Citations

Abstract Background and Objective Management of von Hippel–Lindau (VHL) disease is challenging due to multisystem involvement and limited systemic treatment options. Belzutifan has shown promising efficacy in clinical trials; however, real-world data remain limited. We aimed to evaluate its effectiveness and safety in a real-world cohort. Methods We conducted a retrospective study of 59 patients with VHL disease treated with belzutifan between August 2021 and January 2026. Objective response rates (ORR) for renal cell carcinoma (RCC), central nervous system hemangioblastomas (CNS HB), and pancreatic neuroendocrine tumors (pNET) were assessed by an independent radiologist. Retinal hemangioblastoma outcomes were evaluated through ophthalmology records by chart review. Results Median follow-up was 29 months. ORR was 27.6%, 39.6%, and 85.7% for RCC, CNS HB, and pNET, respectively. Among 13 patients with retinal hemangioblastomas (20 eyes), 17 eyes (85%) showed improvement. At data cutoff, 47 patients (79.6%) remained on treatment, while 12 (20.3%) discontinued (7 due to adverse events, 3 to disease progression, and 2 to other reasons). The most common adverse event was anemia (86.4%). Grade ≥3 events occurred in 10 patients (16.9%). The procedure rate per patient-year decreased from 0.35 in the 3 years prior to treatment to 0.08 during follow-up (Incidence Rate Ratio, 0.23; 95% CI, 0.12–0.47; P < 0.001) Conclusions Belzutifan demonstrated efficacy across VHL-associated lesions, with favorable safety profile. Most adverse events were grade 1–2. A reduction in procedure rate was observed after treatment initiation.

Abstract Background: The limited efficacy of oncolytic virotherapy (OV) in gastrointestinal malignancies has been attributed to an immunologically inert tumor microenvironment. While cisplatin is widely used as a cytotoxic agent, its immunomodulatory effects remain incompletely defined. We hypothesized that cisplatin may reprogram the tumor immune landscape to enable more effective OV-mediated anti-tumor responses. Methods: We evaluated the effects of cisplatin in combination with two distinct oncolytic platforms, vesicular stomatitis virus (VSV) and adenovirus (AdV), across both in vitro and in vivo colorectal cancer models. In vivo efficacy was assessed using MC38 subcutaneous and peritoneal metastatic models, with analysis of tumor growth, survival, and toxicity. Immune profiling was performed using single-cell RNA sequencing (scRNA-seq), flow cytometry, and bulk RNA sequencing to interrogate changes in CD8+ T cell states and functional programs. Guided by these preclinical findings, a clinical trial combining XELOX, PD-1 blockade, and OV therapy was initiated (ChiCTR2500107607). Results: Cisplatin markedly enhanced OV-mediated anti-tumor efficacy across models, resulting in sustained tumor control and improved survival in both subcutaneous and peritoneal disease settings. This effect was conserved across viral platforms, indicating a virus-agnostic interaction. Mechanistically, cisplatin induced a robust interferon (IFN)–dominant transcriptional program, characterized by upregulation of interferon-stimulated genes, including IRF7, IRF9, and ISG15. Single-cell analysis revealed that combination therapy reshaped the CD8+ T cell compartment, promoting the expansion of a population with transcriptional and functional features of central memory T cells (Tcm), alongside reduced exhaustion signatures. These changes were accompanied by enhanced cytokine signaling pathways associated with T cell maintenance and function, including IL-2, IL-7, and IL-15. In vitro, the combination of cisplatin and OV increased tumor cell death and interferon-γ production, supporting a model in which cytotoxic and immunostimulatory effects are mechanistically linked. A phase I clinical trial has been initiated. In gastric cancer, patients with retroperitoneal metastases are being treated with OV in combination with PD-1 blockade (ongoing). In colorectal cancer, the strategy is being evaluated in the neoadjuvant setting with an rectal preservation approach. Conclusions: Our findings identify a previously unrecognized role for cisplatin in priming an interferon-driven immune program that promotes Tcm differentiation and function, thereby enabling durable responses to oncolytic virotherapy. This work provides a mechanistic rationale for leveraging chemotherapy-induced immune reprogramming to enhance viro-immunotherapy and supports the clinical translation of this strategy in gastrointestinal malignancies. Citation Format: Joseph Brandon. Parker, Zhongyi Dong, Tao Liu, Qisen Guo, Haoyu Zhang, Bo Ni, Long Bai, Yiwen Chen, Jiasheng Zong, Xiang Xia, Jiaojiao Zheng, Hoang Tran Pham, Aya Elalfy, Demarcus Ingram, Ahmed Abdel-Hakeem, Muhammad Ali, Shannon Hartzell, Zizhen Zhang, Vivienne Yang. Cisplatin primes an interferon-driven CD8+ central memory T cell program to enable oncolytic virotherapy in gastrointestinal cancer malignancies [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B024.

Abstract Background Diagnosis and risk stratification in rare hematologic malignancies such as myeloproliferative neoplasms (MPNs) – polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) – require expert review of longitudinal, heterogeneous clinical records. This process is cognitively demanding, inconsistently applied, and difficult to scale beyond tertiary centers. No automated phenotyping workflow currently exists for hematologic malignancies. Methods A HIPAA-compliant large language model (LLM) framework for phenotyping MPN was developed to integrate (i) rule-based retrieval of bone marrow biopsy reports, clinical notes, and structured laboratory results from the electronic health record (EHR); (ii) zero-shot extraction of diagnostic and prognostic variables from unstructured text using GPT-4 Turbo; (iii) a clinician-informed source-prioritization algorithm to reconcile conflicting multi-source data; (iv) WHO/ICC-criteria–based diagnostic classification; and (v) NCCN-based risk stratification using the conventional risk model for PV, IPSET-thrombosis for ET, and DIPSS, DIPSS-plus, and MIPSS70/MIPSS70+ v2 for MF. Patients were identified via MPN-related ICD-9/10 codes; cases met 2017 WHO criteria or had a hematologist-documented diagnosis, and controls did not. The cohort was split into a prompt-development set (n = 60) and a held-out test set (n = 450; 75 cases and 75 controls per disease). Ground truth was established by independent dual-clinician chart review with consensus adjudication. LLM performance was evaluated against the ground truth: variable-level extraction using accuracy, F1 score, and Cohen’s kappa; patient-level diagnostic classification using sensitivity, specificity, and Cohen’s kappa; and prognostic risk stratification (among confirmed cases) using accuracy, weighted F1 score, and quadratic-weighted Cohen’s kappa. Wilson 95% confidence intervals (CIs) were used for proportions and bootstrap 95% CIs with 500 resamples for F1 scores. Results The held-out test set included 450 patients (PV: 150; ET: 150; MF: 150) with pathology reports and structured laboratory results, and 172 patients (PV: 52; ET: 55; MF: 65) with clinical notes. From pathology reports, overall variable extraction accuracy and F1 score were 99% (95% CI, 98–100) and 1.00 (0.99–1.00) for PV, 100% (99–100) and 0.99 (0.96–1.00) for ET, and 100% (99–100) and 0.99 (0.97–1.00) for MF. From clinical notes, overall accuracy and F1 score were 96% (91–100) and 0.94 (0.85–1.00) for PV, 100% (100–100) and 1.00 (1.00–1.00) for ET, and 100% (99–100) and 0.98 (0.95–1.00) for MF. Diagnostic sensitivity was 100% (95% CI, 95.1–100.0) for PV, ET, and MF; specificity was 98.7% (92.8–99.8) for PV and 100% (95.1–100.0) for both ET and MF, with Cohen’s kappa of 0.99 for PV and 1.00 for ET and MF. Risk stratification accuracy was 100% with weighted F1 score of 1.00 and quadratic-weighted Cohen’s kappa of 1.00 across all three diseases. A pre-specified source-ablation analysis showed that pathology reports alone were sufficient for diagnosis (sensitivity 98.7% for PV, 100% for ET, 96.0% for MF; specificity 100% across all three subtypes) but inadequate for prognostication (accuracy 69.3% for PV, 93.3% for ET, 77.3% for MF). Adding clinical notes to pathology reports recovered full prognostic accuracy of 100% across all three diseases. Conclusions This first-in-class automated framework achieved expert-level performance for MPN diagnosis and risk stratification from real-world EHR data, establishing a foundation for scalable, standardized phenotyping in rare hematologic malignancies. Prospective, multi-site validation is warranted before clinical deployment.

Abstract Histopathological assessment has served as the gold standard for diagnosing Alzheimer’s disease (AD). Emerging technological advancements, including the development of amyloid positron emission tomography (PET), have enabled early detection of amyloid pathology, one of the neuropathological hallmarks of AD. Genome-wide association study (GWAS) across cohorts of aging and AD, leveraging different measurements of amyloid burden, may facilitate the identification of novel genetic variants that drive the earliest neuropathological changes in AD. This study presents the largest GWAS of brain amyloidosis to date, leveraging amyloid β (Aβ) measured by in vivo amyloid PET and postmortem histopathology from 13,555 individuals of European ancestry. Amyloid positivity was defined as moderate or frequent neuritic plaques according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores for each postmortem cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET cohort to identify the cohort and tracer-specific cut-offs that differentiate amyloid positive and negative populations. In silico and ex vivo analyses further characterized implicated loci, including interrogating the association between bulk and single-nucleus gene expression profiles and AD-related traits. Genetic covariance analysis assessed the extent amyloid PET and postmortem measures reflect the shared genetic architecture of brain amyloidosis. Our combined amyloidosis GWAS identified three established AD risk loci: BIN1 (rs6733839, OR = 1.20, 95% CI 1.14-1.26, P = 1.32 × 10−11), CR1 (rs4844610, OR = 1.24, 95% CI = 1.16-1.32, P = 4.21 × 10−10), APOE (rs429358, OR = 4.01, 95% CI = 3.66-4.38, P = 4.54 × 10−201), and a newly identified brain amyloidosis-associated variant on chromosome 17 (rs35635959, OR = 1.18, 95% CI = 1.12-1.25, P = 1.47 × 10−8). SuSiE fine-mapping identified a single credible set of 15 putative causal variants with rs35635959 as the lead variant. Subsequent eQTL and SuSiE-based colocalization analyses prioritized rs35635959 as a strong eQTL for TUBG2, encoding tubulin gamma 2, which is involved in microtubule organization and synaptic plasticity. Further cell-type-specific characterization of this gene in neurons from dorsolateral prefrontal cortex tissue indicated that decreased TUBG2 expression was associated with increased Aβ burden and AD case status (PFDR < 0.045). Furthermore, our study is the first to report a modest genetic covariance (covariance=0.17, P < 6.54 × 10−8) between the genetic architecture of amyloid burden captured by different modalities. While APOE showed a strong association with both amyloid endophenotypes, the observed genetic covariance was not substantially attenuated after excluding variants within the APOE region (covariance=0.16, P < 1.32 × 10−7). Our results highlight the benefits of leveraging compatible, harmonized AD endophenotypes to increase power to uncover new molecular insights into the etiology of AD neuropathology. Wang et al. present the largest GWAS of brain amyloidosis to date, analysing 13,555 individuals using amyloid PET and postmortem Aβ measures. They identify a novel amyloidosis-associated variant on chromosome 17, demonstrate genetic covariance between modalities, and highlight complex traits sharing genetic architecture with Aβ burden.

e18609 Background: Anemia is a frequent complication of myelofibrosis (MF) and is embedded in widely used prognostic systems, yet contemporary real-world estimates of its association with long-term survival and leukemic transformation remain limited. We evaluated the impact of baseline anemia (hemoglobin [Hb] <10 g/dL) on overall survival (OS) and risk of transformation to acute myeloid leukemia (AML) in adults with MF. Methods: We performed a retrospective cohort study using the TriNetX Research Network, identifying adults (≥18 years) with myelofibrosis and stratifying them by anemia status at index (Hb <10 g/dL). Patients with the outcome of interest prior to each analytic window were excluded. To minimize confounding, cohorts were 1:1 propensity score–matched using nearest-neighbor matching with a caliper of 0.1 pooled standard deviations of the logit of the propensity score, adjusting for demographic factors, comorbidities, iron supplementation, leukocyte count, and platelet count. Balance was assessed using standardized mean differences <0.1. The primary outcome was all-cause mortality and the secondary outcome was transformation to AML, assessed at 1, 3, and 5 years. Risk estimates were calculated, and survival analyses were performed using Kaplan–Meier curves and Cox proportional hazards models, with statistical significance defined as a two-sided p<0.05. Results: After matching, 18,504 patients with MF were identified, of which 51.6% were females and 48.3% were males. The mortality rate in patients with anemia was higher than in those without at years 1, 3, and 5: 21.4%, 33.2%, and 39%, respectively, versus 5.4%, 12%, and 16.9%, respectively. The prevalence of transformation to AML was also higher in patients with anemia at 3.7%, 4.9%, and 5.3% at years 1, 3, and 5, respectively, versus 0.1%, 0.3%, and 0.4% in patients without anemia at those same time points. The HR for mortality in MF patients with anemia when compared to those without anemia at years 1, 3, 5 was statistically significant at 4.57 (95% CI 4.14-5.05, log-rank p<0.01), 3.51 (95% CI 3.28-3.76, log-rank p<0.01), and 3.04 (95% CI 2.87-3.23, log-rank p<0.01) respectively. The HR for transformation to AML in patients with MF with anemia versus those without anemia was statistically significant at years 1, 3 and 5, with HRs of 34.96 (95% CI 19.17-63.75, log-rank p<0.01) 20.75 (95% CI 13.97-30.83, log-rank p<0.01) and 17.07 (95% CI 12.11-24.07, log-rank p<0.01), respectively. Conclusions: In this large, propensity-matched real-world EHR analysis, baseline Hb <10 g/dL was associated with substantially worse OS and a markedly higher risk of AML transformation through 5 years. These findings support anemia as a pragmatic risk marker to inform risk-adapted monitoring, supportive care, and therapeutic decision-making in MF.

e18608 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) that is characterized by bone marrow fibrosis and inefficient hematopoiesis, leading to extramedullary hematopoiesis. Leukocytosis, a common disease manifestation and a minor criterion for the diagnosis of MF, has been associated with poorer clinical outcomes. This study evaluates the long term impact of leukocytosis on clinical outcomes at different time points in the real-world population of patients with MF. Methods: We conducted a retrospective cohort study using de-identified EHR data from the TriNetX Global Federated Health Research Network. Adults (≥18 years) with myelofibrosis were identified using ICD-10 and ICD-O-3 codes and stratified into leukocytosis (WBC ≥25.0 ×10³/µL; L+) and non-leukocytosis (L−) cohorts at the index diagnosis. Patients with prior or current hematopoietic stem cell transplantation were excluded. Cohorts were propensity score–matched 1:1 for demographics, comorbidities, and baseline laboratory values. Outcomes at 1, 3, and 5 years included all-cause mortality, pulmonary embolism, venous thromboembolism, and transformation to acute myeloid leukemia, with hazard ratios estimated using Cox proportional hazards models. Results: After matching, 13237 patients with MF were identified, of whom 52.12% were male, and 47.8% were female. The mean age in L+ and L- was 66.5 +/- 16.6 years and 68.1 +/- 15.5 years, respectively. The mean hemoglobin in L+ was 10.9+/- 2.8 g/dL, and in L- was 12.9+/- 2.3 g/dL. The mean platelet count in L+ was 303.4+/- 294.9 and in L- was 239.5+/- 151.4 ×10³/µL. HR for all-cause mortality in L+ when compared to L- at years 1, 3, and 5 were statistically significant at 4.079 (95% CI 3.691-4.508), 3.215 (95% CI 2.982-3.466), and 2.787 (95% CI 2.608-2.978), respectively, with log-rank p < 0.01. The HR for PE in L+ when compared to L- was statistically significant at years 1, 3, and 5 at 2.014 (95% CI 1.455-2.787), 1.883 (95% CI 1.451-2.787) and 1.659 (95% CI 1.318-2.088) with log-rank p<0.01. HR for VTE in L+ when compared to L- was statistically significant at years 1, 3, and 5 at 2.501 (95% CI 1.937-3 .229), 1.802 (95% CI 1.491-2.178), and 1.561 (95% CI 1.32-1.847) with log-rank p<0.01. Risk of transformation to AML in L+ when compared to L- at years 1, 3, and 5 was significant with HRs being 9.806 (95% CI 6.575-14.627), 8.823 (95% CI 6.334-12.29), 9.371 (95% CI 6.813-12.891) with log-rank p<0.01. Conclusions: In this large real-world, propensity-matched cohort, leukocytosis in myelofibrosis was associated with significantly higher risks of all-cause mortality, thromboembolic events, and transformation to acute myeloid leukemia across 1-, 3-, and 5-year time points. These findings underscore leukocytosis as a powerful adverse prognostic marker in MF and highlight the need for closer surveillance and risk-adapted therapeutic strategies in this high-risk population.

e18607 Background: Progression to myelofibrosis (MF) is associated with worse survival and influences treatment decisions, yet predictors of fibrotic progression in polycythemia vera (PV) and essential thrombocythemia (ET) remain poorly characterized. Methods: Patients with pathologically confirmed PV or ET were identified from a retrospective chart review. Demographics (age, sex, race, ethnicity), clinical features (thrombosis and bleeding history, performance status, symptom burden, organomegaly), bone marrow pathology (cellularity, trilineage hematopoiesis, megakaryocyte proliferation and atypia, fibrosis grade), molecular markers ( JAK2 , CALR , MPL , ASXL1 , EZH2 , TET2 , SRSF2 , IDH1/2 , SF3B1 , TP53 ), cytogenetics, laboratory values, and treatment history (phlebotomy, hydroxyurea, interferon, ruxolitinib) at first bone marrow biopsy were recorded. MF progression was defined as hematologist-confirmed transformation to MF. Kaplan-Meier analyses estimated median MF-free survival (MFS), defined as time to MF progression or death. Univariable followed by multivariable Cox proportional regression were performed to identify candidate MFS predictors. The proportional hazards assumption was assessed using Schoenfeld residuals. Hazard ratios (HR) with 95% confidence intervals (CI) were computed, with p<0.05 indicating statistical significance. Results: A total of 505 PV and 198 ET patients were identified. The majority were White (PV: 92%; ET: 86%). PV patients were predominantly male (54%) whereas ET patients were predominantly female (66%). MF progression occurred in 160 (32%) PV and 32 (16%) ET patients. Death was observed in 139 (28%) PV and 10 (5%) ET patients. Median MFS was 158.5 months (95% CI: 143.0-183.0) for PV and 308.0 months (95% CI: 175.0-NR) for ET. In PV, older age at diagnosis (HR 1.04; 95% CI: 1.02-1.07; p<0.001) and shorter time since PV or ET diagnosis to biopsy (HR 0.995; 95% CI: 0.990-0.999; p=0.048) independently predicted worse MFS. In ET, bone marrow hypercellularity (HR 5.67, 95% CI: 1.40-23.0, p=0.015) independently predicted worse MFS. Conclusions: PV patients demonstrated shorter MFS compared to ET. Older age at diagnosis in PV, whereas bone marrow hypercellularity in ET was significantly associated with fibrotic progression or death. Active surveillance of at-risk patients may facilitate early detection and timely treatment initiation. Disease Variable HR (95%CI) P-value PV Age at diagnosis 1.04 (1.02-1.07) <0.001 Time since PV or ET diagnosis to biopsy 0.995 (0.990-0.999) 0.048 ET Bone marrow hypercellularity 5.67 (1.40-23.0) 0.015

e18605 Background: Patients with myelofibrosis (MF), especially those with marked leukocytosis, face increased risk for thrombotic complications such as pulmonary embolism (PE) and venous thromboembolism (VTE). Hydroxyurea (HU) is often used to control blood counts. However, evidence for HU reducing thrombotic events in MF is limited, and contemporary real-world data on its impact in MF populations with significant leukocytosis remain sparse. Methods: We conducted a retrospective cohort study using the TriNetX research network. Adult patients with MF and leukocytosis (white blood cell count ≥25×10⁹/L) were identified. Patients with prior allogeneic hematopoietic stem cell transplantation were excluded. HU-exposed patients were compared with non-exposed patients using 1:1 propensity score matching. Matching criteria included age, sex, race, comorbidities, and baseline laboratory values when available. The study included 3,590 patients (1,795 per cohort). Primary outcomes were time to PE and VTE at 1, 3, and 5 years. Hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional hazards models. Results: In the propensity-matched cohort, HU exposure was not associated with a statistically significant reduction in thrombotic events. For PE, hazard ratios were numerically higher in the HU-exposed group at 1 year (1.5% vs 1.0%; HR 1.40, 95% CI 0.76–2.56; p=0.278) and 3 years (2.2% vs 1.8%; HR 1.29, 95% CI 0.80–2.08; p=0.289), with a modest increase observed at 5 years (2.8% vs 1.9%; HR 1.57, 95% CI 1.01–2.45; p=0.04). For VTE, no statistically significant differences were observed between HU-exposed and non-exposed patients at any time point (1 year: HR 0.95, 95% CI 0.63–1.44; p=0.821; 3 years: HR 0.97, 95% CI 0.69–1.36; p=0.85; 5 years: HR 1.14, 95% CI 0.84–1.57; p=0.40). Overall, PE and VTE event rates remained low and comparable between cohorts. Conclusions: In this large real-world cohort of patients with myelofibrosis and significant leukocytosis, hydroxyurea exposure was not associated with a statistically significant reduction in thrombotic events, including PE or VTE, over short- or long-term follow-up. Thrombotic event rates were low and generally comparable between hydroxyurea-exposed and non-exposed patients, with no consistent pattern suggesting a protective effect of cytoreductive therapy. Although a modest increase in PE risk was observed at 5 years, this finding was isolated and lacked a consistent temporal pattern, limiting its clinical interpretability. These findings suggest that the role of hydroxyurea in modifying thrombotic risk among MF patients with leukocytosis remains uncertain and highlight the need for individualized treatment decisions and further studies to better define its impact on thrombotic outcomes in this population.

e17004 Background: Living clinical practice guidelines offer the opportunity to keep recommendations aligned with the latest evidence, but they also present a fundamental challenge: as evidence accumulates, panelists cannot sustainably query and synthesize a growing body of literature. In developing ASCO's living metastatic castration-resistant prostate cancer (mCRPC) guideline, we encountered this challenge firsthand. To address it, we developed and evaluated an interactive agentic framework that enables guideline panelists to query evidence in natural language and retrieve structured facts, tables, and figures—with the goal of extending this tool as a clinician-facing companion to enhance guideline accessibility. Methods: The mCRPC systematic review dataset supporting ASCO's clinical practice guideline was used, comprising 212 structured columns capturing trial characteristics, patient populations, and outcomes extracted from 188 references across 88 clinical trials. A large language model (LLM)-based agentic framework was developed employing a coding agent that translates natural language queries into executable scripts for structured evidence retrieval. Claude (Haiku 4.5, Sonnet 4.5, and Opus 4.5) served as the core LLM agents. We constructed a benchmark of 50 fact-based queries with gold-standard answers targeting trial identification, treatment modalities, and endpoint characteristics (e.g., "Which trials evaluated systemic monotherapy?"). Performance was evaluated using exact-match accuracy for final answers, and precision, recall, and F1 score for trial-level retrieval. Results: Across 50 queries, exact-match accuracy ranged from 82% to 86%. Haiku 4.5 and Sonnet 4.5 each achieved 82% (42/50), while Opus 4.5 achieved 86% (43/50). Precision ranged from 0.93–0.97, recall from 0.94–0.96, and F1 scores from 0.91–0.94. Conclusions: This agentic framework enables scalable, auditable, natural language interrogation of guideline evidence, addressing a critical bottleneck in living guideline maintenance. For panelists, it supports rapid, reproducible evidence surveillance during recommendation development. For clinicians, it offers a foundation for an interactive companion tool that transforms static guidelines into queryable resources—enabling personalized evidence retrieval at the point of care. LLM EM Precision Recall F1 claude-haiku-4-5 0.82(42/50) 0.95 0.94 0.91 claude-sonnet-4-5 0.82(42/50) 0.97 0.96 0.93 claude-opus-4-5 0.86(43/50) 0.93 0.96 0.94

e16067 Background: Gastric carcinoma remains a significant cause of cancer mortality in the United States. Although overall mortality rates have declined, persistent disparities exist across racial, age, and geographic groups. For cancer patients, sepsis—a life-threatening infection response—is a major fatal complication. Analyzing linked mortality data is crucial for identifying high-risk populations, understanding the burden of cancer-associated infections, and guiding targeted prevention and treatment strategies to improve outcomes and achieve health. Methods: This cross-sectional study used CDC WONDER mortality data from 1999–2020 for adults aged 25 years and older. Causes of death were identified using ICD-10 codes, and age-adjusted mortality rates (AAMRs) were calculated across sex, race/ethnicity, age, census regions, and urban–rural categories. Mortality trends were assessed using Joinpoint regression to estimate average annual percentage changes (AAPC) with 95% confidence intervals (CIs) and statistical significance. Results: From 1999 to 2020, U.S. stomach cancer mortality declined overall, with AAMRs decreasing from 0.29 to 0.22 per 100,000 (AAPC = –0.8%, 95% CI: –1.64 to 0.04). Significant declines occurred among adults aged 65–74 (APC = –1.7%, 95% CI: –2.32 to –1.05), 75–84 (APC = –1.9%, 95% CI: –2.65 to –1.05), and ≥85 years (APC = –3.0%, 95% CI: –4.02 to –1.99). Adults 45–54 years experienced increasing mortality after 2005 (APC = 5.1%, 95% CI: 2.82 to 7.46), while rates among 55–64 years remained stable. Male mortality declined significantly (AAPC = –1.24%, 95% CI: –1.93 to –0.54), whereas female mortality showed no significant long term change (AAPC = –0.93%, 95% CI: –2.44 to 0.60). Black (AAPC = –2.25%, 95% CI: –3.02 to –1.47) and Hispanic/Latino populations (AAPC = –1.50%, 95% CI: –2.26 to –0.74) experienced significant declines. Regionally, the Northeast showed the largest decline (AAPC = –2.30%, 95% CI: –3.52 to –1.07), while the Midwest, South, and West demonstrated no significant long term trends. Metropolitan areas declined from 1999–2011 (APC = –2.80%, 95% CI: –4.44 to –1.14). Conclusions: While overall U.S. gastric cancer mortality declined from 1999–2020, this progress is uneven. Significant increases among adults aged 45–54 and stable rates for those 55–64 highlight an emerging concern. Furthermore, declining trends are concentrated in specific demographic groups and regions, such as the Northeast, revealing persistent disparities. These findings underscore the need for targeted prevention and research focused on younger adults and lagging geographic areas.