An interdisciplinary consensus on the management of brain metastases in patients with renal cell carcinoma.

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.

NCCN Guidelines® Insights: Central Nervous System Cancers, Version 2.2022.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2-3 oligodendroglioma [1p19q codeleted, IDH-mutant], WHO grade 2-4 IDH-mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non-AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding molecular profiling of gliomas.

Optimization of spectrally selective 180° radiofrequency pulse timings in J-difference editing (MEGA) of lactate.

PURPOSE: J-Difference editing (MEGA) provides an effective spectroscopic means of selectively measuring low-concentration metabolites having weakly coupled spins. The fractional inphase and antiphase coherences are determined by the radiofrequency (RF) pulses and inter-RF pulse intervals of the sequence. We examined the timings of the spectrally selective editing 180° pulses (E180) in MEGA-PRESS to maximize the edited signal amplitude in lactate at 3T. METHODS: The time evolution of the lactate spin coherences was analytically and numerically calculated for non-volume localized and single-voxel localized MEGA sequences. Single-voxel localized MEGA-PRESS simulations and phantom experiments were conducted for echo time (TE) 60-160 ms and for all possible integer-millisecond timings of the E180 pulses. Optimized E180 timings of 144, 103, and 109 ms TEs, tailored with simulation and phantom data, were tested in brain tumor patients in vivo. Lactate signals, broadened to singlet linewidths (~6 Hz), were compared between simulation, phantom, and in vivo data. RESULTS: Theoretical and experimental data indicated consistently that the MEGA-edited signal amplitude and width are sensitive to the E180 timings. In volume-localized MEGA, the lactate peak amplitudes in E180-on and difference spectra were maximized at specific E180 timings for individual TEs, largely due to the chemical-shift displacement effects. The E180 timings for maximum lactate peak amplitude were different from those of maximum inphase coherence in in vivo linewidth situations. CONCLUSION: In in vivo MEGA editing, the E180 pulse timings can be effectively used for manipulating the inphase and antiphase coherences and increasing the edited signal amplitude, following TE optimization.

Spectral fitting strategy to overcome the overlap between 2-hydroxyglutarate and lipid resonances at 2.25 ppm.

PURPOSE: 1 H MRS provides a noninvasive tool for identifying mutations in isocitrate dehydrogenase (IDH). Quantification of the prominent 2-hydroxyglutarate (2HG) resonance at 2.25 ppm is often confounded by the lipid resonance at the same frequency in tumors with elevated lipids. We propose a new spectral fitting approach to separate these overlapped signals, therefore, improving 2HG evaluation. METHODS: TE 97 ms PRESS was acquired at 3T from 42 glioma patients. New lipid basis sets were created, in which the small lipid 2.25-ppm signal strength was preset with reference to the lipid signal at 0.9 ppm, incorporating published fat relaxation data. LCModel fitting using the new lipid bases (Fitting method 2) was conducted along with fitting using the LCModel built-in lipid basis set (Fitting method 1), in which the lipid 2.25-ppm signal is assessed with reference to the lipid 1.3-ppm signal. In-house basis spectra of low-molecular-weight metabolites were used in both fitting methods. RESULTS: Fitting method 2 showed marked improvement in identifying IDH mutational status compared with Fitting method 1. 2HG estimates from Fitting method 2 were overall smaller than those from Fitting method 1, which was because of differential assignment of the signal at 2.25 ppm to lipids. In receiver operating characteristic analysis, Fitting method 2 provided a complete distinction between IDH mutation and wild-type whereas Fitting method 1 did not. CONCLUSION: The data suggest that 1 H MR spectral fitting using the new lipid basis set provides a robust fitting strategy that improves 2HG evaluation in brain tumors with elevated lipids.

Thalamic gliomas in adults: a systematic review of clinical characteristics, treatment strategies, and survival outcomes.

PURPOSE: Thalamic gliomas are rare neoplasms that pose significant surgical challenges. The literature is limited to single-institution retrospective case series. We systematically review the literature and describe the clinical characteristics, treatment strategies, and survival outcomes of adult thalamic gliomas. METHODS: Relevant articles were identified on PubMed, Scopus, and Cochrane databases. Papers containing cases of adult thalamic gliomas with clinical outcome data were included. A comprehensive review of clinical characteristics and survival analysis was conducted. RESULTS: We included 25 studies comprising 617 patients. The median age was 45 years (male = 58.6%). Glioblastoma was the most frequent histological type (47.2%), and 82 tumors were H3 K27M-mutant. Motor deficit was the most common presenting symptom (51.8%). Surgical resection was performed in 69.1% of cases while adjuvant chemotherapy and radiotherapy were administered in 56.3% and 72.6%, respectively. Other treatments included laser interstitial thermal therapy, which was performed in 15 patients (2.4%). The lesion laterality (P = 0.754) and the surgical approach (P = 0.111) did not correlate with overall survival. The median progression-free survival was 9 months, and the overall two-year survival rate was 19.7%. The two-year survival rates of low-grade and high-grade thalamic gliomas were 31.0% and 16.5%, respectively. H3 K27M-mutant gliomas showed worse overall survival (P = 0.017). CONCLUSION: Adult thalamic gliomas are associated with poor survival. Complete surgical resection is associated with improved survival rates but is not always feasible. H3 K27M mutation is associated with worse survival and a more aggressive approach should be considered for mutant neoplasms.

Advanced MRI techniques for transcranial high intensity focused ultrasound targeting.

Magnetic resonance guided high intensity focused ultrasound is a novel, non-invasive, image-guided procedure that is able to ablate intracranial tissue with submillimetre precision. It is currently FDA approved for essential tremor and tremor dominant Parkinson's disease. The aim of this update is to review the limitations of current landmark-based targeting techniques of the ventral intermediate nucleus and demonstrate the role of emerging imaging techniques that are relevant for both magnetic resonance guided high intensity focused ultrasound and deep brain stimulation. A significant limitation of standard MRI sequences is that the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei cannot be clearly identified. This paper provides original, annotated images demarcating the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei on advanced MRI sequences such as fast grey matter acquisition T1 inversion recovery, quantitative susceptibility mapping, susceptibility weighted imaging, and diffusion tensor imaging tractography. Additionally, the paper reviews clinical efficacy of targeting with these novel MRI techniques when compared to current established landmark-based targeting techniques. The paper has widespread applicability to both deep brain stimulation and magnetic resonance guided high intensity focused ultrasound.

In vivo MRS measurement of 2-hydroxyglutarate in patient-derived IDH-mutant xenograft mouse models versus glioma patients.

PURPOSE: To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2-hydroxyglutarate (2HG) production between the preclinical model and patients. METHODS: Five patient-derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental-tumor patients. Spectral fitting was performed with LCModel using in-house basis spectra. Metabolite levels were quantified with reference to water. RESULTS: The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short-TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. CONCLUSION: The similarity of 2HG production between PDX models and parental-tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH-mutation associated metabolic reprogramming.

3D high-resolution imaging of 2-hydroxyglutarate in glioma patients using DRAG-EPSI at 3T in vivo.

PURPOSE: To develop 3D high-resolution imaging of 2-hydroxyglutarate (2HG) at 3T in vivo. METHODS: Echo-planar spectroscopic imaging with dual-readout alternated-gradients (DRAG-EPSI), which was recently reported for 2D imaging of 2HG at 7T, was tested for 3D imaging of 2HG at 3T. The frequency drifts and acoustic noise induced by DRAG-EPSI were investigated in comparison with conventional EPSI. Four patients with IDH-mutant gliomas were enrolled for 3D imaging of 2HG and other metabolites. A previously reported 2HG-tailored TE 97-ms PRESS sequence preceded the DRAG-EPSI readout gradients. Unsuppressed water, acquired with EPSI, was used as reference for multi-channel combination, eddy-current compensation, and metabolite quantification. Spectral fitting was conducted with the LCModel using in-house basis sets. RESULTS: With gradient strength of 4 mT/m and slew rate of 20 mT/m/ms, DRAG-EPSI produced frequency drifts smaller by 5.5-fold and acoustic noise lower by 25 dB compared to conventional EPSI. In a 19-min scan, 3D DRAG-EPSI provided images of 2HG with precision (CRLB <10%) at a resolution of 10 × 10 × 10 mm3 for a field of view of 240 × 180 × 80 mm3 . 2HG was estimated to be 5 mM in a pre-treatment patient. In 3 post-surgery patients, 2HG estimates were 3-6 mM, and the 2HG distribution was different from the water-T2 image pattern or highly concentrated in the post-contrast enhancing region. CONCLUSION: Together with 2HG-optimized PRESS, DRAG-EPSI provides an effective tool for reliable 3D high-resolution imaging of 2HG at 3T in vivo.

Echo-planar spectroscopic imaging with dual-readout alternated gradients (DRAG-EPSI) at 7 T: Application for 2-hydroxyglutarate imaging in glioma patients.

PURPOSE: To develop echo-planar spectroscopic imaging (EPSI) with large spectral width and accomplish high-resolution imaging of 2-hydroxyglutarate (2HG) at 7 T. METHODS: We designed a new EPSI readout scheme at 7 T. Data were recorded with dual-readout alternated gradients and combined according to the gradient polarity. Following validation of its performance in phantoms, the new readout scheme, together with previously reported 2HG-optimized magnetic resonance spectroscopy (point-resolved spectroscopy echo time of 78 ms), was used for time-efficient and high-resolution imaging of 2HG and other metabolites in five glioma patients before treatment. Unsuppressed water, acquired with EPSI, was used as reference for multichannel combination, eddy-current compensation, and metabolite quantification. Spectral fitting was conducted with the LCModel using in-house calculated basis sets. RESULTS: Using a readout gradient strength of 9.5 mT/m and slew rate of 90 mT/m/ms, dual-readout alternated gradients EPSI permitted 1638-Hz spectral width with 6 × 6 mm2 in-plane resolution at 7 T. Phantom data indicated that dual-readout alternated gradients EPSI provides proper metabolite signals and induces much less frequency drifts than conventional EPSI. For a spatial resolution of 0.5 mL, 2HG was detected in tumors with precision (Cramer-Rao lower bound < 10%). The 2HG was estimated to be 2.3 to 3.3 mM in tumors of three patients with biopsy-proven isocitrate dehydrogenase (IDH) mutant gliomas. The 2HG was undetectable in an IDH wild-type glioblastoma. For a radiographically suggested glioma, the estimated 2HG of 2.3 ± 0.2 mM (Cramer-Rao lower bound < 10%) indicated that the lesion may be an IDH mutant glioma. CONCLUSIONS: The data indicated that the dual-readout alternated gradients EPSI can provide reliable high-resolution imaging of 2HG in glioma patients at 7 T in vivo. Magn Reson Med 79:1851-1861, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Acute severe mitral regurgitation after blunt chest trauma.

Myocardial contusion and aortic injury are well-known cardiac complications of blunt chest trauma, but valvular injury is rare. Traumatic valve injuries most commonly involve the aortic valve, with isolated mitral valve injury being quite rare. We report a case of acute severe mitral regurgitation due to ruptured chordae tendineae requiring surgical repair following a motor vehicle accident.

Measurement of glycine in healthy and tumorous brain by triple-refocusing MRS at 3 T in vivo.

Glycine (Gly) has been implicated in several neurological disorders, including malignant brain tumors. The precise measurement of Gly is challenging largely as a result of the spectral overlap with myo-inositol (mI). We report a new triple-refocusing sequence for the reliable co-detection of Gly and mI at 3 T and for the evaluation of Gly in healthy and tumorous brain. The sequence parameters were optimized with density-matrix simulations and phantom validation. With a total TE of 134 ms, the sequence gave complete suppression of the mI signal between 3.5 and 3.6 ppm and, consequently, well-defined Gly (3.55 ppm) and mI (3.64 ppm) peaks. In vivo 1 H magnetic resonance spectroscopy (MRS) data were acquired from the gray matter (GM)-dominant medial occipital and white matter (WM)-dominant left parietal regions in six healthy subjects, and analyzed with LCModel using in-house-calculated basis spectra. Tissue segmentation was performed to obtain the GM and WM contents within the MRS voxels. Metabolites were quantified with reference to GM-rich medial occipital total creatine at 8 mM. The Gly and mI concentrations were estimated to be 0.63 ± 0.05 and 8.6 ± 0.6 mM for the medial occipital and 0.34 ± 0.05 and 5.3 ± 0.8 mM for the left parietal regions, respectively. From linear regression of the metabolite estimates versus fractional GM content, the concentration ratios between pure GM and pure WM were estimated to be 2.6 and 2.1 for Gly and mI, respectively. Clinical application of the optimized sequence was performed in four subjects with brain tumor. The Gly levels in tumors were higher than those of healthy brain. Gly elevation was more extensive in a post-contrast enhancing region than in a non-enhancing region. The data indicate that the optimized triple-refocusing sequence may provide reliable co-detection of Gly and mI, and alterations of Gly in brain tumors can be precisely evaluated.

Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.

Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.

Radiolabeling of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with biotinylated F-18 prosthetic groups and imaging of their delivery to the brain with positron emission tomography.

The avidin-biotin interaction permits rapid and nearly irreversible noncovalent linkage between biotinylated molecules and avidin-modified substrates. We designed a biotinylated radioligand intended for use in the detection of avidin-modified polymer nanoparticles in tissue with positron emission tomography (PET). Using an F-18 labeled prosthetic group, [(18)F]4-fluorobenzylamine, and a commercially available biotin derivate, NHS-PEG4-biotin, [(18)F]-fluorobenzylamide-poly(ethylene glycol)4-biotin ([(18)F]NPB4) was prepared with high purity and specific activity. The attachment of the [(18)F]NPB4 radioligand to avidin-modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles was tested by using PET imaging to measure the kinetics of convection-enhanced delivery (CED) of nanoparticles of varying size to the rat brain. PET imaging enabled the direct observation of nanoparticle delivery by measurement of the spatial volume of distribution of radiolabeled nanoparticles as a function of time, both during and after the infusion. This work thus validates new methods for radiolabeling PEG-biotin derivatives and also provides insight into the fate of nanoparticles that have been infused directly into the brain.

The anatomy of the aging aorta.

Age-associated changes to aortic anatomy and physiology have an effect on hemodynamics and play a large role in the genesis of cardiovascular pathologies including atherosclerosis, congestive heart failure, and aortic aneurysm. Despite their recognized role in hemodynamics, the complete mechanism for aortic aging is still not clear and their full effects on cardiovascular pathologies are unknown. This article serves as a review of the normal anatomy of the human aorta and its known age-associated changes.

Benjamin Hobson (1816-1873): His work as a medical missionary and influence on the practice of medicine and knowledge of anatomy in China and Japan.

Benjamin Hobson was a British missionary and physician who lived in China for twenty years. He founded multiple hospitals in Southern China and used his knowledge of Western medicine to educate Chinese doctors. He wrote several medical textbooks in Chinese of which the first was the A New Theory of the Body (1851). The illustrations from his book were renditions and originals from William Cheselden's Anatomical Tables (1730) and Osteographia (1733).The Japanese version of Hobson's work appeared in Japan during the bakumatsu period (1853-1867), when Japan ended its isolationist foreign policy and began opening itself to the West. During this time, many books from Europe were translated into Chinese to then find their way into Japan. The Chinese anatomy textbook by Hobson (Quanti Xinlun) was instrumental in introducing Western anatomic knowledge to the Chinese and thereby catalyzing a significant change in the practice of medicine in China. A Japanese translation (Zen Tai Shin Ron) of this text published in the 19th century is reviewed.

Two-Stage Training Framework Using Multicontrast MRI Radiomics for IDH Mutation Status Prediction in Glioma.

Purpose To develop a radiomics framework for preoperative MRI-based prediction of isocitrate dehydrogenase (IDH) mutation status, a crucial glioma prognostic indicator. Materials and Methods Radiomics features (shape, first-order statistics, and texture) were extracted from the whole tumor or the combination of nonenhancing, necrosis, and edema regions. Segmentation masks were obtained via the federated tumor segmentation tool or the original data source. Boruta, a wrapper-based feature selection algorithm, identified relevant features. Addressing the imbalance between mutated and wild-type cases, multiple prediction models were trained on balanced data subsets using random forest or XGBoost and assembled to build the final classifier. The framework was evaluated using retrospective MRI scans from three public datasets (The Cancer Imaging Archive [TCIA, 227 patients], the University of California San Francisco Preoperative Diffuse Glioma MRI dataset [UCSF, 495 patients], and the Erasmus Glioma Database [EGD, 456 patients]) and internal datasets collected from the University of Texas Southwestern Medical Center (UTSW, 356 patients), New York University (NYU, 136 patients), and University of Wisconsin-Madison (UWM, 174 patients). TCIA and UTSW served as separate training sets, while the remaining data constituted the test set (1617 or 1488 testing cases, respectively). Results The best performing models trained on the TCIA dataset achieved area under the receiver operating characteristic curve (AUC) values of 0.89 for UTSW, 0.86 for NYU, 0.93 for UWM, 0.94 for UCSF, and 0.88 for EGD test sets. The best performing models trained on the UTSW dataset achieved slightly higher AUCs: 0.92 for TCIA, 0.88 for NYU, 0.96 for UWM, 0.93 for UCSF, and 0.90 for EGD. Conclusion This MRI radiomics-based framework shows promise for accurate preoperative prediction of IDH mutation status in patients with glioma. Keywords: Glioma, Isocitrate Dehydrogenase Mutation, IDH Mutation, Radiomics, MRI Supplemental material is available for this article. Published under a CC BY 4.0 license. See also commentary by Moassefi and Erickson in this issue.

Synthesizing 3D Multi-Contrast Brain Tumor MRIs Using Tumor Mask Conditioning.

Data scarcity and data imbalance are two major challenges in training deep learning models on medical images, such as brain tumor MRI data. The recent advancements in generative artificial intelligence have opened new possibilities for synthetically generating MRI data, including brain tumor MRI scans. This approach can be a potential solution to mitigate the data scarcity problem and enhance training data availability. This work focused on adapting the 2D latent diffusion models to generate 3D multi-contrast brain tumor MRI data with a tumor mask as the condition. The framework comprises two components: a 3D autoencoder model for perceptual compression and a conditional 3D Diffusion Probabilistic Model (DPM) for generating high-quality and diverse multi-contrast brain tumor MRI samples, guided by a conditional tumor mask. Unlike existing works that focused on generating either 2D multi-contrast or 3D single-contrast MRI samples, our models generate multi-contrast 3D MRI samples. We also integrated a conditional module within the UNet backbone of the DPM to capture the semantic class-dependent data distribution driven by the provided tumor mask to generate MRI brain tumor samples based on a specific brain tumor mask. We trained our models using two brain tumor datasets: The Cancer Genome Atlas (TCGA) public dataset and an internal dataset from the University of Texas Southwestern Medical Center (UTSW). The models were able to generate high-quality 3D multi-contrast brain tumor MRI samples with the tumor location aligned by the input condition mask. The quality of the generated images was evaluated using the Fréchet Inception Distance (FID) score. This work has the potential to mitigate the scarcity of brain tumor data and improve the performance of deep learning models involving brain tumor MRI data.

Single-Fraction Versus Fractionated Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM International Multicenter Cohort Study.

PURPOSE: Preoperative stereotactic radiosurgery (SRS) is a feasible alternative to postoperative SRS for resected brain metastases (BM). Most reported studies of preoperative SRS used single-fraction SRS (SF-SRS). The goal of this study was to compare outcomes and toxicity of preoperative SF-SRS with multifraction (3-5 fractions) SRS (MF-SRS) in a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM). METHODS AND MATERIALS: Patients with BM from solid cancers, of which at least 1 lesion was treated with preoperative SRS followed by planned resection, were included from 8 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included prior or planned whole brain radiation therapy. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Propensity score matched (PSM) analyses were performed. RESULTS: The study cohort included 404 patients with 416 resected index lesions, of which SF-SRS and MF-SRS were used for 317 (78.5%) and 87 patients (21.5%), respectively. Median dose was 15 Gy in 1 fraction for SF-SRS and 24 Gy in 3 fractions for MF-SRS. Univariable analysis demonstrated that SF-SRS was associated with higher cavity local recurrence (LR) compared with MF-SRS (2-year: 16.3% vs 2.9%; P = .004), which was also demonstrated in multivariable analysis. PSM yielded 81 matched pairs (n = 162). PSM analysis also demonstrated significantly higher rate of cavity LR with SF-SRS (2-year: 19.8% vs 3.3%; P = .003). There was no difference in adverse radiation effect, meningeal disease, or overall survival between cohorts in either analysis. CONCLUSIONS: Preoperative MF-SRS was associated with significantly reduced risk of cavity LR in both the unmatched and PSM analyses. There was no difference in adverse radiation effect, meningeal disease, or overall survival based on fractionation. MF-SRS may be a preferred option for neoadjuvant radiation therapy of resected BMs. Additional confirmatory studies are needed. A phase 3 randomized trial of single-fraction preoperative versus postoperative SRS (NRG-BN012) is ongoing (NCT05438212).