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e14017 Background: The role of stereotactic radiosurgery (SRS) is well established in the setting of one to four brain metastases (BM), offering effective control with reduced neurocognitive toxicity compared with whole-brain radiotherapy (WBRT). However, for patients with five or more BM, the optimal radiation strategy remains uncertain, and comparative outcome data are limited. We performed a systematic review and meta-analysis to compare overall survival (OS) between SRS and WBRT in patients with ≥ 5 BM. Methods: A systematic review was conducted to identify comparative studies of SRS versus WBRT in patients with ≥5 brain metastases. Retrospective and prospective studies reporting median OS with available cohort sizes were included. Comparative survival was summarized using pooled ratios of median survival within a random-effects meta-analytic framework. Results: Five comparative studies were included, comprising 226 patients treated with SRS and 261 treated with WBRT, including both retrospective and prospective cohorts. Sample-size–weighted summary (with reported medians) showed median OS was 8.1 months with SRS and 7.7 months with WBRT. Pooled analysis demonstrated no significant difference in OS between treatment strategies (ratio of median survival, 1.03; 95% CI, 0.73–1.46; p = 0.81). Conclusions: Among patients with ≥5 BM, SRS and WBRT were associated with comparable OS. These data suggest that OS alone may not guide treatment choice in this population, emphasizing the importance of careful patient selection. As focal therapies are increasingly incorporated into clinical practice for patients with higher intracranial disease burden, prospective, multi-institutional randomized clinical trials are needed to better define optimal management strategies. Summary of included studies reporting median overall survival (OS). Study Study Design SRS (n) WBRT (n) Median OS in SRS cohort (months) Median OS in WBRT cohort (months) Kim et al., 2009 Retrospective 29 39 5.6 7.2 Mizuno et al., 2019 Retrospective 24 20 7.3 7 .2 Li et al., 2020 Prospective, randomized 35 34 7.8 8.9 Bodensohn et al., 2023 Prospective, non-randomized 40 70 10.4 6.5 Aizer et al., 2025 Prospective, randomized 98 98 8.3 8.5

e14016 Background: Postoperative stereotactic radiosurgery (SRS) is utilized following resection of brain metastases (BM), however use is limited by target delineation uncertainty and an increased risk of leptomeningeal disease (LMD). Preoperative SRS allows for precise targeting and is being increasingly utilized in treatment paradigms of resectable BM. Reported outcomes across studies are promising and there are several phase 3 trials which are underway. Therefore, we pooled multiple studies and conducted a meta-analysis to estimate 1-year local control (LC), LMD incidence, and overall survival (OS) following single-fraction preoperative SRS for resectable BM. Methods: We systematically searched PubMed, Embase, and Scopus to identify studies of single-fraction preoperative SRS for resectable BM. For each cohort, data for 1-year LC, 1-year LMD, and 1-year OS, along with corresponding sample sizes, were extracted. A proportion-based meta-analysis was performed to derive pooled estimates and 95% confidence intervals (CIs), with between-study heterogeneity quantified using I². Results: Ten studies published between 2016 and 2025, including both prospective trials and retrospective cohorts, met the inclusion criteria. There were 617 patients treated with single-fraction preoperative SRS. The median age was 60.8 years (range 58-65 years), and the median prescribed dose was 15.8 Gy (range 14.5-17.0 Gy). The pooled 1-year LC rate was 81.9% (95% CI, 76.9-85.9; I² = 43.4%). The pooled 1-year incidence of LMD was 4.6% (95% CI, 2.8-7.4; I² = 0%), and the pooled 1-year OS rate was 60.2% (95% CI, 55.5-64.8; I² = 0%). Sensitivity analyses showed stable pooled estimates, with no single study driving the results. Conclusions: Single-fraction preoperative SRS is associated with low rates of LMD and acceptable LC and OS. In the context of historically reported postoperative SRS outcomes, these results suggest that preoperative SRS represents a promising strategy in selected patients. Randomized trials are needed to define the comparative role and optimal patient selection for preoperative SRS, with ongoing studies (NCT05341739, NCT03741673) expected to clarify its role in the management of resectable BM. Study characteristics and reported outcomes of single-fraction preoperative SRS for BM. Study Study design Number of patients Median age (years) Median dose (Gy) 1-year LTC (%) 1-year LMD (%) 1 year OS (%) Agarwal, 2024 Trial 47 59 NR NR 4.8 NR Higazy, 2025 Trial 35 61 17 82 2.86 NR Li, 2022 Retrospective 24 64 NR 87.6 NR NR Mallela, 2024 Retrospective 26 64.5 NR 77.2 NR NR Murphy, 2024 Trial 35 63 NR 76.6 NR 59 Patel, 2018 Retrospective 12 57.5 NR 49.1 10 74.1 Patel, 2016 Retrospective 66 58.2 14.5 84.1 3.2 NR Prabhu, 2025 Retrospective 124 NR 17 87.2 1.7 64.5 Prabhu, 2025 Retrospective 183 NR 15 86.4 7.3 58.1 Prabhu, 2020 Retrospective 65 NR NR 77.1 4.2 56.3

Background: MELAS is a rare mitochondrial disorder characterized by multisystem involvement, including stroke-like episodes, seizures, and cardiomyopathy. Cardiac involvement in MELAS may include left ventricular dysfunction, arrhythmias, and structural abnormalities, yet the occurrence of cardioembolic stroke as a direct consequence of these manifestations is exceedingly rare. To date, no literature has clearly described this association. Case Presentation: A male in his twenties with known MELAS syndrome, epilepsy, and heart failure with reduced ejection fraction (EF 25%) presented with acute right hemiparesis and aphasia. Investigations: CT angiography and CT perfusion revealed reduced opacification in the left MCA bifurcation and a left M2 thrombus (Figure 1A). The contrast echocardiogram showed a normal-sized left ventricle with severely reduced ejection fraction (25%, down from 30% six months prior), diffuse hypokinesis, grade III diastolic dysfunction, and a left ventricular thrombus, with no patent foramen ovale. Treatment: Given the high suspicion for cardioembolic stroke, the patient received intravenous tenecteplase within the 3-hour window. Mechanical thrombectomy was planned but aborted due to spontaneous recanalization. Post-thrombolytic angiography confirmed reperfusion of the left MCA with residual distal M3 thrombus (Figure 1B).MRI confirmed infarcts in the left MCA distribution and right precentral gyrus, with no evidence of hemorrhagic transformation. Anticoagulation was initiated for secondary prevention. Statins were withheld due to concerns about mitochondrial toxicity. Follow-up: On a 3-month follow-up, the patient remained neurologically stable and continued oral anticoagulation without recurrent events. Discussion: The clinical scenario posed a diagnostic challenge—stroke-like episodes in MELAS are metabolic and typically non-territorial. However, an LV thrombus, territorial infarction, and perfusion mismatch pointed to an ischemic etiology. Timely thrombolysis led to significant neurological recovery. This case highlights the importance of distinguishing cardioembolic stroke from mitochondrial stroke-like events, especially in patients with known cardiac involvement. Conclusion: In MELAS patients with cardiac dysfunction, cardioembolic stroke must be considered when clinical and imaging findings suggest a vascular event. Early recognition and intervention, including thrombolysis, can lead to favorable outcomes.