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This study examines the patient- and hospital-level variation in time to initiation of inpatient management among patients admitted to general medical services.

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

ABSTRACT Background Olfactory neuroblastoma (ONB) exhibits variable recurrence patterns, with significant late recurrences occurring years after treatment. We investigated cutoff periods to define late recurrence and identified predictors that distinguish patients at risk of late recurrence from those considered cured. Methods From a multi‐institutional cohort of 219 ONB patients treated at nine centers, we analyzed 77 patients with documented recurrence. Using a 48‐month cutoff to define early (< 48 months) versus late (≥ 48 months) recurrence, we evaluated 35 clinical, anatomic, and treatment variables using Firth penalized logistic regression across three comparisons: (1) late versus early recurrence timing, (2) late recurrence versus no recurrence, and (3) early recurrence versus no recurrence. Results Thirty‐four of the 77 (44.2%) recurrences were classified as late. Among the 77 patients who recurred, smaller tumor volume (OR 0.243, p = 0.035) and lower novel Dulguerov staging (OR 0.802, p = 0.038) were associated with late, rather than early recurrence. When patients with late recurrence were compared to those who remained disease‐free, radiographic skull base bone involvement was the strongest independent predictor (OR 2.90, 95% CI 1.14–8.64, p = 0.025), and this effect strengthened after adjusting for tumor volume (OR 3.80, p = 0.029). Pathologic dural invasion (OR 3.29, p = 0.013), Kadish stage (OR 2.02, p = 0.026), and T‐stage (OR 1.32, p = 0.040) were also significant. Conclusions A 48‐month cutoff effectively stratifies ONB recurrence risk. Skull base bone involvement independently predicts recurrence when compared to nonrecurrent cases and uniquely persists as a risk factor for late recurrence. These findings establish skull base bone involvement as a novel biomarker for risk‐stratified surveillance protocols.

Abstract Background Machine perfusion represents the most significant breakthrough in liver transplantation (LT) since the discovery of cyclosporin. Yet, the optimal perfusion strategy remains unsettled. Randomized trials demonstrate that hypothermic oxygenated perfusion (HOPE) improves graft survival and function and reduces ischemic cholangiopathy, whereas normothermic machine perfusion (NMP) decreases post-transplant injury. Real-world comparisons are lacking and challenging due to heterogeneity in donor-recipient risk profiles and regional differences. Aims To compare real-world outcomes of HOPE and NMP in LT. Methods We analyzed consecutive NMP-preserved LTs from seven North American centers between 2021 and 2024. We compared NMP to the European HOPE-REAL cohort, comprising HOPE-treated LTs from 22 centers between 2012 and 2021. Analyses were stratifyied by graft type and risk category and adjusted for donor age, donor risk index, and balance of risk score using entropy balancing. Results A total of 470 NMP and 1202 HOPE-treated grafts were analyzed, revealing major differences in risk profiles (Figure 1). In NMP, death-censored graft survivals at 1, 2, and 3 years were &gt;95% in donation after brain death (DBD) and &gt;94% in donation after circulatory death (DCD) grafts. Comparable outcomes were observed in the HOPE cohort with &gt;93%, in DBD, and &gt;87% in DCD after up to 3 years, despite significantly higher donor age and longer functional warm ischemia in the HOPE DCD cohort (Figure 2). After risk adjustment, death-censored graft survival remained similar between both modalities (Table 1). Non-anastomotic biliary stricture rates after DCD-LT were comparable (8.5% vs. 12.4%), independent of whether continuous or end-ischemic NMP was performed. Conclusion This first transatlantic real-world report demonstrates excellent outcomes with both NMP and HOPE despite higher graft risk in Europe. Machine perfusion is the new standard of care in LT, while further understanding is needed regarding the distinct benefits of each modality across risk profiles.Figure 1.Graft risk in NMP and HOPE stratified by graft type. Benchmark case was defined as primary transplant with MELD &lt;20 and BAR score &lt;9, extended criteria as either BMI &gt;30kg/m2, donor age &gt;65 years, CIT &gt;12h. DCD grafts were categorized as definedFor image description, please refer to the figure legend and surrounding text. Figure 2.Death-censored graft survival in liver transplantation following NMP and HOPE stratified by graft type. Abbreviations: NMP (Normothermic Machine Perfusion), HOPE (Hypothermic Oxygenated Perfusion), DBD (Donation after Brain Death), DCD (Donation after circulatory death)For image description, please refer to the figure legend and surrounding text. Table 1.Risk-adjusted comparison of death-censored graft survival between NMP and HOPE.For image description, please refer to the figure legend and surrounding text.

TPS8124 Background: Immune checkpoint inhibitor (ICI)–based regimens are standard first-line therapy for metastatic non–small-cell lung cancer (NSCLC) without actionable driver mutations; however, most patients experience disease progression within 12 months. A subset develop oligoprogression, defined by progression at a limited number of metastatic sites with otherwise controlled disease. Oligoprogression represents a therapeutic window in which local ablative therapy could be used to prolong disease control. In the prior phase II CURB trial, SBRT was shown to significantly prolong progression-free survival (PFS) in patients with oligoprogressive NSCLC. Methods: CCTG-BR38 is an international, multicenter, open-label, randomized phase III trial conducted through the NCI National Clinical Trials Network. Adults with stage IV NSCLC receiving first-line ICI ± chemotherapy who develop ≤5 extracranial oligoprogressive lesions are randomized 1:1 to: (1) switch to second-line standard systemic therapy or (2) SBRT (30 Gy in 3 fractions) to all oligoprogressive sites followed by continuation of the same first-line systemic therapy. Randomization is stratified by type of first-line systemic therapy (ICI alone vs ICI + chemotherapy), number of oligoprogressive lesions (1–2 vs 3–5), and ECOG performance status (0-1 vs 2). Patients with treated, stable brain metastases are eligible. Primary Endpoints: Dual primary endpoints are PFS and overall survival (OS). Secondary endpoints include safety (CTCAE v5.0), patient-reported adverse events (PRO-CTCAE), quality of life (EORTC QLQ-C30/LC13), and cost-effectiveness (EQ-5D-5L; Canadian sites). Optional blood and tissue collection for exploratory biomarker analyses are planned. Statistical Considerations: A total of 320 patients (160 per arm) will be enrolled. The sample size is based on detecting a HR of 0.7 for OS (an improvement in median OS from 10 to 14.3 months) with 80% power using a 1-sided 2% level test (the overall 1-sided 2.5% type I error will be assigned 2% to OS and 0.5% to PFS). Interim analyses for futility and efficacy are planned. Current Status: The trial was centrally activated on April 3, 2025. Accrual is ongoing across Canadian and US NCTN sites. Clinical trial information: NCT06686771 .

INTRODUCTION: Nosocomial infections (NIs) in cirrhosis are associated with high mortality but could be preventable. Logistic regression (LR) models have failed to identify high-risk patients. We aimed to develop machine learning (ML) models to predict NI. METHODS: The CLEARED consortium consists of prospectively enrolled cirrhosis inpatients from >120 centers. Using day-of-admission clinical data, 3 ML approaches (random forest [RF], extreme gradient boosting, and neural networks [NNs]) were used to predict NI. Data were split 80:20 for training and testing stratified by the outcome. Models were compared using area under the receiver operating characteristic curve (AUC). RESULTS: In total, 8,263 patients (55.90 ± 13.34 years; 64.1% men) from 127 centers in 37 countries were included. NI developed in 869 (10.5%), a median of 6 (4–11) days of postadmission. Major NIs were respiratory (29.6%) and urinary tract infection (15.7%), and spontaneous bacterial peritonitis (13.5%). NIs occurred more frequently in patients from low/low-middle income countries and those with severe liver disease, alcohol etiology, and admission infections. NIs were associated with inpatient mortality (31.9% vs 8.1%, P < 0.001) and liver transplantation (4.8% vs 1.9%, P < 0.001). Although the RF model (AUC 0.69) showed good calibration (Brier score 0.09), outperforming extreme gradient boosting, neural network, and LR models (AUC 0.66 for all; LR comparison P = 0.043), no model achieved AUC ≥0.80 for clinical utility. At 10% predicted probability threshold, the RF model demonstrated only 75.4% sensitivity, 52.9% specificity, and 15.9% positive predictive value (PPV). DISCUSSION: NIs cannot be accurately predicted from day-of-admission data using ML models, even in a large, prospective, global cirrhosis cohort. Every hospitalized patient with cirrhosis should receive protocolized infection control measures.

Introduction Angina with no obstructive coronary artery disease (ANOCA) affects millions and is frequently under-recognised because diagnostic pathways and risk tools predominantly target obstructive coronary artery disease (CAD). This protocol describes shared methods for two machine-learning (ML) studies: (1) differentiating ANOCA from stable angina with obstructive CAD and (2) predicting long-term mortality among patients with ANOCA and obstructive CAD. Methods and analysis We will develop and cross-site validate ML classification models using a multicentre retrospective cohort drawn from the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease registry and institutional datasets from the University of Ottawa Heart Institute and the University Health Network. Eligible participants are adults (≥18 years) undergoing initial cardiac catheterisation for chest pain/anginal equivalents since 1995, excluding prior revascularisation, major structural heart disease and predefined non-anginal indications. Outcomes are (1) ANOCA (0% to <50% stenosis) versus obstructive CAD (≥50% stenosis) and (2) 1, 3 and 5-year mortality, modelled separately for ANOCA and obstructive CAD. Model development will use nested cross-validation with stratified k-fold inner-loop tuning and leave-one-site-out cross-validation for repeated external validation. Candidate predictors will be harmonised across sites, filtered for missingness and refined using expert/directed acyclic graph-guided selection plus Boruta and Least Absolute Shrinkage and Selection Operator. Preprocessing includes appropriate encoding, missing-data imputation (multivariate imputation by chained equations) and feature scaling. Algorithms will include elastic-net logistic regression, random forest, LightGBM and multilayer perceptron models; hyperparameters will be optimised via Bayesian optimisation. Performance and threshold tuning will be reported. Explainability and subgroup fairness will be assessed using SHapley Additive exPlanations. Final models will be deployed as a web-based clinical risk calculator. Ethics and dissemination Ethics approval has been obtained from the University of Calgary and the University Health Network (#24-5916). Analyses will use deidentified data in secure environments; only aggregate results will be reported. Findings will be disseminated via peer-reviewed publications, conferences and a web-based calculator.

815 Background: EV, alone or combined with pembrolizumab (EVP), is a standard of care for patients (pts) with aUC. Markers predictive of early or durable treatment response in aUC remain limited. Here, we investigate serial ctDNA monitoring and TP53 VAF as complementary predictors of early EV/EVP response. Methods: This single-institution IRB-approved study included pts with aUC treated with EV/EVP between 1/2021 and 9/2025. Pt demographics, clinicopathologic features, serial Signatera ctDNA results, and somatic tissue next-generation sequencing (NGS) data were abstracted from medical records. Primary refractory disease (PRD) was defined as progressive disease on first restaging scan or earlier clinical progression resulting in death from disease. PRD and progression-free survival (PFS) were assessed using Fisher’s exact and log-rank tests. Results: Out of 158 pts, 67 pts were included in study cohort. Median follow-up was 13.2 months, with 52% of pts alive at time of data cutoff. Clinical characteristics at EV start include median age 69 years (range 41-99), 78% male, 91% white, 15% variant-predominant histologic subtype, 15% upper tract disease, 43% with visceral metastasis (24 lung, 7 liver), 66% frontline treatment (42 EVP, 2 EV), and 34% refractory setting (6 EVP, 17 EV). At first restaging scan, observed response rate was 50%; 23% had PRD. TP53 alterations on NGS were identified in 39 pts (58%); TP53 VAF was available for 36 pts (92%), with median VAF 50.7% (range 8-82%). While TP53 mutation presence did not significantly associate with PFS (hazard ratio [HR] 1.28, 95% CI 0.68-2.42; log-rank p = 0.45), pts with TP53 VAF ≥ 50% had significantly longer PFS compared with TP53 VAF < 50% (HR 0.44, 95% CI 0.18-1.04; log-rank p = 0.03). PRD was more commonly observed with TP53 VAF < 50% than with TP53 VAF ≥ 50% (odds ratio [OR] 0.06, 95% CI 0.01-0.48, p = 0.01). 23 pts (21 EVP, 2 EV) had ≥ 2 serial ctDNA draws ≤ 120 days apart, including baseline draw within 2 months of EV start. Median time between 1 st and 2 nd ctDNA draws was 43 days. 70% (16 pts) had ≥ 90% ctDNA decline and 17% (4 pts) had ctDNA rise. The 2 pts with PRD exhibited ctDNA rise, whereas no pts with ctDNA decline had PRD (p = 0.04). 10 of these pts (43%) had TP53 mutations with available VAF. Of those 5 pts with TP53 VAF ≥ 50%, 3 had ctDNA clearance over 90%, 1 had 0-90% ctDNA clearance, and 1 had ctDNA rise. Of those 5 pts with TP53 VAF < 50%, 2 had ctDNA clearance over 90%, 1 had 0-90% ctDNA clearance, and 2 had ctDNA rise. Conclusions: Integrated serial ctDNA monitoring and tumor TP53 VAF may capture early treatment sensitivity to EV/EVP. Limitations include retrospective analysis, small sample size/power, combined EV/EVP cohort, and lack of centralized imaging review. Further validation in large, prospective cohorts is warranted.

Abstract Diffuse hemispheric glioma, H3 G34‐mutant (DHG‐H3 G34) has been primarily molecularly characterized by methylation profiling and sequencing studies. We describe an integrated histomolecular evaluation including high‐resolution copy number profiling of a series of 60 DHG‐H3 G34 to further our understanding of the spectrum of genetic changes associated with this tumor type. Cases were clinically tested using an 187‐gene mutation and fusion targeted neuro‐oncology next‐generation sequencing panel ( n = 60) and Oncoscan chromosomal microarray ( n = 26) by a single laboratory (2018–2022). A subset of cases had immunohistochemical results for OLIG2 ( n = 42), p53 ( n = 48), and ATRX ( n = 46), and methylation array data ( n = 8). Median age at testing was 21 years (range, 12–50). No significant difference was noted in clinical, histopathological, and mutational profile between pediatric and adult patients. H3‐3A G34 mutations included G34R ( n = 56; 94%), G34V ( n = 3), and a non‐canonical G34E ( n = 1). Concurrent mutations most often involved TP53 ( n = 55; 92%), ATRX ( n = 50; 83%), and PDGFRA ( n = 34; 57%). A reportedly primary tumor was confirmed to be hypermutant and had a PMS2 mutation. A single case also showed an FGFR3::FAM184B fusion. All cases with available chromosomal microarray data had unbalanced genomes, which were often complex (14/26; 54%). The most frequent recurrent copy number abnormalities were losses involving 3q, 4q, 10q, 13q, and 18q, and 17p copy‐neutral loss of heterozygosity (cnLOH) encompassing TP53 . This copy number profile was reminiscent of that seen in Grade 4 IDH‐mutant astrocytomas. Collectively, a TP53 abnormality at copy number (12/26, all cnLOH), sequence (55/60) and protein expression (46/48) level was detected in all 60 cases. In conclusion, integrated high‐resolution copy number and histomolecular analysis expanded the spectrum of genetic changes associated with DHG‐H3 G34, including the presence of universal TP53 abnormalities with frequent cnLOH—a copy number abnormality that has been largely unrecognized—for this new 2021 World Health Organization central nervous system tumor type.