Purpose Prior studies have mixed conclusions about the efficacy and central nervous system (CNS) toxicity profile of combining radiosurgery with anti-programed cell death 1 (PD-1) immune checkpoint inhibition (ICI) for brain metastases. This study evaluates the safety and efficacy of combined radiosurgery and anti-PD-1 ICI for melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) brain metastases (BM). Methods and Materials Forty-one patients with 153 radiation naïve melanoma BM and 33 patients with 118 BM of NSCLC and RCC origin from 2014 through 2019 received radiosurgery and either anti PD-1 receptor inhibition or anti PD-L1 inhibition targeting the PD-1 ligand with less than 4 months separating either therapy. Similar to Radiation Therapy Oncology Group 9005, high-grade CNS toxicity was defined as irreversible grade 3 or any grade 4/5 neurologic event. Salvage resection revealing necrosis and viable tumor was considered grade 4 toxicity and local failure. An increase in greatest cross-sectional diameter of 25% on contrasted magnetic resonance imaging was designated as a local failure. Results Median follow-up was 10 months (range, 1-41 months). Local control was estimated to be 90.3% at 1 year. Distant control was 38.8% at 1 year, and neither local nor distant control were significantly influenced by limiting steroids to the day of treatment ( P = .55, .52 respectively). One-year freedom from high-grade toxicity was 90.4% for patients and 94.6% for tumors. Though melanoma accounted for 41 (55%) patients and 153 (56%) tumors, it accounted for all high-grade toxicities ( P = .03). These patients had some combination of high tumor burden, aggressive steroid taper, and treatment with ipilimumab. Conclusions Stereotactic radiosurgery combined with anti-PD-1 ICI appears to result in a high rate of local tumor control and a low rate of high-grade CNS toxicity, comparable to historical series with radiosurgery alone. High-grade toxicity is more likely in melanoma than RCC and NSCLC. Coming prospective studies will shed light on further questions about treatment timing, steroids, and response.

BACKGROUND AND OBJECTIVES: There is wide variation in treatment planning strategy for central nervous system (CNS) stereotactic radiosurgery. We sought to understand what relationships exist between intratumor maximum dose and local control (LC) or CNS toxicity, and dosimetric effects of constraining hotspots on plan quality of multiple metastases volumetric modulated arc therapy radiosurgery plans. METHODS: We captured brain metastases from 2015 to 2017 treated with single-isocenter volumetric modulated arc therapy radiosurgery. Included tumors received single-fraction stereotactic radiosurgery, had no previous surgery or radiation, and available follow-up imaging. Our criterion for local failure was 25% increase in tumor diameter on follow-up MRI or pathologic confirmation of tumor recurrence. We defined significant CNS toxicity as Radiation Therapy Oncology Group irreversible Grade 3 or higher. We performed univariate and multivariate analyses evaluating factors affecting LC. We examined 10 stereotactic radiosurgery plans with prescriptions of 18 Gy to all targets originally planned without constraints on the maximum dose within the tumor. We replanned each with a constraint of Dmax 120%. We compared V50%, mean brain dose, and Dmax between plans. RESULTS: Five hundred and thirty tumors in 116 patients were available for analysis. Median prescription dose was 18 Gy, and median prescription isodose line (IDL) was 73%. Kaplan-Meier estimate of 12-month LC only tumor volume (HR 1.43 [1.22-1.68] P < .001) was predictive of local failure on univariate analysis; prescription IDL and histology were not. In multivariate analysis, tumor volume impacted local failure (HR 1.43 [1.22-1.69] P < .001) but prescription IDL did not (HR 0.95 [0.86-1.05] P = .288). Only a single grade 3 and 2 grade 4 toxicities were observed; tumor volume was predictive of CNS toxicity (HR 1.58 [1.25-2.00]; P < .001), whereas prescription IDL was not (HR 1.01 [0.87-1.17] P = .940). CONCLUSION: The prescription isodose line had no impact on local tumor control or CNS toxicity. Penalizing radiosurgery hotspots resulted in worse radiosurgery plans with poorer gradient. Limiting maximum dose in gross tumor causes increased collateral exposure to surrounding tissue and should be avoided.

Acute inflammatory response is an active process coincides with resolving phase in myocardial infarction (MI), which enables the leukocyte directed clearance, if failed, lead to non‐resolving inflammation. Leukocyte, particularly macrophages are known to biosynthesize maresin‐1 (MaR1) post‐MI. However, the role of exogenous MaR1 is unclear in heart failure (HF) settings. Young 8–12 week‐old C57BL/6J male mice were subjected to coronary ligation and were treated with MaR1 (4μg/kg; subcutaneous) 3 hours post‐MI for day 1 or until day 5. Post‐MI saline‐injected mice served as MI‐control and no‐MI mice as d0 naïve controls. MaR1‐injected mice reduced LV and lung mass‐to‐body weight ratios compare to MI‐controls indicating decreased edematous hypertrophy and lung edema post‐MI d5. Comprehensive heart function analysis indicate reduced end‐diastolic volume (EDD) and end systolic volume (ESD) in MaR1‐injected mice thereby improved fractional shortening and global longitudinal strain compared to MI‐control at d5 post‐MI. MaR1 activated N‐formyl peptide receptor 2 (FPR2; p<0.05) expression in LV infarct compared to MI‐control group. Leukocyte trafficking analysis revealed that MaR1‐injected mice expedited neutrophil clearance (CD11b+/F4/80−/Ly6G+; 1.2±0.4%) from the infarcted heart compared with MI‐control (4.1±0.3%). Post‐MI, MaR1‐injected mice increased proresolving CD11b+/F480+/Ly6Clo macrophages at post‐MI day 5. MaR1 injected mice displayed higher levels of pro‐resolving markers Mrc‐1 (3.6±.5 fold; p<0.05) and Arg‐1 (5.2±1 fold; p<0.05) at day 1 and day 5 post‐MI compared with MI‐control. MaR1 showed multifactorial benefits by reducing cardiorenal inflammation and reduced NGAL and increased nephrin expression compared to MI‐control is an indicative of limited cardiorenal pathology post‐MI. In conclusion, MaR1 activated resolution sensor FPR2 to facilitate proresolving actions, thereby improved cardiac function and attenuated cardiorenal inflammation in HF pathophysiology.Support or Funding InformationHL132989 to GVH, 16POST31000008 to VKThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

BACKGROUND: Current standard of care (SOC) management of the brain differs between non-small cell lung cancer (NSCLC) & small cell lung cancer (SCLC). For SCLC, WBRT is considered SOC, even for solitary metastasis. In the setting of no-known metastases, prophylactic cranial irradiation (PCI) is considered SOC. SRS is occasionally utilized in SCLC, e.g. in setting of limited metastasis after WBRT/PCI, or limited metastasis after excellent systemic response to extracranial therapy, or if patient declines WBRT. In this study, we sought to understand more about the nature and outcomes of patients with SCLC who received intracranial SRS at our institution. METHODS: We reviewed radiosurgery treatments from 2005 thru 2019 for patients with SCLC who received SRS. Variables included were: time interval between diagnosis/SRS and death, prior WBRT/ PCI, number of targets, performance status, modality (GK or linac), prior surgery, and available follow-up. RESULTS: We identified 92 SRS treatments among 74 patients. 30 received upfront SRS, the remainder as post-WBRT/PCI salvage. Median survival after initial diagnosis was 22.0 months (min = 6.6, max 55.4). Median survival after first SRS was 6.1 months (min = 0.5, max = 40.4). Median recorded KPS was 75.6. Mean number of mets treated was 3.4 (min = 1, max = 12). Prescription dose range was 12 to 20Gy in single fraction, and 25 to 30Gy in five fraction treatment. 53 treatments were performed on Gamma Knife, 37 with linear accelerator. Four patients were treated post-operatively, one patient was treated pre-operatively. CONCLUSIONS: Survival in our cohort of SCLC patients receiving intracranial SRS compared favorably with historical SCLC controls (8-13mo after dx). Future work will seek to clarify whether there is a difference in brain metastasis velocity between patients treated with upfront PCI/WBRT or SRS, and also seek to address the minimum necessary dose to control SCLC metastases.