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Abstract Background Cardiac sarcoidosis (CS) is an infiltrative cardiomyopathy characterized by myocardial granulomatous inflammation, leading to conduction system abnormalities and ventricular arrhythmias. Cardiac resynchronization therapy (CRT) outcomes in CS patients are controversial. The efficacy of CRT with left bundle branch area pacing (LBBAP) in these patients has not yet been elucidated. Objective To evaluate electrocardiographic, echocardiographic and long-term clinical outcomes after CRT with LBBAP in CS patients. Methods In this retrospective multicenter study, conducted between June 2020 and March 2024, patients with a histopathologically confirmed diagnosis of CS with an indication for CRT were included in the analysis. The primary outcome was a composite of all-cause mortality, heart failure related hospitalizations, implantable cardioverter defibrillator shocks and requirement of left ventricular assist device/heart transplant. The primary safety outcome was procedure-related complications. Secondary outcomes included pre- and post-procedural electrocardiographic and echocardiographic parameters and change in NYHA functional class. Results A total of 16 patients were included in the analysis (mean age 66.2 ± 9.4 years; 62.5% female; body mass index 30.4 ± 8.5 kg/m2). Four patients (25%) had isolated CS. The median follow-up was 579 [Q1: 295.5 – Q3: 797.5] days. Five patients (31.25%) experienced the composite outcome. Among these, two patients (12.5%) had acute heart failure related hospitalizations, two patients (12.5%) died due to severe pulmonary hypertension and sepsis complicated by cardiorenal syndrome, respectively; and one patient (6.25%) presented an episode of ventricular tachycardia that was successfully terminated with an implantable cardioverter defibrillator shock. No patients required advanced heart failure therapies. There were no procedure-related complications. There was a significant improvement in paced QRS duration (Pre 156.8 ± 36.2 vs. Post 128.3 ± 22.3 milliseconds, p=0.003), left ventricular ejection fraction (Pre 36.5 ± 10.6% vs. Post 50.4 ± 12.2%, p<0.001), left ventricular end systolic diameter (Pre 52 [39.5 – 84.3] vs. Post 41 [29 – 72] millimeters, p=0.011) and left ventricular end diastolic diameter (Pre 66.7 [48 – 159] vs. Post 61 [44 – 135] millimeters, p=0.023). Ten (62.5%) patients exhibited an improvement ≥ I in NYHA functional class post procedure. Conclusion In CS patients, CRT with LBBAP was associated with significant improvements in electrocardiographic and echocardiographic parameters, as well as NYHA functional class, alongside favorable long-term clinical outcomes by optimizing interventricular dyssynchrony.Graphical abstract ECG and Echo parameters

Abstract Blood-based multicancer early detection (MCED) tests represent a new approach for cancer detection. To gain insights into the utility of various approaches of evaluating a cancer signal detected (CSD) test result, we evaluated diagnostic journeys of a subset of 6,662 participants in PATHFINDER who had a CSD on both an initial and refined version of an MCED test that also provided a prediction of cancer signal origin (CSO). We sought to determine whether CSO prediction–guided diagnostic evaluations led to diagnostic resolution; whether participants with known risk factors for cancer beyond age alone and a negative initial diagnostic evaluation had a cancer diagnosis during study follow-up; the utility of whole-body imaging in reaching diagnostic resolution; and differences in the diagnostic journeys needed to reach diagnostic resolution for both true- and false-positive results. Of the 39 participants in this analysis, 82% (32/39) achieved diagnostic resolution after the initial evaluation, including 78% (25/32) who reached resolution specifically with a CSO prediction–directed workup. Eighteen percent (7/39) required additional evaluation for persistent clinical suspicion of cancer, all of whom achieved resolution (3 with and 4 without cancer). Whole-body imaging contributed to diagnostic resolution in only 49% of CSD cases. Approximately 90% of true- and false-positive cases had imaging tests; more true positives versus false positives (81.0% vs. 38.9%) had nonsurgical and/or surgical procedures. In conclusion, CSO prediction–directed evaluations enabled diagnostic resolution for most participants, although some with negative initial evaluations but persistent suspicion of cancer required additional testing. Prevention Relevance: MCED testing has the potential to increase detection of cancer at earlier stages. As MCED testing is a new technology, there are few data on the diagnostic journeys patients undergo following testing. We observed that for most patients, CSO prediction–directed workups were efficient, leading to diagnostic resolution after initial evaluation.

Abstract Background and Aims Classification and risk stratification in aortic (AR), mitral (MR), and tricuspid regurgitation (TR) remains a significant clinical challenge. This study aimed to develop an artificial intelligence (AI) system to assess valvular regurgitation and stratify MR-progression risk. Methods Using transthoracic echocardiograms (TTEs) at two sites (internal development/test, external test), the DELINEATE-Regurgitation system was developed to classify AR, MR, and TR severity using colour Doppler videos. Methods of summating video-level classifications into study-level predictions were tested, comparing single-view with multiview approaches integrating predictions across multiple videos. Model agreement with cardiologists was assessed by weighted kappa. A separate AI system (DELINEATE-MR-Progression) analysing colour Doppler videos was developed to predict which patients with mild, mild–moderate, and moderate MR were most likely to progress to moderate–severe or severe MR with analysis by Kaplan–Meier and Cox proportional hazards models. Results A total of 71 660 TTEs with 1 203 980 colour Doppler videos were included. The weighted kappa in internal/external test sets for regurgitation classification was 0.81/0.76 for AR, 0.76/0.72 for MR, and 0.73/0.64 for TR using a multiview approach taking all colour Doppler videos in a study, demonstrating substantial agreement with cardiologist interpretation with superiority of multiview over single view approaches. In the progression analysis, the AI score stratified MR-progression risk even when controlled for clinical factors known to be associated with MR progression [internal test set hazard ratio 4.1 (95% confidence interval 2.5–6.6)]. Conclusions An AI system can accurately classify AR, MR, and TR and predict MR progression beyond currently known risk factors.

309 Background: Standard of care (SOC) treatment options for HR-PCa include RT with long-term androgen deprivation (LT-ADT) or RP with selective use of post-operative RT +/- androgen deprivation therapy (ADT). The optimal treatment approach has been assessed in retrospective population-based and multi-center comparisons, which have yielded mixed results with substantial bias. Therefore, we conducted an emulated randomized comparison of RT vs RP in HR-PCa leveraging patients enrolled in RCTs. Methods: We searched Medline for RCTs in HR-PCa with a SOC arm of an RT- or RP-based regimen. Inclusion required similar experimental treatment and contemporaneous enrollment in the same country to reduce bias. This identified 2 trials, NRG/RTOG 0521 (RT+LT-ADT +/- 6 cycles docetaxel [doce]), and CALGB 90203 (RP +/- neoadjuvant 6 cycles doce and ADT). Due to inherent difference in the biochemical recurrence criteria after RT vs RP, we chose inverse probability of treatment weighted (IPTW) cumulative incidence of distant metastasis (DM) as the primary endpoint, considering deaths as competing events. Death after DM was measured to create a harmonized metric of deaths likely attributed to PCa. To assess potential residual selection bias, death without DM to capture non-cancer associated deaths was analyzed. Results: Overall, 1290 patients (RT n=557, RP n=733) were included, with similar median follow-up of 6.4 years. Prior to IPTW, RP patients were significantly younger with lower baseline PSA compared to RT patients. Adjuvant (18%) and salvage therapy (44%) was used in RP cohort. Cumulative incidence of DM was significantly lower in patients who underwent RT compared to RP (8-year DM: 16% vs 23%; p=0.01; subdistribution hazard ratio [sHR] 0.48 [95%CI 0.34-0.69], p<0.001). 8-year rates of death after DM were 10% vs 8% (p=0.72) in the RP and RT patients, respectively. RT patients had significantly greater risk of death without DM (HR 2.09 [1.01-4.34], p=0.048) with early differences measured. On a cross-arm comparison, 8-year cumulative incidence of DM when comparing SOC RT+LT-ADT group versus the doce+ADT+RP group was 18% vs 21%, respectively (sHR 0.75 [0.45-1.24], p=0.26). Conclusions: HR-PCa patients enrolled on RCTs had significantly lower incidence of DM with an RT-based strategy compared to an RP-based approach. Longer follow-up is needed to assess deaths attributed to PCa. Despite the strengths of the comparison (use of cooperative group RCT data, contemporaneous enrollment in the same country, patients fit enough for chemotherapy, and IPTW adjustments) there appears to be residual unmeasured bias, as expected, based on greater early deaths without DM in the RT arm. Utilization of post-operative radiotherapy and ADT+Doce may mitigate differences between RP and SOC RT+LT-ADT.

Abstract Background Patients experiencing ≥1 recurrence of CDI are at elevated risk for subsequent recurrences and complications versus those with an initial CDI episode. Treatment selection for recurrent CDI (rCDI) is influenced by the number of recurrences a patient has experienced. Fecal microbiota spores, live-brpk (VOWST™; formerly SER-109, hereafter referred to as VOS for Vowst Oral Spores) is an oral microbiota-based therapeutic to prevent rCDI in adults with rCDI after antibacterial treatment for rCDI, thought to work by enabling rapid restoration of the microbiome. We report results from an integrated analysis of two Phase 3 trials to further describe safety/efficacy of VOS in patients, stratified by number of prior CDI recurrences. Methods The randomized, controlled ECOSPOR III trial enrolled 182 patients with ≥2 CDI recurrences, and the open-label, single-arm ECOSPOR IV trial enrolled 263 patients with ≥1 CDI recurrence. VOS was given as 4 capsules over 3 consecutive days after completing antibiotic treatment. Treatment-emergent adverse events (TEAEs) were collected through Week 8 after VOS; serious TEAEs/AEs of special interest were collected through Week 24. Efficacy endpoint included rCDI (toxin-positive diarrhea requiring treatment) through Week 8. Results A total of 77 patients had 1, 150 patients had 2, and 121 patients had ≥3 prior CDI recurrences; incidence of TEAEs was 44%, 70%, and 67%, respectively (Table 1). No serious TEAEs, TEAEs of special interest, or TEAEs leading to study withdrawal were considered related to VOS by investigators. TEAEs in ≥15% of patients with 1, 2, or ≥3 prior CDI recurrences were flatulence (6%; 29%; 29%), abdominal pain (6%; 27%; 16%), fatigue (1%; 26%; 20%), abdominal distension (3%; 22%; 20%), and diarrhea (27%; 21%; 23%). On-study recurrence rate through Week 8 in the overall population was 9.5% (95% CI: 6.6%–13.0%); in those with 1 or multiple (≥2) CDI recurrences, rates (95% CI) were 6.5% (2.1%–14.5%) and 10.3% (7.0%–14.6%), respectively. Conclusion This integrated analysis confirms VOS was well tolerated and rCDI rates were low/consistent in patients, regardless of the number of CDI recurrences. Results suggest VOS may be considered in patients with rCDI, regardless of the number of prior CDI recurrences. Disclosures Matthew Sims, MD, PhD, Adaptive Phage Therapeutics: Grant/Research Support|Applied Biocode: Advisor/Consultant|Applied Biocode: Grant/Research Support|Astra Zeneca: Grant/Research Support|Biotest AG: Grant/Research Support|ContraFect: Grant/Research Support|Janssen: Grant/Research Support|Leonard-Meron Biosciences: Grant/Research Support|Novozyme: Grant/Research Support|OpGen: Advisor/Consultant|OpGen: Grant/Research Support|Pfizer: Grant/Research Support|Prenosis: Advisor/Consultant|Prenosis: Grant/Research Support|QIAGEN: Grant/Research Support|Seres: Advisor/Consultant|Seres: Grant/Research Support|Summit Therapeutics: Grant/Research Support|Venatorx: Advisor/Consultant Colleen S. Kraft, MD, MSc, Ferring: Advisor/Consultant|Seres: Advisor/Consultant Lisa von Moltke, MD, Cara Therapeutics: Board Member|Cara Therapeutics: Stocks/Bonds (Public Company)|Seres Therapeutics: Employee|Seres Therapeutics: Stocks/Bonds (Public Company) Brooke Hasson, PhD, Seres Therapeutics: employee|Seres Therapeutics: Stocks/Bonds (Public Company) Maximilian von Eynatten, MD, Nestlé Health Science: Employment Darrell Pardi, MD, AMT, Inc: Grant/Research Support|Boehringer Ingelheim: Grant/Research Support|Exe GI: Grant/Research Support|Immunic: Advisor/Consultant|Lilly: Advisor/Consultant|Rise Therapeutics: Advisor/Consultant|Rise Therapeutics: Grant/Research Support|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Expert Testimony|Vedanta: Advisor/Consultant|Vedanta: Grant/Research Support

Abstract Purpose: NFE2L2/KEAP1/CUL3 mutations have been validated for radioresistance in cell-based assays and animal models. However, clinical validation of these biomarkers has been challenging because of multimodality treatment regimens. This study aims to investigate the association between NFE2L2/KEAP1/CUL3 mutations and patient outcomes, including local failure, locoregional failure, disease-free survival (DFS), and overall survival, using samples from a phase III trial in which patients were treated with radiation monotherapy at two controlled doses. Patients and Methods: We investigated NFE2L2/KEAP1/CUL3 mutations in 250 randomized patients with T2N0 glottic squamous cell carcinoma receiving definitive radiotherapy in the NRG/RTOG 9512 trial. A total of 119 patients had available biospecimens that were subjected to amplicon-based next-generation sequencing to assess for the presence of NFE2L2/KEAP1/CUL3 mutations without regard to outcomes. Mutations in NFE2L2/KEAP1/CUL3 were assessed blinded to clinical outcomes. Cox models (two-sided α = 0.05) were used to evaluate the association with clinical outcomes, performed by an independent statistical team. Results: Nineteen of 119 patients (16.0%) had NFE2L2/KEAP1/CUL3 mutations. Patient, treatment, and tumor characteristics were similar between those with and without mutations. Patients with mutation compared with those without had significantly more local failure [HR = 3.50; 95% confidence interval (CI), 1.56–7.89; P = 0.0025] and locoregional failure (HR = 3.80; 95% CI, 1.80–8.03; P = 0.0005). DFS was significantly worse for the mutated compared with the nonmutated group in the first 2 years (HR = 2.88; 95% CI, 1.46–5.66; P = 0.0022). The median DFS was shorter in the mutation group (10.3 months) versus those with intact NFE2L2/KEAP1/CUL3 (4.2 years). Conclusions: NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer. See related commentary by Rao, p. 1563

SUMMARYDelirium frequently occurs among hospital in-patients, with significant attributable healthcare costs. It is associated with long-term adverse outcomes, including an eightfold increased risk of subsequent dementia. The purpose of this article is to inform clinicians of the best practices for spotting, stopping and treating delirium and provide guidance on common challenging clinical dilemmas. For spotting delirium, suggested screening tools are the 4 ‘A's Test (in general medical settings) and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Prevention is best achieved with multicomponent interventions and targeted strategies focusing on: (a) avoiding iatrogenic causes; (b) brain optimisation by ensuring smooth bodily functioning; (c) maintaining social interactions and normality. Non-pharmacological approaches are the first line for treatment; they largely mirror prevention strategies, but the focus of empirical evidence is on prevention. Although sufficient evidence is lacking for most pharmacological approaches, an antipsychotic at low doses for short durations may be of utility for highly distressing or high-risk situations, particularly in hyperactive delirium, but only as a last resort.

10608 Background: Cancer is one of the most feared diseases. Multi-cancer early detection (MCED) tests have the potential to expand the number of cancers that are detected at earlier stages, which could result in better clinical outcomes. However, behavioral impacts based on MCED test results could affect the utility and value of these tests. Methods: Two independent data sources evaluated the impact of MCED test results on behavioral intentions and perceptions: a survey of the general population and PRO in an MCED clinical trial. A web-based, 30-minute survey of the US general population was used to ascertain attitudes toward a hypothetical MCED test. Eligible respondents were adults aged 40-80 years without a cancer diagnosis in the previous 5 years. The survey assessed the perceived value of negative results (ie, no cancer signal detected [NCSD]) and the projected impact on post-test behaviors. The prospective PATHFINDER study (NCT04241796) of adults aged ≥50 years who underwent MCED cancer screening included PRO assessments. Post-test assessments included: "I am feeling relieved about my test result" from the adapted MICRA and “How likely are you to follow your healthcare provider’s cancer screening recommendations.” The consistency of sentiment after an NCSD MCED result from the online survey and clinical study was assessed. Results: Of the 1073 online survey respondents, 53% were female, 77% White, 14% Black/African American, and 13% Hispanic. Mean age was 58 years. The most common anticipated emotional impacts were relief (84%), happiness (72%), and confidence (69%). Respondents (66-70%) reported they would expect less worry, fear, stress, and anxiety after an NCSD MCED result. The majority (73%) reported they would maintain or improve health behaviors after an NCSD result. NCSD results were projected to lead to an increase in health-related behaviors, including adherence to recommended cancer screening (98%; 68% increase, 30% maintain current level) and regular doctor visits (46%). Of the 6529 PATHFINDER study participants who received NCSD results, 64% were female, 92% White. Mean age was 63 years. 80% of participants (n = 4685/5865) with NCSD felt relief "sometimes" or "often" after their MCED test result. Over 95% of participants (n = 5637/5863) with NCSD indicated they were "likely" or "very likely" to adhere to cancer screening recommendations in the future. Conclusions: Results from a general population survey and a prospective clinical study indicate that an NCSD result may be associated with positive cancer screening intentions and other preventive healthcare behaviors. An NCSD result may also positively impact psychological and emotional health. While these findings suggest that an NCSD result may provide additional value beyond traditional clinical benefits associated with cancer screening, future research is needed to delineate the behavioral impact following MCED screening. Clinical trial information: NCT04241796 .

11059 Background: Some opioid stewardship policies could negatively affect patients with cancer pain. However, patients with cancer are also at risk for opioid related harms, especially with persistent use. We assessed opioid prescribing trends in the context of cancer treatment and patient reported pain in a large health system in Connecticut. Methods: We conducted a retrospective cohort study of opioid-naïve adult patients with solid tumor malignancies diagnosed from 2016 through 2020 within the Yale New Haven Health System. We identified new (≥1 opioid prescription in 0-6 months following diagnosis) and additional (0-6 and 6-9 months) opioid prescriptions. The analysis evaluated all eligible patients as well as two clinical cohorts: patients treated surgically and patients with metastatic cancer. For patients with metastatic cancer and a documented pain score in the electronic health record flowsheet data, we further stratified by any (any score≥1) or no (all scores=0) pain in the 6 months since diagnosis and prior to first opioid, if given. For these patients, we noted therapeutic class of the first opioid. We used a logistic model adjusted for patient demographics to calculate predicted probability of opioid prescription and change over time. Results: A total of 10,868 patients met study criteria. Overall, we observed a decline in new opioid prescribing from 69.0% to 62.7% (p<.001) (Table). Additional opioid use also declined from 23.4% to 20.2% (p=.02). In the surgery cohort, new opioid prescribing fell from 95.7% to 88.2% (p<.001), while additional opioid use was stable over time (approximately 12%). For patients with metastatic cancer with any documented pain, new opioid prescribing was stable over time (approximately 56%). For those with documented pain scores=0, new opioid prescribing declined from 59.7% to 34.2% (p<.001). In these patients, the class listed on the first opioid prescription was analgesia in 86.6% and cough in 13.4%. Conclusions: Overall, and in patients treated with oncological surgeries, our study in a single large US health system suggests a modest, gradual decline in opioid prescribing for patients with cancer over time. On the other hand, among patients with metastatic cancer, opioid prescribing remained stable for those with documented pain and declined steeply for those without documented pain. [Table: see text]