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Abstract Background Cardiomegaly is a clinically significant incidental finding on chest computed tomography (CT) associated with heart failure, arrhythmias, and sudden cardiac death. Qualitative radiologist assessment is variable, and automated AI tools may enable objective opportunistic cardiac volumetry. Purpose To evaluate whether AI-enabled total cardiac volume (TCVAI) derived from non-ECG-gated, non-contrast chest CT can identify cardiomegaly as defined by echocardiography. Materials and Methods This retrospective study included 307 consecutive patients (median age, 67 years; 56% male) who underwent non-contrast chest CT at a single center on 7 scanner types (4 vendors) and clinically indicated echocardiography within 31 days. A commercially available AI tool (AI-Rad Companion, Siemens Healthineers) automatically quantified TCVAI, indexed to body surface area (TCVAI/BSA). Echocardiography reports were reviewed for chamber dilation and left ventricular hypertrophy (LVH), collectively defined as cardiomegaly. Associations between TCVAI/BSA and echocardiographic findings were assessed using correlation, ordinal regression, and receiver operating characteristic (ROC). Interscan repeatability was evaluated in 248 patients with 544 repeat CT examinations. Prespecified sex-specific thresholds were tested in a temporally independent validation cohort of 50 patients. Results Median TCVAI was higher in patients with cardiomegaly than those without (1061.9 vs 798.4 mL; P < .001). TCVAI/BSA was associated with chamber dilation and LVH severity on univariate analysis and remained associated in multivariable ordinal models, except for right ventricular dilation. Discriminatory performance was fair to good, with area under the curve (AUC) 0.81 (95% CI, 0.75-0.87) in men and 0.77 (95% CI, 0.69-0.85) in women. Interscan repeatability was excellent (intraclass correlation coefficient [ICC]: 0.93). In independent validation, performance ranged from sensitivity 89.3%/specificity 27.3% at a high-sensitivity threshold to sensitivity 28.6%/specificity 100% at a high-specificity threshold. Conclusion AI-derived cardiac volume from routine chest CT shows fair to good performance for identifying echocardiography-defined cardiomegaly with high measurement repeatability, supporting a potential role for automated cardiac volumetry as an objective, opportunistic biomarker.

LBA630 Background: Enfortumab vedotin (EV) + pembrolizumab (pembro) is the established first-line standard of care for locally advanced/metastatic urothelial carcinoma and represents a novel neoadjuvant and adjuvant treatment strategy for patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. The randomized phase 3 KEYNOTE-B15/EV-304 study (NCT04700124) evaluates neoadjuvant and adjuvant EV + pembro followed by radical cystectomy plus pelvic lymph node dissection (RC + PLND) vs neoadjuvant chemotherapy followed by RC + PLND in participants (pts) with MIBC who are eligible for cisplatin-based therapy. Methods: Pts with clinical stage T2-T4aN0M0 or T1-T4aN1M0 MIBC (confirmed by central pathology and central imaging assessment) who were eligible for cisplatin-based chemotherapy and RC + PLND were randomized 1:1 to receive either 4 cycles neoadjuvant EV 1.25 mg/kg IV on days 1 and 8 + pembro 200 mg IV on day 1 Q3W, followed by RC + PLND, and adjuvant 5 cycles EV + 13 cycles pembro (EV + pembro arm) vs 4 cycles neoadjuvant gemcitabine 1000 mg/m 2 on days 1 and 8 + cisplatin 70 mg/m 2 on day 1 Q3W, followed by RC + PLND (cis + gem arm). The primary endpoint was event-free survival (EFS) by blinded independent central review. Key secondary endpoints were pathological complete response (pCR) rate by blinded central pathological review and overall survival (OS). Safety was a secondary endpoint; AEs of special interest were based on distinct prespecified lists for each drug. Results: A total of 405 and 403 pts were randomized to EV + pembro and cis + gem, respectively. Median time from randomization to the data cutoff date of October 27, 2025 was 33.6 months (range, 22.5–53.6). Baseline characteristics were generally balanced between groups. EV + pembro significantly improved EFS (median NR vs 48.5 mo; 24-mo estimated EFS rate 79.4% vs 66.2%; HR 0.53, 95% CI 0.41–0.70; 1-sided P <.0001), OS (median NR vs NR; 24-mo estimated OS rate 86.9% vs 81.3%; HR 0.65, 95% CI 0.48–0.89; 1-sided P =.0029), and pCR rate (55.8% vs 32.5%; estimated difference 23.4%, 95% CI 16.7–29.8; 1-sided P <.0001) vs cis + gem. Grade ≥3 treatment-emergent AEs occurred in 75.7% of pts with EV + pembro and 67.2% with cis + gem. Most common grade ≥3 drug-related AE of special interest for EV was skin reactions (14.1%); most common grade ≥3 AE of special interest for pembro was severe skin reactions (13.9%). Conclusions: Neoadjuvant and adjuvant EV + pembro significantly improved EFS, OS, and pCR rate compared with neoadjuvant gem + cis in pts with MIBC who were eligible for cisplatin-based chemotherapy. The safety profile of EV + pembro was consistent with prior experience with the combination. These results support EV + pembro as an effective perioperative treatment option in this setting. Clinical trial information: NCT04700124 .

98 Background: Circulating tumor DNA (ctDNA) monitoring provides an additional clinical tool for assessing treatment response and emerging resistance. We evaluated the real-world (RW) use and results of FoundationOne Monitor (F1Monitor), a tissue-free ctDNA monitoring assay, in patients (pts) with prostate cancer (PCa). Methods: The clinical laboratory developed test, F1Monitor, was available to physicians in a limited pilot with full discretion of test eligibility, timing, and frequency. Therapy type was a non-mandatory field on the order form. CtDNA was detected and quantified by ctDNA tumor fraction (TF); variants were tracked with variant allele frequency (VAF), and the origin [tumor somatic (TS), germline, or clonal hematopoiesis (CH)] was predicted algorithmically. Results: F1Monitor was ordered by 28 physicians for 215 pts with PCa. Therapy data were known for 156 pts: ADT+ androgen receptor pathway inhibitor (ARPI, N = 69/156 pts, 44%), ADT alone (N = 32, 21%), ADT + chemotherapy (chemo, N = 20,13%), ADT + radioligand therapy (RLT, N = 17, 11%), and others (N = 18). Median follow-up was 188 days. Longitudinal testing (≥2 tests) occurred in 64 pts, often (N = 37) when the first test was ctDNA TF positive (+). Median cadence for serial testing (≥3 tests, N = 31) was 42 days (IQR: 35, 59). ctDNA TF was + at any timepoint in 50% (107/215) of pts overall and 53% (82/156) of pts known to be on therapy, trending higher in pts on ADT+chemo (80%) and ADT+RLT (65%). Median and maximum ctDNA TF values were 11% (IQR: 0.9,37.8%) and 89% respectively. Lowest ctDNA TF and reportable TS VAF quantified were 0.13% and 0.04%, respectively. ctDNA TF longitudinal changes were observed in 67% (43/64) of pts: 92% of pts on ADT+chemo, 69% on ADT+RLT, 59% on ADT+ARPI, and 38% of pts on ADT alone. Among pts with ≥2 tests, 39% (25/64) had ctDNA TF increase, including 6/27 (22%) pts that were ctDNA TF negative (-) on the first test. Of pts with ≥2 tests and any ctDNA TF+ result, 35% cleared ctDNA TF in later tests. 33% of pts were persistently ctDNA TF -. Each test reported an average of 5 alterations: ~2 TS short variants, copy number variants, or rearrangements, and ~2 predicted CH variants. HRR variants were detected in 37% (80/215) of pts (31 with ≥2 tests) : persistent in 20 pts, cleared in 7, and newly emerging in 14. At least 50% of alterations in CHEK2 and ATM were predicted CH. Alterations in PI3K pathway genes were detected in 20% (43/215) of pts: (16 with ≥2 tests) persistent in 6 pts, cleared in 5, and newly emerging in 5. Conclusions: In this RW pilot of tissue-free ctDNA monitoring in PCa, F1Monitor demonstrated high sensitivity in clinical practice, detecting ctDNA TF as low as 0.13% and TS VAF as low as 0.04% while distinguishing tumor-derived from predicted CH variants. Importantly, ctDNA TF was + in 53% of pts while on therapy with observed longitudinal changes for 67% of pts, supporting potential utility of ctDNA for monitoring treatment response and emerging resistance.

TPS290 Background: Landmark randomized trials established the survival benefit of adding D to ADT in mCSPC. Building on this foundation, subsequent trials (PEACE-1 and ARASENS) demonstrated further survival improvements when androgen receptor pathway inhibitors (ARPI) were added to the ADT + D backbone. However, the independent contribution of D within the triplet regimen remains unclear given lack of prospective evaluation. Additionally, tumor suppressor gene (TSG) alterations involving TP53, PTEN, and RB1 are frequently observed in PC and are associated with aggressive biology and poor outcomes, providing an opportunity to enhance prognostic accuracy and optimize selection of candidates for treatment intensification. We hypothesize that adding D to ADT plus A will improve survival compared to ADT + A in mCSPC and stratification by TSG status may identify different treatment effects across molecular subgroups. Methods: ASPIRE is an open-label, two-arm, randomized phase 3 study to assess the benefit of D added to ADT plus A for patients with mCSPC. Eligible patients include those with confirmed adenocarcinoma of the prostate with evidence of distant metastatic disease on conventional imaging and are appropriate to receive D. Patients with metachronous low-volume disease or PSMA-PET only disease are excluded. Candidates must have next-generation sequencing (NGS) results from a CLIA-certified tissue test available for TSG status stratification at registration. Eligible patients will receive ADT plus A (240 mg PO daily) +/- D for up to 6 cycles until progression of disease by PCWG3/RECIST version 1.1 criteria. Prior therapy with ADT (with or without ARPI) initiated within 120 days before registration is permitted. The primary endpoint is overall survival (OS). Secondary endpoints include OS by TSG status; radiographic progression-free survival (rPFS); time to castration resistance; symptomatic skeletal event–free survival; time to worsening of disease-related symptoms (NCCN-FACT FPSI-17); safety and tolerability (CTCAE v5.0); PSA90 response at 6 weeks and 6 months; time to PSA progression; and objective response rate in patients with measurable disease. The study will enroll 1200 patients and is currently actively accruing patients. Clinical trial information: NCT06931340 .

INTRODUCTION: Despite the widespread use of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC), many patients remain at risk of progression. Emerging data suggest that normalization of alkaline phosphatase (ALP) and total bilirubin (TB)—particularly when TB < 0.6 times the upper limit of normal (× ULN)—is associated with improved outcomes compared with ALP reduction to < 1.5 × ULN. This study investigated the association between ALP normalization in response to UDCA and long-term clinical outcomes in a real-world cohort of patients with PBC. METHODS: We compared complication-free survival in patients achieving an ALP > ULN and < 1.5 × ULN (adequate response) with those with an ALP ≤ ULN on UDCA monotherapy. Complication-free survival was defined as the absence of serious liver-related clinical events. Restricted mean survival time was used to quantify survival time gained. RESULTS: Patients achieving normal ALP and/or TB ≤ 0.6 × ULN demonstrated significantly improved complication-free survival compared with those with an adequate ALP response. Event-free survival was extended by 1.34 years (95% CI: 0.56, 2.11; P = 0.001) for ALP normalization alone, 3.7 years (95% CI: 3.11, 4.29; P < 0.001) for TB ≤ 0.6 × ULN, and 4.51 years (95% CI: 4.13, 4.88; P < 0.001) for those meeting both criteria. The risk of severe clinical events was reduced in patients achieving ALP normalization (hazard ratio [HR] 0.34; 95% CI: 0.15, 0.80; P = 0.01), TB ≤ 0.6 × ULN (HR 0.23; 95% CI: 0.09, 0.55; P = 0.001), or both (HR 0.14; 95% CI: 0.05, 0.38; P < 0.001). High-risk patients, defined by liver stiffness measurement ≥ 10 kPa or clinical, histological, or laboratory evidence of cirrhosis or portal hypertension, derived the greatest benefit. DISCUSSION: Achieving normal ALP and TB ≤ 0.6 × ULN is associated with significantly improved complication-free survival, particularly in high-risk patients. These findings highlight the potential of biochemical thresholds as a meaningful therapeutic goal in PBC management.

Abstract Endoscopic sleeve gastroplasty (ESG) facilitates 13.6%–16.2% total body weight loss (TBWL) at 12 months, but falls short of that seen with surgical vertical sleeve gastrectomy, in part owing to the retention of the gastric fundus. In adults with obesity, gastric fundal mucosal ablation (GFMA) reduces fasting plasma ghrelin (FPG), hunger, cravings, and accommodation. Combined GFMA-ESG could improve TBWL. This study aimed to evaluate the effectiveness and safety of sequential GFMA followed by ESG in adults with obesity, building on previously published 6-month results of GFMA alone. This was a prospective, first-in-human, two-phase clinical trial. Ten participants underwent GFMA, followed by ESG at month 6, and were followed for 12 months post-ESG (18 months total). GFMA was performed using hybrid argon plasma coagulation to lift and ablate the entire gastric fundal mucosa. ESG was performed using standard full-thickness endoscopic suturing of the gastric body. The primary end point was TBWL; secondary end points were safety and changes in FPG, maximum tolerated volume (MTV), and validated appetite questionnaires. Mean TBWL was 22.5% (SD 8.3%) at month 18. Hunger-related behaviors and eating self-efficacy showed sustained improvements. FPG was decreased at month 6 and returned toward baseline by month 18, while MTV remained suppressed. No serious adverse events occurred. Sequential GFMA-ESG is safe and induces substantial weight loss, reduced MTV of ingested nutrients, and improved behavioral measures. This combination approach builds on prior traditional ESG and GFMA-only results and may represent a promising advancement of endoscopic therapeutic options for weight loss.