IL-6/GP130/JAK/STAT3 Pathway Activation in Pancreatic Ductal Adenocarcinoma and Its Association With Clinical Features: Protocol for a Retrospective Cross-Sectional Study.

Background: The proinflammatory cytokine interleukin 6 (IL-6) contributes to pancreatic tumorigenesis by activating the Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling cascade. Targeting the IL-6/glycoprotein 130 (GP130)/JAK/STAT3 axis may therefore represent a promising therapeutic approach for pancreatic adenocarcinoma. Objective: This study investigates the activation of the IL-6/GP130/JAK/STAT3 pathway in archived biopsy samples from patients with pancreatic adenocarcinoma, quantifying its expression in both tumor and stromal compartments. In addition, potential associations between pathway activation and clinical outcomes are explored, including tumor stage, patient survival, and metabolic parameters such as diabetes, use of oral antidiabetic drugs, insulin therapy, and hemoglobin A1c levels. Methods: We will conduct a retrospective cross-sectional analysis of patients with pancreatic adenocarcinoma treated at the Cantonal Hospital of Fribourg, Switzerland, between 2010 and 2025. Eligible cases are identified through tumor board records. Archived pathology specimens will be immunostained using a phospho-STAT3 antibody to assess GP130 receptor activation. The percentage of positively stained cells will be quantified separately for tumor tissue, stroma, and adjacent normal tissue using QPath software. Sample size calculations are based on the assumption that patients with higher IL-6 pathway activation have poorer prognoses. Detecting a 5% difference in activation requires 84 patients per group for 90% power or 104 per group for 95% power. Diabetes will be analyzed as a dichotomous variable, while IL-6/GP130/JAK/STAT3 activation will be treated as a continuous variable. Descriptive statistics will summarize pathway activation and clinical variables. Mean differences between groups will be compared, and survival outcomes will be evaluated using Cox proportional hazards models. Hazard ratios will be calculated for all metabolic parameters to assess potential associations between pathway activation and diabetes. All analyses will include 95% CIs, with missing data reported transparently. Results: This project is supported by a research grant from the Cantonal Hospital of Fribourg (HFR 2/2021 and 4/2022). It was approved by the Ethics Committee of Bern, Switzerland (project 2024-01215). As of October 12, 2025, clinical records from 150 patients have been identified. Screening of additional patient records from 2024 to 2025 is ongoing. Conclusions: This study represents one of the first translational investigations of IL-6/GP130/JAK/STAT3 signaling in pancreatic adenocarcinoma. By correlating molecular pathway activation with clinical and metabolic features, it will provide new insights into disease heterogeneity and support the development of personalized, pathway-targeted therapeutic strategies.