Circulating inflammatory proteins and gallbladder cancer: Potential for risk stratification to improve prioritization for cholecystectomy in high-risk regions

Abstract

Background: Inflammatory proteins could help identify individuals most likely to have gallbladder cancer (GBC) among those waiting for cholecystectomy.

Methods: We analyzed 49 circulating inflammation-related proteins in 144 patients with GBC and 150 patients with gallstones. We calculated age- and sex-adjusted odds ratios (ORs) and 95% CIs for protein quantiles and GBC versus gallstones. Using proteins associated with early GBC (stage 1-2) that were selected in stepwise logistic regression, we created an inflammation score and explored the potential utility for risk stratification.

Results: 26 proteins (53%) had P values for the trend across categories ≤0.001, with associations for a one category increase ranging from 1.52 (95% CI: 1.20-1.94) for CC motif ligand 4 to 4.00 (95% CI: 2.76-5.79) for interleukin (IL)-8. Soluble tumor necrosis factor receptor 2 (sTNFR2), IL-6, sTNFR1, CC motif ligand 20 (CCL20), vascular cell adhesion molecule 1, IL-16, and granulocyte colony-stimulating factor had P values ≤0.001 for early GBC. Of those, IL-6, IL-16, CCL20, and STNFR1 were included in the inflammation score. In a high-risk setting with a pre-test disease risk of 10% (e.g., elderly patients) and using an inflammation score cutoff that provides 90% sensitivity, 39% of patients on the waiting list would be predicted to be positive, and 23% of those would be predicted to have GBC.

Conclusion: These results highlight the strong associations of inflammatory proteins with GBC risk and their potential clinical utility. Larger studies are needed to identify the most effective combinations of inflammatory proteins for detecting early GBC and precursor lesions.

Keywords: Chemokines; Cytokines; Gallbladder cancer; Inflammation; Risk stratification.

Figure 1

Odds ratios (OR) and 95% confidence intervals (CIs)* between ordinal categories of inflammatory proteins in patients with gallbladder cancer (N=144) compared to those with gallstones (N=150). *Adjusted for age and sex and matched on lot †Passed Bonferroni correction (P<0·001) Note: all markers had 4 categories except IL-29, IL-33, and TSLP, which had 2 categories