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ABSTRACT Aging reshapes the architecture of human skeletal muscle, yet objective tissue‐level markers that capture this process remain limited. We combined large‐scale histology with deep learning to identify reproducible features of muscle aging and to test their biological relevance. We analyzed 974 hematoxylin–eosin whole‐slide images from a population resource using a dual‐attention convolutional neural network and an independent Mask R‐CNN model to quantify nuclear size and density, verified by manual review. The classifier distinguished young from aged muscle with high accuracy (AUC 0.91; accuracy 86.2%), and attention maps consistently highlighted nuclear enlargement and spatial disorganization as salient features. Nuclear diameter increased with age (Spearman's ρ = 0.71, p < 0.0001) across automated and manual measurements. Transcriptomes matched to the same donors showed that samples with larger nuclei were enriched for pathways related to chromatin remodeling, proteostasis, cellular senescence, mitochondrial activity, and telomere regulation, whereas smaller nuclei aligned with anti‐inflammatory and DNA repair programs. External pediatric inflammatory myopathies exhibited nuclear enlargement comparable to aged muscle, suggesting inflammation‐related premature histologic aging. These findings identify nuclear enlargement as a robust, quantifiable feature that integrates structural and molecular signatures of muscle aging. The proposed deep learning–based nuclear morphometry provides a scalable framework for tissue‐level aging biomarkers and suggests a potential “muscle aging clock” applicable to both physiological aging and disease states.

e17134 Background: Despite being the most prevalent malignancy among men, prostate cancer (PC) lacks FDA-approved primary prevention therapies. Current options, such as 5-alpha reductase inhibitors (5-ARIs), offer only modest risk reduction—approximately 23–25%—as shown in the PCPT and REDUCE trials. Emerging preclinical data indicate that GLP-1 receptor agonists (GLP-1RAs) may offer a novel alternative by inhibiting oncogenic pathways and inducing apoptosis in PC cell lines. To investigate this potential, we conducted the first real-world comparative analysis of PC incidence among high-risk men receiving GLP-1RAs versus 5-ARIs. Methods: Using the TriNetX global collaborative network (150M patients), we identified men with elevated PC risk (genetic risk, family history, or high-risk demographics/comorbidities). GLP-1RA users (cohort A) were propensity-score-matched 1:1 with 5-ARI users (cohort B) on demographics, metabolic comorbidities, baseline PSA, BMI and HbA1c. A minimum of 2 month’s prescription was required. The primary endpoint was incident PC. The secondary endpoint was adverse events related to GLP-1RA and 5-ARI. Patients with outcomes before the study inclusion were excluded. Sensitivity and subgroup analyses were performed, adjusting for screening frequency and baseline BMI. Kaplan–Meier curves assessed cumulative incidence, Cox models estimated hazard ratios (HRs, 95% CI), and logistic regression analyzed binary outcomes. Results: After matching, 118,904 high-risk men were identified (59,452 patients per cohort). Cohorts had comparable demographics with a mean age of 48 years, 77% White, 9% Black, and 2% Asian. GLP-1RA users had higher mean A1C (6.3% vs 5.7%) and BMI (38 vs 31), while 5-ARI users had higher mean PSA (3.1 vs 1.3). Median follow-up was 7 years for both cohorts. PC incidence was 2.10% (1,245/59,189) in GLP-1RAs users versus 2.85% (1,689/59,164) in 5-ARI users (NNT 133). GLP-1RAs were associated with a 20% reduction in PC risk (HR: 0.803; CI: 0.746–0.864). Safety outcomes showed that GLP-1RAs were associated with an increased risk of erectile dysfunction and nausea/vomiting. In contrast, GLP-1RAs were associated with lower risks of abdominal pain and constipation. No significant associations were observed for gynecomastia or diarrhea. Conclusions: In this large-scale, head-to-head comparison, GLP-1RAs demonstrated superior efficacy over 5-ARIs, providing a 20% relative risk reduction in PC incidence among high-risk men. Given the global surge in GLP-1RA utilization, these findings suggest a profound public health opportunity: the ability to achieve systemic oncologic protection through existing metabolic therapies. If validated by prospective trials, GLP-1RAs could transition from metabolic blockbusters to a cornerstone of precision oncology and primary cancer prevention.

e16449 Background: Pancreatic cancer (PC) carries a dismal 5-year survival of < 12%, and no FDA-approved agents exist for primary prevention. PC risk is strongly linked to obesity, diabetes, and chronic inflammation. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) directly target obesity-driven inflammatory pathways, reduce metabolic stress, and modulate signaling pathways (PI3K/AKT/mTOR) that drive cancer apoptosis. Based on this biological rationale, we conducted the first large-scale real-world study to evaluate the safety and efficacy of GLP-1RA for primary prevention of PC in high-risk patients. Methods: Leveraging a large real-world database (TriNetX), we identified patients aged 18-90 years with ≥1 PC risk factor (tobacco use, obesity, type 2 diabetes, alcohol use disorder, chronic pancreatitis, first-degree relative with PC, genetic susceptibility to PC) based on ICD-10 codes. Patients were stratified by GLP-1RA exposure into two cohorts: Cohort A (GLP-1RA users with ≥ 2 months of prescriptions) and Cohort B (controls). The primary endpoint was incident PC, and the secondary endpoints were adverse events related to GLP-1RAs. Patients with outcomes before the study window were excluded. Propensity score matching adjusted for confounders. Multivariate logistic regression was used to estimate odds ratios for categorical outcomes, and the Cox proportional hazards model was used to estimate hazard ratios for time-to-event outcomes. Subgroup and sensitivity analyses were employed to validate the strength of our results. Results: Median follow-up was 3,397 days for GLP-1RA users and 2,531 days for controls. Demographics were balanced between cohorts (mean age 42 years; 74% White, 15% Black; 72% female). Among 572,330 high-risk patients (286,165 per cohort), PC incidence was significantly lower among GLP-1RA users (0.05%; 134/286,165) than among non-users (0.13%; 362/286,097), with a 2.6-fold reduction in the absolute incidence of PC among high-risk patients (NNT of 1,255). GLP-1RA use was associated with a 71% reduction in PC incidence (HR 0.289; 95% CI 0.237–0.352). GLP-1RA use was associated with an increased risk of gastrointestinal adverse events, including nausea/vomiting (HR 1.108; 95% CI 1.096–1.121), abdominal pain (HR 1.081; 95% CI 1.066–1.097), diarrhea (HR 1.199; 95% CI 1.182–1.217), and constipation (HR 1.159; 95% CI 1.143–1.176). Conclusions: GLP-1RA use significantly reduced PC incidence by 71% in high-risk patients, the strongest real-world signal yet for a pharmacologic prevention of this lethal malignancy. Although the absolute incidence remained low, the magnitude of the risk reduction underscores the transformative potential of GLP-1RA in preventive oncology. These findings address a critical unmet need in pancreatic oncology. Prospective mechanistic and randomized studies are warranted to validate these associations.

10522 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. While antiviral and metabolic therapies have reduced incidence, scalable pharmacologic strategies for primary prevention (PP) remain a critical unmet need. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated preclinical antitumor activity and the potential to mitigate hepatic lipotoxicity while promoting metabolic reprogramming to stabilize cirrhosis. However, while chemoprevention signals are observed in metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes, the efficacy of GLP-1RAs for PP across diverse liver disease etiologies remains underexplored. To address this gap, we conducted a global, multicenter analysis on the efficacy and safety of GLP-1RAs for the PP of HCC in a pan-etiology high-risk cohort. Methods: A retrospective cohort study was conducted using the TriNetX database (150M patients across 108 health organizations). Adults 18–90 years at elevated HCC risk with ≥ 1 risk factor (chronic viral hepatitis, cirrhosis, MASLD, alcohol use disorder, or hereditary liver disorders) were identified. Cohort A (≥3 months of GLP-1RA) was propensity score-matched 1:1 with Cohort B (non-users) on demographics, HbA1c, BMI, and MELD-Na scores. The primary endpoint was incident HCC, and secondary endpoints were incidence of gastrointestinal (GI) side effects. We employed a 3-month lag period to mitigate immortal time bias. Time-to-event outcomes were assessed via Kaplan-Meier analysis and Cox proportional hazards models. Sensitivity & subgroup analyses were performed to confirm robustness across non-metabolic etiologies. Results: After matching, 592,718 patients were analyzed (296,359 per cohort). Median follow-up was 2,450 days for GLP-1RA users vs 2,114 days for non-users. GLP-1RA use was associated with a 73% reduction in incident HCC (140/296,345 events vs 432/296,198) [HR 0.271 (0.224-0.328)], (NNT=1,015). Notably, the protective effect was most pronounced in non-diabetics [HR 0.179 (0.140-0.229)] and lean patients (BMI < 29) [HR 0.161 (0.103-0.252)]. Risk reductions were sustained across all etiologies, including alcohol liver disease (HR 0.379), cirrhosis (HR 0.456), chronic viral hepatitis (HR 0.477), and MASLD (HR 0.605). GLP-1RA use was associated with a significant increase in GI adverse events. Conclusions: GLP-1RA use was associated with a 73% reduction in incident HCC, consistent across subgroups. The enhanced benefit in non-diabetic and lean cohorts suggests a direct anti-neoplastic mechanism independent of weight loss or glycemic control. The NNT of 1,015 highlights the substantial public health impact of GLP-1RA therapy in preventing a high-mortality malignancy. These findings warrant prospective validation.

10520 Background: Therapeutic options for breast cancer (BC) prevention for high-risk women remain limited, and not all eligible patients opt for endocrine therapy due to concerns related to adverse events (AEs). GLP1RAs are widely used for obesity and type 2 diabetes mellitus; their role in BC primary prevention (PP) in high-risk women with obesity has not been evaluated. Methods: Using the TriNetX Global Network (150 million patients, 108 organizations), we analyzed de-identified records of high-risk women aged 18–90 years with a BMI ≥ 30 who had health care encounters between January 1, 2000, and January 1, 2025, identified via ICD-10 codes. High risk was defined as at least one of the following: genetic predisposition to BC, family history of BC, atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, or dense breasts. Patients were grouped as having GLP1-RA use or no GLP-1RA use. Patients with a prior history of BC or use of endocrine therapy were excluded. GLP-1RA users were propensity score-matched 1:1 with non-users based on demographics, comorbidities, social determinants of health, lifestyle factors, BMI, HbA1c, and prior breast imaging. Incident BC served as the primary endpoint, with key AEs as secondary measures. Kaplan–Meier analysis and Cox proportional hazards models were utilized to assess outcomes, which were further validated through subgroup and sensitivity analyses. Results: Among 80,480 high-risk women with a BMI ≥ 30, 46,581 were assigned to each cohort. Baseline demographics were balanced between cohorts (mean age: 46 years, 70% White, 21% Black). Median follow-up was 2,790 vs 2,630 days for GLP-1RA users and non-users, respectively. BC incidence was 2.95% in GLP-1RA users (1,164/39,495 cases) vs 3.01% in non-users (1,200/39,057 cases) (3.27 vs. 3.57 cases per 1,000 person-years; HR 0.844; 95% CI, 0.779–0.915). GLP-1RA users exhibited an increased risk of endometrial cancer (HR 1.273; 95% CI, 1.088–1.491) and osteoporosis (HR 1.124; 95% CI, 1.054–1.199). No significant association was observed for venous thromboembolism. Gastrointestinal AEs were significantly higher in the GLP-1RA cohort. Conclusions: GLP-1RA use was associated with a modest reduction in BC incidence among high-risk women with obesity in this real-world study. Prospective randomized trials are needed to validate these associations.

10507 Background: Despite advances in understanding leukemogenesis, no validated primary prevention strategies exist. Obesity is a dose-dependent risk factor for leukemia. Emerging data implicate epigenetic regulators, specifically the histone methyltransferase GLP (EHMT1), as a driver of leukemic survival; its inhibition induces cell death in CLL and promotes differentiation in AML. We present the first real-world analysis evaluating GLP-1 receptor agonists (GLP-1RA) for the primary prevention of leukemia in high-risk populations. Methods: Using the TriNetX global research network (150 million patients across 108 healthcare organizations), we identified adults at elevated leukemia risk based on ≥1 factor (prior chemo/radiation, MDS, MPN, family history, genetic syndromes, tobacco use, or BMI ≥30). Patients with ≥2 months of GLP-1RA use were propensity-matched 1:1 to non-users by demographics, comorbidities, and prior chemotherapy. The primary endpoint was the incidence of ALL, AML, CLL, or CML; secondary endpoints were adverse events related to GLP-1RA. Individuals with pre-existing leukemia were excluded. Cox proportional hazards models and sensitivity analyses were used to assess associations. Sensitivity and subgroup analysis confirmed robustness. Results: Of 426,670 high-risk individuals, 213,335 were matched to each cohort; standardized mean differences were <0.1 for all covariates. Across >1.2 million person-years of follow-up, GLP-1RA use was associated with a 63% risk reduction in incident AML (47/213,300 vs 75/213,261; HR 0.37, 95% CI 0.26–0.53; p < 0.001) and a 50% reduction in ALL (42/213,304 vs 53/213,277; HR 0.50, 95% CI 0.33–0.75; p = 0.001). The protective effect for AML remained significant when restricted to patients with prior chemotherapy exposure and was independent of baseline BMI. No significant reductions were observed for CML or CLL. While GI adverse events were higher in the GLP-1RA cohort, the protective signal was consistent across age and ethnic subgroups. Conclusions: This is the first large-scale study to demonstrate a significant reduction in incident AML and ALL using GLP-1 receptor agonists in high-risk patients. By linking clinical metabolic intervention to the EHMT1 epigenetic pathway, these findings provide a novel, scalable pharmacologic strategy for the primary prevention of acute leukemias, potentially transforming the management of high-risk and obese populations.

Abstract Objective The aim of this study was to evaluate a large cohort of gallbladder amyloid cases to determine clinical and morphologic features. Methods Cholecystectomy specimens (N = 118) typed using proteomics-based techniques between 2008 and 2023 were identified. Clinical and morphologic features were reviewed. Results Six amyloid types were identified: ATTR (n = 63, 53.4%), AL (n = 46, 39.0%), AA (n = 4, 3.4%), AApoA1 (n = 2, 1.7%), ALECT2 (n = 2, 1.7%), and AEFEMP1 (n = 1, 0.8%). Amyloidogenic mutations were detected in 3 ATTR cases and 2 AApoA1 cases. Morphologic review (n = 26) revealed perimuscular vessel involvement in all cases. Amyloidosis was an unexpected diagnosis first made on the cholecystectomy specimen in half of the patients with clinical information (n = 10). All 9 patients with follow-up had evidence of systemic disease. In 2 patients, cholecystic involvement was initially missed and only retrospectively identified after the diagnosis of cardiac amyloidosis. Conclusions In patients with clinical data, amyloidosis was often unexpected, the gallbladder was commonly the first tissue sampled with amyloidosis, and all patients had systemic disease. Thorough review of cholecystectomy specimens with careful inspection of perimuscular vessels, coupled with a low threshold for ordering Congo red stain in elderly individuals and amyloid typing using a robust method such as proteomics, can prevent a delay in amyloid diagnosis and management.

ABSTRACTBackgroundAdvances in fibril typing by mass spectrometry have improved the accuracy of amyloidosis diagnosis. Dual amyloidogenic proteins have been reported in deposits in sole and multiple different organs.MethodsFive patients with dual amyloidoses were diagnosed between 1995 and 2022 by Congo red staining and fibril typing using the best available methods at the time of evaluation. Sequencing of TTR and GSN genes was performed. Literature search identified 46 additional cases.ResultsThree patients exhibited Waldenström macroglobulinemia‐associated AL (n = 3) amyloidoses in conjunction with ATTRwt or AGel amyloidosis; two patients featured AL/ATTRwt and AA/ATTRwt amyloidoses. One patient demonstrated dual amyloidoses within one anatomical site; three patients featured two amyloidosis types at different anatomical sites; and one patient had dual amyloid deposits in a single anatomical site along with different sites. The time interval between diagnoses was 0–288 months, with the heart and kidneys being the most affected organs.ConclusionsOur findings underscore the complexity of clinical presentation in amyloidosis, as multiple amyloid types can co‐exist in a single individual and affect various anatomical sites. Accurate assessment of the clinical phenotype and thorough amyloid fibril typing from the target organs are essential for precise diagnosis and tailored treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT00898235