Citations

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common cancer (5-year survival ∼13%), emerging through years-to-decades progression involving chronic fibro-inflammatory injury and precursor transformation processes including ADM and PanIN. KRAS-driven acinar-to-ductal metaplasia (ADM) is among the earliest experimentally tractable and potentially interceptable events; KRAS (mutated in >90% of PDAC) has remained difficult to therapeutically target, particularly for prevention; emerging KRAS inhibitors are developed for treatment of established malignancy rather than early interception. We aimed to prioritize KRAS-axis interception candidates via AI-guided network analysis of TCGA-PAAD restricted to a curated KRAS-driven ADM/PanIN-initiation mechanism module. Methods: The 38-gene module (n=183 TCGA-PAAD samples; 37 genes available, PRSS2 absent) spans KRAS-MAPK, RTKs, TGF-β/SMAD, ECM, inflammation, transcription, tumor suppressors, and ductal/acinar genes from canonical pancreatic-cancer-progression biology, linking established-tumor transcriptomes to early-interception biology. A stability-selected Spearman-correlation network served as the network backbone (PCMCI+/NOTEARS extensions ongoing), paired with patient-level bootstrap filtering (B=200 resamples; ≥70% retention). A composite Interception Score I(v) = α·CB + β·Σ|w| + γ·U + δ·R integrating betweenness centrality, summed edge-weight influence, druggability (literature-curated drug-target prior), and bootstrap robustness ranked candidate interception nodes (unoptimized weights; tuning ongoing). Results: Spearman correlation yielded a 37-node, 248-edge network baseline; bootstrap resampling (B=200) evaluated 856 distinct candidate edges, of which 194 (22.7%) achieved ≥70% retention, defining the stable subgraph used for scoring. The Interception Score placed 7 KRAS-axis genes among the top-10 candidates: ERBB2 (0.953), KRAS (0.743), ERBB3 (0.742), MAPK1 (0.708), EGFR (0.675), MAP2K2 (0.605), and BRAF (0.589). Inflammation (IL6, 0.755), TGF-β/SMAD2 (0.726), and ECM/MMP2 (0.638) also ranked highly, recapitulating PDAC initiation mechanisms (stromal-epithelial crosstalk; inflammatory-fibrotic priming). ERBB2 (HER2), a clinically druggable RTK with approved inhibitors in other malignancies, emerged as the top-ranked candidate, supporting evaluation of HER2-axis signaling for interception in molecularly selected PDAC subsets. These findings align with canonical PDAC biology, supporting biological plausibility prior to formal weight optimization and external validation. Conclusions: AI-guided network analysis of TCGA-PAAD prioritizes biologically coherent KRAS-axis and stromal-inflammatory candidates with clinically available HER2-, EGFR-, MEK-, BRAF-, and KRAS-pathway inhibitors, supporting hypothesis generation for future pancreatic cancer interception studies. Stage-resolved analysis, causal-inference extensions, and sex-/age-stratified validation are ongoing. Citation Format: Jianfu Li, Yingyun Yang, Michael Wallace, Cui Tao, Yan Bi. AI-Driven Network-Based Discovery on TCGA-PAAD Identifies KRAS-Axis Drug-Repurposing Targets for Pancreatic Cancer Interception [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 A029.

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: Early-onset pancreatic cancer (EOPC; age <50 y at diagnosis) is rare (≈1.3/100,000), biologically distinct, and germline-enriched (BRCA1/2, PALB2, ATM, CDKN2A, Lynch). Despite NCCN and CAPS Consortium recognition, its pre-diagnostic electronic health record (EHR) trajectory is uncharacterized. We sought reproducible signatures to guide subtype-aware surveillance for this under-screened young-adult population, where conventional guidelines do not apply. Methods: We assembled an EOPC cohort from Mayo Clinic (3 sites, 2001–2023; n=169 EOPC, n=3,162 older-onset PDAC), identified by ICD-10 C25.0–C25.3, C25.7, C25.9 or ICD-9 157.x with age <50 at first diagnosis. For each patient, 3-year pre-diagnostic trajectories of 10 routine laboratory analytes (bilirubin, CA 19-9, CEA, lipase, amylase, glucose, HbA1c, ALT, AST, alkaline phosphatase) were summarized over 30/90/180/365-day windows (mean, slope, delta; 1,706 features total; 131 retained at ≥10% non-zero). Features were winsorized (1–99 pct), standardized, and projected onto 15 PCA components capturing 81.7% variance. K-means clustering (k=2–6, min cluster fraction ≥10%) was assessed by silhouette and 100-resample bootstrap Adjusted Rand Index (ARI). Cluster signatures were compared against the older-onset PDAC cohort projected into the same component space. Results: Two reproducible pre-diagnostic clusters emerged (k=2; silhouette 0.469; bootstrap ARI 0.440). Cluster A: "occult prodrome" (87.0%; n=147; mean age 44.9 y) showed no clear signal across the 10 monitored analytes, with all analyte z-scores near zero through the 3-year window. Cluster B: "metabolic-biliary active" (13.0%; n=22; mean age 44.4 y) was characterized by elevated mean HbA1c (z=+1.08), rising bilirubin slope (z=+0.54), and rising ALT/alkaline phosphatase slopes (z=+0.51 each), consistent with combined diabetic-onset and biliary-obstructive prodrome. The two-cluster structure reproduced in older-onset Mayo PDAC at 87.3% / 12.7%, nearly identical to the EOPC distribution, indicating a fundamental pre-diagnostic dichotomy of pancreatic cancer rather than an age-specific phenomenon. The dominant occult phenotype across age strata indicates that lab-trajectory–anchored surveillance can only address the active minority and motivates complementary genetic-, demographic-, or imaging-anchored pathways for the occult majority. Conclusions: EOPC pre-diagnostic trajectories partition into a dominant occult prodrome (∼87%) without detectable signal in the 10 routine labs evaluated and a minority metabolic-biliary active prodrome (∼13%) with combined diabetic and obstructive features. The high occult prevalence motivates germline-guided active surveillance for genetically at-risk young adults rather than symptom-driven workup, anchoring next-generation surveillance trial designs in rare and hereditary pancreatic malignancies. External validation in independent institutional cohorts (Mayo Clinic Platform / MERCI, or comparable EHR networks) is the planned next step. Citation Format: Jianfu Li Li, Yingyun Yang, Wallace MIchael, Yan Bi. Pre-diagnostic clinical-trajectory signatures of early-onset pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A046.

ABSTRACT Objective Weight loss is frequently considered a cardinal presenting symptom for patients with Zenker diverticulum (ZD). We hypothesized that weight loss in patients with cricopharyngeal muscle dysfunction (CPMD), with or without diverticula, was associated with the length of symptoms and size of diverticulum. Methods Prospective, multicenter observational study of CPMD patients with and without diverticula reporting unintentional weight loss (+WL) or no weight loss (−WL) prior to enrollment in the Prospective Outcomes of Cricopharyngeal Hypertonicity (POuCH) database. Complications and symptom response using a patient reported outcome measure, the Eating Assessment Tool (EAT‐10), were compared. Results Of 427 patients, 101 (23.6%) were +WL. Median weight loss was 14 pounds (interquartile range [IQR] 10–25). +WL cohort had a mean age of 71.5 (standard deviation [SD] 11.5) vs. 67.9 in −WL (SD 11.6, p = 0.007). Mean preoperative EAT‐10 score was 24.7 in +WL (SD 9.7) and 14.8 in −WL (SD 8.8, p < 0.0001). Higher preoperative weight loss was associated with higher preoperative EAT‐10 ( p < 0.0001, Spearman's ρ = 0.43). Size of diverticulum was associated with WL ( p = 0.003), but weight loss was highest in both large diverticula and CP bars. Duration of symptoms was not associated with weight loss ( p = 0.30). Postoperative complications in +WL and −WL patients were similar ( p = 0.78). Conclusion Unintentional weight loss is common with ZD. Patients with worse dysphagia are more likely to have more weight loss. Weight loss does not increase with the size of the diverticulum or length of symptoms. Surgery has a similar safety profile with greater improvement in dysphagia in patients reporting weight loss. Level of Evidence 3.

Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) &lt;0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend&lt;0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend&lt;0.001 and &lt;0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend&lt;0.001 and &lt;0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

ABSTRACT This study aims to develop MRI‐based 3D statistical shape models for patellar dislocation patients and investigate bone shape features that distinguish between single and recurrent dislocation populations, as well as control and patellar dislocation populations. MRIs from 16 single dislocation patients, 17 recurrent dislocation patients, and 20 control subjects were used to build statistical shape models for femur and patella bones. Bone shape features were extracted and tested for statistical significance ( p < 0.05) for distinguishing the single dislocation group from the recurrent dislocation groups, and the control group from the dislocation group. Statistically significant shape features distinguishing the three groups were identified for both bones. A shallower trochlear groove and smaller patellar ridge told the dislocation groups apart from the control group. A prolonged lateral condyle in femur and a laterally shifted ridge and hood shaped lateral facet in patella distinguished the recurrent dislocation group from the single dislocation group. The study's findings from 3D statistical shape modeling of the femur and patella reveal distinct anatomical differences across control, single dislocation, and recurrent patellar dislocation groups. This advanced understanding aids in identifying individuals at higher risk for initial or recurring patellar dislocations, enabling clinicians to tailor treatment and management strategies more effectively to prevent further dislocations and mitigate potential patellofemoral joint damage.

Cirrhosis remains a major global cause of morbidity and mortality, with rapidly evolving etiologic drivers. This review summarizes the contemporary global epidemiology of cirrhosis, highlighting regional patterns and major transitions in underlying causes to inform prevention and policy. In 2021, cirrhosis and chronic liver disease accounted for ~1.4 million deaths worldwide. Although age-standardized mortality rates have declined in many regions, the absolute burden continues to rise due to population growth and aging. Reductions in hepatitis B and C–related cirrhosis, driven by vaccination, screening, and antiviral therapy, have been offset by a growing contribution from steatotic liver disease. High–sociodemographic index (SDI) regions exhibit lower mortality but increasing prevalence, reflecting improved survival and expanding metabolic risk, whereas low- and lower-middle–SDI regions continue to experience high mortality. Addressing the global burden of cirrhosis will require sustained public health investment focused on viral hepatitis elimination, alcohol-associated harm reduction, metabolic risk management, and equitable access to early detection and care.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Abstract Objective To evaluate whether thyroid dysfunction, including hypothyroidism and hyperthyroidism, is associated with migraine across racial and age groups using a large, multinational electronic health record database. Background Thyroid disorders are highly prevalent worldwide, with hypothyroidism affecting over 200 million individuals and hyperthyroidism affecting approximately 2.5% of adults. Migraine is a leading cause of disability globally. Prior studies have suggested potential links between thyroid dysfunction and migraine, but evidence has been limited by small sample sizes, restricted population diversity, and inadequate control of confounding. Whether associations differ by thyroid subtype, race, or age remains unclear. Methods We performed two parallel retrospective cohort analyses within the TriNetX Global Collaborative Network, comprising over 200 million patients across 21 countries, using patient records from January 2004 to December 2024. Adults aged 18–100 years with hypothyroidism or hyperthyroidism, defined by ≥3 clinical encounters within 20 years, were identified. Individuals with psychiatric disorders (including mood, anxiety, and stress‐related disorders), sleep disorders, epilepsy or recurrent seizures, or known migraine‐related genetic mutations were excluded. Each thyroid cohort was compared with a control group without thyroid disease, with groups balanced on key demographic and clinical characteristics including age, sex, and hypertension; beta‐blocker use was additionally considered in the hyperthyroidism cohort. The primary outcome was diagnosis of migraine (International Classification of Diseases, 10th Revision, code G43) within 5 years of index date. Subgroup analyses were conducted by race (Caucasian, African American/Black, Asian) and age (18–40, 40–65, 65–100 years). Sensitivity analyses assessed robustness to alternative visit thresholds and expanded covariate adjustment. Results A total of 33,327,750 patients were included in the hypothyroidism analysis and 28,182,377 in the hyperthyroidism analysis. Baseline differences between groups were minimized after cohort balancing. Hypothyroidism was associated with higher odds of migraine across all racial groups, strongest among African American/Black (odds ratio [OR] 2.04; 95% confidence interval [CI] 1.91–2.17), followed by White (OR 1.93; 95% CI 1.89–1.96) and Asian (OR 1.83; 95% CI 1.69–1.98). Hyperthyroidism was similarly associated with increased migraine odds, most prominently among White (OR 1.64; 95% CI 1.59–1.70), with smaller but significant associations in African American/Black (OR 1.28; 95% CI 1.14–1.44) and Asian (OR 1.18; 95% CI 1.07–1.29). Elevated odds were observed across all age strata, generally increasing with age. Findings were consistent in sensitivity analyses. Conclusion In this large, multinational real‐world study, both hypothyroidism and hyperthyroidism were independently associated with increased migraine prevalence across diverse racial and age groups. These results highlight thyroid dysfunction as an important comorbid condition in migraine and support further prospective and mechanistic investigation.