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3146 Background: The MTA-cooperative PRMT5 inhibitor BMS-986504 selectively binds to the PRMT5-MTA complex, a synthetic lethal target in MTAP -del cancer cells, while sparing MTAP –wild-type normal cells. In the phase 1 CA240-0007 study, BMS-986504 was well tolerated and had antitumor activity in pts with MTAP -del advanced solid tumors (ORR, 23%; median DOR, 10.5 mo). BMS-986504 also demonstrated dose-dependent reductions in plasma symmetric dimethylarginine (SDMA) levels, a PD biomarker of PRMT5 inhibition. Here, we report expanded PD and genomic analyses and initial results of exploratory proteomic analyses from CA240-0007. Methods: Pts with advanced, unresectable, or metastatic solid tumors with homozygous MTAP -del received BMS-986504 (50–800 mg) in 3-wk cycles. Analyses of SDMA levels and proteomic profiles from paired plasma samples (baseline and C2D1) were performed using mass spectrometry and SomaScan 11K, respectively. Tumor genomic information was extracted from local pathology reports. ORR was assessed per RECIST v1.1. Results: Among 78 pts with paired samples at data cutoff (22 Sept 2025; median f/u, 15.9 mo), dose-dependent reductions were seen in plasma SDMA levels, with the greatest reductions at 400 mg QD (median, 60.3%; n = 31) and 600 mg QD (median, 60.3%; n = 23). Proteomic pathway enrichment analysis demonstrated downregulation of PI3K/Akt/mTOR, Myc target, cell cycle, and DNA damage repair (DDR) pathways with BMS-986504 on C2D1 (n = 87), consistent with the expected effect of PRMT5 inhibition; a trend toward deeper modulation of PRMT5-regulated pathways was observed at higher doses. No proteins at baseline (n = 94) were found to be significantly associated with ORR (false discovery rate > 0.05). Responses in clinically evaluable pts with NSCLC (n = 33) or PDAC (n = 35) were observed regardless of EGFR , KRAS , or TP53 status. In pts with NSCLC, STK11 and SMARCA4 alterations were numerically higher in nonresponders. No gene alterations were associated with response in PDAC, except GABRA6 alterations (n = 2, both responders). A trend toward higher ORRs was seen in pts with alterations in DDR genes ( CHEK2, FANCD2, XRCC4 , and/or MSH2 ), consistent with the role of PRMT5 in DDR via regulation of mRNA splicing. ctDNA analysis will be presented. Conclusions: BMS-986504 demonstrated robust dose-dependent PD effects in pts with advanced solid tumors in plasma SDMA and proteomic analyses. Downregulation of PRMT5-regulated pathways was observed with BMS-986504 treatment. Response was seen regardless of EGFR, KRAS , and TP53 alterations in NSCLC or PDAC, and DDR gene alterations were associated with improved response. These findings further support the MOA of BMS-986504 and its ongoing investigation in the phase 2/3 MountainTAP-9, -29, and -30 studies as a potential treatment option in pts with MTAP -del advanced solid tumors. Clinical trial information: NCT05245500 .

Adoptive cellular immunotherapy (ACT) has revolutionized hematologic malignancies, yet translation to solid tumors has historically been limited. This landscape shifted significantly in 2024 with US Food and Drug Administration approvals of lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy for advanced melanoma, and afamitresgene autoleucel, an engineered T-cell receptor (TCR) therapy for synovial sarcoma. These approvals mark the clinical arrival of ACT for solid tumors and highlight a rapidly expanding therapeutic landscape. Beyond these indications, multiple ACT platforms including TIL, TCR, chimeric antigen receptor (CAR) T-cell, CAR-natural killer, and CAR-macrophage therapies are under active clinical investigation across diverse solid tumor indications. Clinical experience to date has defined key barriers to efficacy, including impaired tumor trafficking, antigen heterogeneity, immunosuppressive tumor microenvironment, and limited cellular persistence. In parallel, rapid advances in cellular engineering are reshaping the field, with the development of armored constructs, logic-gated and multiantigen targeting strategies, innate immune–based platforms, and novel manufacturing approaches including allogeneic and in vivo cell engineering. As ACT enters clinical practice for select solid tumors, distinct toxicity profiles and logistical requirements necessitate careful patient selection and multidisciplinary coordination. Early biomarker testing, timely referral to specialized centers, and familiarity with evolving toxicity management frameworks are increasingly critical. Here, we seek to provide a practice-oriented framework for understanding emerging ACT platforms, clinical data, toxicity considerations, and implementation strategies relevant to contemporary solid tumor oncology care.

ABSTRACT Background Superior vena cava isolation (SVCI) is performed as an adjunct to pulmonary vein isolation (PVI) for atrial fibrillation, yet whether an empiric or trigger‐guided strategy is preferable remains uncertain. Prior meta‐analyses have been largely restricted to index procedures in paroxysmal AF and have not explicitly stratified by ablation strategy. We sought to address these gaps through a systematic review of available randomized evidence. Methods Major databases were searched through November 2025 for RCTs comparing PVI+SVCI versus PVI alone. Trials were stratified by strategy: empiric SVCI (performed irrespective of SVC ectopy) or trigger‐guided SVCI (performed only upon demonstrated SVC triggers). The primary outcome was atrial tachyarrhythmia recurrence (≥30 s) beyond the blanking period. Random‐effects models, pre‐specified subgroup analyses, meta‐regression, and GRADE certainty assessment were performed. Results Eight RCTs ( n = 1231) were included; most enrolled paroxysmal AF, while two incorporated non‐paroxysmal AF subtypes and one evaluated repeat ablation procedures. Overall, SVCI+PVI significantly reduced recurrence versus PVI alone (97/604 vs. 135/627; RR 0.77, 95% CI 0.61–0.97; p = 0.03; I 2 = 0%). On stratified analysis, empiric SVCI demonstrated a significant recurrence reduction (RR 0.70, 95% CI 0.53–0.92; p = 0.01; I 2 = 0%), while trigger‐guided SVCI did not reach statistical significance (RR 0.80, 95% CI 0.37–1.74; p = 0.57; I 2 = 52%). In paroxysmal AF ( n = 1038), adjunctive SVCI significantly reduced recurrence compared with PVI alone (RR 0.68, 95% CI 0.52–0.90; p = 0.01; I 2 = 0%). Fluoroscopy time was longer with SVCI; total procedure duration was comparable. Major complications were infrequent but numerically higher with SVCI+PVI (15/604 vs. 7/627; RR 1.96, 95% CI 0.87–4.38; p = 0.10). Meta‐regression identified no significant effect modifiers. GRADE certainty was high for overall and empiric analyses, and moderate for trigger‐guided SVCI. Conclusions Empiric SVCI significantly reduced AT/AF recurrence as an adjunct to PVI, while trigger‐guided SVCI did not demonstrate a significant benefit. These findings suggest SVC isolation confers benefit independent of prior trigger documentation, supporting the role of empiric SVCI as an adjunct to AF ablation.

ABSTRACT Background Atrial fibrillation (AF) is common in patients with hypertrophic cardiomyopathy (HCM) and is associated with increased morbidity, heart failure (HF) exacerbations, and adverse long‐term outcomes. Although catheter ablation is an established rhythm‐control strategy, data comparing its long‐term clinical outcomes with anti‐arrhythmic drug (AAD) therapy in patients with HCM remain limited. Objective To compare long‐term clinical outcomes of catheter ablation versus medical therapy with AADs in patients with HCM and AF. Methods We conducted a retrospective cohort study using the TriNetX Research Network, a global federated database of electronic health records. Adult patients with HCM and AF between January 2010 and December 2020 were identified and stratified according to treatment with catheter ablation or AAD therapy. Outcomes included all‐cause mortality, HF exacerbations, AAD‐related adverse events, all‐cause hospitalization, ischemic stroke, repeat ablation, need for cardioversion, need for long‐term AAD use, and atrioventricular nodal ablation. A 1:1 propensity score matching (PSM) analysis was performed to balance baseline characteristics. Kaplan–Meier survival analysis and Cox proportional hazards models were used to estimate hazard ratios (HRs). Results After PSM, 3144 patients were included (1572 in each cohort) with a mean follow‐up of approximately 3.4 years. Catheter ablation was associated with lower all‐cause mortality compared with AAD therapy (9.5% vs. 14.8%; HR: 0.60; 95% CI: 0.49–0.74; p < 0.001). Ablation was also associated with reduced risk of HF exacerbations (38.4% vs. 43.3%; HR: 0.79; 95% CI: 0.71–0.88; p < 0.001) and fewer AAD‐related adverse events (8.4% vs. 11.2%; HR: 0.71; 95% CI: 0.55–0.93; p = 0.011). Rates of all‐cause hospitalization (HR: 0.93; p = 0.11) and ischemic stroke (HR: 0.78; p = 0.10) were similar between groups. Conclusion In this large real‐world cohort of patients with HCM and AF, catheter ablation was associated with lower mortality, reduced HF hospitalizations, and decreased AAD therapy‐related adverse events, as compared with medical therapy. These findings suggest that catheter ablation may provide meaningful clinical benefits in selected patients with HCM and AF, although prospective studies are needed to confirm these observations.

Abstract The growing availability of large-scale biomarker datasets has allowed data-driven methods to characterize Alzheimer’s disease biological heterogeneity. However, most prior studies have focused on cohorts of late-onset amnestic cases, leaving early-onset Alzheimer’s disease underexplored. We aimed to characterize tau-PET-based subtypes through a robust data-driven approach in the Longitudinal Early-Onset Alzheimer’s Disease Study. Baseline [18F]Flortaucipir PET scans from 365 amyloid-PET-positive participants with sporadic early-onset Alzheimer’s disease were quantified in the left and right medial temporal, lateral temporal, occipital, parietal, and frontal cortices. Tau PET values were z-scored against 85 amyloid-PET-negative cognitively normal age-matched participants and fitted into Subtype and Stage Inference (SuStaIn)—an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross-sectional data. The derived subtypes were subsequently characterized by baseline and longitudinal clinical, cognitive, MRI, tau and amyloid PET features. We identified three tau-PET-based subtypes: on average, Subtype 1/Typical (n = 144, 40%) showed a predominant bilateral temporoparietal pattern typical of Alzheimer’s disease. Subtype 2/Left temporal (n = 111, 31%) showed predominant left temporal binding. Subtype 3/Posterior (n = 104, 29%) showed early and permeating occipitoparietal involvement. Subtypes did not differ in demographics or global amyloid burden, but were relatively more enriched for specific clinical presentations: S1/Typical for amnestic presentations, S2/Left Temporal for primary progressive aphasia, and S3/Posterior for posterior cortical atrophy. Baseline tau PET subtypes aligned with cortical atrophy patterns and domain-specific cognitive impairment. When follow-up tau PET scans were fitted to SuStaIn trained on baseline data, 85.6% (n = 172/201) of participants retained the same subtype classification, indicating subtype temporal stability, and progressed within subtypes by 0.56 ± 0.70 SuStaIn stage/year. Longitudinal voxel-wise linear mixed-effects modelling revealed tau accumulation patterns for each subtype in regions relatively spared at baseline: occipital lobe accumulation predominated in S1/Typical, bilateral frontal and right temporal in S2/Left Temporal, and bilateral frontotemporal lobes in S3/Posterior. All subtypes showed longitudinal increases in Clinical Dementia Rating-Sum of Boxes, but with slower worsening in S3/Posterior compared with the other subtypes. Our findings reveal robust subtypes in sporadic early-onset Alzheimer’s disease characterized by distinct spatiotemporal tau patterns that parallel differences in clinical presentations and trajectories of neurodegeneration. These subtypes extend beyond traditional clinical syndromes and support a more nuanced framework for individualized prognosis and care. Incorporating tau PET subtyping into clinical trial design could enable more targeted therapeutic approaches for this younger population.

Abstract Background Lung cancer is the leading cause of cancer-related death, and the most common cancer diagnosed globally. Approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC). After initial surgical treatment, adjuvant therapy with conventional or targeted chemotherapy can help optimize survival. These treatments, however, must be tailored to each patients’ problematic situation, including cancer characteristics and goals of care. Shared decision making (SDM) is a method of care by which patients and clinicians work together to form plans of care that advance the patient’s problematic human situation. This method often requires evaluating alternative options, “trying them on” for fit given their practical demands and favorable and unfavorable effects. Tools used within the encounter can facilitate and support SDM conversations, yet none exist for considering care post-surgical treatment of NSCLC. Therefore, we aimed to evaluate the effectiveness of a novel encounter tool for SDM, NSCLC Choice, compared to usual care at improving SDM and reducing decisional conflict for patients with resected early-stage NSCLC considering adjuvant treatment. Methods We will conduct a parallel, patient-level randomized trial comparing NSCLC Choice with usual care. Patients will be eligible if they are adults with stage >1B NSCLC eligible for postsurgical adjuvant chemotherapy. Allocation will be central and post-consent. Patients will be blinded to our trial hypothesis, instead of being invited to evaluate an educational intervention. Our primary outcome is SDM quality, which we will assess using participant reported measures (patient SDM-Q-9) obtained immediately post-encounter and an observer measure estimated from video recording of trial encounters in both arms (OPTION12). With resources to conduct a 100-patient trial, we will have >80% power to detect a 12-point medium difference between arms in patient-reported SDM-Q-9. We will also assess the secondary outcomes of knowledge about the disease and the features of treatment options using an ad hoc questionnaire, decisional conflict using the Decisional Conflict Scale, and patient and clinician satisfaction using the metrics used in prior SDM intervention trials. We will also determine encounter length using video recordings. Discussion In testing NSCLC Choice, we seek to determine the extent to which this intervention can improve care for patients with NSCLC considering adjuvant therapy after surgery. In addition, we expect to determine whether this intervention is satisfactory to participants and feasible in practice. If successful, this study will result in an evidence-based tool for promoting patient-centered conversations around NSCLC and cancer care those fits. Trial Registration: NCT06122064 ClinicalTrials.gov

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

Abstract Aims Mitral valve prolapse (MVP) is a common valvular disorder associated with ventricular arrhythmias (VAs) in a subgroup of patients, known as arrhythmic MVP (AMVP). Arrhythmic MVP patients with malignant VAs typically receive an implantable cardioverter-defibrillator (ICD) for secondary prevention. However, data regarding the incidence of appropriate ICD therapy and the type of arrhythmia recurrence in this population remain scarce. This study aimed to evaluate the incidence of appropriate ICD therapies and type of arrhythmia recurrence in AMVP patients with an ICD implanted for secondary prevention. Methods and results A systematic literature search was conducted in PubMed/MEDLINE and EMBASE databases until January 2025. Studies reporting the incidence of appropriate ICD therapy in AMVP patients were included. A total of 9 studies met the inclusion criteria, resulting in 166 AMVP patients with ICDs for secondary prevention. The mean age was 41.8 years, with 55.8% of patients being female. Over a weighted mean follow-up of 4.9 ± 3.1 years, 34.9% [95% confidence interval (CI): 28.1–42.5] of the patients experienced recurrence of VA. The pooled incidence of appropriate ICD therapies during follow-up was 8.1 per 100 person-years (95% CI: 5.6–10.5, I2: 11.7%). Regarding the type of arrhythmic recurrence, the majority of arrhythmias (53.8%, 95% CI: 44.3–63.0%) were in the form of ventricular fibrillation or polymorphic ventricular tachycardia (VT), while the remaining arrhythmias were reported as monomorphic VT. Among 67 ventricular arrhythmic episodes reported in 7 studies with available data, 65 required shock therapy, corresponding to a shock proportion of 97.0% (95% CI: 89.6–99.6%). Conclusion Arrhythmic MVP patients with ICDs for secondary prevention exhibit a high risk of recurrent arrhythmias, with recurrences in the form of polymorphic VA occurring in more than half of the cases. PROSPERO registration number: CRD42024588610

Background: Contemporary data on trends in survival after incident atrial fibrillation (AF) are limited. Methods: Residents of a 27-county area in southern Minnesota and western Wisconsin with new-onset atrial fibrillation or atrial flutter between 2013 and 2023 were identified. An electronic algorithm requiring 1 inpatient code or 2 outpatient codes separated by >7 days but within 1 year was used to define AF. Patients were followed for all-cause mortality through March 31, 2025. Standardized mortality ratios of observed versus expected survival were calculated, and time trends in survival were examined using Cox regression adjusting for demographics, cardiovascular risk factors, comorbid conditions, and area-level measures of socioeconomic status and rurality. Results: There were 44,930 individuals identified with incident AF from 2013-2023 (56.4% male; mean (SD) age 72.8 (13.5) years; 95.8% were non-Hispanic white). Within the first 90 days, the risk of all-cause mortality was greatly elevated compared with individuals of a similar age and sex distribution in the general population (standardized mortality ratios 12.6, 95% CI, 12.1-13.0 and 3.8, 95% CI, 3.6-4.0 for the first 30 days and 31 to 90 days after diagnosis, respectively). This excess risk was observed for all age groups but was greatest in the youngest age group (standardized mortality ratios among 18-64 year olds for the first 30 days: 49.9, 95% CI, 44.6-55.7 and 31 to 90 days: 11.1, 95% CI: 9.4-13.1; Figure ). In the youngest age group, the excess risk persists through 5 years post AF, however, in the oldest age group the excess risk only persisted through 1 year. Survival within the first 90 days improved over the study period (adjusted hazard ratio [aHR], 0.88; 95% CI, 0.79-0.99 for 2023 vs 2013); likewise, among 90-day survivors, survival improved between 2013 and 2023 (aHR,0.82; 95% CI, 0.76-0.88). These trends were driven by improvements in the younger age groups, particularly for death among 90-day survivors (aHR for 18-64 years, 0.66, 95% CI, 0.52-0.83; 65-74 years: 0.77, 95% CI: 0.65-0.90; 75-84 years, 0.84, 95% CI: 0.75-0.95; 85+ years, 0.99, 95% CI: 0.98-1.01). Conclusion: In a Midwestern community, the excess risk of death is high within the first 90 days after incident AF. Furthermore, survival after AF has improved between 2013 and 2023, with the improvement greatest in younger age groups.

BACKGROUND: Radiofrequency (RF) ablation of premature ventricular complexes (PVCs) originating from the left ventricular summit may be unsuccessful, highlighting the need for alternative approaches. We aimed to assess the efficacy and safety of a novel dual-modality focal catheter in treating left ventricular summit PVCs in patients who had failed previous RF ablation. METHODS: Patients were prospectively enrolled and underwent a redo ablation procedure using an irrigated, contact-force sensing, dual-modality focal catheter (TactiFlex Duo, Abbott) under compassionate use indication. The ablation strategy, including the choice of energy modality (monopolar pulsed field [PF], RF, or both), was left to the operator’s discretion. Safety assessments included serial biomarkers, renal function, and CMR within 36 hours. Efficacy was defined as ≥80% reduction in PVC burden with symptom resolution at 3-month follow-up. RESULTS: Six consecutive patients (4 men; mean age, 53.8±15 years) with symptomatic left ventricular summit PVCs and a prior failed RF ablation (range, 1–2) were prospectively enrolled. All PVCs had an inferior axis, with a left bundle V1 morphology observed in 4 of 6 cases (mean burden, 30.1±5.3%). Acute suppression of PVCs was achieved in all cases. Acute suppression with a single PF application in the great cardiac vein-anterior interventricular vein occurred in 2 patients, while 3 patients required additional RF, PF, or combined RF+PF applications at adjacent sites. One patient with an inaccessible great cardiac vein-anterior interventricular vein was successfully treated in the left ventricular outflow tract with RF+PF application. Transient, reversible left anterior descending vasospasm was observed during PF delivery in 2 of 5 cases that underwent PF application adjacent to a coronary artery, despite pretreatment with intracoronary nitroglycerin without ECG or hemodynamic sequelae. All patients had durable suppression of PVCs at follow-up. CONCLUSIONS: In its first human application, dual-modality ablation was feasible and effective for refractory left ventricular summit PVCs. Transient coronary vasospasm occurred, though it was reversible and without acute clinical consequences.