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e16021 Background: Esophageal cancer (EC) remains highly lethal in the United States, with approximately 22,370 new cases in 2024. Respiratory failure (RF) frequently complicates advanced disease, and deaths involving both conditions have risen substantially since 1999, necessitating population-based mortality analysis. This study aimed to characterize national mortality trends involving EC and RF, with a focus on demographic, geographic, and urban–rural disparities. Methods: We conducted a retrospective analysis of U.S. deaths associated with EC (C15) and RF (J96) among adults aged ≥45 years using data from the Centers for Disease Control and Prevention WONDER database. Age-adjusted mortality rates (AAMRs) per 1 million were computed and stratified by year of death, sex, race, census region, and urbanization. Joinpoint regression estimated Average Annual Percent Changes (AAPC) with 95% confidence intervals (CI). Results: Between 1999 and 2024, 32,348 deaths were attributed to EC and RF. National AAMRs increased during this period from 8.2 to 13.7 (AAPC: 2.18*; 95% CI: 1.70 to 2.67). Males bore a higher mortality burden than females (AAPC: 2.23*; 95% CI: 1.7 to 2.7). Mortality was elevated in both examined age groups (45-64 and 64-85+), with the most significant impact observed among individuals aged 65-85+ years (AAPC: 2.52*; 95% CI: 2.02 to 3.02). Race-stratified analysis revealed non-Hispanic (NH) White individuals demonstrated the most pronounced increase across the study period (AAPC: 2.72*; 95% CI: 2.19 to 3.25). Geographically, the Midwestern census region showed the steepest rise in mortality, with rural counties nationwide exhibiting a similar increase(In Table). Conclusions: Mortality due to EC and RF has increased insidiously over the past two decades, while the literature on the combined effects of diseases remains limited. The burden is disproportionately higher among males, adults aged ≥65 years, and NH White individuals, particularly in Midwestern and rural regions. These disparities highlight a growing public health burden and emphasize the need for targeted prevention, early detection, optimized respiratory and oncologic care, and region-specific policies to mitigate inequities. Variable AAMR 1999 AAMR 2024 AAPC (95% CI) Overall 8.2 13.7 2.18*(1.70-2.67) Gender:FemaleMale 3.714 5.123.8 1.73*(0.89-2.56)2.23*(1.71-2.75) Census region:NortheastMidwestSouthWest 8.277.510.8 15.513.412.214.9 2.43 *(2.05-2.82)3.22 *(2.38-4.07)1.91*(1.06-2.77)1.30 (-0.16-2.80) Age:45-64years65-85+years 415.5 5.727.7 1.37(-0.01-2.78)2.52*(2.02-3.02) Race:HispanicNH WhiteNH Black 5.27.712.8 9.514.411.2 2.54*(1.76-3.33)2.72*(2.19-3.25)-0.41(-1.33-0.52) Urbanization: (1999-2020)MetroNon-Metro 1999 8.56.9 2020 11.313.8 1.34*(0.83-1.85)3.47*(2.25-4.71) *Indicates p<0.05.

e13121 Background: Triple-negative breast cancer (TNBC) lacks reliable prognostic biomarkers beyond standard clinical staging, limiting individualized risk stratification and treatment planning. The neutrophil-to-lymphocyte ratio (NLR), a readily available marker of systemic inflammation, has been proposed as a prognostic indicator in TNBC; however, existing evidence remains inconsistent. We performed an updated systematic review and meta-analysis to evaluate the prognostic value of pretreatment NLR in the contemporary treatment era. Methods: PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov were systematically searched from database inception through January 1, 2026, for randomized and observational studies reporting associations between pretreatment NLR and survival outcomes in TNBC. Two reviewers independently screened studies and extracted data with discrepancies resolved by consensus. Outcomes included overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Hazard ratios (HRs) were pooled using random-effects models. Risk of bias was assessed using ROBINS-I tool. Prespecified subgroup and sensitivity analyses were performed based on NLR cut-off values, follow-up duration, geographic region, and risk of bias. Results: Twenty-three retrospective studies comprising 4,731 patients with TNBC were included. On multivariate analysis, elevated pretreatment NLR was independently associated with poorer OS (HR 2.21, 95% CI: 1.56–3.13) and DFS (HR 1.97, 95% CI: 1.65–2.37. Similar associations were observed on univariate analysis (OS: HR 1.70, 95% CI: 1.07–2.72; DFS: HR 1.84, 95% CI: 1.14–2.98). No statistically significant or consistent association was observed between NLR and PFS. Associations between high NLR and adverse OS and DFS remained robust across prespecified subgroup and sensitivity analyses, representing the largest contemporary synthesis of multivariable-adjusted outcomes in TNBC. Key pooled outcome associations are summarized in Table 1. Conclusions: Elevated pretreatment NLR is independently associated with worse OS and DFS in patients with TNBC, supporting its potential role as a low-cost tool for clinical risk stratification and treatment planning. Given its availability from routine blood tests, NLR may assist in identifying high-risk patients who could benefit from intensified surveillance or therapeutic strategies. Prospective validation in the modern chemo-immunotherapy era is warranted. Summary of pooled associations between pretreatment NLR and survival outcomes in TNBC. Outcome Studies (n) Interpretation Overall survival 14 Worse survival Disease-free survival 15 Worse survival Progression-free survival 3 Inconclusive

Background Documentation burden contributes significantly to psychiatric clinician burnout, with psychiatrists spending an average of three hours per workday on administrative tasks rather than direct patient care. While quantitative studies demonstrate that ambient artificial intelligence (AI) scribes reduce workload and improve documentation quality, the experiential perspectives of clinicians and standardized patients (SPs) remain unexplored, particularly in psychiatry where the therapeutic relationship is central to practice. Our aims were to explore clinician and standardized simulated patient perspectives on ambient AI scribes in psychiatric consultations, examining experiences, concerns, and conditions for successful implementation. Methods This study was part of a cross-sectional quantitative simulation study, where qualitative part was planned a-priori. We conducted focus groups with psychiatrists and SPs following a simulation-based crossover study comparing traditional versus AI-assisted documentation. Data were analyzed using Braun and Clarke’s reflexive thematic analysis framework. Results In this focus group session with eight psychiatrists and four SPs, total six themes were identified: (1) Clinical Presence, whereby reduced documentation barriers were perceived to allow more authentic human connection; (2) Liberation from documentation burden, with clinicians describing cognitive and emotional relief beneficial for their mental health; (3) Clinical Competence Amplified, in which clinicians perceived the AI scribe as enhancing practice through intelligent translation to psychiatric terminology and prompting for missed assessments; (4) Calibrating Trust, where participants navigated initial uncertainty while recognizing the importance of human oversight; (5) Privacy, stigma, and psychiatric exceptionalism, highlighting unique consent and confidentiality considerations for psychiatric populations; and (6) Perceptions of an enhanced standard of care, with both groups expressing strong preference for AI-assisted consultations with conditions for adoption. Conclusion In this exploratory simulation-based qualitative study, AI scribes were perceived as having potential to support more present, patient-centered psychiatric consultations by reducing documentation burden. Implementation should be cautious and requires transparent consent processes, clinician training in behavioral adaptations, robust human oversight, specialty-specific templates, and real-world evaluation with patients receiving psychiatric care.

4589 Background: Recent years have seen a shift in aUC management following approval of enfortumab vedotin–pembrolizumab (EV-P) and gemcitabine/cisplatin plus nivolumab (GC-NIVO) as first-line therapies. Despite improved clinical outcomes, their relative economic value remains uncertain. Herein, we conducted a cost-effectiveness analysis of current 1L regimens in aUC from a U.S. payer perspective using 2026 pricing. Methods: A partitioned survival model with three health states (progression-free [PF], progressed disease [PD], and death) was developed over a 10-year horizon from a U.S. payer perspective. Analyses focused on cisplatin-eligible patients. Survival data were reconstructed from published Kaplan–Meier curves and extrapolated using parametric survival models. Treatment dosing, schedules, and duration were modeled according to trial protocols. Patients receiving gemcitabine/cisplatin without progression were modeled to receive avelumab maintenance (GC→AVEL). Subsequent-line therapy costs were applied at incident progression, and grade ≥3 adverse event costs and disutilities were applied as one-time events. Drug acquisition costs (2026 USD) were based on average sales prices from the Centers for Medicare & Medicaid Services. Costs and quality-adjusted life years (QALYs) were discounted at 3% annually. Incremental cost-effectiveness ratios (ICERs) and net monetary benefit (NMB) were evaluated at willingness-to-pay (WTP) thresholds of $100,000, $150,000, and $200,000 per QALY. Parameter uncertainty was characterized using probabilistic sensitivity analysis. Results: In the base-case analysis, total discounted costs and QALYs were $90,269 and 1.62 for GC→AVEL, $131,836 and 2.09 for GC-NIVO, and $1,451,885 and 2.77 for EV-P. Compared with GC→AVEL, GC-NIVO gained 0.46 QALYs at an incremental cost of $41,567, resulting in an ICER of $89,501 per QALY and positive NMB across all evaluated WTP thresholds. Compared with GC→AVEL, EV-P gained 1.15 QALYs at an incremental cost of $1.36 million (ICER $1.19 million per QALY). Compared with GC-NIVO, EV-P gained 0.68 QALYs at an incremental cost of $1.32 million (ICER $1.93 million per QALY), exceeding all evaluated WTP thresholds. In a scenario analysis limiting EV-P to 10 treatment cycles, total costs decreased to $287,360, with ICERs of $172,000/QALY versus GC→AVEL and $225,000/QALY versus GC-NIVO, remaining above the $150,000/QALY threshold. Conclusions: Using updated 2026 pricing, GC-NIVO is likely to be the most cost-effective first-line regimen for cisplatin-eligible patients with aUC. EV-P offers the greatest clinical benefit but is not cost-effective at current prices. A major limitation of this study is cross-trial variability in study populations and design, limiting the validity of head-to-head economic comparisons.

1617 Background: Large language models (LLMs) are increasingly evaluated for oncology decision support, yet guideline concordance and hallucinations remain variable across cancer types and tasks. Retrieval-augmented generation (RAG) may improve safety by constraining the evidence base used during generation. Prior oncology LLM studies report discordance with guideline-based care, but few describe a reproducible health-system “vetting mechanism” that couples guideline-only retrieval with clinician-scored safety rubrics across multiple oncology domains. Methods: We assembled 316 de-identified oncology cases in a tumor-board template: medical oncology (breast, GI, GU, leukemia; n=216), gynecologic oncology (n=50), and neuro-oncology/CNS metastatic cancer (n=50). Each case was run on three systems: baseline GPT-4 (O1), NCCN-guideline anchored RAG (O2; guideline-constrained retrieval), and a literature-anchored system (OpenEvidence; O3). Oncologists independently scored outputs using a modified Generative Performance Score (mGPS; −1 to +1) combining guideline concordance with hallucination penalties; readability/rationality was scored on a 1–5 Likert scale. Inter-rater reliability was assessed (κ =.63). This workflow was designed as a pre-deployment model credentialing step for health-system governance (source policy → case bank → clinician-scored acceptance criteria). Results: Across all 316 cases (case-averaged), O2 achieved the highest mean total mGPS (0.75) compared with O1 (0.43) and O3 (0.59). In the medical oncology cohort (n=216), O2 outperformed O1 and O3 (mean mGPS 0.72 vs 0.35 and 0.54), with higher guideline concordance (0.85 vs 0.68 and 0.75) and lower hallucination penalties (−0.09 vs −0.25 and −0.19); readability was also highest for O2 (4.17 vs 3.22 and 3.86). In gynecologic oncology (n=50), O2 again performed best (mGPS 0.827) relative to O3 (0.697) and O1 (0.647). In the CNS cohort (n=50), mean composite mGPS favored O2 (0.82) over O3 (0.68) and O1 (0.55), while readability remained stable across models (3.55–3.73). Severe hallucination/unsafe recommendation rate: O1 [26%], O2 [5%], O3 [17%] (pre-specified definition; e.g., major fabricated citation or guideline-discordant harmful recommendation). Conclusions: In a 316-case, multi-domain clinician-scored evaluation, limiting retrieval to oncology guideline sources improved safety-aligned performance relative to unconstrained generation or literature-only anchoring. A guideline-constrained RAG configuration paired with clinician-scored rubrics and tail-risk reporting can serve as a practical health-system vetting mechanism for governance, re-validation, and change control of LLM decision support, including in resource-limited settings where reliable guideline-consistent recommendations are essential.

Background Early-life dysbiosis associated with Cesarean section (C-section) delivery is increasingly recognized as a modifiable risk factor influencing short- and long-term health outcomes. This multidisciplinary expert consensus summarizes the clinical implications of C-section on infant gut microbiota. It proposes evidence-based strategies to mitigate these effects, with a focus on the critical window of the first 1,000 days of life. Methods A multidisciplinary panel of 16 pediatricians, neonatologists, pediatric gastroenterologists, and nutrition experts conducted a targeted narrative review of the literature to inform a structured expert consensus process and participated in an online structured consensus process. Seventeen consensus statements were developed and validated through discussion, expert voting, and commentary, supported by a targeted review of current scientific evidence. Results The expert panel reached consensus on the impact of C-section delivery on early microbiota composition and its clinical relevance, emphasizing that the rising prevalence of C-sections worldwide demands urgent attention. Experts unanimously emphasized the importance of exclusive breastfeeding as the primary strategy to support healthy microbiota development in infants born by cesarean section. When exclusive breastfeeding is not possible, evidence-based nutritional approaches, including selected prebiotics and probiotic strains with documented clinical efficacy, are recognized as promising alternatives for supporting microbial balance. Notably, the panel underscored that not all probiotics are equally effective and recommended shifting toward evidence-based strains shown to help restore gut dysbiosis in this population. Also, experts advocated for continuing microbiota-targeted support throughout the first 1,000 days of life, viewing this developmental window as a critical continuum rather than a limited early-life phase, while acknowledging the need for more long-term data. Additionally, education for healthcare professionals and parents about the long-term implications of C-section delivery was emphasized as a key enabler of the broader adoption of eubiosis-targeted strategies. Conclusions Optimizing microbial colonization in infants born by cesarean section requires a multifaceted approach that prioritizes breastfeeding, supports judicious use of evidence-based nutritional interventions when needed, and emphasizes education and continuity of care across early life. By aligning clinical practice with emerging microbiome science, early-life interventions may reduce dysbiosis-associated risks and improve long-term health outcomes.

OBJECTIVE The aim of this study was to evaluate freedom from tumor progression and clinical outcomes in older adults with small- to medium-sized vestibular schwannoma (VS) managed by observation versus stereotactic radiosurgery (SRS) to better inform optimal management in this patient population. METHODS In this international multicenter study, patients aged ≥ 60 years with Koos grade I or II VS managed by observation or SRS were retrospectively reviewed. Propensity score matching was conducted using patient characteristics, tumor size, and hearing assessments. Outcome measures of freedom from tumor progression, serviceable hearing preservation (SHP), and neurological function (tinnitus, vestibulopathy, House-Brackmann grade, and trigeminal nerve function) were assessed for both groups. RESULTS The observation and SRS groups each comprised 51 matched patients (median age 68 years for both). Ipsilateral serviceable hearing was observed at presentation for 35 patients in each group. The median follow-up duration was 39 months in the observation group versus 27 months in the SRS group (p = 0.5). Tumor progression was significantly lower with SRS than with observation (2% vs 52.9%, p < 0.001). The rate of 5-year freedom from tumor progression was 100% in the SRS group versus 43% (95% CI 29%–64%) in the observation group. The rate of 10-year freedom from tumor progression was 90% (95% CI 73%–100%) in the SRS group versus 20% (95% CI 8.5%–49%) in the observation group. At the last follow-up, hearing loss occurred in 42.9% of the observation group and 51.4% of those who underwent SRS (p = 0.5). The 3-year SHP rate was 68% (95% CI 53%–88%) versus 65% (95% CI 49%–85%) (p = 0.8), and the 5-year SHP rate was 53% in both groups (95% CI 36%–78% in the observation group and 95% CI 35%–79% in the SRS group, p = 0.8). The composite endpoint of tumor progression and/or worsened neurological outcome, including hearing loss, tinnitus, vestibulopathy, facial nerve dysfunction (House-Brackmann grade), or trigeminal dysfunction, demonstrated a significantly lower rate in the SRS group (17.6%) compared with the observation group (66.7%) (p < 0.001). CONCLUSIONS SRS in older patients for management of Koos grade I or II VS resulted in significantly superior rates of freedom from tumor progression, comparable hearing preservation rates, and significantly higher rates of favorable overall radiographic and neurological outcomes than observation alone. Compared with observation, SRS might be the preferred management option in this patient population.

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.

PURPOSE 177Lu-PSMA-617 (LuPSMA) is an approved prostate-specific membrane antigen (PSMA)–targeted radiopharmaceutical therapy for men with metastatic castration-resistant prostate cancer (mCRPC). Older patients, particularly octogenarians, represent a substantial proportion of men with mCRPC but have been traditionally underrepresented in key registrational trials of LuPSMA. METHODS This retrospective multi-institutional study evaluated patients age 80 years and older with mCRPC after chemotherapy treated with ≥1 cycle of LuPSMA from August 2022 to December 2024. Clinical and demographic data were abstracted from electronic medical records. Outcomes included prostate specific antigen (PSA) response (PSA50 and PSA90), progression-free survival (PFS), overall survival (OS), and toxicities. Kaplan-Meier methods estimated PFS/OS; descriptive statistics summarized baseline and safety data. RESULTS Ninety-five patients (median age, 83 years) were included, of whom 36 (38%) and 21 (22%) had a history of cardiac disease or chronic kidney disease, respectively. Median follow-up was 24.1 months (IQR, 6.7-28.1). Patients received a median of five cycles of LuPSMA. Fifty-two (57%) and 21 (23%) patients achieved a PSA50 and PSA90, respectively. Median PFS and OS were 7.3 months (95% CI, 6.4 to 8.7) and 13.5 months (95% CI, 9.7 to 18.8), respectively. Grade ≥3 hematologic toxicities included anemia (n = 19; 20%) and thrombocytopenia (n = 4, 4%); grade ≥3 acute kidney injury occurred in one patient. Fourteen (15%) patients had dose delays, seven (7%) required reductions, and 10 (11%) discontinued therapy due to toxicity. Thirty-seven patients (39%) were hospitalized during therapy, with intensive care unit-level care required in two patients (2%), and there was one treatment-related death. CONCLUSION LuPSMA had comparable outcomes in octogenarians with mCRPC to patients on registrational trials, although 2/5 of patients required hospitalization during therapy. These findings support the feasibility and efficacy of LuPSMA in well-selected older men with mCRPC and suggest a role for closer monitoring of older patients.

Abstract BACKGROUND: Tumor-specific T cells are often characterized by reduced TCR signaling due to central and peripheral tolerance pathways that limit their responsiveness. These signals are further weakened by insufficient co-stimulation and active co-inhibitory pathways, collectively establishing a high threshold for activation. The integration of antigen recognition with co-stimulatory and inhibitory cues ultimately determines whether a T cell becomes activated or remains tolerant. Early TCR signaling must therefore be precisely regulated to prevent autoreactivity while still supporting protective immunity. Although phosphorylation and ubiquitination are well-established regulators of proximal TCR signaling, additional post-translational mechanisms remain less defined. SIRT2, a cytosolic NAD+-dependent deacetylase with emerging roles in immune regulation, has not been examined in the context of TCR signaling. METHODS: We evaluated proximal TCR signaling events in wild-type and SIRT2-deficient T cells using flow cytometry, immunoblotting, calcium flux assays, and RNA-sequencing. SIRT2-associated pathways were defined by mapping its interactome and acetylated substrates through mass spectrometry and immunoprecipitation. We screened LCK post-translational modifications by mass spectrometry and assessed SIRT2 enzymatic activity using an HPLC-based deacetylase assay. Conformational effects of LCK modification were examined using fluorescence-polarization binding assays and AlphaFold structural modeling. SIRT2 was deleted in human tumor infiltrating lymphocytes (TILs) via CRISPR/Cas9, and the impact of SIRT2 targeting was tested in lung cancer patient-derived xenograft models reconstituted with autologous TILs. RESULTS: SIRT2 deficiency amplified proximal TCR signaling, leading to elevated phosphorylation of early signaling mediators and increased calcium flux in both naïve and anergic T cells. Loss of SIRT2 also altered thymic selection dynamics and expanded TCR repertoire diversity. Mechanistically, SIRT2 interacted with and deacetylated LCK, the initiating kinase of proximal TCR signaling. Mass spectrometry identified lysine K228 in the LCK linker region as a SIRT2-regulated deacetylation site that governs LCK conformation and kinase activity. Functionally, SIRT2 inhibition in exhausted mouse and human TILs restored TCR signaling capacity and improved anti-tumor responses. CONCLUSION: Here we identify SIRT2-regulated deacetylation of LCK as a previously unrecognized mechanism that sets the strength and threshold of proximal TCR signaling. Accordingly, SIRT2 targeting reverses the exhausted phenotype of tumor-reactive T cells. Citation Format: Imene Hamaidi, Pingyan Cheng, Soo Young Jun, Min-Hsuan Wang, Min Zhang, Odesha Taylor, Luis Lopez-bailon, Ismail Can, Bin Fang, Anders Berglund, Bradford Perez, Ben Creelan, Andriy Marusyk, Virginia Shapiro, Haitao Ji, Jose R. Conejo-Garcia, Sungjune Kim. Sirt2 dictates TCR activation thresholds through post-translational control of LCK conformational state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4250.