Citations

Backround: Advances in surgical and medical care of children born with congenital heart disease (CHD) has improved survival into adulthood. However, cardiac and non-cardiac morbidity and mortality remain common in adults with CHD (ACHD). We present the causes and predictors of mortality in a large cohort of ACHD patients from the USA. Methods/Approach: We conducted a retrospective review of ACHD patients followed at Mayo Clinic between 1992 - 2024. Mortality was ascertained using the Accruint national data base. Clinical characteristics and primary cause of death were identified from the electronic record. Kaplan-Meier (KM) survival analysis was performed to compare overall survival stratified by CHD severity. Cox proportional hazards regression was used to identify independent predictors of mortality. Results/Data: Amongst 9160 ACHD patients (mean age 38±16y at first visit, 51% males, 23% simple, 59% moderate and 18% severe CHD), mortality occurred in 1430(16%) patients during a mean follow-up of 11±7y. The mean age at death was 68±17 y, 58±17y, and 45±15y in mild, moderate and severe ACHD. KM analysis of survival and cause of death stratified by CHD severity are presented in Figures 2 and 3 respectively. Cause of death could not be ascertained in 33%%. Amongst those with a known cause of death, the proportion of non-cardiac death increased with decreasing severity of CHD. HF death and sudden cardiac death occurred in 11% and 19%. Infection, malignancy and chronic respiratory failure were important non-cardiac causes of death. Significant risk factors for mortality included CHD severity, ventricular arrhythmia, heart failure, declining functional capacity, diabetes and chronic kidney disease as presented in the Fig 1. Conclusion(s): Mortality in ACHD patients is associated with CHD severity, heart failure, ventricular arrhythmia and cardiovascular comorbidities. Early recognition and management of these risk factors may improve long-term survival. As patients with ACHD age, management of cardiovascular and noncardiac risk factors will require development of systems of care specific to this vulnerable population.

Background: Patients with repaired Tetralogy of Fallot (TOF) undergoing pulmonary valve replacement (PVR) are at increased risk of major adverse ventricular arrhythmias and related events (MAREs). Perioperative electrophysiological study (EPS) has been used for risk stratification and guiding future management, but these studies are limited by small sample size. Objectives: To perform a systematic review of outcomes of pre-PVR EPS in TOF patients with PVR. Methods: A comprehensive search of PubMed, Embase, Scopus and Google scholar databases was performed per PRISMA 2020 guidelines. Studies on patients with repaired TOF undergoing PVR with perioperative EPS were included. Data were extracted on study design, sample size, EPS outcomes and MAREs during follow-up. Results: A total of 1,528 patients (age: 35.5±3.8 y; 57% male; LVEF: 57.1±1.5%, RVEF: 42.6±1.5%) were included from 12 studies. EPS was performed in 1212/1528 (79.3%), with sustained VT inducibility in 404 (33.3%)-monomorphic VT in 258 (63.8%), while 808 (66.6%) were non- inducible. 8/12 studies reported the type of PVR (transcatheter-36.8%). 174/293 (59.3%) inducible patients had an ablation (9 studies), while ICD (6 studies) was implanted in 70/263 (26.6%). Follow-up EPS (6 studies) showed 35/230 (15.2%) remained inducible. Overall,113 (9.3%) patients experienced MAREs over a median follow-up ranging from 6 months to 6.7 years. Sustained VT (11/12 studies) occurred in 70/1092 (6.4%), appropriate ICD therapy (7/12 studies) in 13/622 (2.1%) and sudden cardiac death (10/12 studies) in 30/906 (3.3%). Five studies provided MARE data stratified by VT inducibility. 12/164 (7.3%) inducible patients experienced MAREs, compared to 2/318 (0.6%) non-inducible patients. Reported risk factors for MAREs included older age at initial repair and PVR, QRS duration (>180ms), LVEF <45%, RVEF <35%, history of syncope, prior palliative shunts and atrial arrhythmias. Some studies identified MRI-derived scar burden, pulmonary annulus size, and RV/LV volume ratios as additional predictors. Conclusion: TOF patients remain at high risk of VA after PVR with 1/10 patients experiencing MAREs. People with inducible VT had a 12-fold greater risk than people who were non-inducible. EPS identifies a subset of TOF patients at higher arrhythmic risk during PVR and supports tailored ablation and ICD strategies. Prospective multicentre studies are needed to optimize integration of EPS and clinical risk models.

Background: Immunotherapy-based regimens have expanded the treatment landscape for unresectable hepatocellular carcinoma (uHCC); however, real-world data are limited. Methods: This retrospective, observational study used data from electronic medical records from Mayo Clinic sites across the United States. Patients with uHCC who initiated a first-line (1L) systemic therapy between June 2020–October 2022 with ≥2 follow-up visits were included. Treatment patterns, overall survival (OS), and post-index gastrointestinal (GI) bleeding were assessed by GI bleeding risk defined by Child–Pugh Class B or C, pre-index GI bleeding, uncontrolled hypertension, or significant varices and band ligation. Results: Of 186 included patients, 68.8% had GI bleeding risk and 31.2% did not. Atezolizumab plus bevacizumab was the most common 1L systemic therapy in patients with or without GI bleeding risk (72.7% and 29.3%, respectively). Median OS (95% confidence interval) with atezolizumab plus bevacizumab was 12.8 (8.0–19.3) months and not reached in patients with and without GI bleeding risk, respectively. OS rates with atezolizumab plus bevacizumab in patients with or without GI bleeding risk, respectively, were 52.3% and 70.6% at 12 months, 41.6% and 57.8% at 18 months, and 34.6% and 51.3% at 24 months. Post-index GI bleeding with atezolizumab plus bevacizumab occurred in 19.4% and 5.9% of patients with and without GI bleeding risk, respectively. Conclusions: During this study period, atezolizumab + bevacizumab was the most common 1L therapy for patients with uHCC, regardless of GI bleeding risk. OS rates with atezolizumab + bevacizumab were lower in patients with versus without GI bleeding risk. Findings highlight the unmet need for guidance on characteristics-driven treatment decisions.

Abstract The highest risk for liver allograft rejection is within the first weeks to months after a liver transplant; however, while later-stage mechanisms are well described, the initial window at the moment of alloantigen influx (e.g., ~ 1 h post-reperfusion) remains unmapped. T-cell priming is initiated in lymph nodes, yet these sites are rarely profiled in humans and their relationship to rejection risk is unclear. To address this gap, we profiled paired pre- and ~ 1 h post-reperfusion hepatic draining lymph nodes from liver transplant recipients using multiplexed immunofluorescence and GeoMx whole-transcriptome profiling to identify features that predict rejection versus non-rejection. Early after reperfusion, CD4 + and CD8 + T cells became proximal to macrophages in rejection compared to dendritic cells in non-rejection, which also displayed an immunoregulatory-leaning profile marked by PD-1, IDO1, and CD39, suggesting that macrophages and dendritic cells differentially influence early T-cell alloimmunity. These results provide nodal targets for precise immune modulation.

Treatment-induced ovarian function loss is a significant concern for many young patients with breast cancer. Accurately predicting this risk is crucial for counselling young patients and informing their fertility-related decision-making. However, current risk prediction models for treatment-related ovarian function loss have limitations. To provide a broader representation of patient cohorts and improve feature selection, we combined retrospective data from six datasets within the FoRECAsT (Infertility after Cancer Predictor) databank, including 2679 pre-menopausal women diagnosed with breast cancer. This combined dataset presented notable missingness, prompting us to employ cross imputation using the k-nearest neighbours (KNN) machine learning (ML) algorithm. Employing Lasso regression, we developed an ML model to forecast the risk of treatment-related amenorrhea as a surrogate marker of ovarian function loss at 12 months after starting chemotherapy. Our model identified 20 variables significantly associated with risk of developing amenorrhea. Internal validation resulted in an area under the receiver operating characteristic curve (AUC) of 0.820 (95% CI: 0.817–0.823), while external validation with another dataset demonstrated an AUC of 0.743 (95% CI: 0.666–0.818). A cutoff of 0.20 was chosen to achieve higher sensitivity in validation, as false negatives—patients incorrectly classified as likely to regain menses—could miss timely opportunities for fertility preservation if desired. At this threshold, internal validation yielded sensitivity and precision rates of 91.3% and 61.7%, respectively, while external validation showed 92.9% and 60.0%. Leveraging ML methodologies, we not only devised a model for personalised risk prediction of amenorrhea, demonstrating substantial enhancements over existing models but also showcased a robust framework for maximally harnessing available data sources.

BACKGROUND: Intracranial atherosclerosis (ICAS) is associated with an increased risk of early recurrent ischemic stroke. We evaluated whether biomarkers of impaired distal perfusion—specifically, anterior circulation borderzone infarct, and hypoperfusion mismatch volume—were associated with recurrent ischemic stroke within 90 days. METHODS: The BIORISK ICAS (Biomarkers and Recurrence Risk in Symptomatic Intracranial Atherosclerosis) is a multicenter retrospective international study (35 sites) that included hospitalized patients with symptomatic ICAS (50%–99% luminal stenosis of the intracranial vertebral, basilar, distal internal carotid, or proximal middle cerebral artery) from January 2019 to June 2024. The primary outcome was recurrent ischemic stroke in the territory of the symptomatic artery within 90 days. In the primary analysis, the exposure was an acute anterior circulation borderzone infarct. In secondary analysis of the subset with presentation within 72 hours of last known normal and perfusion imaging completed, the exposure of interest was prespecified as hypoperfusion mismatch volume at T max (time to maximum) threshold of 6 seconds, dichotomized at the Youden index. We performed multivariable Cox regression to test associations between exposure variables and the outcome, adjusting for clinically relevant variables and those associated with the outcome ( P <0.1). RESULTS: Of 2050 patients with symptomatic ICAS, 1737 (84.7%) presented within 72 hours of symptom onset, among whom 509 (29.3%) underwent perfusion imaging. The primary analysis included 1891 patients; 174 (9.2%) patients had recurrent ischemic stroke in the symptomatic arterial territory. In adjusted Cox regression models, there was an association between anterior circulation borderzone infarct and recurrent ischemic stroke at 90 days (adjusted hazard ratio, 1.40 [95% CI, 1.02–1.93]). In the perfusion imaging analysis, hypoperfusion mismatch of ≥10 mL was associated with recurrent ischemic stroke (adjusted hazard ratio, 1.83 [95% CI, 1.03–3.28]). CONCLUSIONS: Biomarkers of impaired distal perfusion, anterior circulation borderzone infarct, and hypoperfusion mismatch were associated with increased risk of recurrent ischemic stroke. These findings support the use of perfusion imaging in ICAS as well as future trials investigating early reperfusion in high-risk patients with ICAS.

Importance The effect of cornea donor diabetes on endothelial cell density (ECD) and morphometry after Descemet membrane endothelial keratoplasty (DMEK) is not known. Objective To determine whether endothelial cell loss (ECL) and morphometric changes 1 year after successful DMEK are related to cornea donor’s diabetes status. Design, Setting, and Participants This was a multicenter, double-masked, randomized clinical trial conducted from February 2022 to July 2024 at 28 US clinical sites (46 surgeons) and 13 eye banks. Included in the trial were the eyes of recipients (some of whom received tissue from donors without diabetes and others who received tissue from donors with diabetes) who underwent successful DMEK, primarily for Fuchs endothelial corneal dystrophy, and had at least 1 analyzable postoperative endothelial image. Intervention DMEK performed with a cornea from a donor without or with diabetes, assigned using a minimization procedure to achieve an approximate 2:1 distribution. Main Outcomes and Measures ECD, ECL, coefficient of variation in cell area (CV), and percentage of hexagonal cells (HEX) at 1 year from eye bank and postoperative specular central endothelial images. Results A total 1274 eyes of 982 recipients (mean [SD] age, 70 [8] years; 569 female [57.9%]; 816 [64.1%] with tissue from donors without diabetes and 458 [35.9%] with tissue from donors with diabetes) were included in the study. Preoperatively, mean (SD) central ECD in tissue from donors without diabetes and with diabetes were 2676 (290) cells/mm 2 and 2671 (286) cells/mm 2 , respectively. At 1 year, mean (SD) ECL was 28.3% (16.1%) and 28.0% (17.0%), in the donor groups without and with diabetes, respectively (adjusted mean difference = −0.4%; 95% CI, −2.3% to 1.4%), resulting in a mean (SD) 1-year ECD of 1927 (498) cells/mm 2 and 1920 (496) cells/mm 2 , respectively (adjusted mean difference = 10 cells/mm 2 ; 95% CI, −36 to 56; P = .95). No difference in ECD at 1 year associated with diabetes severity was noted ( P = .97). Mean (SD) CV did not differ at 1 year between the 2 groups of eyes (31.5% [4.1%] vs 31.4% [4.1%]; adjusted mean difference = −0.4%; 95% CI, −0.9% to 0.1%; P = .51), and mean (SD) HEX did not differ at 1 year between the 2 groups of eyes (57.7% [5.8%] vs 57.2% [5.8%]; adjusted mean difference = 0.1%, 95% CI, −0.8% to 0.9%; P = .33). Conclusions and Relevance This randomized clinical trial found that ECL and morphometry 1 year after DMEK were not affected by cornea donor diabetes status. With comparable 1-year graft success with tissue from donors with and without diabetes demonstrated in this trial, these findings support the use of corneas from donors with diabetes for endothelial keratoplasty procedures. Trial Registration ClinicalTrials.gov Identifier: NCT05134480

Importance If the success of Descemet membrane endothelial keratoplasty (DMEK) is not affected by whether the donor has diabetes, then the donor pool should expand. Objective To determine whether the 1-year DMEK success rate is affected by the presence of diabetes in the donor. Design, Setting, and Participants This was a multicenter, double-masked, randomized clinical trial conducted from February 2022 to July 2025 at 28 clinical sites (46 surgeons), with donor corneas provided by 13 eye banks in the US. Included in the study were individuals undergoing low to moderate risk DMEK (95% for Fuchs endothelial corneal dystrophy). Study data were analyzed from April to September 2025. Intervention DMEK performed with a cornea from a donor without or with diabetes, assigned using a minimization procedure (comparable with randomization) to achieve an approximate 2:1 distribution, respectively. Main Outcomes and Measures Graft success at 1 year Results A total of 1097 individuals (1421 study eyes; median [IQR] age, 71 [66-76] years; 631 female [57.5%]) were included in the study. The 1-year cumulative probability of graft success was 96.3% (95% CI, 95.0%-97.5%) among 912 study eyes (64.2%) receiving tissue from donors without diabetes and 97.1% (95% CI, 95.5%-98.4%) among 509 study eyes (35.8%) receiving tissue from donors with diabetes (difference between groups = 0.7 percentage points; 95% CI, −1.2 to 2.6; P = .63). The 1-year cumulative probability of graft success was 96.5% (95% CI, 93.6%-98.9%) in the mild donor diabetes severity subgroup (n = 173) and 97.3% (95% CI, 95.4%-98.8%) in the moderate to severe donor diabetes severity subgroup (n = 336), using a diabetes severity rating scale based on medical history. The rates of primary donor failure, early failure related to surgical complications, and subsequent failure were as follows: 2.5% (23 of 912), 0.7% (6 of 912), and 0.3% (3 of 912), respectively, in recipients of tissue from a donor without diabetes, and 2.6% (13 of 509), 0.4% (2 of 509), and 0%, respectively, among recipients of tissue from a donor with diabetes. There were no failures due to graft rejection. Conclusions and Relevance The 1-year success rate in eyes undergoing DMEK with successfully prepared tissue was very high regardless of donor diabetes status. These results, supported by the separately reported finding that endothelial cell loss and cornea morphometry after 1 year were not affected by donor diabetes status, provide strong support for having no restrictions on the use of tissue from donors with diabetes for DMEK. Trial Registration ClinicalTrials.gov Identifier: NCT05134480

Abstract Molecular profiling reveals that up to 40% of advanced biliary tract cancers (BTCs) harbor actionable genomic alterations amenable to matched targeted therapies. However, conventional trial designs typically evaluate these agents in pretreated populations, resulting in approvals for later-line use. Notably, 25–44% of patients with advanced BTC may become ineligible for treatment after first-line therapy due to disease progression or functional decline, thus the real-world survival outcomes with matched therapies remains poorly characterized. This international collaborative study includes data from Mayo Clinic, Duke Cancer Institute, and National Cancer Center East (Japan), as well as a combined dataset from the SCRUM-Japan GOZILA, MONSTAR-SCREEN-1, and MONSTAR-SCREEN-2 projects. We assessed overall survival (OS) of patients based on the presence of actionable alterations and the receipt of matched therapy. To adjust for confounding, we applied propensity score weighting with inverse probability of treatment and multivariate Cox regression modeling, controlling for age, sex, tumor location, prior resection, and mutational subgroup. Among 1,049 patients that were analyzed, 358 (34.1%) harbored actionable alterations, with 160 (44.7%) receiving matched targeted therapy. The matched group (patients with actionable tumors who received a matched therapy) were significantly associated with longer median OS (23.3 months; 95% CI: 19.5–30.4) compared to the unmatched group (14.7 months; 95% CI: 12.8–17.9) and those with non-actionable tumors (17.1 months; 95% CI: 15.5–18.7; HR 0.57, 95% CI: 0.46–0.71; p < 0.0001). The unmatched group also was associated with the lowest three-year OS rate (13% vs. 35% in matched and 19% in actionable groups, respectively; p<0.0001). On multivariable analysis with patients who received ≥2 lines of therapy, receipt of matched therapy remained an independent predictor of improved OS (HR 0.62; 95% CI 0.43–0.90). These findings support the early integration of targeted therapies in BTC management and underscore the need to overcome systemic barriers to treatment access.