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OBJECTIVE The authors previously evaluated risk and time course of adverse radiation effects (AREs) following stereotactic radiosurgery (SRS) for brain metastases, excluding lesions treated after prior SRS. In the present analysis they focus specifically on single-fraction salvage SRS to brain metastases previously treated with SRS or hypofractionated SRS (HFSRS), evaluating freedom from progression (FFP) and the risk and time course of AREs. METHODS Brain metastases treated from September 1998 to May 2019 with single-fraction SRS after prior SRS or HFSRS were analyzed. Serial follow-up magnetic resonance imaging (MRI) and surgical pathology reports were reviewed to score local treatment failure and AREs. The Kaplan-Meier method was used to estimate FFP and risk of ARE measured from the date of repeat SRS with censoring at the last brain MRI. RESULTS A total of 229 retreated brain metastases in 124 patients were evaluable. The most common primary cancers were breast, lung, and melanoma. The median interval from prior SRS/HFSRS to repeat SRS was 15.4 months, the median prescription dose was 18 Gy, and the median duration of follow-up imaging was 14.5 months. At 1 year after repeat SRS, FFP was 80% and the risk of symptomatic ARE was 11%. The 1-year risk of imaging changes, including asymptomatic RE and symptomatic ARE, was 30%. Among lesions that demonstrated RE, the median time to onset was 6.7 months (IQR 4.7–9.9 months) and the median time to peak imaging changes was 10.1 months (IQR 5.6–13.6 months). Lesion size by quadratic mean diameter (QMD) showed similar results for QMDs ranging from 0.75 to 2.0 cm (1-year FFP 82%, 1-year risk of symptomatic ARE 11%). For QMD < 0.75 cm, the 1-year FFP was 86% and the 1-year risk of symptomatic ARE was only 2%. Outcomes were worse for QMDs 2.01–3.0 cm (1-year FFP 65%, 1-year risk of symptomatic ARE 24%). The risk of symptomatic ARE was not increased with tyrosine kinase inhibitors or immunotherapy before or after repeat SRS. CONCLUSIONS RE on imaging was common after repeat SRS (30% at 1 year), but the risk of a symptomatic ARE was much less (11% at 1 year). The results of repeat single-fraction SRS were good for brain metastases ≤ 2 cm. The authors recommend an interval ≥ 6 months from prior SRS and a prescription dose ≥ 18 Gy. Alternatives such as HFSRS, laser interstitial thermal therapy, or resection with adjuvant radiation should be considered for recurrent brain metastases > 2 cm.

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.

OBJECTIVE The authors’ objective was to examine the safety and efficacy of salvage intracranial cesium-131 brachytherapy in combination with resection of recurrent brain tumors. METHODS The authors conducted a retrospective chart review of consecutive patients treated with intraoperative intracranial cesium-131 brachytherapy at a single institution. Permanent suture-stranded cesium-131 seeds were implanted in the resection cavity after maximal safe tumor resection. The primary outcomes of interest were local, locoregional (within 1 cm), and intracranial control, as well as rates of overall survival (OS), neurological death, symptomatic adverse radiation effects (AREs), and surgical complication rate graded according to Common Terminology Criteria for Adverse Events version 5.0. RESULTS Between 2016 and 2020, 36 patients received 40 consecutive cesium-131 implants for 42 recurrent brain tumors and received imaging follow-up for a median (interquartile range [IQR]) of 17.0 (12.7–25.9) months. Twenty patients (55.6%) with 22 implants were treated for recurrent brain metastasis, 12 patients (33.3%) with 16 implants were treated for recurrent atypical (n = 7) or anaplastic (n = 5) meningioma, and 4 patients (11.1%) were treated for other recurrent primary brain neoplasms. All except 1 tumor (97.6%) had received prior radiotherapy, including 20 (47.6%) that underwent 2 or more prior radiotherapy treatments and 23 (54.8%) that underwent prior resection. The median (IQR) tumor size was 3.0 (2.3–3.7) cm, and 17 lesions (40.5%) had radiographic evidence of ARE prior to salvage therapy. Actuarial 1-year local/locoregional/intracranial control rates for the whole cohort and patients with metastases and meningiomas were 91.6%/83.4%/47.9%, 88.8%/84.4%/45.4%, and 100%/83.9%/46.4%, respectively. No cases of local recurrence of any histology (0 of 27) occurred after gross-total resection (p = 0.012, log-rank test). The 1-year OS rates for the whole cohort and patients with metastases and meningiomas were 82.7%, 79.1%, and 91.7%, respectively, and the median (IQR) survival of all patients was 26.7 (15.6–36.4) months. Seven patients (19.4%) experienced neurological death from progressive intracranial disease (7 of 14 total deaths [50%]), 5 (13.9%) of whom died of leptomeningeal disease. Symptomatic AREs were observed in 9.5% of resection cavities (n = 4), of which 1 (2.4%) was grade 3 in severity. The surgical complication rate was 16.7% (n = 7); 4 (9.5%) of these patients had grade 3 or higher complications, including 1 patient (2.4%) who died perioperatively. CONCLUSIONS Cesium-131 brachytherapy resulted in good local control and acceptable rates of symptomatic AREs and surgical complications in this heavily pretreated cohort, and it may be a reasonable salvage adjuvant treatment for this patient population.

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.

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.

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.

OBJECTIVEConvexity meningiomas are commonly managed with resection. Motor outcomes and predictors of new deficits after surgery are poorly studied. The objective of this study was to determine whether postoperative diffusion-weighted imaging (DWI) was associated with neurological deficits after convexity meningioma resection and to identify the risk factors for postoperative DWI restriction.METHODSA retrospective review of patients who had undergone convexity meningioma resection from 2014 to 2018 was performed. Univariate and multivariate logistic regressions were performed to identify variables associated with postoperative neurological deficits and a DWI signal. The amount of postoperative DWI signal was measured and was correlated with low apparent diffusion coefficient maps to confirm ischemic injury.RESULTSThe authors identified 122 patients who had undergone a total of 125 operations for convexity meningiomas. The median age at surgery was 57 years, and 70% of the patients were female. The median follow-up was 26 months. The WHO grade was I in 62% of cases, II in 36%, and III in 2%. The most common preoperative deficits were seizures (24%), extremity weakness/paralysis (16%), cognitive/language/memory impairment (16%), and focal neurological deficit (16%). Following resection, 89% of cases had no residual deficit. Postoperative DWI showed punctate or no diffusion restriction in 78% of cases and restriction > 1 cm in 22% of cases. An immediate postoperative neurological deficit was present in 14 patients (11%), but only 8 patients (7%) had a deficit at 3 months postoperatively. Univariate analysis identified DWI signal > 1 cm (p < 0.0001), tumor diameter (p < 0.0001), preoperative motor deficit (p = 0.0043), older age (p = 0.0113), and preoperative embolization (p = 0.0171) as risk factors for an immediate postoperative deficit, whereas DWI signal > 1 cm (p < 0.0001), tumor size (p < 0.0001), and older age (p = 0.0181) were risk factors for deficits lasting more than 3 months postoperatively. Multivariate analysis revealed a DWI signal > 1 cm to be the only significant risk factor for deficits at 3 months postoperatively (OR 32.42, 95% CI 3.3–320.1, p = 0.0002). Further, estimated blood loss (OR 1.4 per 100 ml increase, 95% CI 1.1–1.7, p < 0.0001), older age (OR 1.1 per year older, 95% CI 1.0–1.1, p = 0.0009), middle third location in the sagittal plane (OR 16.9, 95% CI 1.3–216.9, p = 0.0026), and preoperative peritumoral edema (OR 4.6, 95% CI 1.2–17.7, p = 0.0249) were significantly associated with a postoperative DWI signal > 1 cm.CONCLUSIONSA DWI signal > 1 cm is significantly associated with postoperative neurological deficits, both immediate and long-lasting. Greater estimated blood loss, older age, tumor location over the motor strip, and preoperative peritumoral edema increase the risk of having a postoperative DWI signal > 1 cm, reflective of perilesional ischemia. Most immediate postoperative deficits will improve over time. These data are valuable when preoperatively communicating with patients about the risks of surgery and when postoperatively discussing prognosis after a deficit occurs.

SummaryCell state evolution underlies tumor development and response to therapy1, but mechanisms specifying cancer cell states and intratumor heterogeneity are incompletely understood. Schwannomas are the most common tumors of the peripheral nervous system and are treated with surgery and ionizing radiation2–5. Schwannomas can oscillate in size for many years after radiotherapy6,7, suggesting treatment may reprogram schwannoma cells or the tumor microenvironment. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas. We find schwannomas are comprised of 2 molecular groups distinguished by reactivation of neural crest development pathways or misactivation of nerve injury mechanisms that specify cancer cell states and the architecture of the tumor immune microenvironment. Schwannoma molecular groups can arise independently, but ionizing radiation is sufficient for epigenetic reprogramming of neural crest to immune-enriched schwannoma by remodeling chromatin accessibility, gene expression, and metabolism to drive schwannoma cell state evolution and immune cell infiltration. To define functional genomic mechanisms underlying epigenetic reprograming of schwannomas, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of cancer evolution and establish a paradigm of epigenetic reprograming of cancer in response to radiotherapy.

Brain metastases occur frequently in advanced melanoma and traditionally require surgery and radiation therapy. New evidence demonstrates that systemic therapies are effective for controlling metastatic melanoma brain metastases. This study evaluated outcomes after resection of melanoma brain metastases treated with systemic therapy, with or without focal radiotherapy.All patients received immunotherapy or BRAF/MEK inhibitors preoperatively or in the immediate 3 months postoperatively. Resection cavity failure, distant central nervous system progression, and adverse radiation effects were reported in the presence and absence of focal radiotherapy using the Kaplan-Meier method.Between 2011 and 2020, 37 resection cavities in 29 patients met criteria for analysis. Of lesions, 22 (59%) were treated with focal radiotherapy, and 15 (41%) were treated with targeted therapy or immunotherapy alone. The 12- and 24-month freedom from local recurrence was 64.8% (95% confidence interval [CI] 42.1%-99.8%) and 46.3% (95% CI 24.5%-87.5%), respectively, for systemic therapy alone and 93.3% (95% CI 81.5%-100%) at both time points for focal radiotherapy (P = 0.01). On univariate analysis, focal radiotherapy was the only significant factor associated with reduction of local recurrence risk (hazard ratio 0.10, 95% CI 0.01-0.85; P = 0.04). There were no significant differences in central nervous system progression-free survival or overall survival between patients who received systemic therapy plus focal radiotherapy compared with systemic therapy alone. BRAF mutation status was reviewed for either the brain metastasis (n = 9 patients, 31%) or the primary site (n = 20 patients, 69%), and patients harboring BRAFFocal radiotherapy with systemic therapy for resected melanoma brain metastases significantly decreased resection cavity recurrence compared with systemic therapy alone. BRAF mutation status correlated with poorer outcomes.

Introduction The management of recurrent craniopharyngioma is complex with limited data to guide decision-making. Some reports suggest reoperation should be avoided due to an increased complication profile, while others have demonstrated that safe reoperation can be performed. For other types of skull base lesions, maximal safe resection followed by adjuvant therapy has replaced radical gross total resection due to the favorable morbidity profiles. Methods Seventy-one patients underwent resection over a 9-year period for craniopharyngioma and were retrospectively reviewed. Patients were separated into primary resection and reoperation cohorts and stratified by surgical approach (endonasal vs. cranial) and survival analyses were performed based on cohort and surgical approach. Results Fifty patients underwent primary resection, while 21 underwent reoperation for recurrence. Fifty endonasal transsphenoidal surgeries and 21 craniotomies were performed. Surgical approaches were similarly distributed across cohorts. Subtotal resection was achieved in 83% of all cases. There were no differences in extent of resection, visual outcomes, subsequent neuroendocrine function, and complications across cohorts and surgical approaches. The median time to recurrence was 87 months overall, and there were no differences by cohort and approach. The 5-year survival rate was 81.1% after reoperation versus 93.2% after primary resection. Conclusion Compared with primary resection, reoperation for craniopharyngioma recurrence is associated with similar functional and survival outcomes in light of individualized surgical approaches. Maximal safe resection followed by adjuvant radiotherapy for residual tumor likely preserves vision and endocrine function without sacrificing overall patient survival.

Risk factors for a postoperative cerebrospinal fluid leak (CSF) after surgery include an intraoperative high flow of CSF, elevated body mass index, defect size, and defect site. In our prior series, a high postoperative CSF leak rate for tumors of the central skull base (planum, sella, and clivus) appeared to be due to graft migration. We changed our closure technique from a single layer of collagen +/- fat graft to a novel graft, termed a "Bow tie" (a tri-layer fat graft with two pieces of collagen matrix), and report our results in this study.Retrospective temporal epoch study of a single otolaryngologist's experience of closing skull base defects in our skull base center from 2005 to 2017.One hundred and forty-nine patients met inclusion criteria in two time periods, pre- and post-introduction of the Bow tie technique. In epoch I, from 2005 to 2013, 79 patients had reconstruction with a single layer of dural graft (25 had additional free fat graft). In epoch II, from 2014 to 2017, 70 patients had reconstruction with the Bow tie.CSF leak rates were 8.7% overall: 15.2% in epoch I and 1.4% in epoch II (p = 0.01). After controlling the procedure, defects with a size greater than 2 cm had a 5.7 greater likelihood of failure. Epoch II had a lower incidence of major complications.Using a single surgeon's experience, the multilayer Bow tie has a significant reduction in postoperative CSF leak and associated major complications for defects of the central skull base.III Laryngoscope, 2022.

Objective Meningioma incidence increases with age, yet limited data exist on how comorbidities impact complication rates in elderly patients undergoing meningioma resection. The objective of this study was to report surgical outcomes and identify risk factors for perioperative complications. Methods We performed a retrospective study of patients 75 years and older undergoing meningioma resection. Outcomes included survival and complications. Major complications were those requiring surgical intervention or causing permanent neurological deficit. Recursive partitioning, Kaplan-Meier survival, univariate and multi-variate (MVA) analyses were performed. Results From 1996 to 2014, 103 patients with a median age of 79 years (IQR 77–83 years) underwent cranial meningioma resection. Median follow-up was 5.8 years (IQR 1.7–8.7 years). Median actuarial survival was 10.5 years. Complications occurred in 32 patients (31.1%), and 13 patients (12.6%) had multiple complications. Major complications occurred in 16 patients (15.5%). Increasing age was not a significant predictor of any (p = 0.6408) or major complication (p = 0.8081). On univariate analysis, male sex, Charlson Comorbidity Index greater than 8, and cardiovascular comorbidities were significantly associated with major complications. On MVA only cardiovascular comorbidities (OR 3.94, 95% CI 1.05–14.76, p = 0.0238) were significantly associated with any complication. All patients with major complications had cardiovascular comorbidities, and on MVA male gender (OR 3.78, 95%CI 1.20–11.93, p = 0.0212) was associated with major complications. Conclusions Cardiovascular comorbidities and male gender are significant risk factors for complications after meningioma resection in patients aged 75 years and older. While there is morbidity associated with meningioma resection in this cohort, there is also excellent long-term survival.

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.

OBJECTIVEHyperostosing sphenoid wing meningiomas cause bony hyperostosis that may extend into the orbit, resulting in proptosis, restriction of extraocular movements, and/or compressive optic neuropathy. The extent of bony removal necessary and the optimal reconstruction strategy to prevent enophthalmos is debated. Herein, the authors present their surgical outcomes and reconstruction results.METHODSThis is a retrospective review of 54 consecutive patients undergoing resection of sphenoid wing meningiomas associated with bony hyperostosis. The majority of cases were operated on by the senior author. Extent of tumor resection, volumetric bone resection, radiographic exophthalmos index, complications, and recurrence were analyzed.RESULTSThe median age of the cohort was 52.1 years, with women comprising 83% of patients. Proptosis was a presenting symptom in 74%, and 52% had decreased visual acuity. The WHO grade was I (85%) or II (15%). The median follow-up was 2.6 years. On volumetric analysis, a median 86% of hyperostotic bone was resected. Gross-total resection of the intracranial tumor was achieved in 43% and the orbital tumor in 27%, and of all intracranial and orbital components in 20%. Orbital reconstruction was performed in 96% of patients. Postoperative vision was stable or improved in 98% of patients and diplopia improved in 89%. Postoperative complications occurred in 44% of patients, and 26% of patients underwent additional surgery for complication management. The most frequent complications were medical complications and extraocular movement deficits. The median preoperative exophthalmos index was 1.26, which improved to 1.12 immediately postoperatively and to 1.09 at the 6-month follow-up (p < 0.001). Postoperatively, 18 patients (33%) underwent adjuvant radiotherapy after subtotal resection. Tumors recurred/progressed in 12 patients (22%).CONCLUSIONSResection of hyperostosing sphenoid wing meningiomas, particularly achieving gross-total resection of hyperostotic bone with a good aesthetic result, is challenging and associated with notable medical and ocular morbidity. Recurrence rates in this series are higher than previously reported. Nevertheless, the authors were able to attain improvement in proptosis and visual symptoms in the majority of patients by using a multidisciplinary approach.

Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy. To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. Our data reveal that regional alterations in chromosome structure underlie clonal transcriptomic, epigenomic, and histopathologic signatures in meningioma. Stereotactic co-registration of sample coordinates to preoperative magnetic resonance images further suggest that high apparent diffusion coefficient (ADC) distinguishes meningioma regions with proliferating cells enriched for developmental gene expression programs. To understand the function of these genes in meningioma, we develop a human cerebral organoid model of meningioma and validate the high ADC marker genes CDH2 and PTPRZ1 as potential targets for meningioma therapy using live imaging, single cell RNA sequencing, CRISPR interference, and pharmacology., Meningiomas are heterogeneous tumours. Here, the authors analysed genetic, epigenetic, and transcriptomic features across spatially-distinct meningioma samples to identify molecular programs underlying tumorigenesis that can be detected preoperatively using magnetic resonance imaging.

BACKGROUND: Brain metastases are a common occurrence, with literature supporting the treatment of a limited number of brain metastases with stereotactic radiosurgery (SRS), as opposed to whole brain radiotherapy (WBRT). Less well understood is the role of SRS in patients with ≥10 brain metastases. METHODS: Patients treated with SRS to ≥10 brain metastases without concurrent WBRT between March 1999 and December 2016 were reviewed. Analysis was performed for overall survival, treated lesion freedom from progression (FFP), freedom from new metastases (FFNMs), and adverse radiation effect. Hippocampal volumes were retrospectively generated in patients treated with up-front SRS for evaluation of dose volume metrics. RESULTS: A total of 143 patients were identified with 75 patients having up-front SRS and 68 patients being treated as salvage therapy after prior WBRT. The median number of lesions per patient was 13 (interquartile range [IQR], 11–17). Median total volume of treatment was 4.1 cm(3) (IQR, 2.0–9.9 cm(3)). The median 12-month FFP for up-front and salvage treatment was 96.8% (95% confidence interval [CI], 95.5–98.1) and 83.6% (95% CI, 79.9–87.5), respectively (P < 0.001). Twelve-month FFNMs for up-front and salvage SRS was 18.8% (95% CI, 10.9–32.3) versus 19.2% (95% CI, 9.7–37.8), respectively (P = 0.90). The mean hippocampal dose was 150 cGy (IQR, 100–202 cGy). CONCLUSIONS: Excellent rates of local control can be achieved when treating patients with >10 intracranial metastases either in the up-front or salvage setting. Hippocampal sparing is readily achievable with expected high rates of new metastatic lesions in treated patients.

Despite reports on the efficacy of checkpoint inhibitor (CPI) immunotherapies for metastatic cancers, there are limited data on the effectiveness of surgery for brain metastases (BMs) that have progressed after previous CPI treatment. We sought to evaluate surgical outcomes for patients undergoing BM resection after failing CPI immunotherapy.A single-center series of patients with BM that had progressed after previous CPI treatment and who underwent surgery was retrospectively reviewed. Outcomes of interest included local tumor progression, leptomeningeal dissemination, and overall survival. Cox proportional hazard models were applied to determine factors associated with outcomes of interest.Over a 16-year period, 26 patients underwent resection of 32 BMs at a median of 1.2 months (range, 2 days-41.1 months) from their last CPI dose. Median censored survival was 7.6 months from surgery and was shorter than the survival of patients without previous CPI exposure (21.9 months; log-rank P = 0.001). Four BMs had local central nervous system progression (16%), and 75% of procedures were associated with distant central nervous system progression within a median time of 3.3 months. Leptomeningeal disease developed after 33.3% of surgeries. Increased time from first BM diagnosis to surgery was associated with increased risk of leptomeningeal disease (hazard ratio by month, 1.07; 95% confidence interval, 1.01-1.14; P = 0.03).Patients who require BM resection after previous CPI treatment have a poor overall prognosis compared with patients without previous CPI exposure. Although local control rates are acceptable, these patients are at high risk for developing distant progression and leptomeningeal disease postoperatively.

Intravestibular schwannomas are rare tumors within the intralabyrinthine region and involve different management considerations compared to more common vestibular schwannomas. In this report, the authors review a case of a 52-year-old woman who presented with hearing loss and vestibular symptoms and was found to have a left intravestibular schwannoma. Given her debilitating vestibular symptoms, she underwent microsurgical resection. In this video, the authors review the relevant anatomy, surgical technique, and management considerations in these patients. The video can be found here: https://stream.cadmore.media/r10.3171/2021.7.FOCVID2187

BACKGROUND Meningiomas of the atrium of the lateral ventricle present a unique operative challenge. Parietal transcortical approaches have been described with an oblique approach, but a strictly paramedian approach may offer advantages in a dominant hemisphere atrial meningioma. OBSERVATIONS The patient presented with several weeks of intermittent headaches. Magnetic resonance imaging (MRI) showed an enhancing intraventricular mass in the atrium of the left lateral ventricle. Three-dimensional reconstructions were created from a preoperative MRI, with 1-mm slices for neuronavigation. Diffusion tensor imaging (DTI) was obtained, and tracts were reconstructed in the patient’s three-dimensional brainspace. DTI tractography delineated a paramedian transparietal corridor devoid of functional white matter tracks. The patient was positioned supine, in a semislouch position. A left parietal craniotomy was performed. Neuronavigation identified a gyrus posterior to the sensory cortex, anterior to the optic radiations and medial to superior longitudinal and arcuate fasciculus fiber tracts. The tumor was debulked to allow mobilization to coagulate capsular blood supply. Gross total resection was achieved. The patient was discharged postoperatively on day 3 without neurological deficits. LESSONS A paramedian transparietal approach to a dominant hemisphere meningioma of the lateral ventricle can be a safe and effective way to resect tumors in this anatomically unique operative corridor.

OBJECTIVERecurrent meningiomas are primarily managed with radiation therapy or repeat resection. Surgical morbidity after reoperation for recurrent meningiomas is poorly understood. Thus, the objective of this study was to report surgical outcomes after reoperation for recurrent non–skull base meningiomas.METHODSA retrospective review of patients was performed. Inclusion criteria were patients with recurrent meningioma who had prior resection and supratentorial non–skull base location. Univariate and multivariate logistic regression and recursive partitioning analysis were used to identify risk factors for surgical complications.RESULTSThe authors identified 67 patients who underwent 111 reoperations for recurrent supratentorial non–skull base meningiomas. The median age was 53 years, 49% were female, and the median follow-up was 9.8 years. The most common presenting symptoms were headache, weakness, and seizure. The WHO grade after the last reoperation was grade I in 22% of cases, grade II in 51%, and grade III in 27%. The tumor grade increased at reoperation in 22% of cases. Tumors were located on the convexity (52%), parasagittal (33%), falx (31%), and multifocal (19%) locations. Tumors involved the middle third of the sagittal plane in 52% of cases. In the 111 reoperations, 48 complications occurred in 32 patients (48%). There were 26 (54%) complications requiring surgical intervention. There was no perioperative mortality. Complications included neurological deficits (14% total, 8% permanent), wound dehiscence/infection (14%), and CSF leak/pseudomeningocele/hydrocephalus (9%). Tumors that involved the middle third of the sagittal plane (OR 6.97, 95% CI 1.5–32.0, p = 0.006) and presentation with cognitive changes (OR 20.7, 95% CI 2.3–182.7, p = 0.001) were significantly associated with complication occurrence on multivariate analysis. The median survival after the first reoperation was 11.5 years, and the 2-, 5-, and 10-year Kaplan-Meier survival rates were 91.0%, 68.8%, and 50.0%, respectively.CONCLUSIONSReoperation for recurrent supratentorial non–skull base meningioma is associated with a high rate of complications. Patients with cognitive changes and tumors that overlap the middle third of the sagittal plane are at increased risk of complications. Nevertheless, excellent long-term survival can be achieved without perioperative mortality.

Author(s): Sloan, Emily A; Cooney, Tabitha; Oberheim Bush, Nancy Ann; Buerki, Robin; Taylor, Jennie; Clarke, Jennifer L; Torkildson, Joseph; Kline, Cassie; Reddy, Alyssa; Mueller, Sabine; Banerjee, Anu; Butowski, Nicholas; Chang, Susan; Mummaneni, Praveen V; Chou, Dean; Tan, Lee; Theodosopoulos, Philip; McDermott, Michael; Berger, Mitchel; Raffel, Corey; Gupta, Nalin; Sun, Peter P; Li, Yi; Shah, Vinil; Cha, Soonmee; Braunstein, Steve; Raleigh, David R; Samuel, David; Scharnhorst, David; Fata, Cynthia; Guo, Hua; Moes, Gregory; Kim, John YH; Koschmann, Carl; Van Ziffle, Jessica; Onodera, Courtney; Devine, Patrick; Grenert, James P; Lee, Julieann C; Pekmezci, Melike; Phillips, Joanna J; Tihan, Tarik; Bollen, Andrew W; Perry, Arie; Solomon, David A

Background Preservation of functional integrity during vestibular schwannoma surgery has become critical in the era of patient-centric medical decision-making. Subtotal tumor removal is often necessary when dense adhesions between the tumor and critical structures are present. However, it is unclear what the rate of tumor control is after subtotal resection (STR) and what factors are associated with recurrence. Objective To determine the rate of residual tumor growth after STR and identify clinical and radiographic predictors of tumor progression. Methods A single-institution retrospective study was performed on all sporadic vestibular schwannomas that underwent surgical resection between January 1, 2002 and December 31, 2015. Clinical charts, pathology, radiology, and operative reports were reviewed. Volumetric analysis was performed on all pre- and postoperative MR imaging. Univariate and multivariate logistic regression was performed to identify predictors of the primary endpoint of tumor progression. Kaplan-Meier analysis was performed to compare progression free survival between 2 groups of residual tumor volumes and location. Results In this cohort of 66 patients who underwent primary STR, 30% had documented progression within a median follow up period of 3.1 yr. Greater residual tumor volume (OR 2.0 [1.1-4.0]) and residual disease within the internal auditory canal (OR 3.7 [1.0-13.4]) predicted progression on multivariate analysis. Conclusion These longitudinal data provide insight into the behavior of residual tumor, helping clinicians to determine if and when STR is an acceptable surgical strategy and to anchor expectations during shared medical decision-making consultation with patients.

The present study aimed to examine the technical feasibility and effectiveness of adapting the radiation dose distributions with three-dimensional (3D) linear couch translations in contrast to full six-dimensional couch maneuvers to correct for rotational shifts during frameless radiosurgical treatment with the Gamma Knife Icon™ (Elekta AB; Stockholm, Sweden).The original magnetic resonance images used for radiosurgery treatment planning (15 targets) were digitally processed to simulate rotational shifts of ±1, ±2, ±3, ±5, and ±10 degrees in the transverse plane and imported back into Leksell GammaPlanThe "uncorrected" treatment plans resulted in a significant deterioration in target coverage (by 8-72%) and selectivity (by 2-42%), with some targets being missed completely with rotations of ±3 or more degrees. In contrast, in all "corrected" treatment plans, the average decreases in target coverage and selectivity were only 1% (maximum values 4-5%).Applications of 3D linear couch translations successfully overcome gross uncertainties in dose distributions caused by up to ±10 degrees of rotational shifts in a target. As a result, rapid dose adaptation with 3D couch translations is unique and effective for frameless radiosurgery with the Gamma Knife Icon™.

The objective of the present study was evaluation of the interrelationships between changes in the skull size and variations in the normal brain radiation dose during Gamma Knife surgery (GKS).With use of systematic modeling within Leksell GammaPlanWith changes in the skull radius within ±3 cm, the maximum absolute deviation in the mean normal brain radiation dose was 0.8%. As the skull radius increased, the mean normal brain radiation dose also increased linearly (confidence level99%) with a positive slope of 0.2% per centimeter of radius length change. The maximum point dose deviations in all evaluated critical anatomical structures did not exceed 0.5%, with an overall trend toward a dose increase in parallel with an increase in the skull radius.The small skull size of pediatric patients may be associated with dosimetric advantages in terms of normal brain sparing during GKS.

OBJECTIVE Diabetes insipidus (DI) following transsphenoidal surgery can adversely impact quality of life and be difficult to manage. This study sought to characterize pre- and perioperative risk factors that may predispose patients to DI after pituitary surgery. METHODS A retrospective review of patients treated at a single institution from 2007 to 2019 was conducted. DI was defined as postoperative sodium > 145 mEq/L and urine output > 300 ml/hr and/or postoperative desmopressin (ddAVP) use. DI was further characterized as transient or permanent. Uni- and multivariate analyses were performed to determine variables associated with postoperative DI. RESULTS The authors identified 2529 patients who underwent transsphenoidal surgery at their institution. Overall, DI was observed in 270 (10.7%) of the 2529 patients, with 114 (4.5%) having permanent DI and 156 (6.2%) with transient symptoms. By pathology type, DI occurred in 31 (46.3%) of 67 craniopharyngiomas, 10 (14.3%) of 70 apoplexies, 46 (14.3%) of 322 Rathke’s cleft cysts, 77 (7.7%) of 1004 nonfunctioning pituitary adenomas (NFPAs), and 62 (7.6%) of 811 functioning pituitary adenomas (FPAs). Final lesion pathology significantly affected DI rates (p < 0.001). Multivariate analysis across pathologies showed that younger age (odds ratio [OR] 0.97, p < 0.001), intraoperative CSF encounter (OR 2.74, p < 0.001), craniopharyngioma diagnosis (OR 8.22, p = 0.007), and postoperative hyponatremia (OR 1.50, p = 0.049) increased the risk of DI. Because surgery for each pathology created specific risk factors for DI, the analysis was then limited to the 1815 pituitary adenomas (PAs) in the series, comprising 1004 NFPAs and 811 FPAs. For PAs, younger age (PA: OR 0.97, p < 0.001; NFPA: OR 0.97, p < 0.001; FPA: OR 0.97, p = 0.028) and intraoperative CSF encounter (PA: OR 2.99, p < 0.001; NFPA: OR 2.93, p < 0.001; FPA: OR 3.06, p < 0.001) increased DI rates in multivariate analysis. Among all PAs, patients with DI experienced peak sodium levels later than those without DI (postoperative day 11 vs 2). Increasing tumor diameter increased the risk of DI in FPAs (OR 1.52, p = 0.008), but not in NFPAs (p = 0.564). CONCLUSIONS In more than 2500 patients treated at a single institution, intraoperative CSF encounter, craniopharyngioma diagnosis, and young age all increased the risk of postoperative DI. Patients with postoperative hyponatremia exhibited higher rates of DI, suggesting possible bi- or triphasic patterns to DI. Greater vigilance should be maintained in patients meeting these criteria following transsphenoidal surgery to ensure early recognition and treatment of DI.

OBJECTIVE Surgical site infection (SSI) is a complication linked to increased costs and length of hospital stay. Prevention of SSI is important to reduce its burden on individual patients and the healthcare system. The authors aimed to assess the efficacy of preoperative chlorhexidine gluconate (CHG) showers on SSI rates following cranial surgery. METHODS In November 2013, a preoperative CHG shower protocol was implemented at the authors’ institution. A total of 3126 surgical procedures were analyzed, encompassing a time frame from April 2012 to April 2016. Cohorts before and after implementation of the CHG shower protocol were evaluated for differences in SSI rates. RESULTS The overall SSI rate was 0.6%. No significant differences (p = 0.11) were observed between the rate of SSI of the 892 patients in the preimplementation cohort (0.2%) and that of the 2234 patients in the postimplementation cohort (0.8%). Following multivariable analysis, implementation of preoperative CHG showers was not associated with decreased SSI (adjusted OR 2.96, 95% CI 0.67–13.1; p = 0.15). CONCLUSIONS This is the largest study, according to sample size, to examine the association between CHG showers and SSI following craniotomy. CHG showers did not significantly alter the risk of SSI after a cranial procedure.

OBJECTIVE Clinical presentations and outcomes of nonfunctional pituitary adenoma (NFPA) resections can vary widely, and very little prior research has analyzed this variance through a socioeconomic lens. This study sought to determine whether socioeconomic status (SES) influences NFPA presentations and postoperative outcomes, as these associations could aid physicians in understanding case prognoses and complications. METHODS The authors retrospectively analyzed 225 NFPA resections from 2012 to 2019 at their institution. Race, ethnicity, insurance status, estimated income, and having a primary care provider (PCP) were collected as 5 markers of SES. These markers were correlated with presenting tumor burden, presenting symptoms, surgical outcomes, and long-term clinical outcomes. RESULTS All 5 examined SES markers influenced variance in patient presentation or outcome. Insurance status’s effects on patient presentations disappeared when examining only patients with PCPs. Having a PCP was associated with significantly smaller tumor size at diagnosis (effect size = 0.404, p < 0.0001). After surgery, patients with PCPs had shorter postoperative hospital lengths of stay (p = 0.043) and lower rates of readmission within 30 days of discharge (OR 0.256, p = 0.047). Despite continuing follow-up for longer durations (p = 0.0004), patients with PCPs also had lower rates of tumor recurrence (p < 0.0001). Higher estimated income was similarly associated with longer follow-up (p = 0.002) and lower rates of tumor recurrence (p = 0.013). Among patients with PCPs, income was not associated with recurrence. CONCLUSIONS This study found that while all 5 variables (race, ethnicity, insurance, PCP status, and estimated income) affected NFPA presentations and outcomes, having a PCP was the single most important of these socioeconomic factors, impacting hospital lengths of stay, readmission rates, follow-up adherence, and tumor recurrence. Having a PCP even protected low-income patients from experiencing increased rates of tumor recurrence. These protective findings suggest that addressing socioeconomic disparities may lead to better NFPA presentations and outcomes.

Objective Resection of intramedullary spinal ependymomas carries great risk of postoperative neurological deficits. The objective of this study was to describe our experience using co-neurosurgeon teams to address intramedullary ependymomas to determine if the use of 2 experienced attending neurosurgeons with expertise in both neurosurgical oncology and spine pathology can improve outcomes for intramedullary ependymoma resections. Methods We retrospectively compared surgical and disease control outcomes in intramedullary ependymoma cases performed by co-neurosurgeon (one neurosurgical oncologist and one neurosurgeon trained in spinal surgery) and single-neurosurgeon teams over a 13-year period at a single institution. Results Co-neurosurgeons performed resections in 34 (47.9%) patients, and a single neurosurgeon performed resections in 37 (52.1%) patients. There were no significant differences in the frequency of gross total resection in the co-neurosurgeon versus single-neurosurgeon group (85.7% vs. 78.4%, P = 0.45). Posterior spinal fusion was more common in the co-neurosurgeon group (35.3%) compared with the single-neurosurgeon group (8.1%) (P = 0.01). Two (5.9%) patients in the co-neurosurgeon group and 5 (13.5%) patients in the single-neurosurgeon group had complications requiring surgical revision (P = 0.28). Recurrence rates were similar in both groups (5.9% vs. 10.8%, P = 0.50). At last follow-up, 76% of patients who presented with mild or no deficits remained functionally independent. Conclusions Resection of intramedullary ependymomas by co-neurosurgeon teams resulted in similar rates of gross total resection, postoperative complications, and recurrence compared with surgeries performed by a single neurosurgeon. Functional neurological outcomes were not impacted by co-neurosurgeons performing ependymoma resections.

Purpose/objective(s) Management of progressive brain tumors following high dose radiotherapy is controversial. In select cases, surgical resection can provide rapid relief of regional mass effect and edema, and highly focal adjuvant re-irradiation can be administered in the form of brachytherapy. Permanent low-dose rate cesium-131 brachytherapy may offer dosimetric and radiobiologic advantages over other isotopes. The purpose of this study was to examine the safety and efficacy of intracranial cesium-131 brachytherapy after surgical resection in a heavily pre-treated patient cohort. Materials/methods A retrospective chart review was conducted of all patients treated with intraoperative intracranial cesium-131 brachytherapy from an institutional database. Treatment consisted of maximal safe resection followed by implantation of suture-stranded cesium-131 seeds, maintaining approximately 10mm spacing between seeds, with a planned target dose of 80 Gy to 5mm depth. Local failure was defined as recurrence in or contacting the resection cavity after salvage resection and brachytherapy. Regional failure was defined as recurrence within 10mm of the resection cavity. Recurrence was defined as a new lesion or growth of ≥25% in any axial dimension on interval MRI. Toxicity was collected based on CTCAE 4.0. Results A total of 35 patients with a median imaging follow up of 17.0 months (interquartile range [IQR] 9.7-25.9) underwent 41 consecutive cesium-131 implants between 2016 and 2020. 20 patients (59%; N = 22 implants) were treated for recurrent brain metastasis, 12 patients (34%; N = 16 implants) were treated for recurrent atypical (N = 8) or anaplastic meningioma (N = 4), and 3 patients (9%) were treated for recurrent glioma (N = 2) or hemangiopericytoma (N = 1). A majority of lesions had received prior surgery (N = 28, 66.7%, range 0-3 prior surgeries) and 34 patients had received prior high dose radiation. 34 of 41 (82.9%) tumors had received prior radiosurgery, and 12 (29.2%) had undergone prior external beam radiation (range 50-60 Gy). 17 of 41 lesions (41.5%) had radiologic evidence of adverse radiation/treatment effect (ARE) prior to salvage therapy. Median tumor size was 3.0cm (IQR 2.3-3.7). Overall actuarial local/loco-regional control at 1-year was 91.6%/84.7% (89.8%/88.9% for metastases and 100%/82.5% for meningiomas). Crude loco-regional control was 86.3% for metastases, 75% for meningiomas, and 66.7% for other lesions. Symptomatic ARE following treatment was observed in 9.8% (N = 4) resection cavities. The surgical complication rate was 14.6% (N = 6 total, N = 3 [7.3%] grade 3-5) including 1 peri-operative death. Conclusion Cesium-131 brachytherapy in this heavily pre-treated cohort resulted in good local control and an acceptable rate of symptomatic adverse radiation effect and toxicity and may be a reasonable treatment option for this select population. Author disclosure W.C. Chen: None. M. Lafreniere: None. C. Phuong: None. M. Lometti: None. O. Morin: None. B.P. Ziemer: None. H. Vasudevan: Research Grant; Children's Tumor Foundation. Patent/License Fees/Copyright; Genentech, Eli Lilly. S. Hervey-Jumper: None. P.V. Theodosopoulos: None. S. Magill: None. S.E. Fogh: Independent Contractor; Accuray. J.L. Nakamura: None. L. Boreta: None. P.K. Sneed: None. M.W. McDermott: Chair; Miami Baptist. D. Raleigh: None. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.

PURPOSE/OBJECTIVE(S) Previous studies have characterized dose gradient patterns for various hypo-fractionated brain radiosurgery (hSRS) treatment platforms. The Gamma Knife Icon (GKI) has consistently exhibited either superior or non-inferior peripheral dose fall-off and normal brain sparing characteristics when compared to other Linac-based hSRS treatment platforms. Given the prevalence of Linac-based treatments, identifying planning techniques to optimize treatment parameters is desirable. In this study, we investigated a novel Linac-based treatment approach that aimed to create the sharpest dose fall-off for hSRS of large brain lesions. MATERIALS/METHODS A cohort of patient cases (n = 10) with single brain lesions (volume 27.6+/-8.1 mL, range 20.-42.1 mL) treated with GKI at our institution were selected as sample test cases for our study. A non-coplanar unconstrained VMAT (NCU-VMAT) treatment planning approach was developed, and its script was implemented on a commercial treatment planning system for clinical Linac treatment equipped with the latest high-definition multi-leaf collimators (MLCs). Treatment plans produced via the NCU-VMAT approach were then compared against further optimized treatment plans from GKI, as well as conventional coplanar and non-coplanar VMAT treatment planning approaches. The comparison was carried out using DVH-derived parameters including target volume coverage, target dose conformity, modified dose fall-off index defined as the volume of 50% prescribed target dose divided by the target volume (PIV50). RESULTS For each case studied, NCU-VMAT achieved practically identical target coverage (0.98 ± 0.01) and Paddick dose conformity index (0.87 ± 0.02) compared to optimized GKI treatments. The mean PIV50 values were 2.99 ± 0.14, 3.77 ± 0.22, and 3.36 ± 0.19 for optimized GKI, conventional coplanar, and non-coplanar VMAT treatment plans, respectively. These results were in excellent agreement with previously published studies. However, the NCU-VMAT technique yielded a mean PIV50 of 2.41 ± 0.07. This represents an improvement of approximately 40% (P < 0.001, paired two-tailed Student t-test) over all existing approaches including GKI. Further analyses revealed that PIV50 of NCU-VMAT approached the theoretical minimum for all the studied cases. CONCLUSION Our results demonstrate that in treatment of large brain tumors, a treatment planning approach using Bremsstrahlung x-ray based Linacs can achieve superior dose fall-off for intracranial hSRS compared to GKI. We dispel the myth that physical characteristics of Cobalt γ-rays are needed to create the sharpest dose fall-off. Given the prevalence of Linac-based treatments compared to GKI, we present a novel optimized planning technique that achieves a new benchmark of sharpest dose fall-off. AUTHOR DISCLOSURE T. Nano: None. O. Morin: None. B.P. Ziemer: None. D. Raleigh: None. L. Boreta: None. J.L. Nakamura: None. S.E. Fogh: Independent Contractor; Accuray. P.K. Sneed: None. S. Hervey-Jumper: None. P.V. Theodosopoulos: None. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.L. Ma: Patent/License Fees/Copyright; University of California Regents.