Citations

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Abstract Introduction: Glioblastoma (GBM) tumors contain distinct cell lineages, including treatment-sensitive cells (TSCs) relying on aerobic glycolysis and treatment-resistant persister cells (TRPCs) dependent on lipid metabolism. Our systems biology-based, spatial multi-omics and multi-targeted approach decodes a critical node in GBM progression, lipid acquisition in TRPCs, and validates this through a retrospective analysis of statin-treated patients, offering clinical insights into the potential benefits of targeting lipid metabolism in high TRPC signature GBM patients. Methods: We performed spatial transcriptomics and proteomics, combined with 3D rendering of the tumor microenvironment (TME) and geospatially resolved single-cell neighborhood analysis of IHC-stained GBM tissues using our custom-developed SNAQ algorithm to investigate the immune microenvironment and lipid distribution specific to TSCs and TRPCs. To characterize lipid dynamics, we employed flow cytometry, time-lapse imaging, and holotomography to track lipid transfer from Tumor-Associated Myeloid Cells (TAMCs) to TRPCs. A critical node for GBM progression was identified through in vivo survival and tumor progression studies that assessed effects of genetic targeting of CCR2 and pharmacological targeting of CSF1R and FABP3. Retrospective analysis was conducted on 4,085 GBM patients to evaluate the effect of statin treatment on GBM outcomes based on their TRPC signature. Results: Our study establishes the skewed accumulation of TAMCs within the TRPC microenvironment through upregulation of the CCL2/7-CCR2 and CSF1-CSF1R pathways. TAMCs actively transfer lipids to TRPCs to fulfill their metabolic demands. Targeting elements responsible for lipid incorporation in TRPCs, such as CCR2, CSF1R, and FABP3 in vivo, resulted in tumor immune microenvironment remodeling, significant tumor growth reduction, and improved survival. This reinforces the critical role of metabolic communications via lipid trafficking in TRPCs as an essential node in GBM progression. Our retrospective study showed that GBM patients with elevated TRPC signatures, typically associated with shorter survival, had no significant survival differences when treated with lipid-lowering statins. This suggests statins may disrupt lipid metabolism in TRPCs, reducing TAMC lipid support and improving patient outcomes. Conclusion: Our study highlights lipid trafficking in TRPCs as a key mechanism in GBM progression, suggesting that targeting TAMC recruitment and lipid acquisition in TRPCs may offer a promising therapy. Additionally, our retrospective analysis highlights the potential of transcriptomic profiling for patient stratification based on TRPC signature expression levels, enabling the identification of patients to benefit from lipid metabolism-targeted therapies. Citation Format: Avirup Chakraborty, Changlin Yang, Diana Feier, Aryeh Silver, Nyla T. Searl, Miruna Anica, Avinash Pittu, Illena West, Olusegun O. Sobanjo, Ethan D. Hodge, Mia K. Engelbart, Srabasti Sengupta, Nagheme Thomas, Christina Von Roemeling, Maryam Rahman, Matthew Sarkisian, Jianping Huang, Jeffrey Harrison, Duane A. Mitchell, Loic P. Deleyrolle. Disrupting lipid metabolism in GBM: A systems biology approach to targeting treatment-resistant persister cells and tumor associated myeloid cell-mediated support [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB082.

PURPOSE Survival for patients with melanoma has recently improved. The propensity of melanoma to metastasize to the brain remains a common and serious feature of this disease. The purposes of this study were to evaluate prognostic factors for patients with newly diagnosed melanoma brain metastases (MBMs) in a large cohort treated with modern multimodal therapies, compare those results with those in prior eras, and update the Melanoma Graded Prognostic Assessment (GPA). METHODS Univariable and multivariable (MVA) analyses of prognostic factors and treatments associated with survival were performed on 1,796 patients with newly diagnosed MBM treated between January 01, 2015, and December 31, 2021, using a multi-institutional retrospective database. Multiple imputation was used to address missingness of potential predictors. Significant variables in combined MVA were used to update the Melanoma GPA. Comparisons were made with legacy cohorts. RESULTS Median survivals for cohorts A (1985-2007, n = 481), B (2006-2015, n = 823), and C (2015-2021, n = 1,796) were 6.7, 9.8, and 16.6 months and median follow-up times were 40.1, 43.6, and 48.8 months, respectively. In combined MVA, significant prognostic factors for survival were higher Karnofsky Performance Status, fewer MBMs, absence of extracranial metastases, lower serum lactate dehydrogenase, and no immunotherapy before MBM. These factors were incorporated into the updated Melanoma GPA. The combined median and 3-year survivals for patients with GPA 0-1, 1.5-2, and 2.5-4.0 were 5.4, 13.2, and 43.2 months and 12.4%, 28.8%, and 51.6%, respectively. CONCLUSION Prognostic factors have changed and survival has improved for patients with MBM but varies widely by GPA. The updated Melanoma GPA calculator (BrainMetGPA), available free online, can be used to estimate survival, individualize treatment, stratify clinical trials, guide surveillance, and augment clinical trial eligibility. Multidisciplinary treatment is essential. Trials are needed to elucidate the optimal sequencing of various therapeutic modalities.

The integration of immersive virtual reality (IVR) in orthopedic surgery offers a platform for surgeon-to-surgeon collaboration. This paper explores a new use case of IVR-based collaboration among orthopedic surgeons, focusing on three key areas: surgical training, procedural planning, and remote peer to peer collaboration. Immersive virtual reality enables surgeons to engage in immersive, interactive environments where complex anatomical structures and surgical techniques can be visualized in three dimensions. This fosters more efficient communication, precise surgical planning, shared learning experiences and an opportunity to enhance 3D visual spatial intelligence. This case study highlights how surgeons in different geographic locations can collaborate, sharing knowledge and expertise in real time without the constraints of physical presence. This connectivity provides a platform for skill acquisition, and the practice of surgical techniques while creating an opportunity for a mentor to educate a remote learner. Moreover, IVR facilitates the rehearsal of a procedure, potentially contributing to improved patient outcomes by reducing errors and enhancing preoperative planning and education. In the context of orthopedic surgery, the ability to virtually simulate surgeries in a collaborative setting represents a novel advancement. IVR also allows for the customization of surgical scenarios, providing surgeons with repeated exposure to common and rare, complex cases, thus broadening their experience base. By supporting a connected surgical community, IVR-based surgeon-to-surgeon collaboration has the potential to create opportunities for educators and learners to connect and learn in a meaningful manner.

Abstract Endometriosis (EMS) is a prevalent systemic disorder impacting 10% of women of reproductive age, characterized by the growth of endometrial-like tissue outside the uterine cavity, chronic inflammation, and fibrosis, leading to pain, infertility, and organ dysfunction. Despite its widespread occurrence, the pathogenesis of EMS remains elusive, and current treatments are inadequate, with recurrence post-surgery being a significant issue. Notably, EMS displays features reminiscent of malignancy, including genetic mutations and clonal cell proliferation. The presence of tertiary lymphoid structures (TLSs) within lesions indicates a potential role of immune dysfunction in disease progression. This study aims to explore immune mechanisms underlying EMS through three specific aims: 1) Analyzing cellular, molecular, and spatial characteristics of T and B cell interactions; 2) Defining the functional phenotype of immune cells involved; and 3) Investigating the B cell antigen receptor repertoire and the specificity of locally produced antibodies. Techniques such as single-cell RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence, are employed. The outcomes provide insights into immune contributions to EMS pathology and guide the development of novel diagnostic and therapeutic strategies. Citation Format: Ariana F Rahman, Khashayarsha Khazaie, Elika Javaheri, Yohannes Woldeamanuel. Characterizing immune dysregulation and tertiary lymphoid structures in endometriosis: Pathogenic insights and therapeutic implications [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B081.

Abstract Metastasis accounts for the overwhelming majority of cancer deaths. In prostate cancer and many other solid tumors, progression to metastasis is associated with drastically reduced survival outcomes, yet the mechanisms behind this progression remain largely unknown. ATPase family AAA domain containing 2 (ATAD2) is an epigenetic reader of acetylated histones that is overexpressed in multiple cancer types and usually associated with poor patient outcomes. However, the functional role of ATAD2 in cancer progression and metastasis has been relatively understudied. Here, we employ genetically engineered mouse models of prostate cancer bone metastasis, as well as multiple independent human cohorts, to show that ATAD2 is highly enriched in bone metastasis compared with primary tumors and significantly associated with the development of metastasis. We show that ATAD2 expression is associated with MYC pathway activation in patient datasets and that, at least in a subset of tumors, MYC and ATAD2 can regulate each other’s expression. Using functional studies on mouse bone metastatic cell lines and innovative organ-on-a-chip bone invasion assays, we establish a functional role for ATAD2 inhibition in reducing prostate cancer metastasis and growth in bone. Implications: Our study highlights ATAD2 as a driver of prostate cancer progression and metastasis and suggests it may constitute a promising novel therapeutic target.

Introduction Mechanical thrombectomy for ischemic stroke has traditionally been performed via transfemoral access (TFA). However, newer literature on the subject suggests that trans‐radial access (TRA) may be equally efficacious. Materials and Methods Using relevant keywords, online databases (including Pubmed, Google Scholar, Embase, and Cochrane) were queried from inception until May 2024. Abstracts and full texts were screened according to Preferred Reporting Items for Systematic Reviews and Meta‐analysis (PRISMA) guidelines to shortlist studies that met the inclusion criteria. Risk of bias assessment was performed according to the New Castle Ottawa Scale and Cochrane risk of bias tool 2.0. All dichotomous outcomes were reported as odds ratio (OR) with 95% confidence interval (CI). RevMan software was used to perform the statistical analysis. Results Thirteen observational studies and one randomized clinical trial were included in this meta‐analysis. The total sample size was 4973, of which 4074 patients (81.2%) were included in the TFA group and 899 (18.8%) were included in the TRA group. No significant differences were observed between the two groups in terms of successful recanalization (OR=0.92; 95% CI 0.66‐1.27; p =0.60), first‐pass recanalization (OR=0.84; 95% CI 0.69‐1.01, p =0.06), access to reperfusion time (mean difference ‐2.99 minutes; 95% CI ‐8.33 to 2.44, p =0.27) and favorable functional outcome. Mortality and rates of intracranial hemorrhage were comparable between the two groups as well, but access site complications were significantly lower in the TRA group (OR=0.57; 95% CI 0.37‐0.88; p =0.01). Conclusion Trans‐radial access for thrombectomy in large vessel acute ischemic strokes is comparable to trans‐femoral access in terms of efficacy and has a lower incidence of access site complications. Randomized clinical trial data on head‐to‐head comparison of two techniques is limited, underscoring the importance of conducting pragmatic clinical trials.

ABSTRACTBackgroundOlfactory neuroblastoma (ONB) is a rare sinonasal malignancy primarily treated with surgery. For tumors arising from the olfactory area, traditional treatment involves transcribriform resection of the anterior cranial fossa. Surgery can be performed with unilateral or bilateral resection depending on extent of involvement; however, there are currently no studies comparing outcomes between the two.MethodsProspective and retrospective data on primary ONB patients were collected from a multicenter registry involving eight academic sites. Propensity score matching (PSM) was used to create patient cohorts with similar baseline characteristics. Cox proportional hazards and Kaplan Meier analyses assessed overall survival (OS). Logistic regression assessed associations between extent of resection (unilateral versus bilateral) and tumor recurrence or postoperative cerebrospinal fluid (CSF) leak.ResultsA total of 187 ONB patients (47.6% female) with an average age of 53.6 ± 15.1 years were analyzed. Most tumors were unilateral (81.3%) and predominantly Kadish C (58.3%) or Hyams II (55.8%). Overall, 56.7% of patients underwent bilateral resection. Fifty‐four patients experienced tumor recurrence and nine had postoperative CSF leaks. Following PSM (n = 45/group), extent of resection was not associated with mortality (hazard ratio [HR] 1.73; p = 0.407) or OS (p = 0.400). There was no association between extent of resection and recurrence (odds ratio [OR] 0.90; p = 0.814) or postoperative CSF leak (OR 1.54; p = 0.647).ConclusionsFor ONB tumors where unilateral resection may be feasible and oncologically sound, the decision for unilateral versus bilateral resection showed no significant effect on survival, recurrence, or postoperative CSF leak. Oncologic outcomes may be comparable when resection is tailored to individual patient and tumor characteristics.