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Abstract Introduction Left atrial-to-coronary sinus (LA-to-CS) shunting through the APTURE transcatheter shunt system aims to unload the LA while preserving the interatrial septum. This article aims to examine the 3-year health status, functional capacity, and clinical outcomes of the ALT-FLOW Early Feasibility Study (EFS). Methods Device safety, patency, and echocardiographic parameters, but also symptoms, health status, and exercise capacity were assessed in patients with left ventricular ejection fraction (LVEF) > 40% (n & 95). Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score predicted 3-year all-cause mortality was compared with observed mortality assessed by Kaplan–Meier analysis using adjudicated events. Predicted and observed HF hospitalization (HFH)-free survival rates were also compared. Results At 3 years, the safety profile remained stable with no new safety signals, and all implanted shunts remained patent. 76.3% of patients improved by at least one NYHA class, and mean KCCQ Overall Summary Scores increased by 25 points from baseline (P < .0001). The 6-min walk distance improved by an average of 39 m (P & .002). These benefits were consistent regardless of baseline pulmonary vascular resistance (PVR). Right heart echocardiographic parameters after 3 years were stable, though a reduction in TAPSE was observed, primarily in the high PVR subgroup. The observed 3-year survival was significantly higher than the MAGGIC-predicted survival (84.4% vs 70.2, respectively; P & .009), as well as the HFH-free survival (68.0% vs 24.0%, respectively; P < 0001). Conclusion In patients with HF and LVEF >40%, the APTURE LA-to-CS shunting confirmed an acceptable safety profile with stable right heart parameters and sustained improvements in symptoms, quality of life, and functional capacity at 3 years. Observed survival and HFH were superior to MAGGIC predictions.

Introduction Psychological comorbidities can negatively impact outcomes of spinal cord stimulation (SCS) for chronic pain. While psychological assessment is commonly required before SCS implantation, evidence supporting its impact on outcomes is limited, and such assessments may be unnecessary for many patients and contribute to delays in care. Our center implemented a screening tool incorporating validated questionnaires and a mental health checklist to triage the need for formal psychological evaluation. This prospective, observational cohort study compared outcomes of SCS trials and implants between patients who bypassed (fast track: FT) versus those who underwent a formal assessment by a psychologist (AP). Methods Data were collected from patients undergoing SCS trials between July 2017 and December 2021. The screening tool used thresholds on validated questionnaires assessing anxiety, depression, catastrophizing, and opioid misuse risk, along with a checklist capturing significant anxiety or depression, self-harm, substance abuse, or mental-health-related hospitalization. Patients screening positive underwent an AP; others proceeded directly to trial (FT). 1 year post implantation outcomes were collected, with successful implantation defined as ≥30% pain reduction from baseline. Results Of 171 patients (114 AP, 57 FT), trial-to-implant rates were similar (72% AP vs 70% FT, p=0.811). The proportion of responders at 1 year post implant was also comparable (53% AP vs 60% FT, p=0.927). Multivariate logistic regression identified that higher baseline pain intensity (adjusted OR (aOR) 0.70, 95% CI 0.53 to 0.92, p=0.011) and use of tricyclic antidepressants (aOR 0.15, 95% CI 0.04 to 0.56, p=0.005) were associated with implant failure, whereas pain duration >10 years was associated with implant success (aOR 3.09, 95% CI 1.06 to 9.02, p=0.039). Conclusions This screening tool effectively identifies patients who can bypass routine psychological assessment without compromising 1 year SCS outcomes. Implementation can streamline patient flow, reduce wait times, and reserve psychological resources for those who need formal evaluation.

LBA629 Background: Whether BCG strain influences clinical efficacy is unclear. BCG shortages and a reliance on a single strain may impact disease outcomes. Evidence also suggests that priming with intradermal (ID) BCG vaccination prior to intravesical (IVe) BCG enhances anti-tumor immunity and cancer clearance. Co-primary objectives address these issues. Methods: The trial design calls for 924 eligible patients with BCG naïve non-muscle invasive bladder cancer (NMIBC) (HG Ta/T1 +/- CIS or CIS alone) with negative purified protein derivative (PPD) to be randomized in a 1:1:1 ratio, to IVe TICE (Arm 1), IVe Tokyo-172 (Arm 2), or ID + IVe Tokyo-172 (Arm 3) BCG, stratifying on age group and clinical stage. IVe BCG included 6 weekly instillations (induction) and three weekly instillations (maintenance) at 3 and 6 months (mo), then every 6 mo for 3 years. Objective 1 tests whether Tokyo-172 BCG is non-inferior (NI) to TICE BCG, specifying a NI hazard ratio=1.34 (84% power). Objective 2 tests whether priming with ID prior to IVe Tokyo-172 is superior to IVe Tokyo-172 (HR=0.71, 83% power). The primary endpoint is high-grade recurrence-free survival (HG-RFS) censored at last cystoscopy, using a one-sided α=0.021 for each test. A Cox model adjusting for the stratification factors is used. Secondary endpoints include adverse events, 6-mo biopsy-proven complete response (CR) in patients with CIS +/- Ta, T1, duration of CR, PPD conversion and HG-RFS, progression-free survival (PFS) and quality of life. Max follow-up is 5 years. Results: 1000 (984 eligible) patients were enrolled from 2/17-12/20. Median (IQR) follow up is 4.6 (3.6, 5.0) yrs. Median age (range) is 70 yrs (26, 99), 17% are female, 9% are non-white, and 34% had CIS at entry. HG-RFS, CR, duration of CR at 4 yrs, and PFS were similar among arms (Table). PPD conversion occurred in 29% and was not correlated with HG-RFS. Gr 1-2 AE rate was similar (67%, 71%, and 67%) and Gr 3-4 (no Gr 5s) rate was 6%, 11%, and 14% for Arms 1,2, and 3, respectively. Conclusions: Tokyo-172 is non-inferior to TICE BCG in terms of HG RFS and CIS CR and is similar for PFS. Gr 3-4 AE rate is higher with Tokyo-172. Priming with Tokyo-172 BCG does not improve HG RFS. PPD conversion is not prognostic. Clinical trial information: NCT #03091660 . CIS Component N (eligible) 5-yr HG RFS HG RFSHR (95.8% CI) @ 5-yrPFS PFS HR(95% CI) @ CR %(95% CI) 4 yr CR duration Tice Ive 333 (330) 58% 79% 62%; 71/114(53%, 71%) 80% Tokyo Ive 332 (327) 64% *0.82(0.63, 1.08) 79% *0.99(0.70, 1.39) 60%; 66/110(50%, 69%) 83% Tokyo ID + Ive 335 (327) 63% **1.00(0.76, 1.33) 77% **1.07(0.76, 1.51) 63%; 69/109(54%, 72%) 80% 3 mo. PPD + conversionY vs. N 782 evaluable225 (29%)557 (71%) 69%67% ^HR=0.91(0.68, 1.22) * Tokyo-172 vs. Tice, ** Tokyo Priming vs. Tokyo no priming. ^conversion to PPD + vs. – @ adjusted for 2 strat factors (and arms for PPD model). PFS event = MIBC, metastasis, or death.

46 Background: Primary results from the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study demonstrated that rucaparib significantly improved radiographic progression-free survival (rPFS) vs physician’s choice of DTX or an ARPI. ECOG PS is used as a predictor of prostate cancer survival. In this post hoc analysis, we report results from the BRCA1/2 subgroup of pts stratified by ECOG PS. Methods: Pts with disease progression after 1 prior second-generation ARPI in any setting were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX or ARPI (abiraterone acetate or enzalutamide). Primary endpoint was rPFS by independent radiology review (IRR). Objective response rate (ORR) for pts with measurable disease and overall survival (OS) were key secondary endpoints. Crossover from physician’s choice to rucaparib was allowed after radiographic progression was confirmed by IRR. Data cutoff was August 25, 2022. Results: Of 302 pts in the BRCA1/2 population, 147 had an ECOG status of 0 (97 rucaparib; 50 physician’s choice) and 155 had ECOG 1 (104 rucaparib; 51 physician’s choice). Baseline characteristics and demographics were generally similar between arms for pts in the ECOG 0 and ECOG 1 groups. Median rPFS favored rucaparib vs physician’s choice for pts with ECOG 0 (11.4 vs 8.2 months; HR, 0.48 [95% CI, 0.30-0.76]) and ECOG 1 (10.9 vs 6.1 months; HR, 0.48 [95% CI, 0.31-0.74]) (Table). Additionally, rPFS favored rucaparib for ECOG 0 and ECOG 1 including those whose prespecified physician’s choice was ARPI or docetaxel (Table). The confirmed ORR (95% CI) of rucaparib vs physician’s choice for ECOG 0 was 54% (37%–69%) vs 16% (3%–40%); the ORR for ECOG 1 was 37% (22%–53%) vs 18% (5%–40%), respectively. Median OS was similar between arms for rucaparib or physician’s choice; median OS was 23.7 vs 21.7 months (HR, 0.91 [95% CI, 0.61–1.37]) for ECOG 0 and 21.8 vs 20.4 months (HR, 0.85 [95% CI, 0.58–1.24]) for ECOG 1. Conclusions: Rucaparib improved rPFS and ORR in pts with BRCA-mutated prostate cancer with an ECOG PS of 0 or 1. OS was similar for these groups in both arms. These data support rucaparib as a treatment option for pts with BRCA-mutated mCRPC, whether ECOG 0 or 1. Clinical trial information: NCT02975934 . Median rPFS in patients in the ECOG 0 and ECOG 1 groups. Rucaparib, n Physician’s choice, n rPFS Rucaparib, median months rPFS Physician’s choice, median months HR (95% CI) rPFS, ECOG 0 97 50 11.4 8.2 0.48 (0.30–0.76) rPFS, ECOG 1 104 51 10.9 6.1 0.48 (0.31–0.74) rPFS, physician’s choice ARPI, ECOG 0 51 24 11.2 5.6 0.42 (0.22–0.78) rPFS, physician’s choice docetaxel, ECOG 0 46 26 11.5 8.8 0.49 (0.24–0.98) rPFS, physician’s choice ARPI, ECOG 1 52 17 11.2 4.5 0.33 (0.16–0.68) rPFS, physician’s choice docetaxel, ECOG 1 52 34 10.7 7.1 0.59 (0.34–1.01)

382 Background: Androgen receptor signaling drives prostate cancer (PC) progression, and genes involved in androgen production, uptake, and conversion (APUC) are key therapeutic targets. We previously defined a 6-APUC gene set ( HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, and CYP17A1 ), that identified metastatic PC with favorable prognosis and predict docetaxel benefit. However, the expression landscape and clinical relevance of APUC genes have not been interrogated in localized PC. Methods: We analyzed the expression of 21 APUC genes in 55,329 radical prostatectomy tumor samples that underwent Decipher prostate genomic classifier (GC) testing (Veracyte Inc) between 2016-2024. Baseline clinical/pathologic factors were retrieved from Decipher GRID database (NCT02609269). Associations between gene expression quartiles with PathoGenomic Risk Factors (PGRF) including Very High Decipher score >0.85 (VHD), Grade Group (GG) 4-5, LNI and SVI were examined. Associations with distant metastatic (DM) outcomes and metastasis free survival (MFS) were evaluated using logistic regression in Mayo545 and Cox regression in Meta855 RP cohorts, respectively. Results: High expression of SRD5A2 was associated with favorable PGRF (lower odds ratio (OR), p<0.0001), lower rate of development of DM (OR 0.36, p<0.05), and longer MFS (Hazard ratio (HR) 0.51, p<0.05). HSD17B6 showed similar results for PGRF (lower OR, p<0.0001), DM (OR 0.58, p<0.05) and longer MFS (HR 0.39, p<0.05) despite being associated with GG4-5 and SVI+ in samples with VHD. In contrast, high expression of SRD5A3 and HSD17B10 had high OR for PGRFs (p<0.0001). High expression of SLCO2B1 , an androgen uptake gene, had the strongest association with GG4-5 and SVI/LNI (p<0.001 for both). We noted that SRD5A2 lacked correlation with SRD5A1 and SRD5A3 , which instead correlated with each other. Compared to all APUC genes, SRD5A2 had limited correlations with almost all APUC genes, including ones that exhibited robust cross correlation with each other . Similar to our prior finding, most APUC genes demonstrated negative correlation with AR expression and AR activity signatures. Key outcomes were validated based on transcriptomic data from 492 samples from TCGA database. Conclusions: Comprehensive analysis of 21 APUC genes in over 55,000 PC identified distinct, context-dependent associations with metastatic outcomes and clinical and molecular risk factors. Notably, high SRD5A2 expression was associated with lower odds of high-risk features and metastatic outcomes, whereas SRD5A1 and SRD5A3 linked to adverse outcomes, suggesting critical yet divergent roles among 5-alpha-reductase family members. These findings underscoring androgen-metabolic heterogeneity and highlighting SRD5A2 as a potential biomarker of indolent biology in localized prostate cancer.

160 Background: To our knowledge, no tools are available to guide care in oligometastatic prostate cancer (omPC). Here, we leveraged individual patient-level data pooled from 8 randomized trials in the X-Met collaboration to construct CEREBRO, a tool for predicting patient-specific responses to various treatment scenarios. Methods: Patients with omPC from the STOMP, ORIOLE, SABR COMET, EXTEND continuous ADT, EXTEND intermittent ADT, ARTO, RADIOSA, and RAVENS trials were included. 6 patients (1%) with missing data were excluded. Treatment scenarios were defined as active surveillance (AS), metastasis-directed therapy (MDT), systemic therapy (ST), or MDT+ST. To account for varying baseline hazards, Weibull models were fit for overall survival (OS); progression-free survival (PFS); and castration-resistance free survival (CRFS) for patients with hormone-sensitive disease. Endpoint definitions were harmonized per X-Met framework. Results: Of 600 patients included (treatment scenarios: AS=50; MDT=153; ST=172; MDT+ST=225), 405 (67%) had hormone-sensitive omPC. With median follow-up of 38 months, median PFS, CRFS, and OS of all patients were 18, 70, and 84 months. In order of relative contribution, inputs for predicting outcomes were: treatment scenario, stage, prostate-specific antigen annotated by ADT status, metachronous vs synchronous presentation, imaging type, number of metastases, hormone sensitivity, and age. The model for each endpoint showed robust fit, calibration, superiority against the null model (per the likelihood ratio test), and risk stratification (Table). Median PFS times for model-defined low-, intermediate-, and high-risk strata were 46 months, 18 months, and 7 months ( p <0.0001). In addition, the PFS and OS models also showed strong discrimination via c index and a large interval of risk probabilities with additive clinical utility per decision-curve analysis (Table). A public webpage will be made available to facilitate prospective trial stratification, patient counseling for patient-specific outcome predictions for each potential treatment scenario, and forecasts comparing outcomes between treatment scenarios. Conclusions: CEREBRO is a high-performance tool, trained on robust prospective data from 8 randomized trials with routinely collected clinical variables, for predicting risk and treatment outcomes in omPC. Given the uncertainties in optimal timing of MDT and combination with ST, this tool has been built to facilitate current decision making. External validation is planned. Model summary. Endpoint C index (95% CI) Calibration Likelihood ratio p Risk strata p Net clinical utility observed between thresholds PFS 0.72 (0.70-0.75) 1.04 <0.0001 <0.0001 0.2-1.0 CRFS 0.63 (0.60-0.70) 1.01 0.02 0.004 0.2-0.5 OS 0.81 (0.76-0.86) 1.01 <0.0001 <0.0001 0.05-1.0

Pancreatic exocrine insufficiency (PEI) is an under-recognised cause of chronic diarrhoea in patients with neuroendocrine tumours (NETs). If left untreated or undertreated, PEI can lead to complications such as oxalate nephropathy (ON), which may result in loss of kidney function and potentially limit oncologic treatment options, including peptide receptor radionuclide therapy (PRRT). We present a man in his late 60s with a small bowel NET who developed persistent, uncontrolled diarrhoea for several years. The diarrhoea was attributed to multiple factors, including secretory NET (ie, carcinoid syndrome), bile acid diarrhoea and PEI secondary to somatostatin analogue therapy. Due to financial constraints, the patient was unable to consistently take pancreatic enzyme replacement therapy (PERT). Years after the diagnosis of NET, the patient developed a new onset worsening of kidney function. Further work-up, including a kidney biopsy, confirmed ON, which significantly limited subsequent treatment options, including PRRT. Routine screening for PEI and early initiation of PERT should be considered in all NET patients with chronic diarrhoea to prevent ON and preserve future treatment options.

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

The expanding application of spinal stimulation therapies in spinal cord injury (SCI) rehabilitation necessitates a critical reexamination of cardiovascular (CV) responses to these interventions. A key question arises: How should blood pressure (BP) responses to stimulation be interpreted, and does the conventional definition of autonomic dysreflexia (AD) adequately capture these phenomena? Researchers remain divided—some classify BP elevations during stimulation as AD, while others attribute them to intentional neuromodulation targeting sympathetic preganglionic neurons. This review scrutinizes the various AD definitions in the literature, including the conventional threshold (systolic BP increase >20 mmHg), revealing substantial limitations in research contexts. While symptomatic AD occurs in only 4-7% of stimulation study participants, asymptomatic BP increases are considerably more frequent. This established threshold lacks robust physiological rationale and creates significant interpretive challenges, particularly when evaluating interventions designed to modulate BP responses. The current limitations of guideline-based definitions of AD challenge research interpretation and clinical translation. Although several publications describe AD as “unregulated” or “uncontrolled,” it has not yet been incorporated into formal guideline definitions. This review underscores the need for a collaborative effort to refine AD definitions in research, particularly in the context of spinal stimulation. Future consensus development should address whether uniform thresholds should apply across different contexts, how to integrate heart rate dynamics and absolute BP values alongside symptomatic status, and how to meaningfully distinguish therapeutic BP modulation from adverse autonomic responses. This is essential for standardizing research approaches, optimizing stimulation parameters, and ensuring efficacy and safety as spinal stimulation technologies advance clinically.