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Immune checkpoint inhibitors (ICIs) have improved cancer prognosis significantly, but their use has been avoided in liver transplant recipients (LTr) due to poorly characterized rejection risk. Data surrounding rejection risk are extremely suboptimal, with highly variable immunosuppression approaches and follow-up, and do not account for the learning curve in managing immunosuppression in the setting of ICI. A standardized institutional clinical practice protocol was developed in 2021 for immunosuppression management to facilitate ICI therapy with prospective close follow-up for immunosuppression levels and allograft function. Of 20 LTr, 12 (60%) were male, 18 (90%) were Caucasian, with a mean age of 54.0 (SD 11.2) years. However, 13/20 had 2 or more failed cancer therapies before ICI. Hepatocellular carcinoma ​(HCC) (N=7), lung (N=3), and melanoma (N=3) were the most frequent. Time from first ICI treatment to death was <30 days (N=5), 30–59 days (N=4), 60–89 days (N=1), and >90 days (N=6). Most deaths were cancer-related, reflecting the late stage of disease. ICI toxicity occurred in 3 LTr; pneumonitis (N=1, 5%), myocarditis (N=1, 5%), and acute cellular rejection (N=1, 5%). Four patients remain alive 178–341 days with stable allograft function and slow reduction in immunosuppression. Three out of 4 patients have a partial cancer response, and 1 with slowed progression of disease. ICI treatment in the immunosuppressed LTr is feasible with careful immunosuppression management and follow-up. Demonstrating a low rejection risk should allow for earlier utilization of these agents to improve cancer prognosis. Optimizing rejection risk with cancer response requires ongoing study.

Goals: A systematic review and meta-analysis of published clinical validity studies was conducted to evaluate the predictive performance of the TSP-9 test. Background: Identifying patients with Barrett’s esophagus (BE) who will progress to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) is challenging. The tissue systems pathology (TSP-9) test can predict risk of progression to HGD/EAC in BE patients. Study: Databases were searched for studies that assessed the clinical validity of TSP-9, and data describing progressors, non-progressors, TSP-9 results, and hazard ratios (HR) with 95% confidence intervals (CIs) were extracted. Odds ratios (OR), sensitivity, specificity, and prevalence-adjusted positive and negative predictive values (PPV adj /NPV adj ) were calculated and used for meta-analysis. Results: Six studies met eligibility criteria, comprising 699 patients. ORs and HRs for TSP-9 had mean common effect size estimates of 6.52 (95% CI: 4.40-9.66, P <0.0001, I 2 =33%) and 6.66 (95% CI: 4.59-9.66, P <0.0001, I 2 =0%), respectively, for predicting progression to HGD/EAC. Mean common effect size estimates were 61% (95% CI: 54%-68%) for sensitivity, 81% (95% CI: 78%-84%) for specificity, 28% (95% CI: 17%-42%) for PPV adj (high risk), 14% (95% CI: 9%-21%) for PPV adj (high/int risk), and 97% (95% CI: 96%-98%) for NPV adj with minimal inter-study heterogeneity ( I 2 =79%, 21%, 0%, 0%, and 0%, respectively). Conclusions: Effect estimates of TSP-9 performance demonstrate that the test provides risk stratification for BE patients. The TSP-9 test can provide clinically impactful results to enable escalation of care for high-risk patients or to identify low-risk patients who can be safely managed with routine surveillance.

Background: Gastric cancer remains one of the leading causes of death globally and a major health concern. This study aims to analyze gastric cancer-related mortality trends over 2 decades. Methods: The CDC WONDER database was used to analyze and stratify de-identified death certificates from 1999 to 2022 across the United States. Trends in age-adjusted mortality rates (AAMR) were assessed using the Joinpoint Regression Program to determine annual percentage changes. Results: Overall, AAMR decreased from 79.26 in 1999 to 44.81 in 2022. Men and older adults had the highest AAMRs. Non-Hispanic (NH) Black or African Americans had the highest AAMR, while NH Whites had the lowest. Geographically, the Northeast had the highest AAMR, and metropolitan areas had higher AAMRs than nonmetropolitan areas. Conclusion: Gastric carcinoma has a poor prognosis, and although the general trend is decreasing across all sociodemographic areas, further research is required for targeted interventions and health policies for high-risk populations.

BACKGROUND: Fontan conversion (FC) is associated with a lower risk of atrial arrhythmias and thromboembolism, but it is unknown whether FC improves long-term survival. The purpose of this study was to assess the impact of FC on transplant-free survival. METHOD: Adults with Fontan palliation were divided into 3 groups: (1) atriopulmonary Fontan connection; (2) atriopulmonary Fontan and subsequent FC to total cavopulmonary connection (TCPC); (3) TCPC at initial Fontan operation. The risk of death/transplant was compared between the 3 groups using Cox regression analysis. RESULTS: We studied 534 patients (age 27±9 years; males [N=298; 56%]). Patients were divided into atriopulmonary Fontan group (N=199, 37%); FC-TCPC (N=138, 26%); and TCPC (N=197, 37%). The FC-TCPC and TCPC groups have similar 15-year incidence of death/transplant (42% versus 47%; P =0.8), even after excluding the 8% operative mortality in the FC-TCPC group (38% versus 47%; P =0.3). On multivariable analyses, neither FC nor the type of Fontan connection was associated with death/transplant. Rather, the risk factors for death/transplant were older age, hepatorenal dysfunction, heart failure, and higher Fontan pressures. The prevalence and severity of these comorbidities increased with age, suggesting that these factors reflect the duration of Fontan physiology, rather than the type of Fontan connection. CONCLUSIONS: These findings, in addition to the high operative mortality associated with FC, suggest that this may not be the optimal treatment option for most adults with atriopulmonary Fontan presenting with Fontan failure. Duration of Fontan physiology rather than the type of Fontan connection may be the main determinant of outcomes.

Importance Accumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit. Objective To assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD. Design, Setting, and Participants This was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025. Interventions Participants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks. Main Outcomes and Measures Participants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer’s Disease Rating Scale (iADRS) and Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker. Results Analyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score ( R 2 , 0.73 [95% CI, 0.37-0.97]) and CDR-SB score ( R 2 , 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 ( R 2 , 0.86 [95% CI, 0.73-0.97]), p-tau181 ( R 2 , 0.88 [95% CI, 0.77-0.97]), and GFAP ( R 2 , 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL ( R 2 , 0.03 [95% CI, 0.00-0.54]). Conclusions and Relevance The findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies. Trial Registration ClinicalTrials.gov Identifier: NCT04437511