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The limited success of immune checkpoint inhibitors (ICIs) in the adjuvant setting for glioblastoma highlights the need to explore administering ICIs prior to immunosuppressive radiation. To address the feasibility and safety of this approach, we conducted a phase I study in patients with newly diagnosed Grade 3 and Grade 4 gliomas. Patients received nivolumab 300 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until disease progression or unacceptable toxicity. Fifteen patients were treated, with four patients on dexamethasone at treatment initiation and five tumors having MGMT promoter methylated. Treatment began a median of 38 days post-surgery. The most common treatment-related adverse events (AEs) were rash, pruritus, fatigue, nausea, and anorexia. Grade 3 AEs were lipase increased ( n  = 2), anorexia ( n  = 1), pruritus ( n  = 1), and rash ( n  = 3), and one Grade 4 cerebral edema occurred. Median progression-free survival (mPFS) was 1.3 months and median overall survival (mOS) was 19.3 months (95% CI, 12.9-NA). Three patients deferred conventional radiochemotherapy for over seven months while ten eventually received it. Progressing tumors tended to exhibit higher LAG-3 levels at baseline compared to shrinking tumors. Analysis of paired pre-treatment and post-progression tissue ( n  = 5) showed trends of up-regulated TGF-β, ERBB2, ERBB3, and ERBB4 signaling pathways, downregulated PPAR signaling, decreased B cell proportions, and increased monocytes proportions in tumors post-treatment. We show nivolumab plus ipilimumab can be safely administered prior to standard radiotherapy for newly diagnosed gliomas and is operationally feasible. Clinicaltrials.gov NCT03425292 registered February 7, 2018.

Purpose: Accurate and automated early survival prediction is critical for patients with glioblastoma (GBM) as their poor prognosis requires timely treatment decision-making. To address this need, we developed a deep learning (DL)-based end-to-end workflow for GBM overall survival (OS) prediction using pre-resection basic structural multiparametric magnetic resonance images (Bas-mpMRI) with a multi-institutional public dataset and evaluated it with an independent dataset of patients on a prospective institutional clinical trial., Materials and Methods: The proposed end-to-end workflow includes a skull-stripping model, a GBM sub-region segmentation model and an ensemble learning-based OS prediction model. The segmentation model utilizes skull-stripped Bas-mpMRIs to segment three GBM sub-regions. The segmented GBM is fed into the contrastive learning-based OS prediction model to classify the patients into different survival groups. Our datasets include both a multi-institutional public dataset from Medical Image Computing and Computer Assisted Intervention (MICCAI) Brain Tumor Segmentation (BraTS) challenge 2020 with 235 patients, and an institutional dataset from a 5-fraction SRS clinical trial with 19 GBM patients. Each data entry consists of pre-operative Bas-mpMRIs, survival days and patient ages. Basic clinical characteristics are also available for SRS clinical trial data. The multi-institutional public dataset was used for workflow establishing (90% of data) and initial validation (10% of data). The validated workflow was then evaluated on the institutional clinical trial data., Results: Our proposed OS prediction workflow achieved an area under the curve (AUC) of 0.86 on the public dataset and 0.72 on the institutional clinical trial dataset to classify patients into 2 OS classes as long-survivors (>12 months) and short-survivors (<12 months), despite the large variation in Bas-mpMRI protocols. In addition, as part of the intermediate results, the proposed workflow can also provide detailed GBM sub-regions auto-segmentation with a whole tumor Dice score of 0.91., Conclusion: Our study demonstrates the feasibility of employing this DL-based end-to-end workflow to predict the OS of patients with GBM using only the pre-resection Bas-mpMRIs. This DL-based workflow can be potentially applied to assist timely clinical decision-making., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Neuroendocrine tumor (NET) brain metastases (BM) are rare malignancies which frequently bear a poor prognosis and have the potential to secrete hormones. The optimal treatment approach for these metastases remains unclear, with significant heterogeneity occurring both across and within primary tumor types, and outcome data are limited. Pancreatic neuroendocrine tumor (pNET) BM may be particularly aggressive. While stereotactic radiosurgery (SRS) for other NET BM has previously been described, no report has specifically investigated SRS for management of pNET BM., Methods: A comprehensive literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Search terms included ("neuroendocrine tumor" OR "neuroendocrine neoplasm" OR "neuroendocrine carcinoma" OR "NET") AND ("brain metastasis" OR "brain metastases" OR "intracranial metastases") AND ("stereotactic radiosurgery" OR "stereotactic body" OR "CyberKnife" OR "GammaKnife")., Results: Our search strategy yielded 230 articles. After screening, a total of 16 articles with 256 patients were identified. Number of patients per study cohort ranged from 1 to 101 (mean = 16). Ten articles were single case reports. The most commonly investigated primary site was lung (5 studies), followed by skin (2 case reports), and uterine cervix (2 case reports). Median survival post-SRS ranged from 5 to 42 months. Median tumor volume ranged from 0.08 cm 3 to 33.62 cm 3 . Local control rate was provided in 3 of 6 of the reviewed retrospective analyses. A pulmonary cohort of 101 patients reported a recurrence rate of 13.8 % at 12 months. A pulmonary case series similarly reported local progression in only 1 of 8 patients. The mixed primary cohort (33 patients) had a long-term local failure rate of 16.7 %. In addition, we describe a first reported individual case of pNET BM treated with SRS. Nearly 6-years after initial pNET diagnosis, multiple intracranial enhancing lesions were found, which were subsequently treated with SRS. Follow-up imaging demonstrated a statistically significant decrease in lesion diameter (p < 0.001), with none of the 18 BM progressing., Conclusion: Given the recently increase in age-adjusted incidence of NET BM, determining an optimal treatment approach for these malignancies is of growing importance. Prognosis generally remains poor, with BM being a significant predictor of overall survival. Our review indicated large variability in outcomes both between and within primary tumor types, suggesting a need for further investigation of predictive molecular biomarkers. In addition, to the authors' knowledge, this represents the first reported case of pNET BM successfully treated with SRS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Choriocarcinoma (CC) is a rare and aggressive form of germ cell tumor. There is limited evidence describing clinical outcomes in patients with primary CC and brain metastases (BM). Only a few single case reports have documented the use of stereotactic radiosurgery (SRS) for CC BM., Methods: We retrospectively assessed patients who were treated with SRS for pure CC BM from 1998 to 2024. Lesion follow-up sizes and local tumor control status were evaluated after SRS treatment using response evaluation criteria in solid tumors criteria. A comprehensive literature search was performed for CC BM in accordance with PRISMA guidelines., Results: In our series, 3 patients with 7 CC BM underwent SRS. Two were male with testicular CC and one was female with gestational CC. The median diameter of the lesions was 8 mm, with a median volume of 0.14 cm 3 at treatment. Magnetic resonance imaging at 3 and 6 months showed reductions in median diameters to 6 mm and 4 mm, respectively. At the last follow-up visits, one lesion had local progression at 15 months after SRS and 1 lesion had sustained complete response. The systematic review yielded 249 articles. After screening, 18 reports were identified for CC BM. Among these reports, only 3 single case reports document outcomes of SRS for CC BM., Conclusions: SRS is a feasible and viable approach for CC BM, particularly in cases where immediate surgical management is not necessary. This is the largest report to date evaluating the outcome of CC BM treated with SRS., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bilateral orbital metastases are extremely rare, and no previous literature has reported bilateral multiple orbital metastases treated with stereotactic radiosurgery (SRS). We present the impressive images of a patient with history of metastatic leiomyosarcoma with newly diagnosed bilateral multiple orbital metastases. The pre-SRS magnetic resonance imaging (MRI) showed 1 right and 2 left orbital metastatic lesions. The patient underwent SRS, and the post-SRS MRI at 2 months showed a decrease in size of the treated lesions. The positron emission tomography scan at 5 months after the treatment showed no avid F-fluorodeoxyglucose uptakes in the 3 orbital metastases. The presenting symptoms were all improved after the treatment with no adverse effects from the SRS. Our interesting images show the presence of multiple lesions in the orbital spaces with excellent treatment response post SRS. This is the first report of a patient who has bilateral and multiple orbital metastases that were successfully treated with standalone SRS., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: This study aimed to assess the results of primary stereotactic body radiotherapy (SBRT) for spinal bone metastases (SBM) originating from lung adenocarcinoma (ADC). We considered the revised Tokuhashi score (rTS), Spinal Instability Neoplastic Score (SINS), and genetic characteristics., Methods: We examined adult patients with lung ADC who underwent primary SBRT (using the CyberKnife System) for SBM between March 2012 and January 2023., Results: We analyzed data from 99 patients, covering 152 SBM across 194 vertebrae. The overall local control (LC) rate was 77.6% for SBM from lung ADC, with a LC rate of 90.7% at 1 year. The median period for local progression (LP) occurrence was recorded at 10.0 (3-52) months. Additionally, Asian patients demonstrated higher LC rates than White patients. Utilizing the rTS and SINS as predictive tools, we revealed that a poor survival prognosis and an unstable spinal structure were associated with increased rates of LP. Furthermore, the presence of osteolytic bone destructions and pain complaints were significantly correlated with the occurrence of LP. In the cohort of this study, 108 SBM underwent analysis to determine the expression levels of programmed cell death ligand 1 (PD-L1). Additionally, within this group, 60 showed mutations in the epidermal growth factor receptor (EGFR) alongside PD-L1 expression. Nevertheless, these genetic differences did not result in statistically significant differences in the LC rate., Conclusion: The one-year LC rate for primary SBRT targeting SBM from lung ADC stood at 90.7%, particularly with the use of the CyberKnife System. Patients achieving LC exhibited significantly longer survival times compared to those with LP., Competing Interests: Disclosure The authors affirm that the content of this article was developed without any commercial or financial relationships that could be considered as potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Atrial arrhythmias occur in 20-40% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and are associated with an increased risk of sustained ventricular arrhythmias and inappropriate implantable cardioverter-defibrillator shocks. The pathophysiology of atrial arrhythmias in ARVC remains unclear. Most cases of gene-positive ARVC are linked to pathogenic variants in the desmosomal gene plakophilin-2 (PKP2). Here, we test the hypothesis that loss of PKP2 expression leads to pro-arrhythmic changes in atrial cardiomyocytes. Atrial cells/tissue were obtained from a cardiac-specific, tamoxifen-activated model of PKP2 deficiency (PKP2cKO). By contrast to PKP2cKO ventricular myocytes, PKP2cKO atrial cardiomyocytes presented no significant differences in intracellular calcium (Ca 2+ i ) transient dynamics, sarcoplasmic reticulum load or action potential morphology. PKP2cKO atrial cardiomyocytes showed elevated reactive oxygen species levels, increased frequency and amplitude of Ca 2+ sparks, and increased diastolic [Ca 2+ ] i compared to control; the latter two parameters were further increased by isoproterenol exposure and reversed by exposure to ryanodine receptor blocker dantrolene. We speculate that these isoproterenol-dependent effects may impact on the exercise-related atrial arrhythmia risk in ARVC patients. Despite absence of changes in Ca 2+ i transient dynamics, PKP2cKO atrial cardiomyocytes showed enhanced sarcomere shortening and impaired sarcomere relaxation. Orthogonal transcriptomic analysis of human(GTEx) and PKP2cKO atrial tissue led to identification of 41 transcripts depending on PKP2 expression. Biochemical follow-up confirmed reduced abundance of sarcomeric protein myosin binding protein C, potentially playing a role in cellular shortening and relaxation changes observed. Our findings provide novel insights into the role of PKP2 in atrial myocardium with potential implications to therapeutic management of atrial fibrillation in patients with PKP2-related ARVC. KEY POINTS: Atrial arrhythmias occur in a large group of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a cardiac disease mostly caused by pathogenic variants in the desmosomal gene plakophilin-2 (PKP2). Exercise is considered to be an independent risk factor for arrhythmias consequent to PKP2 deficiency. We show that loss of PKP2 expression affects cellular calcium handling and electrophysiology differently in left atrial vs. ventricular myocardium and causes extensive atrial fibrosis. PKP2-deficient atrial cardiomyocytes present increased spontaneous sarcoplasmic reticulum calcium release events, further enhanced by isoproterenol exposure and reversible by a ryanodine receptor blocker (dantrolene). In addition, PKP2-deficient atrial myocytes exhibit impaired relaxation and enhanced sarcomere shortening, most probably related to reduced abundance of myosin binding protein C. We speculate that cellular effects reported upon isoproterenol impact on the exercise-related atrial arrhythmia risk in ARVC patients. We further propose that therapeutic approaches aimed at mitigating ventricular damage may be effective to treat the atrial disease in ARVC., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Background: Genetic testing is a cornerstone in the assessment of many cardiac diseases. However, variants are frequently classified as variants of unknown significance, limiting the utility of testing. Recently, the DeepMind group (Google) developed AlphaMissense, a unique artificial intelligence-based model, based on language model principles, for the prediction of missense variant pathogenicity. We aimed to report on the performance of AlphaMissense, accessed by VarCardio, an open web-based variant annotation engine, in a real-world cardiovascular genetics center., Methods and Results: All genetic variants from an inherited arrhythmia program were examined using AlphaMissense via VarCard.io and compared with the ClinVar variant classification system, as well as another variant classification platform (Franklin by Genoox). The mutation reclassification rate and genotype-phenotype concordance were examined for all variants in the study. We included 266 patients with heritable cardiac diseases, harboring 339 missense variants. Of those, 230 (67.8%) were classified by ClinVar as either variants of unknown significance or nonclassified. Using VarCard.io, 198 variants of unknown significance (86.1%, 95% CI, 80.9-90.3) were reclassified to either likely pathogenic or likely benign. The reclassification rate was significantly higher for VarCard.io than for Franklin (86.1% versus 34.8%, P <0.001). Genotype-phenotype concordance was highly aligned using VarCard.io predictions, at 95.9% (95% CI, 92.8-97.9) concordance rate. For 109 variants classified as pathogenic, likely pathogenic, benign, or likely benign by ClinVar, concordance with VarCard.io was high (90.5%)., Conclusions: AlphaMissense, accessed via VarCard.io, may be a highly efficient tool for cardiac genetic variant interpretation. The engine's notable performance in assessing variants that are classified as variants of unknown significance in ClinVar demonstrates its potential to enhance cardiac genetic testing.

Background: While genetic testing of tumors is commonly used to inform the selection of systemic therapies, there is limited evidence for the application of radiotherapy for brain cancer. Recent studies have shown that Kelch-like ECH-associated protein 1 (KEAP1), a key regulator of cellular responses to oxidative and electrophilic stress, is associated with radioresistance in multiple cancer types. Several studies have reported the clinical significance of KEAP1 mutation in brain metastasis; however, the effect of KEAP1 mutations on radioresponse in meningioma has never been reported., Observations: The authors present the case of a 40-year-old female with a KEAP1 mutation-positive atypical meningioma that was initially treated with resection followed by intensity-modulated radiation therapy (IMRT). Recurrence was observed at 15 months, requiring reoperation and adjuvant stereotactic radiosurgery (SRS). An excellent treatment response was observed at 7 months post-SRS with an improvement in reported symptoms, although bevacizumab was required for the resolution of radiation necrosis observed 2 months post-SRS., Lessons: To the authors' knowledge, this is the first report of KEAP1-mutant meningioma, including its clinical course after comprehensive management. Notably, treatment included multimodal radiotherapy with IMRT followed by SRS. SRS led to an excellent treatment response at the 7-month follow-up. However, radiation necrosis developed after both radiotherapy treatments, suggesting that radiological modification can be beneficial in patients with KEAP1 mutations. https://thejns.org/doi/10.3171/CASE24387.

Background: Combined catheter ablation (CA) with percutaneous left atrial appendage closure (LAAC) may produce comprehensive treatment for atrial fibrillation (AF) whereby rhythm control is achieved and stroke risk is reduced without the need for chronic oral anticoagulation. However, the efficacy and safety of this strategy is still controversial., Methods: This meta-analysis was reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Medline, Scopus, and Cochrane Central Register of Controlled Trials were systematically searched to identify relevant studies. The risk of bias was assessed using the Modified Newcastle-Ottawa scale and Cochrane risk of bias tool. Eligible studies reported outcomes in patients with AF who underwent combined CA and LAAC vs CA alone. Studies performing CA without pulmonary vein isolation were excluded., Results: Eight studies comprising 1878 patients were included (2 RCT, 6 observational). When comparing combined CA and LAAC vs CA alone, pooled results showed no difference in arrhythmia recurrence (risk ratio (RR) 1.04; 95% confidence interval (CI) 0.82-1.33), stroke or systemic embolism (RR 0.78; 95% CI 0.27-2.22), or major periprocedural complications (RR 1.28; 95% CI 0.28-5.89). Total procedure time was shorter with CA alone (mean difference 48.45 min; 95% CI 23.06-74.62)., Conclusion: Combined CA with LAAC for AF is associated with similar rates of arrhythmia-free survival, stroke, and major periprocedural complications when compared to CA alone. A combined strategy may be as safe and efficacious for patients at moderate to high risk for bleeding events to negate the need for chronic oral anticoagulation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Home residency programs can provide medical students with opportunities for networking, mentorship, research, and exposure to surgeries. The goal of this project was to understand the potential impact of home surgical residencies on student match rates into specific surgical specialties., Methods: This 5-year retrospective study (2019-2023) analyzed 12,916 matched applicants from 155 United States MD programs through publicly available match lists. Odds ratios (ORs) were used to determine the likelihood of students from institutions with home surgical residency programs (home programs) matching into desired surgical specialties compared to students from institutions without home programs. Additional variables included the Alpha Omega Alpha and the Gold Humanism Honor Society statuses of the medical school, the number of faculty, and the type of residency program., Results: Of the matched applicants, 11,442 had home programs resulting in a 39.1% match rate into surgical specialties compared to a 22.3% match rate for students without a home program (OR: 1.76) (P < 0.001). Of the applicants with a home program compared to those without a home program, 69.2% matched into an academic residency (OR: 1.06), 7.7% matched into a community residency (OR: 0.90), 13.6% matched into a combined residency (OR: 0.95), and 2.5% matched into a military residency (OR: 1.31)., Conclusions: Medical students graduating from institutions with home programs were 1.76 times more likely to match into a surgical residency program compared to those graduating from institutions without a home program. Future studies should look at how access to certain resources may influence a student's match rate., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: This study aimed to retrospectively evaluate the efficacy of stereotactic body radiotherapy (SBRT) for pain relief in patients with painful spinal bone metastases (SBMs) and to identify key factors contributing to treatment outcomes., Methods: The authors conducted a retrospective analysis of adult patients who underwent SBRT for painful solid tumor SBMs between March 2012 and January 2023. During this period, SBRT was performed adhering to the International Spine Radiosurgery Consortium guidelines and international consensus recommendations for target volume delineation. To be included, patients needed to experience persistent pain directly associated with SBMs, warranting regular opioid treatment. Positive pain relief post-SBRT was defined by three criteria: 1) a decrease in the severity of pain; 2) reduction in opioid dosage; and 3) concurrent improvement in daily activities. The revised Tokuhashi score and Spine Instability Neoplastic Score were used to identify crucial factors influencing treatment outcomes., Results: This study included 377 patients, covering 576 lesions across 759 vertebrae. Of these, 332 lesions showed significant pain relief within 3 months following SBRT. Lower pain relief rates were observed in patients with a revised Tokuhashi score of 0-8 or in patients with diabetes mellitus. In contrast, higher relief rates were linked to treating a single painful SBM in 1 SBRT course, and greater contouring of the involved sectors according to International Spine Radiosurgery Consortium guidelines and international consensus recommendations. The highest pain relief rate was observed in patients with prostate cancer (73.8%), whereas the lowest rate was observed in patients with hepatocellular carcinoma (36.4%). The presence of pre-SBRT vertebral fractures, the dosage and fraction of SBRT, and the use of concurrent systemic cancer therapies or antiresorptive agents, including bisphosphonates and denosumab, did not notably influence the pain relief efficacy of SBRT. Comprehensive medical records 6 months after SBRT treatment were available for only 362 lesions. The overall rate of pain relief observed was 32.6%., Conclusions: SBRT is an effective treatment approach for managing painful SBMs, achieving a pain relief rate of 57.6% within 3 months and maintaining a rate of 32.6% at 6 months after treatment. The transition to osteoblastic lesions may potentially improve the stability of SBMs, indicated by lower Spine Instability Neoplastic Score, which in turn could extend pain relief management.

Background: Facial nerve hemangiomas (FNHs) are rare tumors that primarily occur near the geniculate ganglion in the temporal bone. Despite their rarity, they can cause significant facial nerve dysfunction. The optimal management approach for FNHs remains uncertain, with surgery being the mainstay but subject to debate regarding the extent of resection and preservation of the facial nerve., Methods: Systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We queried the PubMed/Medline (accessed on 5 March 2024) electronic database using combinations of the following search terms and words text: "geniculate ganglion hemangioma", "ganglional hemangioma", "hemangioma of the facial nerve", "facial hemangioma", and "intratemporal hemangioma"., Results: We identified a total of 30 literatures (321 patients). The most common site involved for the facial nerve hemangioma was the geniculate ganglion area followed by internal auditory canal, tympanic segment, labyrinthine segment and mastoid involvement. All patients were treated with conservative management or surgery. We report a 48-year-old female patient with HB grade 2 facial palsy and hemifacial spasm underwent SRS using Cyberknife technology. The treatment targeted the FNH in the left internal acoustic canal near the geniculate ganglion. Six months post-treatment, clinical improvement was evident, and lesion control was confirmed in a follow-up brain MRI., Conclusion: The rarity of FNHs contributes to the lack of consensus on optimal management. This illustrative case demonstrates the feasibility of SRS as a standalone treatment for FNHs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Vestibular schwannomas (VSs) are benign tumors often monitored over time, with measurement techniques for assessing growth rates subject to significant interobserver variability. Automatic segmentation of these tumors could provide a more reliable and efficient for tracking their progression, especially given the irregular shape and growth patterns of VS., Methods: Various studies and segmentation techniques employing different Convolutional Neural Network architectures and models, such as U-Net and convolutional-attention transformer segmentation, were analyzed. Models were evaluated based on their performance across diverse datasets, and challenges, including domain shift and data sharing, were scrutinized., Results: Automatic segmentation methods offer a promising alternative to conventional measurement techniques, offering potential benefits in precision and efficiency. However, these methods are not without challenges, notably the "domain shift" that occurs when models trained on specific datasets underperform when applied to different datasets. Techniques such as domain adaptation, domain generalization, and data diversity were discussed as potential solutions., Conclusions: Accurate measurement of VS growth is a complex process, with volumetric analysis currently appearing more reliable than linear measurements. Automatic segmentation, despite its challenges, offers a promising avenue for future investigation. Robust well-generalized models could potentially improve the efficiency of tracking tumor growth, thereby augmenting clinical decision-making. Further work needs to be done to develop more robust models, address the domain shift, and enable secure data sharing for wider applicability., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Objectives: Ependymoma is commonly classified as World Health Organization grade 2 with the anaplastic variant categorized as grade 3. Incomplete resection or anaplastic features can result in unfavorable outcomes. Stereotactic radiosurgery (SRS) provides a minimally invasive approach for recurrent ependymomas. Our study investigates the efficacy and safety of SRS for grade 2 and 3 ependymomas in pediatric and adult populations., Methods: We conducted a retrospective analysis on 34 patients with 75 ependymomas after CyberKnife SRS between 1998 and 2023. Fourteen were pediatric (3-18 years), and 20 were adult (19-75 years) patients. The median age was 21 years, and the median tumor volume was 0.64 cc. The median single-fraction equivalent dose was 16.6 Gy, with SRS administered at 77% of the median isodose line., Results: After a median follow-up of 42.7 months (range: 3.8-438.3), 22.7% of ependymomas progressed. The 5-year local tumor control rate was 78.1%, varying between 59.6% and 90.2% for children and adults, with grade 2 at 85.9% compared with 58.5% for grade 3 tumors. The 5-year overall survival rate was 73.6%, notably higher in adults (94.7%) than in children (41%), and 100% for grade 2 but decreased to 35.9% for grade 3 patients. The 5-year progression-free survival rate was 68.5%, with 78.3% and 49.2% for adults and children, respectively, and a favorable 88.8% for grade 2, contrasting with 32.6% for grade 3 patients. Symptom improvement was observed in 85.3% of patients. Adverse radiation effects occurred in 21.4% of pediatric patients., Conclusion: Our study supports SRS as a viable modality for pediatric and adult patients with grade 2 and 3 ependymomas. Despite lower local tumor control in pediatric and grade 3 cases, integrating SRS holds promise for improved outcomes. Emphasizing careful patient selection, personalized treatment planning, and long-term follow-up is crucial for optimal neurosurgical outcomes., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.)

Background: Many patients with mildly to moderately reduced left ventricular ejection fraction (LVEF) who require permanent pacemaker (PPM) implantation do not have a concurrent indication for implantable cardioverter-defibrillator (ICD) therapy. However, the risk of ventricular tachycardia/ventricular fibrillation (VT/VF) in this population is unknown., Objective: The aim of this study was to describe the risk of VT/VF after PPM implantation in patients with mildly to moderately reduced LVEF., Methods: Retrospective analysis was performed of 243 patients with LVEF between 35% and 49% who underwent PPM placement and did not meet indications for an ICD. The primary end point was occurrence of sustained VT/VF. Competing risks regression was performed to calculate subhazard ratios for the primary end point., Results: Median follow-up was 27 months; 73% of patients were male, average age was 79 ± 10 years, average LVEF was 42% ± 4%, and 70% were New York Heart Association class II or above. Most PPMs were implanted for sick sinus syndrome (34%) or atrioventricular block (50%). Of 243 total patients, 11 (4.5%) met the primary end point of VT/VF. Multivessel coronary artery disease (CAD) was associated with significantly higher rates of VT/VF, with a subhazard ratio of 5.4 (95% CI, 1.5-20.1; P = .01). Of patients with multivessel CAD, 8 of 82 (9.8%) patients met the primary end point for an annualized risk of 4.3% per year., Conclusion: Patients with mildly to moderately reduced LVEF and multivessel CAD undergoing PPM implantation are at increased risk for the development of malignant ventricular arrhythmias. Patients in this population may benefit from additional risk stratification for VT/VF and consideration for upfront ICD implantation., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Cavernous malformations (CMs) originating from spinal nerve roots are rare but can present with rapidly progressing neurological deficits. Therefore, quick identification and treatment are essential., Observations: The authors present the case of a 52-year-old male presenting with headaches and gait disturbance, found to have a CM of the C1 nerve root. The patient underwent successful suboccipital craniectomy and C1 laminectomy, with complete resection of the lesion, preservation of the cervical spinal nerve roots, and symptomatic improvement postoperatively., Lessons: This is the first presentation in the literature of a CM originating from the C1 nerve root. The authors show complete resection of the lesion with preservation of the C1 nerve root. Nerve root lesions usually show insidious symptomatic onset. Quick identification and resection are recommended to prevent permanent neurological disability. https://thejns.org/doi/10.3171/CASE2456.

Background and Objectives: Hemangiopericytomas are infrequent vascular tumors originating from Zimmermann pericytes. The conventional treatment involves gross total resection, followed by adjuvant radiotherapy. Nevertheless, their tendency to infiltrate dural sinuses, high vascularity, and anatomic complexity pose challenges for radical resection, leading to a significant risk of recurrence. Stereotactic radiosurgery (SRS) has emerged as a promising adjuvant therapy to address these challenges. Our study provides the largest single-institutional retrospective, aiming to evaluate the effectiveness and safety of SRS as a treatment modality for residual, recurrent, and metastatic hemangiopericytomas., Methods: From 1998 to 2023, 27 patients with 101 tumors underwent CyberKnife SRS at Stanford University Medical Center. The median age was 51 years at the time of treatment. The median follow-up period from SRS was 103 months (range: 6-250). All patients underwent upfront surgical resection. The median tumor volume was 1.5 cc. The median single-fraction equivalent dose was 19 Gy. The SRS was administered at the 76% of the median isodose line (range: 64-89)., Results: Of the 101 treated tumors, 24 (23.8%) progressed with a median time to recurrence of 30 months. At 10 years, the rates of local tumor control (LTC), overall survival (OS), and progression-free survival (PFS) were 74.3%, 80.8%, and 67%, respectively. In patients with metastatic lesions, the LTC rates were significantly greater when compared with those with residual or recurrent tumors. There was no significant difference between patients with residual, recurrent, and metastatic hemangiopericytomas in OS and PFS. Notably, no cases of radiation-induced adverse events were detected., Conclusion: SRS leads to excellent LTC, PFS, and OS at 10 years with negligible risk for adverse events. Therefore, it is an effective and safe management modality for patients with residual, recurrent, and metastatic hemangiopericytomas., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Background: Choroid plexus carcinomas (CPCs) are rare malignant brain tumors primarily affecting children younger than 2 years old. These tumors originate from the choroid plexus epithelium and are a subtype of choroid plexus tumors, which account for 1%-4% of pediatric brain tumors. Although CPCs often show a notably high recurrence rate after surgery, the standard treatment approach remains gross-total resection (GTR) of the tumor, given the lack of clinical data supporting the effectiveness of adjunct treatment options such as radiotherapy or chemotherapy., Observations: A 16-year-old female with a history of a recurrent cranial CPC resistant to surgery and radiotherapy was treated with CyberKnife stereotactic radiosurgery (SRS), following resection. The procedures successfully maintained local disease control for 41 months; however, there was a subsequent recurrence, ultimately leading to the death of the patient., Lessons: CPC treatment remains challenging. SRS can be used as a viable adjunct to surgery, which remains the gold standard, although it can also be considered for nonsurgical candidates or when GTR cannot be achieved. Nevertheless, it is crucial to conduct additional research to explore diverse approaches for radiosurgery, including its role as the primary treatment modality versus its combination with surgery, radiotherapy, or chemotherapy. https://thejns.org/doi/10.3171/CASE23748.

Background: Catheter ablation (CA) for ventricular tachycardia (VT) can be a useful treatment strategy, however, few studies have compared CA to medical therapy (MT) in the sarcoidosis population., Objective: To assess in-hospital outcomes and unplanned readmissions following CA for VT compared to MT in patients with sarcoidosis., Methods: Data was obtained from the Nationwide Readmissions Database between 2010 and 2019 to identify patients with sarcoidosis admitted for VT either undergoing CA or MT during elective and non-elective admission. Primary endpoints were a composite endpoint of inpatient mortality, cardiogenic shock, cardiac arrest and 30-day hospital readmissions. Procedural complications at index admission and causes of readmission were also identified., Results: Among 1581 patients, 1217 with sarcoidosis and VT underwent MT compared to 168 with CA during non-elective admission. 63 patients admitted electively underwent CA compared with 129 managed medically. There was no difference in the composite outcome for patients undergoing catheter ablation or medical therapy during both non-elective (9.0 % vs 12.0 %, p  = 0.312) and elective admission (3.2 % vs. 7.8 %, p  = 0.343). The most common cause of readmission were ventricular arrhythmias (VA) in both groups, however, those undergoing elective CA were less likely to be readmitted for VA compared to non-elective CA. The most common complication in the CA group was cardiac tamponade (4.8 %)., Conclusion: VT ablation is associated with similar rates of 30-day readmission compared to MT and does not confer increased risk of harm with respect to inpatient mortality, cardiogenic shock or cardiac arrest. Further research is warranted to determine if a subgroup of sarcoidosis patients admitted with VT are better served with an initial conservative management strategy followed by VT ablation., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chirag R. Barbhaiya reports a relationship with Abbott that includes: speaking and lecture fees. Chirag R. Barbhaiya reports a relationship with 10.13039/501100005035BIOTRONIK Inc that includes: funding grants, non-financial support, and speaking and lecture fees. Chirag R. Barbhaiya reports a relationship with Medtronic Inc. that includes: speaking and lecture fees. Douglas Holmes reports a relationship with 10.13039/100001316Abbott that includes: funding grants and non-financial support. Alexander Kushnir reports a relationship with Biosense Webster Inc. that includes: consulting or advisory and speaking and lecture fees. Larry A. Chinitz reports a relationship with Abbott that includes: speaking and lecture fees. Larry A. Chinitz reports a relationship with Medtronic Inc that includes: funding grants, non-financial support, and speaking and lecture fees. Larry A. Chinitz reports a relationship with 10.13039/501100005035BIOTRONIK Inc that includes: funding grants, non-financial support, and speaking and lecture fees. Larry A. Chinitz reports a relationship with 10.13039/100007497Biosense Webster Inc that includes: funding grants, non-financial support, and speaking and lecture fees. Anthony Aizer reports a relationship with 10.13039/100001316Abbott that includes: funding grants and non-financial support. Anthony Aizer reports a relationship with 10.13039/501100005035BIOTRONIK Inc that includes: funding grants and non-financial support. Chirag R. Barbhaiya reports a relationship with ZOLL Medical Corporation that includes: speaking and lecture fees. Anthony Aizer reports a relationship with 10.13039/100007497Biosense Webster Inc that includes: consulting or advisory, funding grants, and non-financial support. Anthony Aizer reports a relationship with 10.13039/100008497Boston Scientific Corporation that includes: funding grants and non-financial support. Anthony Aizer reports a relationship with 10.13039/100004374Medtronic Inc that includes: funding grants and non-financial support. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Background/Objectives : Medulloblastoma is the most common malignant brain tumor in children. In recent decades, the therapeutic landscape has undergone significant changes, with stereotactic radiosurgery (SRS) emerging as a promising treatment for recurrent cases. Our study provides a comprehensive analysis of the long-term efficacy and safety of SRS in recurrent medulloblastomas across both pediatric and adult patients at a single institution. Methods : We retrospectively reviewed the clinical and radiological records of patients who underwent CyberKnife SRS for recurrent cranial medulloblastomas at our institution between 1998 and 2023. Follow-up data were available for 15 medulloblastomas in 10 patients. The cohort comprised eight pediatric patients (ages 3-18) and two adult patients (ages 19-75). The median age at the time of SRS was 13 years, the median tumor volume accounted for 1.9 cc, the median biologically equivalent dose (BED) was 126 Gy, and the single-fraction equivalent dose (SFED) was 18 Gy. The SRS was administered at 75% of the median isodose line. Results : Following a median follow-up of 39 months (range: 6-78), 53.3% of the medulloblastomas progressed, 13.3% regressed, and 33.3% remained stable. The 3-year local tumor control (LTC) rate for all medulloblastomas was 65%, with lower rates observed in the adult cohort (50%) and higher rates in pediatric patients (67%). The 3-year overall survival (OS) rate was 70%, with significantly higher rates in pediatric patients (75%) compared to adult patients (50%). The 3-year progression-free survival (PFS) rate was 58.3%, with higher rates in pediatric patients (60%) compared to adult patients (50%). Two pediatric patients developed radiation-induced edema, while two adult patients experienced radiation necrosis at the latest follow-up, with both adult patients passing away. Conclusions : Our study provides a complex perspective on the efficacy and safety of CyberKnife SRS in treating recurrent cranial medulloblastomas across pediatric and adult populations. The rarity of adverse radiation events (AREs) underscores the safety profile of SRS, reinforcing its role in enhancing treatment outcomes. The intricacies of symptomatic outcomes, intertwined with factors such as age, tumor location, and prior surgeries, emphasize the need for personalized treatment approaches. Our findings underscore the imperative for ongoing research and the development of more refined treatment strategies for recurrent medulloblastomas. Given the observed disparities in treatment outcomes, a more meticulous tailoring of treatment approaches becomes crucial.

Purpose: To determine whether sampling of the disc or bone is more likely to yield positive tissue culture results in patients with vertebral discitis and osteomyelitis (VDO)., Materials and Methods: Retrospective review was performed of consecutive patients who underwent vertebral disc or vertebral body biopsy at a single institution between February 2019 and May 2023. Inclusion criteria were age ≥18 years, presumed VDO on spinal magnetic resonance (MR) imaging, absence of paraspinal abscess, and technically successful percutaneous biopsy with fluoroscopic guidance. The primary outcome was a positive biopsy culture result, and secondary outcomes included complications such as nerve injury and segmental artery injury., Results: Sixty-six patients met the inclusion criteria; 36 patients (55%) underwent disc biopsy, and 30 patients (45%) underwent bone biopsy. Six patients required a repeat biopsy for an initially negative culture result. No significant demographic, laboratory, antibiotic administration, or pain medication use differences were observed between the 2 groups. Patients who underwent bone biopsy were more likely to have a history of intravenous drug use (26.7%) compared with patients who underwent disc biopsy (5.5%; P = .017). Positive tissue culture results were observed in 41% of patients who underwent disc biopsy and 15% of patients who underwent bone biopsy (P = .016). No vessel or nerve injuries were detected after procedure in either group., Conclusions: Percutaneous disc biopsy is more likely to yield a positive tissue culture result than vertebral body biopsy in patients with VDO., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Plasmacytoma, a rare plasma cell disorder, often presents as a solitary or multiple tumors within the bone marrow or soft tissues, typically associated with multiple myeloma. Extramedullary plasmacytomas (EMPs), particularly those located in the external auditory canal (EAC), are exceedingly rare and pose significant treatment challenges given their location, anatomical complexity, and high risk of recurrence., Observations: The authors report the case of a 72-year-old male with a history of multiple myeloma, presenting with recurrent left EAC plasmacytoma. After initial conventional radiotherapy for the lesion, a recurrence was documented in 7 years. The patient subsequently underwent stereotactic radiosurgery, which proved successful, leading to complete resolution of the lesion without any long-term adverse effects or radiation-related complications over a 45-month period., Lessons: This case is a unique instance of utilizing stereotactic radiosurgery for recurrent EMP in the EAC, highlighting its potential as an effective approach in managing complex plasmacytomas.

Women with mutations in the human BRCA2 gene ( hBRCA2 ) have an increased risk of developing breast and ovarian cancer throughout their lifetime. hBRCA2 transcribes proteins necessary for gene repair through homologous recombination (HR). In order to better understand the role of hBRCA2 in response to specific types of DNA damage, the present study evaluated HR in the budding yeast, Saccharomyces cerevisiae , using wildtype (WT) and rad52Δ mutant cells subject to spontaneous and UV damage in the presence or absence of hBRCA2. As expected, rad52Δ genotypes yielded lower recombination frequencies compared to WT in both spontaneous and UV exposure experiments. However, there was no significant difference between rad52Δ mutants with or without hBRCA2. Interestingly, higher UV exposure resulted in a relative increase in HR for only the rad52Δ mutant genotypes. The results demonstrate that hBRCA2 complementation may not be as substantial in spontaneous or UV DNA damage compared to double-strand break DNA damage, as previous work has shown., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2024 by the authors.)

Essential tremor (ET) is one of the most common adult movement disorders. As the worldwide population ages, the incidence and prevalence of ET is increasing. Although most cases can be managed conservatively, there is a subset of ET that is refractory to medical management. By virtue of being "reversible", deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of the thalamus is one commonly accepted intervention. As an alternative to invasive and expensive DBS, there has been a renaissance in treating ET with lesion-based approaches, spearheaded most recently by high-intensity focused ultrasound (HIFU), the hallmark of which is that it is non-invasive. Meanwhile, stereotactic radiosurgical (SRS) lesioning of VIM represents another time-honored lesion-based non-invasive treatment of ET, which is especially well suited for those patients that cannot tolerate open neurosurgery and is now also getting a "second look". While multiple SRS platforms have been and continue to be used to treat ET, there is little in the way of dosimetric comparison between different technologies. In this brief technical report we compare the dosimetric profiles of three major radiosurgical platforms (Gamma Knife, CyberKnife Robotic Radiosurgery, and Zap-X Gyroscopic Radiosurgery (GRS)) for the treatment of ET. In general, the GRS and Gamma Knife were shown to have the best theoretical dosimetric profiles for VIM lesioning. Nevertheless the relevance of such superiority to clinical outcomes requires future patient studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Marianayagam et al.)

Objective: Synovial sarcoma (SS) is a relatively rare type of soft-tissue sarcoma that is commonly treated with surgery, radiation, chemotherapy, and palliative care. Stereotactic radiosurgery (SRS) is an emerging approach that shows promise in treating CNS conditions, but it has not been studied for SS. The authors present a systematic review that explores the effectiveness of different treatments, with a focus on SRS, for managing spinal SS., Methods: A systematic PubMed search was conducted that covered studies from 1964 to 2022, yielding 70 relevant studies. Inclusion criteria encompassed primary and metastatic spinal SS, various treatment modalities, patient age 17 years or older, English-language studies, retrospective series, and case reports. Based on these criteria, 26 studies were included in this review and 44 were excluded., Results: Of the included studies, 15 patients from 9 studies were treated with surgical intervention followed by both conventional radiotherapy (RT) and chemotherapy, 10 patients from 10 studies were treated with surgery followed by RT, 5 studies comprising 8 patients were exclusively treated with surgery, 5 cases in 3 studies were treated with surgery plus concomitant chemotherapy, 4 patients in 2 studies were treated with SRS, and only 1 study reported treatment without surgery and with chemotherapy and RT. The median progression-free survival and overall survival periods observed in the SRS-treated patients were 37 months and 60 months, respectively, which were higher than those of any other treatment method or combination used., Conclusions: The authors' study offers a thorough review of spinal SS treatments. They are hopeful that this will aid clinicians in informed decision-making for better patient outcomes.

Background and Objectives: Stereotactic radiosurgery (SRS) has been an attractive treatment modality for both cranial and spinal hemangioblastomas, especially for multiple lesions commonly associated with von Hippel-Lindau (VHL) disease. This study aims to provide the largest long-term analysis of treatment efficacy and adverse effects of SRS for cranial and spinal hemangioblastomas at a single institution., Methods: We evaluated the clinical and radiological outcomes of patients with hemangioblastomas treated with CyberKnife SRS at our institute from 1998 to 2022. The follow-up data were available for 135 hemangioblastomas in 35 patients. Twenty-eight patients had 123 hemangioblastomas associated with VHL, and 7 had 12 sporadic hemangioblastomas. The median age was 36 years, and the median tumor volume accounted for 0.4 cc. The SRS was administered with the median single-fraction equivalent dose of 18 Gy to the 77% median isodose line., Results: At a median follow-up of 57 months (range: 3-260), only 20 (16.2%) of the VHL-associated and 1 (8.3%) sporadic hemangioblastomas progressed. The 5-year local tumor control rate was 91.3% for all hemangioblastomas, 91.7% among the sporadic lesions, and 92.9% in patients with VHL. SRS improved tumor-associated symptoms of 98 (74.8%) of 131 symptomatic hemangioblastomas, including headache, neck pain, dizziness, visual disturbances, dysesthesia, ataxia, motor impairment, seizures, and dysphagia. Two patients developed radiation necrosis (5.7%), and 1 of them required surgical resection., Conclusion: SRS is a safe and effective treatment option for patients with hemangioblastomas in critical locations, such as the brainstem, cervicomedullary junction, and spinal cord, and in patients with multiple hemangioblastomas associated with VHL disease., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Objective: Temporal coordination between oscillations enables intercortical communication and is implicated in cognition. Focal epileptic activity can affect distributed neural networks and interfere with these interactions. Refractory pediatric epilepsies are often accompanied by substantial cognitive comorbidity, but mechanisms and predictors remain mostly unknown. Here, we investigate oscillatory coupling across large-scale networks in the developing brain., Methods: We analyzed large-scale intracranial electroencephalographic recordings in children with medically refractory epilepsy undergoing presurgical workup (n = 25, aged 3-21 years). Interictal epileptiform discharges (IEDs), pathologic high-frequency oscillations (HFOs), and sleep spindles were detected. Spatiotemporal metrics of oscillatory coupling were determined and correlated with age, cognitive function, and postsurgical outcome., Results: Children with epilepsy demonstrated significant temporal coupling of both IEDs and HFOs to sleep spindles in discrete brain regions. HFOs were associated with stronger coupling patterns than IEDs. These interactions involved tissue beyond the clinically identified epileptogenic zone and were ubiquitous across cortical regions. Increased spatial extent of coupling was most prominent in older children. Poor neurocognitive function was significantly correlated with high IED-spindle coupling strength and spatial extent; children with strong pathologic interactions additionally had decreased likelihood of postoperative seizure freedom., Significance: Our findings identify pathologic large-scale oscillatory coupling patterns in the immature brain. These results suggest that such intercortical interactions could predict risk for adverse neurocognitive and surgical outcomes, with the potential to serve as novel therapeutic targets to restore physiologic development., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objectives: We investigated characteristics of left atrial conduction in patients with HCM, paroxysmal AF and normal bipolar voltage., Background: Patients with hypertrophic cardiomyopathy (HCM) exhibit abnormal cardiac tissue arrangement. The incidence of atrial fibrillation (AF) is increased fourfold in patients with HCM and confers a fourfold increased risk of death. Catheter ablation is less effective in HCM, with twofold increased risk of AF recurrence. The mechanisms of AF perpetuation in HCM are poorly understood., Methods: We analyzed 20 patients with HCM and 20 controls presenting for radiofrequency ablation of paroxysmal AF normal left atrial voltage(> 0.5 mV). Intracardiac electrograms were extracted from the CARTO mapping system and analyzed using Matlab/Python code interfacing with Core OpenEP software. Conduction velocity maps were calculated using local activation time gradients., Results: There were no differences in baseline demographics, atrial size, or valvular disease between HCM and control patients. Patients with HCM had significantly reduced atrial conduction velocity compared to controls (0.44 ± 0.17 vs 0.56 ± 0.10 m/s, p = 0.01), despite no significant differences in bipolar voltage amplitude (1.23 ± 0.38 vs 1.20 ± 0.41 mV, p = 0.76). There was a statistically significant reduction in conduction velocity in the posterior left atrium in HCM patients relative to controls (0.43 ± 0.18 vs 0.58 ± 0.10 m/s, p = 0.003), but not in the anterior left atrium (0.46 ± 0.17 vs 0.55 ± 0.10 m/s, p = 0.05). There was a significant association between conduction velocity and interventricular septal thickness (slope = -0.013, R 2  = 0.13, p = 0.03)., Conclusions: Atrial conduction velocity is significantly reduced in patients with HCM and paroxysmal AF, possibly contributing to arrhythmia persistence after catheter ablation., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: Leiomyosarcoma (LMS) is a rare, aggressive soft-tissue sarcoma that seldom spreads to the bone. The spine can be either the site of LMS osseous metastases or the primary tumor site. The optimal treatment option for spinal LMS is still unclear. The authors present a cohort of patients with spinal LMS treated with either upfront surgery or upfront CyberKnife stereotactic radiosurgery (SRS)., Methods: The authors retrospectively studied the clinical and radiological outcomes of 17 patients with spinal LMS treated at their institution between 2004 and 2020. Either surgery or SRS was used as the upfront treatment. The clinical and radiological outcomes were assessed. A systematic review of the literature was also conducted., Results: Of the 17 patients (20 spinal lesions), 12 (70.6%) were female. The median patient age was 61 years (range 41-80 years). Ten patients had upfront surgery for their spinal lesions, and 7 had upfront CyberKnife radiosurgery. The median follow-up was 11 months (range 0.3-130 months). The median overall survival (OS) for the entire cohort was 13 months (range 0.3-97 months). In subgroup analysis, the median OS was lower for the surgical group (13 months, range 0.3-50 months), while the median OS for the SRS group was 15 months (range 5-97 months) (p = 0.5). Forty percent (n = 4) of those treated with surgery presented with local recurrence at a median of 6.7 months (range 0.3-36 months), while only 14% (n = 1) of those treated with CyberKnife radiosurgery had local recurrence after 5 months. Local tumor control (LTC) rates at the 6-, 12-, and 18-month follow-ups were 72%, 58%, and 43%, respectively, for the SRS group and 40%, 30%, and 20%, respectively, for the surgery group (p < 0.05). The literature review included 35 papers with 70 patients harboring spinal LMS; only 2 patients were treated with SRS. The literature review confirms the clinical and radiological outcomes of the surgical group, while data on SRS are anecdotal., Conclusions: The authors present the largest series in the literature of spinal LMS and the first on SRS for spinal LMS. This study shows that LTC is statistically significantly better in patients receiving upfront SRS instead of surgery. The OS does not appear different between the two groups.

Physicians are expected to be educators and leaders, but few medical schools offer dedicated coursework or training to prepare medical students to meet those expectations. Since 2018, Rocky Vista University College of Osteopathic Medicine has offered a longitudinal Academic Medicine and Leadership (AML) Track in which medical students acquire knowledge and develop skills for academic medicine and leadership that will enhance their ability to become effective educators and leaders in their clinics, hospitals, professional associations, communities, and affiliated medical schools. This paper describes the novel AML Track, its learning activities, and some of its emerging outcomes., Competing Interests: Competing InterestsThe authors declare no competing interests., (© The Author(s) 2023.)

Background: Bone marrow mesenchymal stem cell (BM-MSC)-derived extracellular vesicles (ExoFlo) convey the immunomodulatory and regenerative properties of intact BM-MSCs. This study aimed to determine the safety and efficacy of ExoFlo as treatment for moderate to severe ARDS in patients with severe COVID-19., Research Question: Do two doses of ExoFlo safely reduce mortality in COVID-19-associated moderate to severe ARDS compared with placebo?, Study Design and Methods: A prospective phase 2 multicenter double-anonymized randomized placebo-controlled dosing trial was conducted at five sites across the United States with infusions of placebo, 10 mL of ExoFlo, or 15 mL of ExoFlo on days 1 and 4. Patients (N = 102) with COVID-19-associated moderate to severe ARDS were enrolled and randomized to treatment. Adverse events were documented throughout the study. The primary outcome measure was all-cause 60-day mortality rate. Secondary outcomes included time to death (overall mortality); the incidence of treatment-emergent serious adverse events; proportion of discharged patients at 7, 30, and 60 days; time to hospital discharge; and ventilation-free days., Results: No treatment-related adverse events were reported. Mortality (60-day) in the intention-to-treat population was reduced with 15 mL ExoFlo mixed with 85 mL normal saline (ExoFlo-15) compared with placebo (not significant, χ 2 , P = .1343). For the post hoc subgroup analyses, 60-day mortality was decreased with ExoFlo-15 compared with placebo (relative risk, 0.385; 95% CI, 0.159-0.931; P = .0340; n = 50). With ExoFlo-15, a relative risk of 0.423 (95% CI, 0.173-1.032; P = .0588; n = 24) was determined for participants aged 18 to 65 years with moderate to severe ARDS. Ventilation-free days improved with ExoFlo-15 (P = .0455; n = 50) for all participants aged 18 to 65 years., Interpretation: The 15 mL dose of ExoFlo was found to be safe in patients with severe or critical COVID-19-associated respiratory failure. In participants aged 18 to 65 years, the risk reduction in 60-day mortality was further improved from subjects of all ages in the intention-to-treat population after two doses of 15 mL of ExoFlo compared with placebo., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT04493242; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: A. L. L. is CMO at Direct Biologics. J. T. R. is a PhD at Direct Biologics. S. Q. and V. S. are prior associate CMOs at Direct Biologics. None declared (S. S., D. J. P., T. I. M., B. P. W., J. J. W., M. A.)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Conotruncal defects due to developmental abnormalities of the outflow tract (OFT) are an important cause of cyanotic congenital heart disease. Dysregulation of transcriptional programs tuned by NKX2-5 (NK2 homeobox 5), GATA6 (GATA binding protein 6), and TBX1 (T-box transcription factor 1) have been implicated in abnormal OFT morphogenesis. However, there remains no consensus on how these transcriptional programs function in a unified gene regulatory network within the OFT., Methods: We generated mice harboring a 226-nucleotide deletion of a highly conserved cardiac enhancer containing 2 GATA-binding sites located ≈9.4 kb upstream of the transcription start site of Nkx2-5 ( Nkx2-5 ∆enh ) using CRISPR-Cas9 gene editing and assessed phenotypes. Cardiac defects in Nkx2-5 ∆enh/∆enh mice were structurally characterized using histology and scanning electron microscopy, and physiologically assessed using electrocardiography, echocardiography, and optical mapping. Transcriptome analyses were performed using RNA sequencing and single-cell RNA sequencing data sets. Endogenous GATA6 interaction with and activity on the NKX2-5 enhancer was studied using chromatin immunoprecipitation sequencing and transposase-accessible chromatin sequencing in human induced pluripotent stem cell-derived cardiomyocytes., Results: Nkx2-5 ∆enh/∆enh mice recapitulated cyanotic conotruncal defects seen in patients with NKX2-5, GATA6 , and TBX1 mutations. Nkx2-5 ∆enh/∆enh mice also exhibited defects in right Purkinje fiber network formation, resulting in right bundle-branch block. Enhancer deletion reduced embryonic Nkx2-5 expression selectively in the right ventricle and OFT of mutant hearts, indicating that enhancer activity is localized to the anterior second heart field. Transcriptional profiling of the mutant OFT revealed downregulation of important genes involved in OFT rotation and septation, such as Tbx1, Pitx2 , and Sema3c . Endogenous GATA6 interacted with the highly conserved enhancer in human induced pluripotent stem cell-derived cardiomyocytes and in wild-type mouse hearts. We found critical dose dependency of cardiac enhancer accessibility on GATA6 gene dosage in human induced pluripotent stem cell-derived cardiomyocytes., Conclusions: Our results using human and mouse models reveal an essential gene regulatory network of the OFT that requires an anterior second heart field enhancer to link GATA6 with NKX2-5-dependent rotation and septation gene programs., Competing Interests: Disclosures None.

Background: Glioblastoma (GBM) is the most common primary brain tumor with poor patient prognosis. Spinal leptomeningeal metastasis has been rarely reported, with long intervals between the initial discovery of the primary tumor in the brain and eventual spine metastasis., Observations: Here, the authors present the case of a 51-year-old male presenting with 7 days of severe headache, nausea, and vomiting. Magnetic resonance imaging of the brain and spine demonstrated a contrast-enhancing mass in the pineal region, along with spinal metastases to T8, T12, and L5. Initial frozen-section diagnosis led to the treatment strategy for medulloblastoma, but further molecular analysis revealed characteristics of isocitrate dehydrogenase-wild type, grade 4 GBM., Lessons: Glioblastoma has the potential to show metastatic spread at the time of diagnosis. Spinal imaging should be considered in patients with clinical suspicion of leptomeningeal spread. Furthermore, molecular analysis should be confirmed following pathological diagnosis to fine-tune treatment strategies.

Purpose: Belzutifan is a Hypoxia Inducible Factor 2-alpha inhibitor approved in 2021 by the FDA for the treatment of renal cell carcinoma (RCC) in patients with Von-Hippel Landau (VHL) disease. These patients can also present with central nervous system (CNS) hemangioblastomas (HBs). We aim to study the effectiveness and adverse effects of belzutifan for CNS HBs, by reporting our preliminary institutional experience., Methods: We present a series of VHL patients with CNS HBs undergoing treatment with belzutifan for RCC. All the included patients met the RECIST inclusion criteria. The clinical and radiological outcome measures included: Objective response rate (ORR), time-to-response (TTR), adverse events (AE), and patient response. Patient response was classified as partial response (PR), complete response (CR), progressive disease (PD), or stable disease (SD)., Results: Seven patients with 25 HBs were included in our study. A belzutifan dose of 120 mg/day PO was administered for a median of 13 months (range 10-17). Median follow up time was 15 months (range 10-24). An ORR of 71% was observed. The median TTR was 5 months (range: 1-10). None of the patients showed CR, while 5 patients (71.4%) showed PR and 2 (28.5%) showed SD. Among patients with SD the maximum tumor response was 20% [increase/decrease] of the lesion diameter. All the patients experienced decreased hemoglobin concentration, fatigue, and dizziness. None of the patients experienced severe anemia (grade 3-4 CTCAE)., Conclusion: Belzutifan appears to be an effective and safe treatment for CNS hemangioblastoma in VHL patients. Further clinical trials to assess the long-term effectiveness of the medication are required., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Trigeminal neuralgia (TN) is a paroxysmal, unilateral, brief, shock-like pain in ≥1 divisions of the trigeminal nerve. It can result from multiple causes; however, TN secondary to stroke is very rare., Methods: We present the case of TN secondary to pontine infarction treated with incremental doses of neuropathic pain medication for >5 years before conservative management failed. He was then treated with stereotactic radiosurgery (SRS). Additionally, we conducted a systematic review using standard PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines for all the cases of TN with brainstem stroke from 1976 to 2022., Results: Our patient was an 82-year-old man. Magnetic resonance imaging demonstrated a pontine lesion consistent with stroke. The Barrow Neurological Institute (BNI) score at presentation was 5. He received a marginal dose of 60 Gy to the 80% isodose line in a single fraction to a volume of 0.05 cm 3 . The immediate post-treatment BNI score was 0 and remained at 0 for 3 months, when he experienced recurrence. The recurrence was treated with oxcarbazepine. His pain remained well controlled with a lower dose of oxcarbazepine, and he had no adverse effects at 1 year of follow-up with a BNI score of 3. The systemic review identified 21 case reports with a combined cohort of 25 patients with TN secondary to stroke. Only 3 patients were treated with SRS, 2 of whom reported symptom improvement at 6 months and 8 months of follow-up with no adverse events., Conclusions: Our case and literature review demonstrate durable and effective treatment with SRS, which can be considered a safe and effective treatment option for patients with stroke-associated TN., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: PFTK1/Eip63E is a member of the cyclin-dependent kinases (CDKs) family and plays an important role in normal cell cycle progression. Eip63E expresses primarily in postnatal and adult nervous system in Drosophila melanogaster but its role in CNS development remains unknown. We sought to understand the function of Eip63E in the CNS by studying the fly ventral nerve cord during development., Results: Our results demonstrate that Eip63E regulates axogenesis in neurons and its deficiency leads to neuronal defects. Functional interaction studies performed using the same system identify an interaction between Eip63E and the small GTPase Rho1. Furthermore, deficiency of Eip63E homolog in mice, PFTK1, in a newly generated PFTK1 knockout mice results in increased axonal outgrowth confirming that the developmental defects observed in the fly model are due to defects in axogenesis. Importantly, RhoA phosphorylation and activity are affected by PFTK1 in primary neuronal cultures. We report that GDP-bound inactive RhoA is a substrate of PFTK1 and PFTK1 phosphorylation is required for RhoA activity., Conclusions: In conclusion, our work establishes an unreported neuronal role of PFTK1 in axon development mediated by phosphorylation and activation of GDP-bound RhoA. The results presented add to our understanding of the role of Cdks in the maintenance of RhoA-mediated axon growth and its impact on CNS development and axonal regeneration., (© 2023. The Author(s).)

Background: Choroid plexus papillomas (CPPs) are rare intraventricular brain tumors derived from the epithelium of the choroid plexus. Gross total resection has traditionally been considered curative, but residual tumor or recurrence remains possible. Stereotactic radiosurgery (SRS) has become a more important strategy for subtotally resected and recurrent tumors. The evidence-based rationale of SRS treatment for residual or recurrent CPP in adult patients is still lacking because of the rarity of the disease., Methods: We retrospectively reviewed the cases of histopathologically confirmed patients with residual or recurrent CPP treated with SRS at our institute in the adult population between 2005 and 2022. Three patients, with 5 lesions, were identified, with a median age of 63 years. Patients presented initially with hydrocephalus-related symptoms, although ventriculomegaly was noted in only 1 patient radiographically. The tumor location was most commonly in the fourth ventricle or along the foramen of Luschka. Treatment was delivered in a single fraction in 4 lesions and in 3 fractions in 1 patient. The median follow-up was 26 months., Results: The local tumor control rate for the lesions was 80%. One patient developed a new lesion outside the SRS field, and 1 lesion developed progression without the need for subsequent treatment. There was no significant shrinkage of the lesions radiographically. None of the patients showed radiation-related adverse events. No patients required surgical management after SRS treatment at our institution. Based on the literature review, our case series was the second largest retrospective series from a single institution on SRS for recurrent or residual CPP., Conclusions: SRS for patients with recurrent or residual CPP was a safe and effective treatment modality in this case series. Larger studies are encouraged to validate the role of SRS in the treatment of recurrent or residual CPP., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: When polygenic risk score (PRS) is derived from summary statistics, independence between discovery and test sets cannot be monitored. We compared two types of PRS studies derived from raw genetic data (denoted as rPRS) and the summary statistics for IGAP (sPRS)., Results: Two variables with the high heritability in UK Biobank, hypertension, and height, are used to derive an exemplary scale effect of PRS. sPRS without APOE is derived from International Genomics of Alzheimer's Project (IGAP), which records ΔAUC and ΔR 2 of 0.051 ± 0.013 and 0.063 ± 0.015 for Alzheimer's Disease Sequencing Project (ADSP) and 0.060 and 0.086 for Accelerating Medicine Partnership - Alzheimer's Disease (AMP-AD). On UK Biobank, rPRS performances for hypertension assuming a similar size of discovery and test sets are 0.0036 ± 0.0027 (ΔAUC) and 0.0032 ± 0.0028 (ΔR 2 ). For height, ΔR 2 is 0.029 ± 0.0037., Conclusion: Considering the high heritability of hypertension and height of UK Biobank and sample size of UK Biobank, sPRS results from AD databases are inflated. Independence between discovery and test sets is a well-known basic requirement for PRS studies. However, a lot of PRS studies cannot follow such requirements because of impossible direct comparisons when using summary statistics. Thus, for sPRS, potential duplications should be carefully considered within the same ethnic group., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction Glioblastoma (GBM) is the most common malignant adult brain tumor and is invariably fatal. The standard treatment for GBM involves resection where possible, followed by chemoradiation per Stupp's protocol. We frequently use stereotactic radiosurgery (SRS) as a single-fraction treatment for small (volume ≤ 1cc) nodular recurrent GBM to the contrast-enhancing target on T1 MRI scan. In this paper, we aimed to evaluate the safety and efficacy of SRS for patients with contrast-enhancing satellite nodules in recurrent GBM. Methods This retrospective study analyzed the clinical and radiological outcomes of five patients who underwent CyberKnife (Accuray Inc., Sunnyvale, California) SRS at the institute between 2013 and 2022. Results From 96 patients receiving SRS for GBM, five (four males, one female; median age 53) had nine distinct new satellite lesions on MRI, separate from their primary tumor beds. Those nine lesions were treated with a median margin dose of 20 Gy in a single fraction. The three-, six, and 12-month local tumor control rates were 77.8%, 66.7%, and 26.7%, respectively. Median progression-free survival (PFS) was seven months, median overall survival following SRS was 10 months, and median overall survival (OS) was 35 months. Interestingly, the only lesion that did not show radiological progression was separate from the T2-fluid attenuated inversion recovery (FLAIR) signal of the main tumor. Conclusion Our SRS treatment outcomes for recurrent GBM satellite lesions are consistent with existing findings. However, in a unique case, a satellite nodule distinct from the primary tumor's T2-FLAIR signal and treated with an enlarged target volume showed promising control until the patient's demise. This observation suggests potential research avenues, given the limited strategies for 'multicentric' GBM lesions., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Park et al.)

Solid tumors metastasizing to the brain are a frequent occurrence with an estimated incidence of approximately 30% of all cases. The longstanding conventional standard of care comprises surgical resection and whole-brain radiotherapy (WBRT); however, this approach is associated with limited long-term survival and local control outcomes. Consequently, stereotactic radiosurgery (SRS) has emerged as a potential alternative approach. The primary aim of SRS has been to improve long-term control rates. Nevertheless, rare observations of abscopal or out-of-field effects have sparked interest in the potential to elicit antitumor immunity via the administration of high-dose radiation. The blood-brain barrier (BBB) has traditionally posed a significant challenge to the efficacy of systemic therapy in managing intracranial metastasis. However, recent insights into the immune-brain interface and the development of immunotherapeutic agents have shown promise in preclinical and early-phase clinical trials. Researchers have investigated combining immunotherapy with SRS to enhance treatment outcomes in patients with brain metastasis. The combination approach aims to optimize long-term control and overall survival (OS) outcomes by leveraging the synergistic effects of both therapies. Initial findings have been encouraging in the management of various intracranial metastases, while further studies are required to determine the optimal order of administration, radiation doses, and fractionation regimens that have the potential for the best tumor response. Currently, several clinical trials are underway to assess the safety and efficacy of administering immunotherapeutic agents concurrently or consecutively with SRS. In this review, we conduct a comprehensive analysis of the advantages and drawbacks of integrating immunotherapy into conventional SRS protocols for the treatment of intracranial metastasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yoo, Park, Choi, Marianayagam, Lim, Meola and Chang.)

Objective: Esthesioneuroblastoma (ENB), also known as olfactory neuroblastoma, is a rare, malignant tumor of neuroectodermal origin that arises from the olfactory neuroepithelium. In this study the authors present the first series in the literature on distant brain metastases (BMs) secondary to ENB that were treated with stereotactic radiosurgery (SRS), to evaluate the safety and effectiveness of SRS for this indication., Methods: A retrospective analysis of clinical and radiological outcomes of patients with ENB who underwent CyberKnife (CK) SRS at a single center was conducted. The clinical and radiological outcomes of patients, including progression-free survival, overall survival, and local tumor control (LTC) were reported., Results: Between 2003 and 2022, 32 distant BMs in 8 patients were treated with CK SRS at Stanford University. The median patient age at BM diagnosis was 62 years (range 47-75 years). Among 32 lesions, 2 (6%) had previously been treated with surgery, whereas for all other lesions (30 [94%]), CK SRS was used as their primary treatment modality. The median target volume was 1.5 cm3 (range 0.09-21.54 cm3). CK SRS was delivered by a median marginal dose of 23 Gy (range 15-30 Gy) and a median of 3 fractions (range 1-5 fractions) to a median isodose line of 77% (range 70%-88%). The median biologically effective dose was 48 Gy (range 21-99.9 Gy) and the median follow-up was 30 months (range 3-95 months). The LTC at 1-, 2-, and 3-year follow-up was 86%, 65%, and 50%, respectively. The median progression-free survival and overall survival were 29 months (range 11-79 months) and 51 months (range 15-79 months), respectively. None of the patients presented adverse radiation effects., Conclusions: In the authors' experience, SRS provided excellent LTC without any adverse radiation effects for BMs secondary to ENB.

Purpose: To assess diagnostic performance of quantitative ultrasound (QUS) biomarkers in assessing hepatic steatosis., Methods: We prospectively recruited 125 participants (mean age 54 years) who underwent liver QUS, magnetic resonance imaging (MRI), and laboratory tests within 30 days in this IRB approved study. Based on MRI-proton density fat fraction (MRI-PDFF) and MRE, we divided 125 participants into normal liver, nonalcoholic fatty liver (NAFL) and liver fibrosis (≥F1) groups. We examined diagnostic performance of ultrasound attenuation coefficient (AC), normalized local variance (NLV), superb microvascular imaging-based vascularity index (SMI-VI), and shear wave velocity (SWV) for determining hepatic steatosis and fibrosis using area under receiver operating characteristic curve (AUC). We also analyzed correlations of QUS biomarkers to MRI using Spearman correlation coefficient., Results: We observed significant differences in AC, NLV, and SMI-VI among the three groups (22 participants with normal liver, 78 with NAFL, and 25 with liver fibrosis). AUC of AC, NLV, and SMI-VI for determining ≥ mild steatotic livers (MRI-PDFF ≥5%) was 0.95, 0.90, and 0.92, respectively. AUC of SWV for determining ≥ F1 liver fibrosis was 0.93. The correlation of MRI-PDFF was positive to AC (r = 0.91) and negative to NLV (r = -0.74), SMI-VI (r = -0.8) in NAFL group. There was a significant difference in regression slope of AC to MRI-PDFF in livers with and without ≥F1 (0.84 vs 0.91, P = .02)., Conclusions: QUS biomarkers have high sensitivity and specificity to determine and grade hepatic steatosis and detect liver fibrosis. The effect of liver fibrosis on the performance of QUS biomarkers in quantifying liver fat content warrants further investigation., (© 2023 American Institute of Ultrasound in Medicine.)

Objective: Brain metastases (BMs) secondary to sarcoma are rare, and their incidence ranges from 1% to 8% of all bone and soft tissue sarcomas. Although stereotactic radiosurgery (SRS) is widely used for BMs, only a few papers have reported on SRS for sarcoma metastasizing to the brain. The purpose of this study was to evaluate the safety and effectiveness of SRS for sarcoma BM., Methods: The authors retrospectively reviewed the clinical and radiological outcomes of patients with BM secondary to histopathologically confirmed sarcoma treated with SRS, either as primary treatment or as adjuvant therapy after surgery, at their institution between January 2005 and September 2022. They also compared the outcomes of patients with hemorrhagic lesions and of those without., Results: Twenty-three patients (9 females) with 150 BMs secondary to sarcoma were treated with CyberKnife SRS. Median age at the time of treatment was 48.22 years (range 4-76 years). The most common primary tumor sites were the heart, lungs, uterus, upper extremities, chest wall, and head and neck. The median Karnofsky Performance Status on presentation was 73.28 (range 40-100). Eight patients underwent SRS as a primary treatment and 15 as adjuvant therapy to the resection cavity. The median tumor volume was 24.1 cm3 (range 0.1-150.3 cm3), the median marginal dose was 24 Gy (range 18-30 Gy) delivered in a median of 1 fraction (range 1-5) to a median isodose line of 76%. The median follow-up was 8 months (range 2-40 months). Median progression-free survival and overall survival were 5.3 months (range 0.4-32 months) and 8.2 months (range 0.1-40), respectively. The 3-, 6-, and 12-month local tumor control (LTC) rates for all lesions were respectively 78%, 52%, and 30%. There were no radiation-induced adverse effects. LTC at the 3-, 6-, and 12-month follow-ups was better in patients without hemorrhagic lesions (100%, 70%, and 40%, respectively) than in those with hemorrhagic lesions (68%, 38%, and 23%, respectively)., Conclusions: SRS, both as a primary treatment and as adjuvant therapy to the resection cavity after surgery, is a safe and relatively effective treatment modality for sarcoma BMs. Nonhemorrhagic lesions show better LTC than hemorrhagic lesions. Larger studies aiming to validate these results are encouraged.

Introduction: Granulocyte-macrophage colony-stimulating factor (GM-CSF), a protein produced in the lung, is essential for pulmonary host defense and alveolar integrity. Prior studies suggest potential benefits in several pulmonary conditions, including acute respiratory distress syndrome and viral infections. This trial evaluated the effect of the addition of inhaled sargramostim (yeast-derived, glycosylated recombinant human GM-CSF) to standard of care (SOC) on oxygenation and clinical outcomes in patients with COVID-19-associated acute hypoxemia., Materials and Methods: A randomized, controlled, open-label trial of hospitalized adults with COVID-19-associated hypoxemia (oxygen saturation <93% on ≥2 L/min oxygen supplementation and/or PaO2/FiO2 <350) randomized 2:1 to inhaled sargramostim (125 mcg twice daily for 5 days) plus SOC versus SOC alone. Institutional SOC before and during the study was not limited. Primary outcomes were change in the alveolar-arterial oxygen gradient (P(A-a)O2) by day 6 and the percentage of patients intubated within 14 days. Safety evaluations included treatment-emergent adverse events. Efficacy analyses were based on the modified intent-to-treat population, the subset of the intent-to-treat population that received ≥1 dose of any study treatment (sargramostim and/or SOC). An analysis of covariance approach was used to analyze changes in oxygenation measures. The intubation rate was analyzed using the chi-squared test. All analyses are considered descriptive. The study was institutional review board approved., Results: In total, 122 patients were treated (sargramostim, n = 78; SOC, n = 44). The sargramostim arm experienced greater improvement in P(A-a)O2 by day 6 compared to SOC alone (least squares [LS] mean change from baseline [SE]: -102.3 [19.4] versus -30.5 [26.9] mmHg; LS mean difference: -71.7 [SE 33.2, 95% CI -137.7 to -5.8]; P = .033; n = 96). By day 14, 11.5% (9/78) of sargramostim and 15.9% (7/44) of SOC arms required intubation (P = .49). The 28-day mortality was 11.5% (9/78) and 13.6% (6/44) in the sargramostim and SOC arms, respectively (hazard ratio 0.85; P = .76). Treatment-emergent adverse events occurred in 67.9% (53/78) and 70.5% (31/44) on the sargramostim and SOC arms, respectively., Conclusions: The addition of inhaled sargramostim to SOC improved P(A-a)O2, a measure of oxygenation, by day 6 in hospitalized patients with COVID-19-associated acute hypoxemia and was well tolerated. Inhaled sargramostim is delivered directly to the lung, minimizing systemic effects, and is simple to administer making it a feasible treatment option in patients in settings where other therapy routes may be difficult. Although proportionally lower rates of intubation and mortality were observed in sargramostim-treated patients, this study was insufficiently powered to demonstrate significant changes in these outcomes. However, the significant improvement in gas exchange with sargramostim shows this inhalational treatment enhances pulmonary efficiency in this severe respiratory illness. These data provide strong support for further evaluation of sargramostim in high-risk patients with COVID-19., (© The Association of Military Surgeons of the United States 2022.)