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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 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.

Background Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas. Methods Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems. Results The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). The increase in area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07–0.17, P

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.

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

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

BACKGROUND Resection of brain metastases (BMs) can help with local disease control, yet predictors of leptomeningeal disease (LMD) after surgery are not well defined. This study examined rates and predictors of LMD in patients who underwent resection of a BM. METHODS A retrospective, single-center study was conducted examining LMD risk for adult patients with a BM that underwent resection with postoperative adjuvant radiation. Logistic regression analyses and a supervised machine learning algorithm (Random forest) were implemented to identify factors within the cohort that were associated with LMD. RESULTS Of the 182 patients in the cohort, 43 patients (23.6%) developed LMD in the postoperative setting with 18 cases of classical LMD (9.9%) and 25 cases of nodular LMD (13.7%). Median censored time to LMD was not reached, and 6-, 12-, and 24-month LMD-free rates from surgery were 93%, 86.3%, and 71.8%, respectively. Median time from surgery to classical and nodular LMD were 13.1 and 9.5 months, respectively (Log-rank p=0.71). Patients diagnosed with classical LMD had worse survival outcomes from LMD diagnosis compared to nodular LMD (2.6 vs 9.7 mo, Log-rank p=0.02), and LMD-subtype was significantly associated with overall survival from the date of surgery (classical vs nodular vs none: 16.1 vs 20 vs 36.7 mo, p CONCLUSIONS Classical-type LMD is associated with worse prognosis compared to nodular-type LMD. Absence of extracranial disease at the time of surgery was the most consistent factor associated with LMD on follow-up.

BACKGROUND In patients with brain metastases (BM) from EGFR-positive non-small cell lung cancer (NSCLC), recent data indicated that treating with CNS-penetrant tyrosine kinase inhibitors such as osimertinib may enable deferring radiotherapy (RT) in select patients. The purpose of this study was to describe the radiographic response of newly diagnosed BM to osimertinib with or without stereotactic radiosurgery or whole brain radiotherapy, to identify parameters that may guide early versus delayed salvage RT. METHODS In this single-institution retrospective study, 35 patients with 186 newly diagnosed BM started on osimertinib between 2014 and 2020 were reviewed. BM with tumor volume ≥ 0.1 cm3 were included in the volumetric analyses (N=106 BM). Survival was estimated with the Kaplan-Meier method, and univariable analysis was performed using log-rank tests. Cox proportional hazards was used for multivariable analyses for local control (LC), distant brain failure (DBF), and overall survival (OS). RESULTS Of the 35 patients, 8 (23%) received osimertinib alone. Median follow-up was 29 months. The 1- and 2-year LC rates were 94% and 86%. The 1- and 2-year OS rates were 89% and 66%. Median time to DBF was 24 months. Patients treated with osimertinib and RT were more likely to have a significant radiographic volumetric response at early follow-up (4-12 weeks after treatment initiation) compared to osimertinib alone (median volumetric response of –80% vs. –41%, p=0.05). On per lesion analysis, early volumetric response of ≥ 80% was associated with improved LC (3-year LC 98% vs 72%, p=0.04). CONCLUSIONS The combination of osimertinib and CNS RT is associated with greater early volumetric response in patients with BM from EGFR-positive NSCLC compared to osimertinib alone. BM with significant initial radiographic response remain well-controlled in the long term. Patients whose BM demonstrate limited initial volumetric response may benefit from targeted RT to provide long term control.

BACKGROUND Safety of immunotherapy (IO) and targeted therapy (TT) with stereotactic radiosurgery (SRS) in melanoma brain metastases (MBM) treatment remains incompletely understood. We aim to identify whether timing of IO/TT in relation to SRS impacts rates of adverse radiation effect (ARE) in MBM. METHODS Retrospective review of patients with MBM treated with SRS and IO/TT within three months prior and one year after SRS, from 2011-2021 at a single institution with at least two months MRI follow-up, identified 108 patients with 939 unique MBM meeting criteria. ARE was confirmed on independent imaging review. Concurrent IO/TT was defined as receiving IO/TT within 4 weeks before or after SRS. Data analysis was performed with the univariate cox proportional hazard model and Kaplan-Meier method. RESULTS Median radiographic follow-up from time of SRS was 16months. IO/TT was initiated prior to SRS for 681 (72.5%) metastases and after SRS for 258 (27.5%) metastases. 837 (89.1%) metastases received concurrent IO/TT. Most common IO agents were ipilimumab (n=416), nivolumab (n=448), and pembrolizumab (n=203). Most common TT agents were dabrafenib (n=548), trametinib (n=540), and vemurafenib (n=81). 2-year local progression-free survival (PFS), distant intracranial PFS, and overall survival were 94.1%, 33.3%, and 55.2%, respectively. 55 (5.9%) metastases in 33 (30.6%) patients experienced ARE. Median time to ARE was 5mo (IQR 4-9mo). Of those who experienced ARE, 22 (66.7%) patients were symptomatic and treated with steroids; 12 (36.4%) patients underwent surgical intervention. ARE rates were not impacted by concurrent vs nonconcurrent IO/TT (5.5% vs 4.9%, p=0.34) nor IO/TT initiation pre vs post SRS (6.0% vs 5.4%, p=0.61). CONCLUSION IO/TT in conjunction with SRS resulted in low ARE rates as compared to historical controls in the pre-IO/TT era. Timing of IO/TT in relation to SRS may not significantly impact ARE rates in MBM treatment.

PURPOSE: The purpose of this study is to describe outcomes after pediatric radiosurgery for malignant CNS lesions. METHODS: Retrospective chart review was performed for 31 pediatric patients treated at a single institution with Gamma Knife stereotactic radiosurgery (SRS) for primary or metastatic CNS malignancies between 2000-2020. RESULTS: 25 patients were treated with SRS for focal recurrences of primary CNS malignancies, 1 patient was treated in the adjuvant setting after initial resection, and 5 patients were treated for brain metastases. Primary CNS histologies included ependymoma (n=14), glioma (n=4), medulloblastoma (n=2), and meningioma (n=2). 65% were WHO grade 3 or 4. 71% of patients had received a prior course of involved-field external beam radiation to the brain to a median dose of 59.4 Gy in 33 fractions. Median age at SRS was 14 years (range 4-21). Radiosurgery was predominantly performed in a single fraction to a median dose of 17 Gy to a total of 42 targets among 29 patients. Two patients underwent fractionated radiosurgery to 30 Gy in 5 fractions for larger lesions. Median follow up after SRS was 44 months. 7 patients (23%) had no evidence of disease after SRS at a median follow up of 39 months. 6 patients (19%) developed local recurrence at the site of their treated lesion at a median of 13 months after SRS. 20 patients (65%) developed recurrent disease in the CNS outside of the radiosurgery field at a median of 11 months after SRS. 4 patients developed toxicity from SRS related to radiation treatment effect, all of which occurred within 1 year of SRS. CONCLUSIONS: SRS for malignant CNS lesions in the pediatric population provides effective local control and is well-tolerated. However, there remains a substantial risk of distant CNS failures given the nature of recurrent or metastatic disease in these patients.