Citations

Early allograft failure (EAF) after living donor liver transplantation (LDLT) remains a clinical challenge. Existing prediction models developed for deceased donor transplantation poorly apply to LDLT due to distinct surgical and physiological factors. This study identifies clinical determinants of EAF and develops an LDLT-specific prediction model. We conducted a multicenter retrospective cohort study from 17 high-volume LDLT centers (January 2016–December 2020) with external validation at a tertiary center in Saudi Arabia (January 2015–December 2022). The primary outcome was EAF (graft loss or patient death ≤90 d). Multivariable mixed-effects logistic regression identified preoperative/intraoperative risk factors. The EAGLE-LDLT model was constructed using postoperative laboratory values. Performance was compared against established models (EAD, MEAF, A2ALL) using ROC analysis and decision curve analysis. The development cohort included 2944 adult LDLT recipients (67.7% male; median age 55 y; median MELD 14) with a 5.5% EAF rate. External validation included 1020 recipients (median MELD 21, 6.7% EAF). Independent risk factors for EAF were MELD (OR 1.06, 95% CI 1.04–1.08), donor BMI (OR 1.05, 95% CI 1.00–1.10), portal vein thrombosis (OR 1.73, 95% CI 1.13–2.63), and hepaticojejunostomy (OR 1.58, 95% CI 1.06–2.36). The EAGLE-LDLT model incorporating peak ALT (>468 U/L), peak INR (>1.9), and bilirubin (>3.5 mg/dL) and INR (>1.3) at POD7, demonstrated superior discrimination (AUC=0.81) compared with MEAF (AUC=0.77, p =0.004), EAD (AUC=0.67, p <0.001), and A2ALL (AUC=0.65, p <0.001). EAGLE-LDLT achieved balanced sensitivity (75.0%) and specificity (73.7%), effectively stratifying patients into high-risk (15% of patients; 40.4% EAF incidence) and low-risk groups. Preoperative and intraoperative clinical factors predict EAF in LDLT. The EAGLE-LDLT model accurately identifies LDLT recipients at the highest risk for EAF postoperatively.

Context.— The US Food and Drug Administration (FDA) Emergency Use Authorization (EUA) for SARS-CoV-2 assays encompassed both in vitro diagnostic and laboratory-developed tests. Related testing data and documents from EUAs were published on the FDA website as PDF files, constituting a rich data resource. Objective.— To highlight the value of structured descriptive and validation data and provide recommendations on improving the quality, accessibility, and shareability of the FDA’s digital resources. Design.— SARS-CoV-2 diagnostics EUAs and related files were acquired from the FDA, and data were extracted through an iterative manual or automated process with quality assurance in accordance with a set of data entry definitions to generate a data product (ie, data analysis and presentation of data into tables, graphs, and reports, optionally including different data sets) that could be disseminated. Results.— Four challenges limited the usability of FDA EUA data, including (1) distinguishing EUA tests owing to similar names or inconsistent naming conventions; (2) document location and tracking owing to inconsistent EUA document identifiers, resource locators, and versioning; (3) data location and retrieval owing to heterogeneous structure and data formatting within EUA documentation; and (4) maintenance of existing data owing to lack of clear and traceable communication around EUA amendments. Conclusions.— Converging efforts from disparate groups to extract and synthesize FDA test data reveal an unaddressed need for better organization and communication. Existing FDA data reporting systems must be improved and adapted for the demands of the connected data science era.

Objective: To establish international benchmark values for relevant outcome parameters in robotic Whipple. Summary Background Data: For safe adoption of surgical innovation, robust quality control is essential. Benchmarking is a validated tool for assessing surgical performance. Recent international consensus identified establishing benchmark values for robotic Whipple as top priority. Methods: We analyzed consecutive patients undergoing robotic Whipple between 2020-2023 with a minimum one-year follow-up. Reference centers were required to perform ≥15 cases/year, be scientifically active in the field, and maintain a prospective database. Benchmark criteria included benign or resectable malignant disease without neoadjuvant therapy, arterial resection, major co-morbidities, or significant previous abdominal surgery. Benchmarks were established for 13 outcome parameters. Result: The benchmark cohort comprised 418 patients from 12 centers across four continents. Benchmark values were: conversion rate ≤4.3%, transfusion rate ≤2.1%, 6-month mortality ≤2.2%, major complications ≤23.2%, and CCI® ≤20.9. Clinically relevant pancreatic fistula (grade B/C) and hemorrhage (grade B/C) rates were ≤23.6% and ≤12.7%, respectively. For pancreatic ductal adenocarcinoma (n=123), the benchmark for lymph node yield was ≥20. Higher surgical difficulty was associated with increased overall postoperative morbidity (R 2 =0.38, P =0.019), higher center caseload with reduced pancreas-specific complications (R 2 =0.28, P =0.044). Independent POPF predictors included duct diameter ≤4 mm (OR 1.37, 95% CI: 1.03, 1.82), anticoagulation (OR 2.45, 95% CI: 1.47, 3.99), and indication other than PDAC (OR 2.33, 95% CI: 1.68, 3.27). Conclusions: This study establishes the first international benchmarks for robotic Whipple, demonstrating oncologic outcomes and morbidity comparable to open surgery with the benefits of minimally invasive surgery.

Abstract Exercise training improves cardiovascular health and reduces the risk for future cardiovascular events and mortality. However, emerging evidence suggests that Masters athletes may have a higher prevalence of cardiovascular abnormalities, such as atrial arrhythmias, coronary atherosclerosis, aortic dilatation, and myocardial fibrosis, compared to their less active peers. The clinical management of Masters athletes may be challenging as available guidelines for such conditions are generally based on data derived from symptomatic sedentary patients, limiting their applicability to highly trained individuals. Other unique challenges in the clinical assessment of Masters athletes include differences in symptomatic presentations compared to sedentary individuals, potential resistance to the initiation of pharmacologic treatment, and the increasing availability of consumer wearable health data that may provide relevant information on their cardiovascular health status. The purpose of this joint EAPC/ESC and ACC Clinical Consensus Statement is to provide an in-depth update on the current state of knowledge on abnormal cardiovascular findings in Masters athletes. We present an expert-based approach on the diagnostic assessment, management, and prognosis of (i) atrial fibrillation, (ii) bradyarrhythmias, (iii) ventricular arrhythmias, (iv) coronary atherosclerosis, (v) aortic dilatation, (vi) myocardial fibrosis, and (vii) exercise-induced arrhythmogenic cardiomyopathy. Clinical challenges, areas of ongoing controversy, and uncertainty and the potential underlying mechanisms are discussed. We also present future perspectives and research directives to further refine current best practice strategies. This includes the need for clinical outcome studies, dedicated randomized controlled trials in athletes, and international registries with diverse populations and longitudinal follow-up to evaluate the natural history of cardiac abnormalities and facilitate development of evidence-based approaches in the clinical management of Masters athletes with cardiovascular abnormalities.

566 Background: FGFR inhibitors (FGFRi) have an established role in treating FGFR2-altered (alt) cholangiocarcinoma (CCA). Tinengotinib, a novel FGFRi, has shown promising activity overcoming acquired resistance to prior FGFRi. We present biomarker analyses evaluating tinengotinib’s ability to overcome prior FGFRi resistance and to elucidate mechanism of resistance to tinengotinib. Methods: Eligible patients (pts) with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy were treated with tinengotinib 10 mg daily across 4 Cohorts: A1: FGFR2 fusion (fus) with primary progressive disease (PD) on prior FGFRi; A2: FGFR2 fus with PD after prior response to FGFRi; B: FGFR alt without FGFR2 fus; C: FGFR wild-type. Efficacy was assessed by RECIST v1.1. All pts underwent liquid biopsy for circulating tumor DNA (ctDNA) at baseline; additional timepoints include cycle 3 day 1 (C3D1), time of PD, and end of treatment (EOT). Samples were analyzed using FoundationOne Liquid panel. Results: 27 out of 55 enrolled pts had biomarker samples collected at baseline and C3D1. Among them, pts in A1 (n=10, 107 mutations (mut)), B (n=8, 90 mut) and C (n=5, 74 mut) showed a significant decrease in short variant allele frequencies (VAF) from baseline to C3D1 by a median relative VAF reduction of 100% (p<0.0001) for each of the three cohorts. Although a median relative VAF reduction of 33.3% was seen in A2 (n=4, 15 mut), this was not significant (p=0.6093) likely due to low baseline mutation burden. A ≥50% reduction in ctDNA was associated with improved progression free survival (p<0.0014). Additionally, 100% of median relative reductions in FGFR2 kinase domain (KD) mut were seen in A1 and B (p<0.0001, 95% CI 100-100% and p=0.0156, 95% CI 83.6-100%, respectively), with 92% and 57% clearance of initial FGFR2 KD mut by C3D1. In a subgroup of 10 pts with biomarker sampling at baseline and EOT, 3 pts in A1 with acquired resistance showed emergence of novel FGFR2 mut, loss of FGFR-sensitive mut and new mut in alternate pathways (e.g., AKT, EGFR, RAS/MAPK) while retaining the original FGFR2 fus. 1 pt from B developed resistance due to new FGFR2 rearrangements and FGFR2 mut. 4 FGFR wild-type pts from C developed resistance involving mut in TP53, KRAS, and other oncogenic drivers. Conclusions: These findings provide genomic evidence that tinengotinib may overcome resistance to prior FGFRi treatment in FGFR2 fus-positive CCA, as reflected by significantly reductions in ctDNA VAFs and frequent clearance of FGFR2 KD mutations. The emergence of resistance alterations including de novo FGFR2 mutations and bypass pathways activations indicates acquired resistance that may limit long-term benefit. These results support further investigation with expanded biomarker sampling to better characterize resistance evolution and guide therapy optimization in an ongoing Phase 3 trial. Clinical trial information: NCT04919642 .

Coxsackievirus B3 (CVB3) is a picornavirus that causes systemic inflammatory diseases including myocarditis, pericarditis, pancreatitis, and meningoencephalitis. We have previously reported that CVB3 induces mitochondrial fission and mitophagy while inhibiting lysosomal degradation by blocking autophagosome-lysosome fusion. This promotes the release of virus-laden mitophagosomes from host cells as infectious extracellular vesicles (EVs), enabling non-lytic viral egress. Transient receptor potential vanilloid 1 (TRPV1), a heat and capsaicin-sensitive cation channel, regulates mitochondrial dynamics by inducing mitochondrial membrane depolarization and fission. In this study, we found that TRPV1 activation by capsaicin dramatically enhances CVB3 egress from host cells via EVs. Released EVs revealed increased levels of viral capsid protein VP1, mitochondrial protein TOM70, and fission protein phospho-DRP1. Moreover, these EVs were enriched in heat shock protein HSP70, suggesting its role in facilitating infectious EV release from cells. Furthermore, TRPV1 inhibition with capsazepine and SB-366791 significantly reduced viral infection in vitro. Our in vivo studies also found that SB-366791 significantly mitigates pancreatic damage and reduces viral titers in a mouse model of CVB3 pancreatitis. Given the lack of understanding regarding factors that contribute to diverse clinical manifestations of CVB3, our study highlights capsaicin and TRPV1 as potential exacerbating factors that facilitate CVB3 dissemination via mitophagy-derived EVs.

Facial pain disorders, most notoriously trigeminal neuralgia, cause substantial suffering, functional impairment, disability, and impaired quality of life. However, most pain medicine practitioners have had only limited education on the evaluation, diagnosis, and treatment of facial pain. Furthermore, this limited education often contains commonly held myths about facial pain diagnosis. These myths can result in misdiagnoses that lead to ineffective medications, interventions, or surgeries and prolonged pain. Therefore, the American Society of Regional Anesthesia and Pain Medicine’s Headache and Facial Pain Special Interest Group convened a multidisciplinary group of neurologists, anesthesiologists, and dentists to identify and dispel pervasive myths in facial pain diagnosis.

Abstract Secondary central nervous system (CNS) large B-cell lymphoma (SCNSL) occurs in the de novo setting, as a CNS-isolated relapse, or synchronous (concomitant CNS and systemic) relapse. SCNSL is a devastating event without therapeutic consensus. Thus, we aimed to evaluate treatment outcomes in an international cohort. Progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR, estimated using competing-risk models) were reported. Prognostic factors were identified in a 6-month landmark multivariate analysis. Outcomes after thiotepa autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy (CAR-T) delivered at relapse were compared after propensity score matching (PSM). A total of 1139 patients were included in the analysis (de novo: 537; relapsed SCNSL: 602). Two-year PFS estimates were 40.4%, 43.9%, and 16.2% for de novo SCNSL, CNS-isolated relapse, and synchronous relapse, respectively. Patients with CNS-isolated relapse demonstrated low rates of systemic recurrence (24-month CIR, 6%). Thiotepa-ASCT correlated with longer survival in de novo SCNSL (PFS: hazard ratio [HR], 0.57; P = .005; and OS: HR, 0.62; P = .023) and CNS-isolated relapses (PFS: HR, 0.55; P = .002; and OS: HR, 0.39; P&lt; .0001). ASCT (thiotepa or no thiotepa) also associated with improved survival in synchronous relapses (PFS: HR, 0.57; P = .023; and OS: HR, 0.48; P = .019). Higher survival with thiotepa-ASCT than CAR-T was observed after PSM (PFS: HR, 0.45; P = .005 and OS: HR, 0.41; P = .014). These data support thiotepa-ASCT in eligible patients, particularly de novo disease and CNS-isolated relapses. CNS-isolated relapse was infrequently associated with systemic recurrence, supporting treatment regimens adopted from primary CNS lymphoma.

Abstract Background Gastrointestinal (GI) cancer remains a major global health challenge. This study provides updated 2022 estimates of GI cancer incidence and mortality worldwide, along with projections of incident cases and deaths through 2050 to inform cancer control strategies. Methods In this population‐based study, data from the GLOBOCAN 2022 database were used to examine incidence and deaths associated with GI cancer. By using global demographic projections, this study estimated the projected number of incident cases and deaths until the year 2050. Results By 2050, the global burden of GI cancer is projected to reach 9.06 million incident cases (+85%) and 6.42 million deaths (+93%) from 2022. Increases in incidence are projected for both females (+87%) and males (+83%), as are increases in mortality for both females (+97%) and males (+91%). Whereas the Western Pacific region will have the highest absolute burden, with 3.88 million new cases and 2.79 million deaths, the greatest relative increase is expected in Africa, with incidence and deaths rising by 157% and 160%, respectively. As measured by the Human Development Index (HDI), the steepest increases are projected in low (+151% incidence; +152% deaths) and medium (+112% incidence; +114% deaths) HDI countries. Overall, all GI cancer types are projected to increase, led by pancreatic cancer in incidence (+95%) and colorectal cancer in deaths (+103%). Conclusions GI cancer incidence and deaths are expected to nearly double by 2050, with increases across sexes, cancer types, and regions, especially in lower HDI countries.

ABSTRACT Objective To determine the test performance of cutaneous phosphorylated alpha‐synuclein (P‐SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls. Methods This is the first subgroup analysis of the Synuclein‐One study, a prospective, blinded study evaluating P‐SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control ( N = 151) and DLB ( N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P‐SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40–99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately. Results After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P‐SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA. Interpretation In this prospective, blinded, cross‐sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P‐SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P‐SYN detected. These results support a role for skin biopsy detection of P‐SYN in patients with DLB. Trial Registration NCT04700722