Outcomes of radiation-induced meningiomas treated with stereotactic radiosurgery.

PURPOSE: Data on the efficacy and safety of stereotactic radiosurgery (SRS) for treatment of radiation-induced meningiomas (RIMs) are limited. METHODS: A single institution database of Cobalt-60 SRS cases from 08/1999 to 10/2020 was reviewed. Radiation-induced meningiomas were identified using Cahan's criteria. Endpoints included overall survival (OS), progression free survival (PFS), local control (LC), treatment failure, and treatment toxicity. Univariate and multivariate analyses were performed using cox proportional hazard models. RESULTS: A total of 29 patients with 86 RIM lesions were identified. Median follow-up after SRS was 59 months. The median dose prescribed to the 50% isodose line was 14 Gy (range 12-20 Gy). The actuarial 5-yr OS and PFS were 96% and 68%, respectively. Patients treated for recurrent RIMs had a significantly lower PFS (45% vs 94% at 3 yr, p < 0.005) than patients treated in the upfront setting. Patients with presumed or WHO grade I RIMs had a significantly greater PFS (3-year PFS 96% vs 20%) than patients with WHO grade II RIMs (p < 0.005). On a per-lesion basis, local control (LC) at 1-, 3-, and 5-yrs was 82%, 76%, 74%, respectively. On multivariate analysis, female gender was associated with improved LC (p < 0.001), while marginal doses > 14 Gy were associated with worse local control (p < 0.001). Grade I-III toxicity following treatment was 9.0%. CONCLUSIONS: Stereotactic radiosurgery is a safe and effective treatment option for radiographic RIMs, WHO grade I RIMs, or lesions treated in the upfront setting. WHO grade II lesions and recurrent lesions are at increased risk for disease progression.

Long term survivors of stereotactic radiosurgery for brain metastases: do distant brain failures reach a plateau and what factors are associated with a brain metastasis velocity of zero?

PURPOSE: Life expectancy continues to increase for patients with brain metastases treated with stereotactic radiosurgery (SRS). The present study sought to retrospectively analyze brain metastasis patients who have survived 2 years or more, and assess for what factors may predict for a final brain metastasis velocity (BMV) of zero. METHODS: This was a single-institution retrospective study of 300 patients treated with SRS from 2001 to 2019 for brain metastases who survived greater than 2 years after first SRS. Final BMV is calculated by summing all metastases through the observed time divided by the total time in years. A BMV of zero is defined as at least 2 years of imaging follow-up without distant brain failure (DBF). RESULTS: Median age at first SRS is 61 (IQR: 53, 70). Kaplan-Meier estimated median overall survival is 4.9 years and time to DBF is 1.5 years (95% CI 1.2, 2.0). Twenty-eight (9.3%) patients underwent subsequent WBRT. One hundred and one (33.7%) patients never had any further brain metastases (BMV = 0) at a median follow-up time of 3.3 years. Median BMV is 0.4 (IQR: 0, 1.4). Distant brain failures reach a plateau at 4 years where the cumulative incidence of DBF is 82%. 70% of first time DBFs have occurred by 2 years. Factors significantly associated with a BMV of zero include fewer brain metastases at first SRS (HR 1.1; p = 0.0004) and Caucasian race (HR 1.5; p = 0.03). CONCLUSION: Approximately one third of brain metastasis patients who live beyond 2 years after initial SRS have a BMV of zero. DBFs appear to reach a plateau at 4 years. Factors significantly associated with a BMV of zero include Caucasian race and having had a single brain metastasis at first SRS.

Local control outcomes for combination of stereotactic radiosurgery and immunotherapy for non-small cell lung cancer brain metastases.

BACKGROUND: Previous series have demonstrated CNS activity for immune checkpoint inhibitors, yet no prior data exists regarding whether this activity can improve outcomes of stereotactic radiosurgery. METHODS: In this single institution retrospective series, the clinical outcomes of 80 consecutive lung cancer patients treated with concurrent immune checkpoint inhibitors and stereotactic radiosurgery were compared to 235 in the historical control cohort in which patients were treated prior to immune checkpoint inhibition being standard upfront therapy. Overall survival was estimated using the Kaplan Meier method. Cumulative incidence of local progression was estimated using a competing risk model. RESULTS: Median overall survival time was improved in patients receiving upfront immunotherapy compared to the historical control group (40 months vs 8 months, p < 0.001). Factors affected overall survival include concurrent immunotherapy (HR 0.23, p < 0.0001) and KPS (HR 0.97, p = 0.0001). Cumulative incidence of local failure in the historical control group was 10% at 1 year, compared to 1.1% at 1 year in the concurrent immunotherapy group (p = 0.025). Factors affected local control included use of concurrent immunotherapy (HR 0.09, p = 0.012), and lowest margin dose delivered to a metastasis (HR 0.8, p = 0.0018). CONCLUSION: Local control and overall survival were both improved in patients receiving concurrent immune checkpoint inhibitors with radiosurgery compared to historical controls. While these data remain to be validated, they suggest that brain metastasis patients may benefit from concurrent use of immunotherapy with SRS.

Fueling the future of neurosurgery: increasing trends in female enrollment expanding the neurosurgical workforce from 2010 to 2019.

OBJECTIVE: Regular reporting on recruitment of women into neurosurgery is a mechanism to track the progress of minority inclusion and diversity. For more than 20 years, half of US medical students have been women, yet a disproportionate minority pursue a career in neurosurgery. The authors previously published data tracking women in neurosurgery for the prior decade from 2000 to 2009, which showed an increasing match rate of women over time, from 18 women matched at the beginning of the decade to 36 matched at the end. They now present updated data on the matriculation of women into neurosurgical residencies across the most recent decade, from 2010 to 2019. METHODS: Public databases from the Association of American Medical Colleges were analyzed for applicants to neurosurgical residency from 2010 to 2019. Demographic data for those matched was obtained from the American Medical Association Masterfile and analyzed for year of match and gender. Secondary outcomes included program location, age, and gap year(s) between medical school and residency. RESULTS: Women made up 18.8% (394/2094) of residents matched into neurosurgery from 2010 to 2019, compared to 12% during the previous decade. There was an increase in overall match rate of 2.2% per year (male + female) from 2010 to 2019, representing the predicted need for expansion of the neurosurgical workforce to meet national needs. Women made up the majority of this expansion, rising by 5.5% over the time period (p = 0.002), compared to men increasing by 1.4% over the time period (p = 0.096). The percentage of women applicants who matched was 34.4%, compared to men at 38.6% (p = 0.009). There was no significant difference in gender with regard to age, number of gap years, or program location. CONCLUSIONS: The number of women matching into neurosurgery has continued to increase across the last 2 decades. Despite this, there remains significant disparity between the number of men and women matching into neurosurgery. Ongoing mitigation of barriers to recruitment of women into neurosurgery is critical. The authors' data highlight the fact that women are important to fueling the expansion of the neurosurgical workforce.

Delayed Imaging Changes 18 Months or Longer After Stereotactic Radiosurgery for Brain Metastases: Necrosis or Progression.

OBJECTIVE: Imaging changes after stereotactic radiosurgery (SRS) can occur for years after treatment, although the available data on the incidence of tumor progression and adverse radiation effects (ARE) are generally limited to the first 2 years after treatment. METHODS: A single-institution retrospective review was conducted of patients who had >18 months of imaging follow-up available. Patients who had ≥1 metastatic brain lesions treated with Gamma Knife SRS were assessed for the time to radiographic progression. Those with progression ≥18 months after the initial treatment were included in the present study. The lesions that progressed were characterized as either ARE or tumor progression based on the tissue diagnosis or imaging characteristics over time. RESULTS: The cumulative incidence of delayed imaging radiographic progression was 35% at 5 years after the initial SRS. The cumulative incidence curves of the time to radiographic progression for lesions determined to be ARE and lesions determined to be tumor progression were not significantly different statistically. The cumulative incidence of delayed ARE and delayed tumor progression was 17% and 16% at 5 years, respectively. Multivariate analysis indicated that the number of metastatic brain lesions present at the initial SRS was the only factor associated with late radiographic progression. CONCLUSIONS: The timing of late radiographic progression does not differ between ARE and tumor progression. The number of metastatic brain lesions at the initial SRS is a risk factor for late radiographic progression.

Brain metastases from renal cell carcinoma: Effects of novel systemic agents on brain metastasis outcomes.

OBJECTIVE: The objective of this study was to examine survival outcomes in 136 patients with renal cell carcinoma with metastases to the brain who were treated with radiation combined with immunotherapy or tyrosine kinase inhibitor compared to those who were treated with radiation therapy alone. METHODS: The Wake Forest Gamma Knife prospective database was searched for all patients with renal cell carcinoma brain metastases. Outcome measurements included overall survival, determined via the Kaplan-Meier Method, and cumulative incidence of local and distant failure, determined using the Fine Gray competing risks analysis with death as a competing risk for the 136 patients included. RESULTS: Overall survival for the entire population at 6 months, 12 months, and 24 months was 67%, 47% and 30%, respectively. For the TKI (non-immunotherapy-treated) population (n = 37), overall survival was 75%, 61%, and 40% at 6 months, 12 months, and 24 months, respectively. For the immunotherapy-treated population (n = 35), overall survival was 85%, 64%, and 50% at 6 months, 12 months, and 24 months, respectively. Overall survival was significantly increased for patients who received radiation with either immunotherapy or TKI (p < 0.0001). CONCLUSION: Prior series of patients with brain metastases of multiple histologies have demonstrated an improvement in the local efficacy of stereotactic radiosurgery when combined with systemic agents. We found that patients treated with targeted agents and patients treated with immunotherapy demonstrated a trend towards improvement over patients treated in the era prior to the advent of either classes of novel therapies.

Five-year survivors from brain metastases treated with stereotactic radiosurgery: Biology, improving treatments, or just plain luck?

Background: Improvements in therapies have led to an increasing number of long-term survivors of brain metastases. The present series compares a population of 5-year survivors of brain metastases to a generalized brain metastases population to assess for factors attributable to long-term survival. Methods: A single institution retrospective review was performed to identify 5-year survivors of brain metastases who received stereotactic radiosurgery (SRS). A historical control population of 737 patients with brain metastases was used to assess similarities and differences between the long-term survivor population and the general population treated with SRS. Results: A total of 98 patients with brain metastases were found to have survived over 60 months. No differences between long-term survivors and controls were identified with regards to the age at first SRS (P = .19), primary cancer distribution (P = .80), and the number of metastases at first SRS (P = .90). Cumulative incidence of neurologic death at 6, 8 and 10 years for the long-term survivor cohort was 4.8%, 16%, and 16% respectively. In the historical controls, cumulative incidence of neurologic death reached a plateau at 40% after 4.9 years. A significant difference in the distribution of burden of disease at the time of the first SRS was found between the 5-year survivors and the control (P = .0049). 58% of 5-year survivors showed no evidence of clinical disease at the last follow-up. Conclusion: Five-year survivors of brain metastases represent a diverse histologic population, suggesting a small population of oligometastatic and indolent cancers exist for each cancer type.

Collagen deposition within brain metastases is associated with leptomeningeal failure after cavity-directed radiosurgery.

Background: Leptomeningeal failure (LMF) represents a devastating progression of disease following resection of brain metastases (BrM). We sought to identify a biomarker at time of BrM resection that predicts for LMF using mass spectrometry-based proteomic analysis of resected BrM and to translate this finding with histochemical assays. Methods: We retrospectively reviewed 39 patients with proteomic data available from resected BrM. We performed an unsupervised analysis with false discovery rate adjustment (FDR) to compare proteomic signature of BrM from patients that developed LMF versus those that did not. Based on proteomic analysis, we applied trichrome stain to a total of 55 patients who specifically underwent resection and adjuvant radiosurgery. We used competing risks regression to assess predictors of LMF. Results: Of 39 patients with proteomic data, FDR revealed type I collagen-alpha-1 (COL1A1, P = .045) was associated with LMF. The degree of trichrome stain in each block correlated with COL1A1 expression (ß = 1.849, P = .001). In a cohort of 55 patients, a higher degree of trichrome staining was associated with an increased hazard of LMF in resected BrM (Hazard Ratio 1.58, 95% CI 1.11-2.26, P = .01). Conclusion: The degree of trichrome staining correlated with COL1A1 and portended a higher risk of LMF in patients with resected brain metastases treated with adjuvant radiosurgery. Collagen deposition and degree of fibrosis may be able to serve as a biomarker for LMF.

Blood-brain barrier disruption defines the extracellular metabolome of live human high-grade gliomas.

The extracellular microenvironment modulates glioma behaviour. It remains unknown if blood-brain barrier disruption merely reflects or functionally supports glioma aggressiveness. We utilised intra-operative microdialysis to sample the extracellular metabolome of radiographically diverse regions of gliomas and evaluated the global extracellular metabolome via ultra-performance liquid chromatography tandem mass spectrometry. Among 162 named metabolites, guanidinoacetate (GAA) was 126.32x higher in enhancing tumour than in adjacent brain. 48 additional metabolites were 2.05-10.18x more abundant in enhancing tumour than brain. With exception of GAA, and 2-hydroxyglutarate in IDH-mutant gliomas, differences between non-enhancing tumour and brain microdialysate were modest and less consistent. The enhancing, but not the non-enhancing glioma metabolome, was significantly enriched for plasma-associated metabolites largely comprising amino acids and carnitines. Our findings suggest that metabolite diffusion through a disrupted blood-brain barrier may largely define the enhancing extracellular glioma metabolome. Future studies will determine how the altered extracellular metabolome impacts glioma behaviour.

Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas.

Genetic alterations help predict the clinical behavior of diffuse gliomas, but some variability remains uncorrelated. Here, we demonstrate that haploinsufficient deletions of chromatin-bound tumor suppressor NFKB inhibitor alpha (NFKBIA) display distinct patterns of occurrence in relation to other genetic markers and are disproportionately present at recurrence. NFKBIA haploinsufficiency is associated with unfavorable patient outcomes, independent of genetic and clinicopathologic predictors. NFKBIA deletions reshape the DNA and histone methylome antipodal to the IDH mutation and induce a transcriptome landscape partly reminiscent of H3K27M mutant pediatric gliomas. In IDH mutant gliomas, NFKBIA deletions are common in tumors with a clinical course similar to that of IDH wild-type tumors. An externally validated nomogram model for estimating individual patient survival in IDH mutant gliomas confirms that NFKBIA deletions predict comparatively brief survival. Thus, NFKBIA haploinsufficiency aligns with distinct epigenome changes, portends a poor prognosis, and should be incorporated into models predicting the disease fate of diffuse gliomas.

Outcomes and Principles of Patient Selection for Laser Interstitial Thermal Therapy for Metastatic Brain Tumor Management: A Multisite Institutional Case Series.

BACKGROUND: Laser interstitial thermal therapy (LITT) is an emerging treatment modality for both primary brain tumors and metastases. We report initial outcomes after LITT for metastatic brain tumors across 3 sites at our institution and discuss potential strategies for optimal patient selection and outcomes. METHODS: International Classification of Diseases, Ninth Revision and Tenth Revision codes were used to identify patients with malignant brain tumors treated via LITT across all 3 Mayo Clinic sites with at least 6 months follow-up. Local control was based on radiologic and clinical evidence. Overall survival was measured from time of receiving LITT until death or end of the study period. RESULTS: Twenty-three patients were treated for progression of a single (n = 21) or multiple (n = 2) previously radiated metastatic lesions and/or radiation necrosis. Median age was 56 years (interquartile range, 47-66.5 years). LITT achieved local control of the lesion in most patients with metastatic tumors or radiation necrosis (n = 18; 81.8%) for the duration of follow-up. One patient did not have local control data available. Thirteen (56.5%) patients remained alive at the end of the study period. No other patients died of their treated disease during the study period; 5 of 10 deaths were attributable to central nervous system progression outside the treated lesion. Although median survival for this cohort has not yet been reached, the current median survival is 16 months (interquartile range, 12-48.5 months) after LITT for metastatic/radiation necrosis lesions. CONCLUSIONS: LITT was associated with sustained local control in 81.8% of patients treated for radiographic progression of metastatic central nervous system disease.

Clinical outcomes of dose-escalated re-irradiation in patients with recurrent high-grade glioma.

Background: Re-irradiation for recurrent gliomas is a controversial treatment option with no clear standard dose or concurrent systemic therapy. Methods: This series represents a single-institution retrospective review of patients treated with re-irradiation for recurrent high-grade glioma. After 2012, patients were commonly offered concurrent bevacizumab as a cytoprotective agent against radiation necrosis. Kaplan-Meier method was used to estimate overall survival and progression-free survival. Cox proportional hazards regression was used to identify factors associated with overall survival and progression-free survival. Results: Between 2001 and 2021, 52 patients underwent re-irradiation for a diagnosis of recurrent high-grade glioma. 36 patients (69.2%) had a histologic diagnosis of glioblastoma at the time of re-irradiation. The median BED10 (biological equivalent dose 10 Gy) of re-irradiation was 53.1 Gy. Twenty-one patients (40.4%) received concurrent bevacizumab with re-irradiation. Median survival for the entire cohort and for glioblastoma at the time of recurrence patients was 6.7 months and 6.0 months, respectively. For patients with glioblastoma at the time of recurrence, completing re-irradiation (HR 0.03, P < .001), use of concurrent bevacizumab (HR 0.3, P = .009), and the BED10 (HR 0.9, P = .005) were predictive of overall survival. Nine patients developed grade 3-5 toxicity; of these, 2 received concurrent bevacizumab and 7 did not (P = .15). Conclusion: High dose re-irradiation with concurrent bevacizumab is feasible in patients with recurrent gliomas. Concurrent bevacizumab and increasing radiation dose may improve survival in patients with recurrent glioblastoma.