (12- and 24-month OS: 64% and 50%). ICI-naive patients had longer OS (50.5 vs. 17.6 months; P = 0.007) and iPFS (15.1 vs. 5.9 months) than those with prior ICI. On multivariable analysis, prior ICI (HR 2.23, 95% confidence interval [CI] 1.13-4.41), prior BRAF/MEKi (HR 2.26, 95% CI 1.01-5.04), and ≥11 SRS-treated lesions (HR 3.22, 95% CI 1.43-7.21) predicted worse outcomes, while higher graded prognostic assessment (GPA) favored OS (HR 0.46, 95% CI 0.29-0.75). At 24 months, local progression was 11%, distant 49%, radionecrosis 7%, and leptomeningeal disease 4%. CONCLUSION:Concurrent SRS with ipi/nivo provides durable intracranial control with low toxicity. Patients with prior ICI or targeted therapy represent a high-risk subgroup with poorer outcomes, supporting exploration of intensified or novel strategies.

Background/Objectives Stereotactic radiosurgery and photon therapy for the locoregional management of head and neck paragangliomas (HNPGLs) has been shown to provide long-term tumor control and symptomatic relief. We report proton therapy outcomes for HNPGLs at a single institution and describe SRS and IMRT outcomes as institutional context for modality selection. The primary goal is to report outcomes including tumor control, toxicity, and overall recovery, while evaluating differences across radiation modalities. Materials/Methods This is a retrospective review of 52 adult patients with 54 non-metastatic HNPGLs receiving radiation therapy in a single institution. There were nine tumors treated with intensity-modulated radiation therapy (IMRT), 23 with stereotactic radiosurgery (SRS), and 22 with proton therapy. Median dose was 45 Gy (cobalt Gray equivalent [CGE]). Results Out of 52 patients (14 male, 38 female) with a current median age of 65 (range 27-93), there were 30 jugular paragangliomas (PGLs), 1 tympanic PGL, 8 jugulotympanic PGLs, 3 vagal PGLs, 11 carotid body tumors, and 1 spinal PGL. The median age at the start of treatment was 59.5 years (range 18-85). Median follow-up was 50.3 months (range 3.6-147.2 months) with 52 (100%) patients alive at last follow-up. Local control, distant control, and overall survival were 98%, 100%, and 100%, respectively. No grade 3-5 toxicities were reported. At the end of follow-up, 53 (98%) tumors had a partial treatment response or were stable and 20 (37%) experienced a decrease in volume. Of the 20 tumors that had a decrease in volume, 8 were treated with proton therapy, 8 with SRS, and 4 with IMRT. Proton therapy was used more frequently for larger or anatomically complex tumors; SRS was preferred for small, well-circumscribed lesions; and IMRT was selected for moderate-sized or irregularly shaped tumors near critical structures before proton therapy was available. Conclusion Proton therapy was particularly useful in treating large or anatomically-complex tumors, while SRS and IMRT offered strong outcomes for smaller or anatomically suitable lesions. We report favorable feasibility, local tumor control, survival, and toxicity of proton therapy for HNPGLs.

Introduction Intracerebral hemorrhage (ICH) constitutes 10-15% of all strokes in the United States and has a 30-40% mortality rate. The Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation III (MISTIE III) trial showed no significant functional benefit of minimally invasive catheter drainage (MICD) and postoperative thrombolysis compared to medical management. Our objective is to evaluate how the results of the MISTIE III trial corresponded to changes in ICH evacuation procedure volumes. Materials and methods We used an aggregated dataset containing Medicare Part B procedure data from 2013 to 2023. We calculated the normalized volume of MICD procedures, supratentorial craniotomies, and infratentorial craniotomies for ICH evacuation. We normalized the volumes by calculating the percentage of all neurosurgical procedures that included ICH evacuation for each year. We used an interrupted time series (ITS) to find statistically significant changes in volumes before (βpre) and after (βpost) 2019, when the MISTIE III results were published. Results Normalized MICD volumes increased slightly before 2019 (βpre = 0.0001, p = 0.022). After 2019, MICD volumes increased more dramatically over the long term than would have been expected based on the pre-2019 trend (βpost = 0.0028, p < 0.001). However, supratentorial and infratentorial craniotomy volumes, as well as overall ICH evacuation volumes across all procedure types, showed no significant long-term change (p = 0.091, p = 0.18, p = 0.68, respectively). Conclusions The results of MISTIE III did not show a benefit of MICD over medical management for ICH with respect to the primary outcome of functional independence. We found that, despite these results, MICD evacuation procedure volumes increased significantly after the publication of the MISTIE III results. However, this association is only correlative, and other factors besides MISTIE III could have affected procedure volumes.

While ipilimumab/nivolumab has demonstrated promising intracranial activity among patients with melanoma brain metastases (BM), patients with prior immune checkpoint inhibition (ICI) exposure may be at higher risk of worse intracranial disease control. We evaluated outcomes of patients with melanoma BM treated with ipilimumab/nivolumab and stereotactic radiosurgery (SRS) with or without prior ICI. Overall survival (OS) and intracranial progression-free survival (iPFS) were estimated from SRS using a non-parametric method, and Cox proportional hazards models were used to test clinically relevant factors. 64 consecutive patients with 393 treated BM between 2015 and 2024 were included with median follow-up of 20.2 months from SRS. 34 (53%) patients were alive at analysis. The 2-year OS and iPFS for the entire cohort was 52.1% and 36.4%, respectively. 32 patients (50%) had prior exposure to ICI. Performance status, age, number of BM, and receipt of surgery were not significantly different among patients with or without prior ICI. Patients with prior ICI had smaller BM (largest median diameter 19 mm vs 22.5 mm, p=0.022) and were less likely to have extracranial metastases (53.1% vs 78.1%, p=0.035). Patients with prior ICI exposure trended towards worse iPFS (median iPFS 4.3 months vs 13.5 months, p = 0.29) and had worse survival after SRS (median OS 17.6 months vs 50.5 months, p = 0.017). On univariate analysis, receipt of prior ICI (HR 2.16, 95% CI 1.13 – 4.11, p = 0.019), no upfront surgery (HR 0.38, 95% CI 0.20 – 0.72, p = 0.003), and number of treated BM (HR 1.04, 95% CI 1 – 1.08, p = 0.043) were significantly associated with OS. While ipilimumab/nivolumab with SRS demonstrates encouraging intracranial control, patients with prior ICI exposure are at higher risk of poor outcomes and may benefit from additional treatment strategies.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) for brain arteriovenous malformations (AVMs) can cause radiation-induced changes (RIC), but its interactions with AVM embolization are not well established. The aim of this study was to assess the effect of previous embolization on RIC in SRS-treated AVM patients. METHODS: Data of AVM patients treated with single-session SRS from 1987 to 2018 were retrieved from the International Radiosurgery Research Foundation. Univariable and stepwise backward logistic regression models were used to identify RIC predictors. Patients were stratified into those who received pre-SRS embolization (E + SRS) vs those who did not (SRS-only). Radiologic RIC (rRIC) was the primary end point. Secondary outcomes included symptomatic RIC (sRIC) and permanent symptomatic RIC (pRIC). RESULTS: Among 1187 AVM patients, the mean age was 36.4 years (SD 16.8), with 50.4% female patients. AVMs had a mean untreated AVM volume of 5.2 cm 3 . A total of 130 patients (11%) underwent neoadjuvant embolization (E + SRS). The overall rRIC and sRIC rates were 32.8% and 12.1%, respectively, with time to rRIC and sRIC being significantly longer in the E + SRS vs SRS-only cohorts (103.6 ± 339.4 vs 11.3 ± 12.5 and 60.4 ± 262.9 vs 9.5 ± 9.0 months, respectively). Seizures at presentation and ≥3-cm untreated AVM volume significantly correlated with a higher likelihood of rRIC (adjusted odds ratio [aOR] 2.32 [1.25-4.30] and aOR 2.77 [1.24-6.16], respectively). Age and pre-SRS embolization were associated with a significantly lower risk of rRIC (aOR 0.97 [0.96-0.99] and aOR 0.32 [0.13-0.74], respectively). The E + SRS cohort had significantly reduced odds of rRIC (aOR = 0.37 [0.15-0.89]) and pRIC (aOR = 0.04 [0.00-0.30]) after adjusting for significant covariates. CONCLUSION: Seizures at presentation and larger untreated AVM volume were independently associated with an increased risk of rRIC, whereas older age and pre-SRS embolization were protective. Notably, patients who underwent embolization before SRS had lower odds of rRIC and pRIC, with delayed onset of complications compared with SRS-only.

Introduction and Objectives:The expanded endonasal approach (EEA) is historically associated with high rates of postoperative cerebrospinal fluid (CSF) leak. Therefore, many surgeons advocate for routine lumbar drain (LD) placement despite mixed evidence of their efficacy. We report outcomes for anterior and central skull base reconstructions after EEA without LDs. Design Setting and Participants:A retrospective review was conducted evaluating consecutive patients undergoing EEAs for resection of central and anterior skull base pathology from 2015 to 2024 at two academic institutions. Main Outcome Measures:Incidence of postoperative CSF leak. Results:Eighty-five patients underwent a total of 89 EEAs. Patients were predominantly female (62.9%) with an average age of 45.1 years (range 11 months-84 years). Tumors included primarily craniopharyngiomas (49.4%) and meningiomas (46.1%). No LDs were placed perioperatively, and there was an 100% intraoperative high-flow CSF leak rate. Skull base reconstruction was performed using pedicled nasoseptal flaps (NSFs) in all cases, tensor fascia lata grafts in 82 cases, and fat grafts in 78 cases. The postoperative CSF leak rate was 7.9%. Suprasellar tumors were associated with lower rates of postoperative CSF leak compared with tuberculum sella and planum sphenoidale pathology ( p  = 0.030), whereas meningiomas trended toward higher CSF leak rates compared with craniopharyngiomas ( p  = 0.059). Conclusion:We report a low rate of postoperative CSF leak without LD placement after EEA. Our results suggest that successful skull base reconstructions may be performed with multilayered closures using vascularized NSFs without the need for routine CSF diversion.

While ipilimumab and nivolumab has demonstrated promising intracranial activity among patients with melanoma brain metastases (BM), patients with prior systemic therapy exposure may be at higher risk of poor intracranial disease control and benefit from upfront local therapy. We evaluated outcomes of patients with BMs treated with ipilimumab/nivolumab and stereotactic radiosurgery (SRS). Overall survival (OS) and intracranial progression-free survival (PFS) were estimated from SRS using a non-parametric method, and Cox proportional hazards models were used to test clinically relevant factors. A total of 68 consecutive patients with 413 treated BMs between 2015 and 2025 were included with median follow-up of 19.3 months from SRS. At the time of analysis, 34 (53%) patients were alive. The 2-year OS and intracranial PFS for the entire cohort was 49.5% and 36.1%, respectively. 34 patients (50%) had prior exposure to immune checkpoint inhibition (ICI) and 13 patients (19%) had exposure to prior BRAF/MEK inhibition. On univariable analysis, factors significantly associated with worse OS included receipt of prior ICI (HR 2.3, 95% CI 1.24 - 4.26, p = 0.008) and BRAF/MEK inhibition (HR 2.37, CI 1.21-4.67, p = 0.012). Upfront brain metastasis resection was associated with improved OS (HR 0.39, 95% CI 0.21 – 0.73, p = 0.003). Patients with prior ICI exposure trended towards worse intracranial PFS (median intracranial PFS 5.9 months vs 15.1 months, p = 0.12) and had worse survival after SRS (median OS 17.6 months vs 50.5 months, p = 0.007). While ipilimumab/nivolumab demonstrates encouraging intracranial control and survival among patients with melanoma brain metastases, patients with prior ICI or targeted therapy exposure are at higher risk of poor outcomes and may benefit from additional treatment strategies.

BACKGROUND:The amino acid transporters alanine-serine-cysteine transporter 2 (ASCT2) and L-type amino acid transporter 1 (LAT1) are the primary transporters of essential amino acids in cancer. ASCT2 and LAT1 are overexpressed in solid tumors and have been associated with poor survival. These transporters may hold prognostic significance and offer potential theranostic utility in the treatment of glioma. The aims of this study are twofold: (1) to determine whether ASCT2 and LAT1 mRNA expression are related to glioma grade and survival; and (2) to characterize ASCT2 and LAT1 expression in low-grade glioma (LGG) and high-grade glioma (HGG). METHODS:Survival and mRNA expression data for both ASCT2 and LAT1 were obtained from The Cancer Genome Atlas (TCGA), accessed via the cBio Cancer Genomics Portal. GraphPad Prism was used to conduct a Kaplan-Meier survival analysis. Immunohistochemistry images were obtained from the Human Protein Atlas (HPA) database and analyzed with QuPath for ASCT2 and LAT1 expression in the cytoplasm and at the endothelium. RESULTS:Query of TCGA resulted in 49 samples from 28 patients, which were evaluated for ASCT2 and LAT1 expression. Cytoplasmic staining of mRNA for ASCT2 and LAT1 was not associated with glioma grade or survival. Higher mRNA expression of ASCT2 correlated with worse survival (p=0.002) in LGG but not in HGG. mRNA expression of LAT1 did not have any prognostic value. QuPath analysis of samples from the HPA showed increased staining for both ASCT2 and LAT1 at the endothelium in both LGG and HGG. Endothelial expression of ASCT2 and LAT1 correlated with glioma grade. CONCLUSION:In our small study conducted with open-access data, ASCT2 and LAT1 did not appear to have prognostic value. However, both ASCT2 and LAT1 staining were increased at the endothelium compared to normal brain tissue. These amino acid transporters may play an important role in tumor proliferation and support theranostic approaches to glioma.

Background Spine surgery is a shared domain between neurosurgery and orthopedic surgery, yet the exact differences between the two specialties have not been fully elucidated. The aim of this study is to investigate the differences in procedural volume and the recent trends indicating shifting roles of these two specialties in spine surgery. Understanding these trends is critical for workforce planning, training, and interdisciplinary collaboration. Methods This study analyzed the publicly available Medicare Part B dataset containing procedure-level data from 2013 to 2022. After filtering, we analyzed data from 1,695 and 1,531 spine neurosurgeons and orthopedic surgeons, respectively. Results Spine neurosurgeons have a higher volume of new patient office visits than orthopedic spine surgeons (median per surgeon from 2013-22: 1015 (IQR: 793.5) vs. 948 (807.8), respectively) (p<0.01). However, orthopaedic spine surgeons have a higher volume of established patient visits (3736 [3561.5] vs. 1894.5 [1749.3]) (p<0.0001) and overall spinal procedure volumes (576 [562] vs. 480 [468.5]) (p<0.0001). Additionally, the majority of all spinal deformity and ALIF procedures are performed by orthopaedic surgeons (61.8% and 68.2%, respectively), but neurosurgeons are performing an increasing proportion of these procedures over time (p<0.0001). Conversely, although the majority (66.1%) of all cervical procedures are performed by neurosurgeons, orthopedic surgeons are performing an increasing proportion of these procedures (p<0.0001). Conclusions Although orthopedic spine surgeons are performing a higher volume of procedures than spine neurosurgeons, both specialties are slowly conducting a greater proportion of certain types of procedures that have been historically dominated by other specialties.

OBJECTIVE:There is limited consensus on endoscopic skull base surgery (ESBS) reconstruction principles. This study aims to generate comprehensive themes regarding ESBS reconstruction by pooling the experiences of ESBS experts, with comparison to a literature review of current published evidence. METHODS:Structured qualitative interviews of ESBS experts regarding postoperative management and reconstruction of various defect locations were conducted. RESULTS:A total of 68 experts comprising 40 academic teams across 13 countries with an average of 18 years of ESBS experience were included. We propose 10 stepwise algorithms for common skull base reconstruction scenarios based on these expert interviews. When available, the nasoseptal flap is used for all high_flow cerebrospinal leak defects. Multilayered reconstruction is favored at all anatomical subsites with increasing number of layers for increasing defect size and complexity. Heterogeneity exists in terms of inlay technique and materials, free grafting versus various pedicled flap options for low-flow defects or in the absence of a nasal septum, nasal packing, tissue sealant, lumbar drain use, and postoperative management. Commonalities and discrepancies between experts were summarized. CONCLUSION:Skull base reconstruction and post-ESBS management is highly complex with a wide variety of practice patterns and expert strategies. Further research of higher quality evidence is warranted to identify optimal management patterns, though the current work aims to inform surgeons on these controversial areas by drawing from numerous experiences.

Cavernous malformations are a well-described complication of intracranial radiation; however, have only once previously been described within a vestibular schwannoma following radiotherapy. We report a case of a 78-year-old woman presenting with new hemifacial spasm 16-years following fractionated radiotherapy for a vestibular schwannoma, with imaging suggesting the formation of a cavernous malformation within the tumor. The patient underwent translabyrinthine resection, with final pathology confirming the diagnosis of a cavernous malformation within the vestibular schwannoma. This case highlights the need to maintain a broad differential in patients with new symptoms following radiotherapy for vestibular schwannomas, including hemifacial spasm. Cavernous malformations should be considered among potential radiation-related complications in patients with vestibular schwannoma. Level of Evidence: IV

Objective: Surgery remains the first line treatment for meningiomas and can benefit from fluorescence-guided surgical techniques such as second-window indocyanine green (SWIG). In the current study, we compared the use of the standard SWIG dose of 5.0 mg/kg relative to 2.5 mg/kg indocyanine green (ICG) in meningioma patients. Methods: Patients were prospectively enrolled in an IRB-approved study of SWIG and received either the standard dose of 5.0 mg/kg or a reduced dose of 2.5 mg/kg of ICG around 24 h prior to their surgery. Intraoperative nearinfrared fluorescence imaging was performed with exo- and endoscopic systems. Signal-to-background ratio (SBR) was calculated to quantify fluorescence and was compared between 5.0 mg/kg and 2.5 mg/kg ICG. All patients received pre-operative MRI and, in select cases, the pre-operative MRI was correlated to intraoperative fluorescence imaging. Results/Discussion: In the current study, we found no significant difference in the SBR of meningiomas in patients that were administered with either 5.0 mg/kg or 2.5 mg/kg ICG. However, in five patients that received the standard-dose SWIG regimen of 5.0 mg/kg ICG we observed dose-related fluorescence quenching - referred to as "inversion" - that interfered with tumor visualization during fluorescence-guided surgery (FGS). When correlated to pre-operative MRI, a similar rim pattern was observed around the primary tumor on T2 FLAIR, which, in retrospect, could be used as a predictor for inversion during FGS in meningioma patients receiving standard-dose ICG. Conclusion: This study demonstrated that a reduced ICG dose was as effective as standard-dose SWIG in meningioma patients. We therefore recommend to adjust the standard ICG dose for meningioma patients to 2.5 mg/ kg particularly when rim enhancement is observed on pre-operative T2 FLAIR.

Introduction: Frailty metrics have become a means of capturing a patient’s ability to tolerate the stressors of operative intervention and subsequent risk of poor postoperative outcomes. The objective of this study was to assess the impact of frailty in patients undergoing open and endoscopic resection of olfactory groove meningiomas.

BACKGROUND AND OBJECTIVES:The purpose of this systematic review was to provide a comprehensive overview of the available literature on 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence-guided surgery (FGS) for the resection of brain metastases (BMs). METHODS:A comprehensive search of the PubMed database for literature on 5-ALA use in BMs surgery was performed. For inclusion, BMs studies had to have data on the observed intraoperative fluorescence available. Additional data categories included the number of metastatic tumors, 5-ALA dosage and timing, the imaging system (eg, microscope) used, imaging wavelength(s), fluorescence grading ("simple" and "detailed"), fluorescence consistency (heterogeneous vs homogeneous), intracranial tumor location, metastatic primary tumor location, and extent of resection, among others. RESULTS:Twenty-three articles published between 2007 and 2022 met the inclusion criteria. These studies comprised 1709 total patients; 870 metastatic samples were collected from 855 patients with 377 (43.3%) fluorescence-negative and 493 (56.7%) fluorescence-positive samples. The pooled overall prevalence of fluorescence-positive metastatic lesions was 66% (95% CI 55%-75%; I2 = 85%, P < .01). The fluorescence grading was as follows: (a) simple fluorescence (n = 599): 295 (49.3%) fluorescence-negative and 304 (50.8%) fluorescence-positive samples and (b) detailed fluorescence (n = 271): 82 (30.3%) no fluorescence, 107 (39.5%) weak fluorescence, and 82 (30.3%) strong fluorescence. A total of 764 lesions had primary tumor site data available: 702 lesions had fluorescence data with 384 (54.7%) fluorescence-positive samples. CONCLUSION:FGS using 5-ALA/PpIX in BMs demonstrates varying benefits as an adjunct for maximizing the extent of resection. Thus, preoperative knowledge of the primary tumors' origin may inform surgeons regarding the potential utility of 5-ALA/PpIX for FGS management of BMs.

Gadolinium enhancement of brain tumors on preoperative MRI scans defines the location of great majority of brain tumors prior to craniotomy. The method of dye accumulation is considered to be nonspecific. In a similar manner, we have administered high dose indocyanine green to patients undergoing craniotomy for brain tumor surgical resection. Optical imaging in a delayed fashion demonstrates indocyanine green retention within the tumor with excellent tumor to background signal. This technique -- Second Window ICG -- can provide surgical benefit with respect to early localization.

The complexity of intracranial anatomy and pathologies warrants the optimization of multimodal techniques to ensure safe and effective surgical treatment. Endoscopy is being more widely implemented in intracranial procedures as an important visualization tool, as it can offer panoramic views of deep structures while reducing the invasiveness of approaches. Fluorophores are frequently utilized to augment the identification of intracranial anatomic landmarks and pathologies. This chapter discusses the integration of these two surgical adjuncts, highlighting the key fluorophores used in endoscopic neurosurgery and their clinical applications.

Introduction: Sociodemographic determinants of healthcare outcomes are well documented across many fields of surgical diseases. We investigated the impact of race, gender, and median household income on the costs and surgical outcomes of patients undergoing endonasal endoscopic pituitary surgery to determine the role of these determinants.