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ABSTRACT Background Eosinophilic esophagitis is associated with epithelial barrier dysfunction. Epidemiologic studies suggest environmental factors promote disease pathogenesis. The common household detergent sodium dodecyl sulfate (SDS) induces epithelial barrier dysfunction and eosinophilic inflammation in mice. We hypothesized that acute SDS exposure would compromise the esophageal mucosal barrier in humans. Methods Healthy adults brushed with 2 g of an SDS‐containing toothpaste. Esophageal impedance was measured continuously pre‐/post‐toothbrushing to assess the effect of toothpaste on epithelial barrier function. SDS was measured in saliva using a methylene blue anionic substances assay. Participants completed 1‐h esophageal string tests (ESTs) pre‐/post‐toothbrushing and protein isolates from EST eluates from the proximal and distal esophagus were analyzed by tandem mass tag mass spectrometry. Results Ten of twelve subjects completed the clinical study. SDS in the initial expectorate measured immediately after toothbrushing varied markedly (median: 321.40 μg/mL; range: 169.90–1243.00 μg/mL) and was detectable in saliva in 80% of subjects (median: 9.55 μg/mL; range: 0–123.40 μg/mL) at 60 min post toothbrushing. Esophageal mucosal impedance decreased within 30 min of toothbrushing ( p < 0.01). Toothbrushing increased salivary viscosity and proteins associated with mucosal defense in EST eluates. The tight junction pathway was downregulated while the salivary secretion and complement and coagulation cascades pathways were upregulated in the proximal esophagus. Conclusion In healthy individuals, SDS remained detectable in saliva for a prolonged period after toothbrushing at concentrations previously shown to disrupt esophageal epithelial barrier function in vitro. Toothbrushing with an SDS‐containing toothpaste was associated with reduced esophageal mucosal impedance, altered salivary properties, and activated mucosal immune responses.

Background The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood. Objective The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology. Methods For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology. Results We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004). Conclusions In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.

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.

4119 Background: TP53 mutations are frequent genetic alterations in cancers and also prevalent in biliary tract cancer (BTC). In non-small cell lung cancer, TP53 mutations have been reported to enhance immune checkpoint inhibitor (ICI) efficacy and improve outcomes. However, their impact on BTC remains unclear. This study investigated the clinico-molecular characteristics, prognosis, and ICI efficacy in TP53 -mutated BTC. Methods: Patient data were collected from the SCRUM-Japan GOZILA and MONSTAR-SCREEN-1/2 databases (Japan) and the Duke university and Mayo clinic databases (U.S.), which included patients receiving first-line ICI therapy. Comparisons between TP53 wild-type (WT) and mutation groups were performed in the Japanese cohort. Subsequently, analyses were expanded to include U.S. patients, focusing on comparisons between non-ICI and ICI groups. Tumor Immune Dysfunction and Exclusion (TIDE) scores were calculated using MONSTAR-SCREEN-2 whole transcriptome sequencing (WTS) data to evaluate ICI responsiveness, and gene set enrichment analysis (GSEA) explored pathways associated with TP53 mutations. Results: In the Japanese cohort (n=594), TP53 mutations were identified in 311 patients (52.4%). KRAS , ERBB2 , CDKN2A , and SMAD4 alterations were more frequent in the TP53 mutation group, while IDH1, BAP1 , and FGFR2 fusions were more common in the WT group. Multivariable analysis showed TP53 mutations were independent prognostic factors for poor outcomes (progression-free survival [PFS]: HR 1.37, 95% CI: 1.11–1.69, P=0.003; overall survival [OS]: HR 1.36, 95% CI: 1.06–1.75, P=0.017). Incorporating the U.S. cohort (n=625; non-ICI: 548; ICI: 77), no significant differences in overall response rate (ORR) or disease control rate (DCR) were observed in the non-ICI group between the groups. However, in the ICI group, TP53 mutations tended to show higher ORR (21.1% vs. 38.5%, P=0.16) and DCR (47.4% vs. 66.7%, P=0.14). In the non-ICI group, TP53 mutations were associated with worse PFS (HR 1.46, median PFS: 7.4 vs. 5.3 months, P<0.001), whereas, in the ICI group, no significant difference was observed; however, a trend toward better PFS was seen in the TP53 mutation group (median PFS: 5.0 vs. 6.4 months, P=0.163). TIDE scores were significantly lower in the TP53 mutation group, indicating higher ICI responsiveness. GSEA revealed enrichment of oxidative phosphorylation and hypoxia pathways. Conclusions: TP53 mutations are independent prognostic factors for poor outcomes in BTC. However, patients with TP53 mutations may derive greater benefits from ICIs, underscoring the importance of tailored therapeutic strategies in TP53- mutated BTC.

PURPOSE This study aimed to investigate the clinicomolecular profiles and the efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy in HER2 -amplified biliary tract cancer (BTC). METHODS This study was an international collaboration that used combined data from the prospective SCRUM-Japan GOZILA and MONSTAR-SCREEN in Japan and retrospective reviews in the United States; patients with advanced BTC who had received systemic therapy were included. The clinicomolecular profiles were evaluated in an exploratory cohort, whereas the efficacy of HER2-targeted therapy was assessed in a biomarker-selected cohort. RESULTS Of the 439 patients in the exploratory cohort, 43 (10%) had HER2 amplification. The frequencies of coalterations were higher in patients with HER2 amplification versus patients without HER2 amplification including HER2 mutations (26% v 5%, P < .001), TP53 mutations (84% v 61%, P = .003), and BRAF amplification (9% v 2%, P = .030). There were no KRAS mutations identified in patients with HER2- amplified BTC. No significant difference in overall survival (OS) was observed between patients with and without HER2 amplification (median, 17.7 v 16.9 months; hazard ratio [HR], 0.95 [95% CI, 0.65 to 1.40]). Of the 60 patients with HER2 -amplified BTC in the biomarker-selected cohort (43 from Japan and 17 from the United States), the OS was significantly longer in 29 patients who received HER2-targeted therapy than in those who did not receive HER2-targeted therapy (median, 24.3 v 12.1 months; HR, 0.39 [95% CI, 0.23 to 0.82]). Multivariate analysis identified HER2-targeted therapy as an independent prognostic factor for OS (HR, 0.29 [95% CI, 0.14 to 0.58]; P < .001). CONCLUSION HER2 amplification was found in 10% of advanced BTC and was not identified as an independent prognostic factor for OS. Patients with HER2 -amplified BTC derive significant benefit from HER2-targeted therapy.

BACKGROUND: A preservation system, the Organ Care System (OCS; TransMedics) uses normothermic pulsatile perfusion during organ transport for heart transplantation. This system has demonstrated favorable outcomes in hearts recovered from extended-criteria donors after brain death (DBD) and donors after circulatory death (DCD). METHODS: The OCS Heart Perfusion Registry collects data on US heart transplantations using the OCS, static cold storage (SCS), or thoracoabdominal normothermic regional perfusion (NRP) and donor hearts recovered from DBD or DCD donors. We analyzed donor and recipient characteristics and posttransplantation outcomes in patients transplanted with OCS donor hearts (either DBD or DCD) compared with SCS hearts, and with OCS hearts from DCD donors compared with those recovered with NRP followed by SCS. Propensity score matching was used in survival analyses to adjust for differences among recipient characteristics. RESULTS: Between 2021 and 2023, 3225 consecutive heart transplantations enrolled from 56 centers were analyzed in the Heart Perfusion Registry. The OCS was used in 854 of 3225 heart transplantations (26.4%), among which 340 (39.8%) were DBD and 514 (60.2%) were DCD donors, whereas 2174 DBD donors were recovered with SCS and another 197 DCD donors with NRP techniques. The OCS-DBD group experienced a greater number of organ offer refusals before final acceptance (13 versus 6; Wilcoxon rank sum, P <0.001) and a longer transport distance (667 miles versus 232 miles; Wilcoxon rank sum, P <0.001) compared with SCS-DBD. Survival at 12 months was similar between the 2 groups (89.9% for OCS-DBD versus 90.6% for SCS-DBD; marginal Cox model, P =0.54). Among the OCS-DCD and SCS-DBD groups, survival at 12 months was also similar (91.0% versus 92.5%, respectively; marginal Cox model, P =0.32). The OCS-DCD and NRP-DCD groups demonstrated similar survival (91.0% versus 91.7%, respectively; log rank, P =0.63), although the transport distance was longer in OCS-DCD compared with DCD with NRP followed by SCS (400 miles versus 223 miles; Wilcoxon rank sum, P <0.001). By 2023, 90% of all OCS donor management and recovery was performed with dedicated organ recovery teams. CONCLUSIONS: We demonstrate that real-world implementation of the OCS for DBD donors (using predominantly a dedicated recovery team) is associated with expanded donor criteria, longer transport distance, and excellent posttransplantation outcomes. In OCS-DCD donors, outcomes parallel those of donors recovered with NRP-DCD and compare favorably with DBD donor organs.

Importance Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.