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Abstract Background RSV is a common respiratory infection that causes significant morbidity in SOTR. However, risk factors for complications such as hypoxic respiratory failure, mechanical ventilation, and secondary infections have not been well described. Methods This retrospective, international, multicenter cohort study is actively recruiting SOTR hospitalized with RSV. Here, we analyzed data from Mayo Clinic (Rochester, Florida, Arizona), Miami Transplant Institute, Cleveland Clinic, and Royal Melbourne Hospital between 2016 and 2019. Secondary infection was defined as culture positive infection within 90 days of RSV diagnosis. Whenever appropriate, logistic and Cox regression analysis were conducted to identify risk factors. Survival functions were estimated using the Kaplan-Meier method.Figure 1:Forest plots of multivariable logistic regression models for risk factors for A) hypoxia, B) secondary infections, C) mechanical ventilation. Note: all variables included are the ones statistically significant on univariate analysis. Abbreviations: CI, confidence interval; OR, Odds ratio; LRTI: lower respiratory tract infection. Results 233 SOTRs (58.8% male; median, 61 years), including 77 (49.1%) kidney, 23 (9.9%) liver, 79 (33.9%) lung, and 38 (16.3%) heart transplants (Table). Hypoxic respiratory failure, mechanical ventilation, and secondary infection were seen in 98 (42.1%), 23 (9.9%), and 58 (24.9%) patients, respectively. After multivariate analysis, age >60 years, symptoms and imaging evidence of lower respiratory tract infection (LRTI) were associated with oxygen requirement (Figure 1A); similar results were observed in an analysis of the lung transplant cohort only. Risk factors on multivariate analysis for secondary infection include a history of rejection within six months and mechanical ventilation (Figure 1B). Risk factors for mechanical ventilation included age >60 years and LRTI on imaging (Figure 1C) after multivariate analysis. Seventeen (7.3%) patients died within 90 days of diagnosis. Cox univariate analysis identified age >60 years and LRTI on imaging, secondary infections, mechanical ventilation and hypoxia on admission were associated with higher mortality (Figure 2 and 3).Figure 2:Forest plot with Cox proportional hazards models. Note: only univariate results shown, multivariate not done due to low number of events. Conclusion This multicenter study of SOTR hospitalized with RSV identified older age ( >60 years old) as a risk factor for hypoxic respiratory failure, mechanical ventilation and death. Mechanical ventilation and a history if rejection within six months of RSV were associated with increased risk of secondary infections, identifying them as high-risk that needs close surveillance for this complication.Figure 3:Effects of A) Age older than 60 years old and B) mechanical ventilation on 90 day probability of survival after RSV infection Disclosures Michelle Yong, MBBS, FRACP, MPH, PhD, MSD: Grant/Research Support|MSD: Honoraria|Takeda: Advisor/Consultant Yoichiro Natori, MD, Eurofin/Viracor: Honoraria|Nobel Pharma: Advisor/Consultant

Abstract Background Prosthetic valves are considered a risk factor for endocarditis however diagnosing prosthetic valve endocarditis (PVE) is complicated by acoustic shadowing on echocardiography. In 2023, the ISCVID published an update to the Duke Criteria (Duke 2023) which intended to increase the sensitivity in diagnosing PVE. The purpose of this study was to examine how TAVR infective endocarditis (TAVR-IE) was diagnosed at our institution 90 Day Mortality Kaplan Meier Curve Methods HERON was utilized to match cases between ACC/STS databases and the EMR at The University of Kansas Health System (TUKHS). Patients with bacteremia occurring after a TAVR were reviewed. Each case was evaluated if they met rejected/possible/definitive endocarditis criteria in the Modified Duke Criteria (Duke 2005) and the Duke 2023 Criteria. To adjudicate the diagnosis, an expert panel reviewed all cases that met definitive endocarditis criteria in any edition of the Duke Criteria. Results A total of 2371 TAVRs were conducted at TUKHS from 2012 to 2023. We identified 146 cases of post procedure bacteremia. We excluded 53 cases leaving 93 in the cohort. Transeophageal echocardiography was utilized in about half of the cases (TTE 73, TEE 45). F-FDG positron emission tomography/CT was done in six patients and Cardiac CT in one patient. Cultures returning with Enterococcus spp (16). viridans group streptococci (15), and Staphylococcus spp. (15) had similar incidence. About half had either atypical organisms (40) on 2005 Duke criteria or polymicrobial growth (7). Definitive criteria were met in 18 and 21 patients for the Duke 2005 and Duke 2023 Criteria respectively. Two cases had minor microbiological criteria upgraded to major in Duke 2023. One case was promoted to definitive endocarditis based on Cardiac CT. Upon adjudication the panel agreed with Duke 2023 Criteria classification. Sensitivity was calculated 85%/100% for Duke 2005 and Duke 2023 Criteria respectively. Kaplan Meier curves calculated no significant difference of 3 month mortality between TAVR patients who had met definitive criteria and those who did not. (Figure #1) Conclusion The 2023 ISCVID Duke Criteria in this study appeared to have superior sensitivity for TAVR-IE when compared to the older Modified Duke Criteria published in 2005. Disclosures Larry M. Baddour, MD, UpToDate, Inc.: Royalty payments (authorship duties). Wissam El Atrouni, MD, ViiV Healthcare: Advisor/Consultant

Abstract Background Moderate-severe mitral annulus calcification (MAC) and left ventricular (LV) diastolic dysfunction are both linked to increased risks of heart failure and mortality. Assessing LV diastolic function (LVDF) in moderate-severe-MAC by echocardiography is frequently challenging and unreliable. We recently validated an AI-ECG model for LVDF. We aimed to determine if this tool can predict long-term mortality in patients with moderate-severe-MAC and whether it can help establish MAC-specific echocardiographic LVDF parameter cutoffs. Methods This retrospective study included all patients from the AI-ECG LVDF study test cohort who underwent comprehensive transthoracic echocardiography confirming moderate-severe-MAC and ECG within fourteen days of each other at Mayo Clinic between 09/2001 and 06/2022. AI-ECG LVDF was determined based on the index ECG. Patients were categorized based on AI-ECG into groups representing normal/grade-1 LVDF, grade-2 LVDF, or grade-3 LVDG (DF-1, DF-2, and DF-3, respectively). Results Of 2,506 patients with moderate-severe-MAC [mean age 77, 64.1% females], 709 (28.3%), 1,510 (60.3%), and 287 (11.5%) were classified as DF-1, DF-2, and DF-3, respectively. Worse LVDF grade was associated with older age, male sex, lower LV ejection fraction, and higher rates of noncardiovascular and cardiovascular comorbidities. Over a median follow-up of 2.8 years, 1,059 (42.3%) patients died. In multivariable survival analysis, DF-2 [adjusted hazard ratio (aHR) 1.43, 95% confidence interval (95%CI) 1.21-1.68] and DF-3 (aHR 1.54, 95%CI 1.22-1.93) were independently associated with a higher risk of death (figure). Findings were also consistent after adjusting to mitral inflow gradients. When comparing LVDF echocardiographic parameters in controls without MAC matched by age, sex, left ventricular ejection fraction, and AI-ECG DF grade, significant differences were observed. Patients with moderate to severe MAC generally exhibited lower e' velocities, higher TR velocities, elevated E/e' ratios, and increased LAVi. Interestingly, the E/A ratio between MAC patients and their matched controls across AI-ECG LVDF grades remained consistent. Conclusion AI-ECG LVDF predicts mortality risk in patients with moderate-severe-MAC, regardless of mitral inflow gradients. Utilizing AI-ECG LVDF might aid in the risk stratification of patients with significant MAC.

Abstract Background AI-enhanced electrocardiogram (AI-ECG) is a cost-effective tool for left ventricular dysfunction screening. However, its cost-effectiveness for other forms of structural heart disease (SHD) is unknown. While AI-ECG is inexpensive, the relatively low positive predictive value (PPV) of many models can lead to high costs from unnecessary follow-up tests like transthoracic echocardiography (TTE). Therefore, strategies to improve the yield of AI-ECG-based screening are needed. Purpose To evaluate the cost savings of a stepwise approach to SHD screening using AI-ECG followed by point-of-care ultrasound (POCUS) compared to AI-ECG alone. Methods 286 adult outpatients undergoing AI-ECG were randomly selected to undergo same-day POCUS. All participants were required to have a recent TTE, our gold standard for SHD diagnosis, for comparison purposes. We evaluated four SHDs: aortic stenosis, cardiac amyloidosis, hypertrophic cardiomyopathy, and left ventricular dysfunction (defined as left ventricular ejection fraction <50%). The costs of AI-ECG ($75/test) and TTE ($1,305/test) were sourced from Healthcare Bluebook, while the cost of POCUS ($100/test) was independently estimated. We compared the costs of screening with AI-ECG alone to stepwise screening with AI-ECG followed by POCUS. Costs were analyzed for two paradigms: screening for all forms of SHD in parallel and screening for each SHD individually. Results AI-ECG alone identified potential SHD in 125 out of 286 patients. When compared to TTE, only 39 out of 125 were true positives (31% PPV). Among the AI-ECG-positive patients, POCUS demonstrated findings of SHD in 52 out of 125 cases. When compared to TTE, this stepwise approach yielded 32 true positives and 20 false positives (62% PPV). In the parallel screening paradigm, the cost per patient diagnosed with SHD was $4,733 with AI-ECG alone, which decreased to $3,182 with stepwise screening (33% cost savings). For the individual SHD screening paradigm, cost reductions were as follows: aortic stenosis ($18,724 to $6,315, 66% savings), cardiac amyloidosis ($21,023 to $12,230, 42% savings), hypertrophic cardiomyopathy ($9,883 to $6,175, 38% savings), and left ventricular dysfunction ($4,019 to $3,582, 11% savings). Conclusions Stepwise SDH screening with AI-ECG followed by POCUS markedly reduces costs compared to AI-ECG alone. The greatest cost savings for individual SHD screening were observed for aortic stenosis and cardiac amyloidosis, conditions where AI-ECG models have lower PPVs. Parallel screening for multiple SHDs is also less costly than screening for any individual SHD alone. Therefore, a parallel screening approach may maximize SHD detection while minimizing screening costs. Stepwise Screening Approach for SHD SDH Screening Costs

Importance Normothermic machine perfusion (NMP) has been shown to reduce peritransplant complications. Despite increasing NMP use in liver transplant (LT), there is a scarcity of real-world clinical experience data. Objective To compare LT outcomes between donation after brain death (DBD) and donation after circulatory death (DCD) allografts preserved with NMP or static cold storage (SCS). Design, Setting, and Participants This single-center, retrospective observational cohort study included all consecutive adult LTs performed between January 2019 and December 2023 at the Mayo Clinic in Arizona. Data analysis was performed between February 2024 and June 2024. Outcomes of DBD-SCS, DBD-NMP, DCD-SCS, and DCD-NMP transplants were compared. Exposure DBD and DCD livers preserved on NMP or SCS. Main Outcomes and Measures The primary outcomes were early allograft dysfunction (EAD), intraoperative transfusion, and post-LT hospital resource use, including length of stay (LOS) and readmissions. Secondary outcomes included acute kidney injury (AKI) and 1-year graft and patient survival. Results A total of 1086 LTs were included in the following 4 groups: DBD-SCS (n = 480), DBD-NMP (n = 63), DCD-SCS (n = 264), and DCD-NMP (n = 279). Among LT recipients, median (IQR) age was 60.0 years (52.0-66.0); 399 LT recipients (36.7%) were female. DCD-NMP had the lowest EAD rate (17.5%), followed by DCD-SCS (50.0%), DBD-NMP (36.8%), and DBD-SCS (27.3%) ( P < .001). DCD-NMP had the lowest intraoperative transfusion requirement compared to all other groups. Hospital and intensive care unit (ICU) LOS were shortest in DCD-NMP (median [IQR] hospital LOS, 5.0 days [4.0-7.0]; P = .01; median [IQR] ICU LOS, 1.5 days [1.2-3.1]; P = .01). One-year cumulative readmission probability was 86% lower for DCD-NMP vs DCD-SCS (95% CI, 0.09-0.22; P < .001) and 53% lower for DBD-NMP vs DBD-SCS (95% CI, 0.26-0.87; P < .001). AKI events were lower in DCD-NMP (31.1%) vs DCD-SCS (47.4%) ( P = .001). Compared to SCS, the NMP group had a 78% overall reduction in graft failure (hazard ratio [HR], 0.22; 95% CI, 0.10-0.49; P < .001). For those receiving DCD allografts, the risk reduction was even more pronounced, with an 87% decrease in graft failure (HR, 0.13; 95% CI, 0.05-0.33; P < .001). NMP was significantly protective from patient mortality vs SCS (HR, 0.31; 95% CI, 0.12-0.80; P = .02). Conclusions and Relevance In this observational high-volume cohort study, NMP significantly improved LT clinical outcomes and reduced hospital resource use, especially in DCD allografts. NMP may enhance access to LT by addressing the challenges historically linked with DCD liver use.

TPS788 Background: MSLN is a desirable candidate for targeted therapy given its limited expression in normal tissues and its overexpression in several malignancies, including PANC, mesothelioma, non-small cell lung, and ovarian cancers (TCGA 2022). MSLN-targeted CAR T and T-cell receptor therapies have shown promising clinical activity; however, on-target, off-tumor toxicity, including fatal events, have occurred (1-3). Autologous logic-gated Tmod CAR T therapies address the challenges of on-target, off-tumor toxicity by combining 2 CARs: activating and blocking receptors. The activator recognizes a tumor-associated antigen present on the surface of both tumor and normal cells; the blocker prevents CAR T activity when it binds HLA-A*02, which is present in normal cells and often lost in tumor cells. Thus, in patients with tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells due to retained HLA-A*02 expression (4). HLA-A*02 LOH is observed in various solid tumors, including ~20% of PANC (5). Two autologous CAR T therapies are currently under investigation: A2B530, targeting carcinoembryonic antigen, in the EVEREST-1 trial, and A2B694, targeting MSLN, in the EVEREST-2 trial, described herein. A2B694 may provide a therapeutic window to treat patients with PANC and other MSLN-expressing solid tumors exhibiting HLA-A*02 LOH due to its unique discriminatory mechanism. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 for recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including PANC. Eligible patients must have exhausted options of potentially curative therapy and have recurrent disease. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), in which patients with tumor-associated HLA-A*02 LOH are identified via next-generation sequencing (Tempus AI, Inc) and leukapheresis product is collected. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess the primary endpoint overall response rate per RECIST v1.1 and secondary endpoints progression-free survival and overall survival. The first patient was dosed on April 24, 2024 and dose escalation is ongoing. 1. Beatty, et al. Gastroenterology . 2018. 2. Haas, et al. Mol Ther . 2023. 3. Hong, et al. ESMO 2021. Abstr 9590. 4. Hamburger, et al. Mol Immunol . 2020. 5. Hecht, et al. J Clin Oncol . 2022. Clinical trial information: NCT06051695 .

TPS311 Background: Approximately 45% of dMMR/MSI-H metastatic colorectal cancer (mCRC) in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC patients (pts) may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Within the AtezoTRIBE 8-pt dMMR CRC subgroup treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first progression event at ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow-up has been reduced; as has measurable disease per RECIST. Primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival, objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). Sample size has been modified with the accrual goal of 120 pts randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues at U.S. sites. Current accrual (as of 9-20-2024): 100/120. Clinical trial information: NCT02997228 .

TPS310 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Current accrual (as of 9-20-2024): 500/1,912. Clinical trial information: NCT05174169 .

Objective: Pediatric patients with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) undergo aggressive multimodality treatment. This single institutional analysis of outcomes in this group explored factors associated with local control and survival. Methods: Patients ≤18 years old diagnosed with NRSTS between 10/1990-11/2021 who received radiotherapy (RT) were retrospectively identified. Overall Survival (OS) and disease-free survival (DFS) analyses were performed using Kaplan Meier methods. Cumulative incidence of local and distant failure were estimated. Univariate analysis was performed. Results: Fifty-one pediatric patients with NRSTS were included. Extremity tumors were most common (33/51, 65%), with 80% T1 or T2 (AJCC 8 th ) and 90% non-metastatic. Surgery in 49/51 (96%) resulted in 32 (65%) R0 resections. All received RT (median EQD2 50 Gy, range 42.4-76.9), with brachytherapy or intraoperative (IORT) boosts in 21 cases (41%) (mean EQD2 24.5 Gy). Thirty-four (66.7%) received chemotherapy. With 5.7 years median follow up, 5-year OS and DFS were 70.7% and 67.9%, respectively. Positive margins were significantly associated with worse OS on univariate analysis. Two-year local failure incidence for EBRT was 18.1% and 5.3% for EBRT+boost (HR 3.67, p=0.24). Among 6 observed local failures, 5 occurred after EBRT alone, 3 of which had positive margins. Among the EBRT+boost group, 2 had positive margins, neither with local recurrence. Conclusion: Multimodality treatment of pediatric NRSTS results in 5-year OS and DFS around 70%. R0 resection is essential to optimize outcomes in this population. Although incidence of R1 resections has declined in the modern era, IORT/brachytherapy boost may have a role in selected patients at high-risk for local recurrence.

ObjectiveThe ADVOCATE trial demonstrated that treatment of active granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) with avacopan was noninferior in achieving remission at week 26 and superior for sustained remission at week 52 compared with a prednisone taper. This analysis of ADVOCATE evaluated the efficacy and safety of avacopan in patients with ear, nose, throat (ENT), or lung manifestations.MethodsThis post hoc analysis included patients enrolled in ADVOCATE with ENT or lung manifestations at baseline. Outcomes included remission at weeks 26 and 52, respiratory tract manifestations over time, relapse rate, glucocorticoid‐related toxicity, health‐related quality of life (HRQoL), and safety.ResultsADVOCATE included 144 patients with ENT manifestations (avacopan: n = 75, prednisone taper: n = 69) and 142 with lung manifestations (avacopan: n = 71, prednisone taper: n = 71). Among patients with ENT manifestations, remission was achieved at week 26 by 72.0% (avacopan group) and 71.0% (prednisone taper group) and was sustained at week 52 by 62.7% (avacopan) and 53.6% (prednisone taper). Among patients with lung manifestations, remission was achieved at week 26 by 73.2% (avacopan) and 66.2% (prednisone taper) and sustained at week 52 by 67.6% (avacopan) and 53.5% (prednisone taper). The relapse rate, glucocorticoid toxicity, and measures of HRQoL favored avacopan for both respiratory tract manifestation groups. Safety was comparable across treatment groups.ConclusionPatients with GPA or MPA with ENT or lung manifestations demonstrated similar responses to avacopan, reflecting results reported in the overall ADVOCATE trial population and supporting the administration of avacopan in these subgroups.