Citations

BACKGROUND: Degenerative mitral regurgitation (DMR) due to valve prolapse predominates in men, but sex-specific differences are poorly understood due to a lack of quantitative and sex-stratified studies. METHODS: The international MIDA-Q (Mitral Regurgitation International Database-Quantitative) registry enrolled 3274 men and 2331 women with greater than or equal to mild DMR prospectively quantified, comprehensively characterized, and long-term follow-up. RESULTS: Women were more symptomatic despite lower effective regurgitant orifice (ERO, 27±18 versus 38±22 mm 2 , standardized mean difference 0.54; P <0.0001) and regurgitant volume (46±26 versus 61±31 mL/beat, standardized mean difference 0.52; P <0.0001), even for similar mitral lesions. With increasing ERO, women showed lower regurgitant volume, higher heart rate, lower blood pressure, but left ventricular size response in women was smaller in absolute measures while larger when body surface area normalized, with higher ejection fraction and cardiac index (all P <0.0001). Incidence of mitral valve surgery was similar in symptomatic women and men, but lower in asymptomatic women versus men (adjusted hazard ratio, 0.80 [0.69–0.94]; P =0.008) for similar ERO, linked to smaller left ventricular diastolic absolute diameter ( P <0.0001). Excess mortality under medical management (of severe versus mild ERO) was similar in women (adjusted hazard ratio, 1.67 [1.24–2.24]; P =0.0007) and men (adjusted hazard ratio, 1.63 [1.27–2.09]; P <0.0001) and versus expected survival (2.12 [1.51–2.98] in women and 2.27 [1.75–2.94] in men). However, moderate ERO (20–39 mm 2 ) was associated with significant excess mortality in women (1.47 [1.19–1.77] versus mild). In men, the corresponding hazard ratio did not reach statistical significance. Postoperative survival was similar in men and women. CONCLUSIONS: Women with DMR present with lower ERO and regurgitant volume than men and with considerable adaptive differences to increasing DMR severity versus men. Asymptomatic women are less referred to surgery than men of similar DMR severity, linked to smaller absolute left ventricular size. Severe DMR by similar quantitative thresholds causes similar excess mortality in men and women; moderate quantitative DMR shows a trend for higher excess mortality versus expected in women than men, requiring further confirmation. These data emphasize the importance of quantitative DMR and left ventricular remodeling assessment in men and women for appropriate clinical management.

Abstract Aims Prognosis in tricuspid regurgitation (TR) is shaped by complex clinical and haemodynamic interactions, complicating risk stratification. We aimed to use explainable artificial intelligence (EAI) to model these relationships and identify key predictors of outcomes. Methods and results We analysed long-term all-cause mortality in a large prospective registry of patients with native TR across the full severity spectrum. Patients underwent detailed clinical evaluation and quantitative Doppler-echocardiography. Supervised EAI models were applied to identify and rank predictors of mortality under medical therapy, capturing non-linear associations and interactions among baseline characteristics. Among 9761 patients [mean age 73 ± 15 years; 56.9% women; effective regurgitant orifice area (EROA) 40 (30–56) mm2; regurgitant volume 39 (29–53) mL/beat; 42% severe TR], 2676 deaths occurred during 3.8 ± 4.6 years of follow-up. EAI identified and ranked 20 prognostic determinants of survival. Haemodynamic measures, led by elevated pulmonary-artery systolic and right-atrial pressures, were strongest, followed by age and comorbidity. TR-related variables ranked next, led by right ventricular dysfunction and EROA, which outperformed integrative TR grade and TRIScore. Left-ventricular parameters were less influential. Non-linear effects, including those involving ejection fraction, and interactions such as higher EROA-related risk with elevated pulmonary pressures or lower TRIScore (both P &lt; 0.03) were observed. Proportional hazards models confirmed EROA as the strongest TR severity marker (P &lt; 0.0001), with excess mortality beginning at 40 mm2 and increasing further at 60 mm2. Conclusion EAI ranked mortality predictors in TR, highlighting patient factors, haemodynamics, TR-specific measures, and left-ventricular function. Among TR-specific measures, EROA and TRIScore were most prognostic. Recognizing their impact can refine risk stratification, guide intervention timing, and inform long-term management.

Importance Adjuvant chemotherapy regimens may be administered after pancreatic resection for adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMNs), although the evidence supporting their use is limited. Objective To evaluate the survival benefit associated with contemporary adjuvant chemotherapy regimens after resection in A-IPMNs between 2017 and 2023. Design, Setting, and Participants This retrospective cohort study was an international, multicenter study with 69 participating centers across Europe, North America, South America, and the Asia-Pacific region. Patients undergoing resection for A-IPMNs were included. Data were analyzed from May to August 2025. Intervention Contemporary adjuvant chemotherapy regimens, such as gemcitabine-capecitabine (GemCap); 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX), modified FOLFIRINOX (mFOLFIRINOX), and S-1. Main Outcome and Measure Overall survival (months). Results Among 1321 patients (median [IQR] age 70 [63 to 76] years; 713 males [54.0%] and 608 females [46.0%]), 781 patients (59.1%) received adjuvant chemotherapy, while in 181 patients (13.7%) it was omitted due to poor patient fitness. Of patients who received adjuvant chemotherapy, 568 patients (72.6%) received contemporary regimens, including GemCap (232 patients [29.7%]), FOLFIRINOX (176 patients [22.5%]), mFOLFIRINOX (71 patients [9.1%]), and S-1 (70 patients [9.0%]). The median (IQR) follow-up for the cohort was 64.2 (40.4 to 85.0) months, and the median overall survival was 73.8 months (95% CI, 66.4 to 81.9 months). After 90-day landmark analysis and exclusion of patients ineligible for chemotherapy, adjuvant chemotherapy vs no adjuvant chemotherapy (propensity score–matched populations, 243:243 patients) was not associated with improved overall survival (median, 82.3 months; 95% CI, 78.2 months to not applicable [NA] vs not reached; 95% CI, 75.3 months to NA; P = .58). Contemporary regimens vs no adjuvant chemotherapy (propensity score–matched populations, 309:309 patients) was not associated with longer survival, and a mean survival benefit greater than 4.2 months over 5 years was excluded (difference in restricted mean survival, 1.26 months; 95%, −1.72 to 4.24 months). Treatment outcomes did not vary by chemotherapy regimen or disease characteristic (eg, N stage or carbohydrate antigen 19-9 level). Conclusions and Relevance In this study, contemporary adjuvant chemotherapy was not associated with improved overall survival in A-IPMNs, and a randomized clinical trial is indicated.

Abstract Objectives Sarcomatoid urothelial carcinoma (sUC) is associated with poor clinical outcomes. Herein, we evaluated clinicopathologic features (including PD-L1 expression) for institutional cases. Methods Sixty-five patients with sUC treated by radical cystectomy were matched for age, sex, and pathologic stage to 190 patients with pure urothelial carcinoma (UC). Outcomes were evaluated using the Kaplan-Meier method. Immunohistochemistry (IHC) results for tumor-specific PD-L1 expression in sUC were quantified using H-scores (range, 0-300). Cases with constitutive PD-L1 expression (cPD-L1; H-score ≥240) were evaluated for amplification events using fluorescence in situ hybridization (n = 28), mate-pair sequencing (Mpseq; n = 6), RNA sequencing (n = 5), and targeted next-generation sequencing (n = 8). PD-L1 regulatory pathways were evaluated using gene set enrichment analysis in the Cancer Hallmark dataset. Results Most patients with sUC had advanced disease (≥pT2, 62/65, 95%), without significant differences in overall and cancer-specific survival, when matched to pure UC. Median PD-L1 H-scores using different clones were 100 (SP142), 120 (SP263), and 195 (22C3). cPD-L1 was seen in 43% (28/65) of cases of sUC that were enriched for TP53, TERT, and CDKN2A/B alterations. PD-L1 amplification was identified in 7 (of 28, 25%) of these cases. Bionformatics analysis consistently identified IL6-JAK-STAT3 and interferon α/γ signaling in sUC with cPD-L1 expression. Conclusions Our results suggest that cPD-L1 expression in most sUC occurs secondary to IL6-JAK-STAT3 and interferon α/γ signaling. This provides a biologic rationale for evaluating response to immunotherapy in this patient population.

Importance Total pancreatectomy (TP) is indicated for advanced pancreatic cancer or multifocal tumors. Furthermore, TP may be performed to avoid the risk of pancreatic fistula in selected patients to improve the perioperative risk profile. Objective To define reference values for TP based on a low-risk cohort treated at expert centers. Design, Setting, and Participants This multicenter study analyzed outcomes from patients undergoing primary TP for malignant or benign lesions from 25 international expert centers from January 2017 to November 2023. Low-risk patients undergoing TP (LR-TP) were without vascular resections or significant comorbidities. Exposures TP. Main Outcomes and Measures Twenty reference values were derived from the 75th or the 25th percentile of the median values of all centers. Outcomes of LR-TP were compared with a cohort of TP with vascular resection, TP due to high-risk pancreatic anastomosis, and the benchmark values for low-risk pancreatoduodenectomy. Results Of 994 patients, 333 (33.5%; median [IQR] age, 66 [58-72] years; 171 male [51.4%]) qualified as the LR-TP cohort. Reference values included blood loss (≤1000 mL), major complications (≤37%), 3-month postoperative mortality (&amp;lt;6%), and retrieved lymph nodes (≥29). Compared with TP with vascular resections, reference cutoffs were not met for major complications (51% vs LR-TP ≤37%) and 90-day mortality (11% vs LR-TP ≤6%). For TP due to high-risk anastomosis, failure to rescue rate (38% vs ≤6%) and 90-day mortality (11% vs LR-TP ≤6%) were not met. Compared with pancreatoduodenectomy, reference values for postoperative mortality were 3 times higher for LR-TP (≤2% vs ≤6%) and less for resected lymph nodes (≥16 vs ≥29). Conclusions and Relevance This case-control study provided global reference values for TP, indicating significantly higher postoperative morbidity and mortality compared with pancreatoduodenectomy. Perioperative morbidity of TP was especially increased in patients with vascular resections. These reference values can serve for quality control of pancreatic surgery.

Background Left ventricular (LV) end‐systolic enlargement in severe degenerative mitral‐regurgitation (MR) is a class I surgical trigger. Whether it occurs disproportionately to less‐than‐severe MR due to mitral valve prolapse and is associated with mortality are unknown. We aimed to analyze prevalence and association with survival of disproportionate LV enlargement in less‐than‐severe MR. Methods A multicenter cohort international study enrolled 2848 consecutive patients (52% women, 69±16 years) with degenerative MR prospectively quantified and graded mild or moderate. Primary end point was survival under medical management. Secondary outcome was survival throughout follow‐up stratified by performance of early mitral surgery within 3 months postdiagnosis. Results Among LV remodeling parameters (abnormal end‐diastolic diameter, LV end‐systolic diameter [LVESD] absolute and indexed), LVESD ≥40 mm (present in 12.4%) was the sole independent associate of reduced survival (5‐year 70±3 versus 76±9%; P =0.009). LVESD ≥40 mm was independently linked to larger body surface area, effective regurgitant orifice, and left atrium, and to male sex and diabetes. With multivariable comprehensive adjustment, LVESD ≥40 mm (adjusted hazard ratio [aHR], 1.25 [95% CI, 1.005–1.53]; P =0.04) remained associated with excess mortality under medical management, even after adjustment for lowered ejection fraction (aHR, 1.49 [95% CI, 1.13–1.95]; P =0.004) and in all patient subsets. Among patients with moderate degenerative MR and LVESD ≥40 mm, 22% underwent mitral surgery within 3 months, which was associated with superior survival, even after comprehensive adjustment (aHR, 0.11 [95% CI, 0.005–0.51]; P =0.002). Conclusions Disproportionate LV enlargement in patients with less‐than‐severe degenerative MR is common, particularly with larger bodies, regurgitation, and overall cardiac remodeling. LVESD ≥40 mm is associated with worse survival independent of all baseline characteristics, even lowered ejection fraction, and represents a marker for risk stratification of patients who are generally not yet considered for medical or surgical/interventional treatment.

Abstract Aims Functional tricuspid regurgitation (FTR) associated with degenerative mitral regurgitation (DMR) accentuates the severity of heart failure and is a marker of poor prognosis. Little is known about FTR associated with asymptomatic DMR. Methods and results The study included 1249 asymptomatic patients with moderate or severe DMR from the Mitral Regurgitation International Database-Quantitative (MIDA-Q) registry (mean age 64 ± 15 years, 25% female). Despite the asymptomatic status, absent/trivial FTR was noted in only 42%, mild in 34.5%, moderate in 11%, and severe FTR in 12.5%. Patients with higher FTR grades were older and more often female and had higher EuroScore II, larger left atrial volumes, and more atrial fibrillation (all P &lt; 0.05). Patients with moderate or severe FTR had comparable 5-year survival (64 ± 4% and 65 ± 4%) and lower than patients with no/trivial FTR(96 ± 1%, P &lt; 0.001). After adjustment for key prognostic factors, including age, left ventricular dilatation and dysfunction, DMR severity, left atrial dilatation, and pulmonary hypertension, ≥moderate FTR remained a strong predictor of mortality (HR = 2.08 [1.17–3.72], P = 0.013). Sensitivity analysis showed stable impact of ≥moderate FTR among patients with/without pulmonary hypertension, in women and men and for any other subset. For patients who underwent mitral valve surgery, post-operative survival rates were similar between those with no/trivial FTR and those with ≥moderate or severe FTR (P = 0.76), suggesting that surgery could reduce the excess mortality related to preoperative FTR. Conclusions Among asymptomatic patients with significant DMR, ≥moderate FTR is frequent and independently associated with higher mortality, independently of traditional guideline-based risk factors. These findings suggest that ≥moderate FTR should lead to consideration of early mitral surgery to improve outcomes.

Background The prevalence and impact of right ventricular dysfunction (RVD) in degenerative mitral regurgitation (DMR) is unknown. We aimed to determine whether RVD assessed by echocardiography in routine clinical practice is independently associated with mortality in patients with DMR. Methods and Results We used data from the MIDA‐Q (Mitral Regurgitation International DAtabase‐Quantitative) registry, which included patients with isolated DMR due to mitral valve prolapse from January 2003 to January 2020 from 5 tertiary centers across North America, Europe, and the Middle East. A cohort of 2917 (mean age: 66 years, 70.8% male patients, follow‐up: 5.2 [3.3–8.3] years) consecutive patients with severe DMR was included and long‐term mortality was analyzed. RVD, identified in 426 (14.6%) patients, was associated with reduced 8‐year survival (55%±3% versus 77%±1%; P <0.001), overall and in all subgroups of patients, even after comprehensive adjustment including left ventricular dilatation and dysfunction, DMR severity, pulmonary pressures, and surgery (adjusted hazard ratio, 1.44 [95% CI, 1.17–1.77]; P <0.001). This excess mortality was observed under medical management (adjusted hazard ratio, 1.57 [95% CI, 1.20–2.05]; P =0.001) and after surgical correction of mitral regurgitation (adjusted hazard ratio, 1.45 [95% CI, 1.02–2.05]; P =0.039). Patients with RVD undergoing surgery within 3 months of diagnosis experienced a better 8‐year survival (73%±4% versus 43%±4%; P <0.001), even after adjustment (adjusted hazard ratio, 0.44 [95% CI, 0.29–0.67]; P <0.001) despite an increase of 1‐month postoperative mortality (7.1% versus 0.5% for patients without RVD; P <0.001). Conclusions RVD is observed in 14.6% of severe DMR and exhibits a powerful and independent association with excess mortality partially attenuated by mitral surgery. Therefore, assessment of right ventricular systolic function should be included in routine DMR evaluation and in the clinical decision‐making process.