Citations

Purpose To explore the relationship between systemic comorbidities and presenting tumor T category in patients with uveal melanoma. Methods Single-center, retrospective cohort study of patients with posterior uveal melanoma initially diagnosed between January 2000 and December 2016. Univariate and multivariate ordinal logistic regression analyses were performed to identify comorbidities associated with presenting tumor T category, as classified by AJCC criteria. Results Initial presenting AJCC T category was T1 in 190 (43%), T2 in 130 (29%), T3 in 89 (20%), and T4 in 38 (9%). The most common comorbidities present were hypertension (250 patients, 56%), hyperlipidemia (211, 47%), obesity (137, 31%), and diabetes mellitus (87, 19%). Of these, obesity ( p = 0.034), hypertension ( p = 0.017), and diabetes mellitus ( p < 0.001) were associated with earlier presenting T category on univariate ordinal logistic regression. After multivariate regression, only diabetes mellitus ( p = 0.01) and obesity ( p = 0.04) remained significantly associated with earlier T category on initial presentation. Conclusion Among patients presenting with uveal melanoma, diabetes mellitus and obesity were associated with earlier presenting T category, which could reflect earlier detection of uveal melanoma in patients undergoing annual diabetic retinopathy screening examinations or having more frequent contact with the healthcare system. Larger studies should further explore this association and examine the utility of increased ocular screening in early detection of uveal melanoma.

Key Points Atrial fibrillation after kidney transplantation is common and is associated with poor prognosis. Artificial intelligence applied to 12-lead electrocardiograms pretransplant accurately predicts the risk of new-onset atrial fibrillation in our cohort. High-risk artificial intelligence electrocardiography score was independently associated with increased risk of mortality and allograft failure. Background Incident atrial fibrillation (AF) is common after kidney transplantation (KTx) and is associated with worse clinical outcomes. Artificial intelligence electrocardiography (AI-ECG) algorithms have demonstrated efficacy in predicting risk of new-onset AF in the general population; however, their prognostic value in KTx recipients is relatively unknown. Methods Retrospective analysis was conducted on KTx recipients without AF, with at least one pretransplant ECG between 2011 and 2021 across three tertiary centers in the United States (Mayo Clinic sites in MN, AZ, and FL). A previously validated AI-ECG algorithm estimated the probability of incident AF for each patient. Based on AI-ECG probabilities, patients were categorized into high-risk and low-risk groups, with the optimal AI-ECG score cutoff determined. The incidence of new-onset AF, allograft failure, and mortality was compared between groups. Results Overall, 6246 patients (age 53.5±13.8 years; 58.9% male) were included. Pretransplant AI-ECG probability of AF ≥5% was the optimal cutoff for high risk of incident AF (sensitivity 72%, specificity 62%). High-risk scores were associated with true new-onset AF at 30 days (adjusted hazard ratio [aHR], 2.89; 95% confidence intervals [CI], 2.05 to 4.09; P < 0.001), 3 years (aHR, 2.54; 95% CI, 1.99 to 3.26, P < 0.001), and 5 years post-transplant (aHR, 2.48; 95% CI, 1.99 to 3.09, P < 0.001). High-risk AI-ECG scores were also associated with increased mortality (aHR, 1.56; 95% CI, 1.30 to 1.88, P < 0.001) and overall allograft failure (aHR, 1.50; 95% CI, 1.30 to 1.75, P < 0.001) through the 5-year follow-up. Conclusions This pretransplant AI-ECG parameter identified patients at increased risk of new-onset AF post-KTx and provided prognostic utility. Overall, this easy to obtain tool allows for risk stratification of patients who may benefit from closer monitoring, targeted risk factor modification, and early intervention.

Abstract Introduction Cardiac arrest (CA) is the sudden cessation of cardiac activity, leading to haemodynamic collapse and high mortality. Advanced life support (ALS) standardises resuscitation, but the post-return of spontaneous circulation (ROSC) period remains turbulent and poorly understood. Up to 50% of patients who achieve ROSC struggle to maintain spontaneous circulation, leading to re-arrest, typically within minutes. Post-cardiac arrest syndrome (PCAS), involving brain injury and ischaemia-reperfusion injury, plays a key role in re-arrest. Pressure-volume loop (PVL) analysis offers insight into load-independent cardiac biomechanics in the post-ROSC period. The aim of this study is to explore the feasibility of PVL analysis in a swine model of CA. Methods This swine study utilised a ventricular fibrillation (VF) cardiac arrest model in combination with PVL analysis. The experiment included four phases: animal preparation, VF induction, resuscitation, and post-ROSC care. Yorkshire swine (45-70 kg) were sedated, anaesthetised, and VF was induced via an endocavitary electrode attached to a battery. After that, the animals were divided into 3-minute and 6-minute arrest groups before commencing ALS. Standard ALS protocols were followed, including CPR, defibrillation, and drug administration. If ROSC was obtained, animals underwent a 3-hour critical care period. Cardiac indices were compared between baseline and end-of-study values. Results Eight adult Yorkshire swine were enrolled in the study, with a mean weight of 50.2 ± 2.9 kg. VF induction was successfully achieved, and PVL data were collected in all animals except one, establishing a successful porcine VF CA model. In the resuscitation phase, all animals in the 3-minute group achieved ROSC, as opposed to one in the 6-minute group. Post-ROSC metabolic changes included acidaemia, elevated lactate and potassium, partially resolving by study end. Right ventricle PVL data were unreliable, while left ventricle PVL was reliable in 3 of 5 ROSC animals. Preload-recruitable stroke work (PRSW) data were found to be more reliable than the End-Diastolic Pressure-Volume Relationship (ESPVR), with a significant increase in LV PRSW of 34 ± 12% observed post-ROSC in all surviving animals (p&lt;0.001). Discussion This study demonstrates the feasibility of applying PVL analysis to a post-ROSC swine model of cardiac arrest (CA). As expected, warm ischaemic time predicted ROSC, but PVL analysis offered valuable insights into load-independent parameters. While data quality issues hindered ESPVR analysis, PRSW was successfully evaluated, revealing a significant increase post-ROSC, highlighting its potential to guide the development of future therapeutic targets for post-ROSC interventions. The small sample size and technical challenges limited the scope of conclusions, emphasising the need for larger studies.Kaplan-Meier Curve and cycles to ROSC (A) LV PVL, (B) PRSW Pre and Post-ROSC

Abstract Background Ankle-brachial indices (ABI) predict mortality and major cardiovascular events (MACE); however, they are unable to assess the severity of peripheral artery disease in patients with non-compressible vessels. Toe brachial indices (TBI) are less affected by non-compressibility and could be good predictors of cardiovascular morbidity and mortality. Purpose To evaluate the predictive value of TBI for MACE and all-cause mortality in a large population. Methods The initial ABIs and TBIs of all patients referred to a noninvasive vascular laboratory were obtained. We categorized patients based on the worse TBI from either leg, and each patient was classified as normal (&gt;0.8), borderline (0.8-0.61), mild-moderate PAD (0.6 - 0.21) and severe PAD (≤0.2). MACE occurring after the study were identified using ICD9/10 and procedural CPT codes and included myocardial infarction, coronary revascularization, or stroke. Survival analysis was performed using the Kaplan-Meier method with log-rank test to compare survival curves between groups. Results Of 13551 patients, we excluded 643 (5%) in whom TBI could not be obtained. Patient characteristics can be found in Table 1. There were 4,924 MACE and 3,125 deaths during the median follow up time of 8.39 years (Table1). There was a significant difference of MACE incidence (p &lt;0.001) and mortality (p&lt;0.001) by TBI categories, and the curves separate before the 1-year mark (Figure 1A and B). Conclusion TBI is a good predictor of MACE and all-cause mortality in the short and long term and can be obtained in 95% of patients.

Abstract Background Short QT syndrome type 1 (SQT1) is a genetic channelopathy caused by gain-of-function variants in the KCNH2-encoded Kv11.1 potassium channel, responsible for the repolarising IKr current. These variants lead to pathologically shortened cardiac repolarisation and QT intervals on 12-lead ECG, predisposing patients to life-threatening ventricular arrhythmias and sudden cardiac death. Purpose To investigate the therapeutic efficacy of our KCNH2-specific suppression-replacement gene therapy (KCNH2-SupRep) in transgenic SQT1 rabbits generated by cardiac-specific overexpression of KCNH2-N588K. Methods KCNH2-SupRep was developed by combining a custom-designed KCNH2 shRNA with its corresponding shRNA-immune KCNH2 cDNA, packaged into a single AAV9 vector and delivered directly into the aortic root via a Swan Ganz catheter (1E10 vg/kg). Therapeutic efficacy was evaluated in vivo by 12-lead ECG recordings pre- and three weeks post-therapy, ex vivo by optical voltage mapping, and at the cellular level by patch-clamp, calcium imaging, and qPCR in ventricular cardiomyocytes (VCMs) isolated from adult transgenic SQT1 and wild-type (WT) rabbits. Results In vivo, KCNH2-SupRep normalized the heart-rate corrected QT interval (QTc) in transgenic SQT1 rabbits towards WT levels (baseline-SQT1: 153±4ms vs SupRep-SQT1: 167±5ms, p=0.0002; Fig. 1A), without adversely impacting repolarisation heterogeneity. No such QTc changes were observed in sham-treated SQT1 rabbits (sham-SQT1) (baseline-SQT1: 155±4ms vs sham-SQT1: 146±5ms, p=0.1422). Ex vivo, at a 2.5Hz stimulation frequency, KCNH2-SupRep therapeutically prolonged the APD90 in SupRep-SQT1 hearts (176±4ms) near WT levels (179±4ms), compared to untreated (UT)-SQT1 (154±4), and resolved the pathologically increased apicobasal APD90 heterogeneity observed in UT-SQT1 hearts, supporting an anti-arrhythmic effect of KCNH2-SupRep (Fig. 1B). At the cellular level, at a 1Hz stimulation frequency, KCNH2-SupRep prolonged the APD90 in VCMs isolated from SupRep-SQT1 rabbits (363±11ms) closer to WT levels (404±14ms) as compared to UT- (314±12ms) and sham-SQT1 (322±11ms; Fig. 1C). Moreover, KCNH2-SupRep restored the cellular surrogate of the electro-mechanical window (cEMW, Ca2+ transient duration – APD) and normalized IKr in nearly 50% of VCMs (Fig. 1D), in line with a 50-60% suppression of the mutant KCNH2 transcript. This partial therapeutic effect on IKr may explain the incomplete APD90 normalization in individual VCMs. Nonetheless, both in vivo and ex vivo, this partial therapeutic effect was sufficient to completely restore the electrical properties. Conclusion This proof-of-concept study is the first to demonstrate the efficacy of gene therapy in treating SQT1 in a medium-sized animal model. KCNH2-SupRep rescued the disease phenotype in vivo, ex vivo and at cellular levels in transgenic SQT1 rabbits.Therapeutic efficacy of KCNH2-SupRep

Background: Stromal hyaluronic acid (HA) poses a physical barrier and protects tumor cells from immune surveillance. Stroma targeting with pegylated human recombinant PH20 hyaluronidase (PEGPH20) demonstrated improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies in tumor models. This multicenter phase II study of PEGPH20 plus pembrolizumab evaluated the efficacy, safety and immune and stromal biomarkers in patients with HA-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA). Patients and Methods: Patients were treated with PEGPH20 3 µg/kg IV weekly and pembrolizumab 200 mg IV in 3-week cycles. Tumor and blood samples were collected at baseline and on-study for biomarker analyses. Results: Between May and November 2019, 38 patients were screened and 8 treated, with median age 68 years (range 60–73) and median two (range 1–4) prior therapies. The study was closed to accrual early by pharmaceutical sponsor. Treatment was well tolerated, with expected grade 1/2 musculoskeletal toxicities. Best response was stable disease in 2 of 7 evaluable patients (29%). Median overall and progression-free survival were 7.2 months (95% CI 1.2–11.8) and 1.5 months (95% CI 0.9–4.4), respectively. Prolonged survival (range 10.2–27.6 months) occurred in patients treated with subsequent chemotherapy. Higher baseline tumor T cell receptor (TCR) clonality correlated with longer survival. Conclusions: Pembrolizumab with PEGPH20 was safe but did not have significant efficacy in refractory HA-high metastatic PDA.

BACKGROUND: Recent randomized trials have demonstrated that for patients with severe tricuspid regurgitation (TR), transcatheter tricuspid valve interventions (TTVI) improve patients’ symptoms, function, and quality of life and that the amount of health status improvement correlates with the extent of TR reduction. Defining this relationship in greater detail can potentially provide insight into device selection and patient-specific treatment goals. We therefore sought to better understand the relationship between both baseline TR severity and change in TR after TTVI and the extent of improvement in health status after TTVI. METHODS: As part of the Tri-QOL (Kansas City Cardiomyopathy Questionnaire Validation in Tricuspid Valve Disease) study, data from 11 studies of TTVI devices were transferred to the US Food and Drug Administration to harmonize and anonymize before analysis by an independent center. This secondary, observational analysis used patient-level data from the 6 single-arm studies of patients who underwent TTVI to explore the association of change in KCCQ-OS with TR grade using multivariable models, adjusted for age, sex, chronic lung disease, and baseline KCCQ-OS. The primary model included TR grade at baseline, TR grade at 1 month, and the interaction between the two. RESULTS: Among 1056 patients with ≥severe TR who underwent TTVI, mean age was 79.1±7.1 years, 60.3% were female, and mean baseline Kansas City Cardiomyopathy Questionnaire-overall summary score [KCCQ-OS] was 49.5±22.3. Baseline TR grade was severe in 33.5%, massive in 35.9%, and torrential in 30.6%. One-month after TTVI, TR was none/trace in 21.7%, mild in 27.2%, moderate in 28.1%, and ≥evere in 23.1%, while the mean change in KCCQ-OS was 17.0±21.3 points. In a multivariable model that included TR grade at baseline, TR grade at 1 month, and their interaction, there was a strong association between reduction in TR and improvement in KCCQ-OS, with no consistent evidence of a threshold of TR grade below which there was no further improvement in KCCQ-OS. However, among patients with baseline torrential TR, the extent of health status improvement plateaued for patients achieving moderate or less TR at 1 month (ie, a 3-grade improvement from baseline). CONCLUSIONS: Health status improvement after TTVI was most strongly associated with the degree of TR reduction, although there was minimal additional improvement for most patients beyond a 3-grade reduction in TR. These findings support the goal of achieving mild or less TR with TTVI, although patients with torrential TR at baseline may be well served if moderate TR can be achieved.

Background and Aims: Older age increases susceptibility to metabolic dysfunction–associated steatotic liver disease (MASLD), but whether it impacts response to therapies, and how the therapies impact regulators of biological aging, are poorly understood. Statins inhibit the mevalonate pathway to block cholesterol biosynthesis and are widely used in MASLD patients to reduce cardiovascular disease. Whether statins prevent progression to cirrhosis is under investigation. However, the molecular effects of statins in human liver, particularly in the context of aging, remain poorly defined. Approach and Results: We analyzed liver transcriptomes and matched clinical data from 368 adults enrolled in the Duke MASLD Biorepository with a focus on age-dependent responses and the interplay between senescence and ferroptosis, a regulated death process that is constrained by the mevalonate pathway. Serum ALT, AST, and LDL cholesterol levels were lower in statin users of both sexes, particularly among older individuals. Transcriptome analyses revealed that statin use is strongly associated with suppression of senescence-related pathways. Statin use is also associated with increased activation of pathways linked to ferroptosis. Both responses persisted after propensity score matching to control for clinical confounders and were validated in an independent obese cohort. Conclusions: Age-dependent transcriptional remodeling in the liver differs in statin users and non-users. Pathways involved in senescence are suppressed while those that promote ferroptosis are induced in statin users. These results suggest that statins may suppress biological aging in MASLD by acting as senolytics and highlight the complex, context-specific roles of senescence in liver adaptation and remodeling.

This cohort study evaluates the reduction in risk of high-grade serous carcinoma among women undergoing opportunistic bilateral salpingectomy in Canada.