Serial serum interleukin-8 trajectories are associated with progression from Helicobacter pylori-associated precancerous lesions to gastric cancer: a prospective longitudinal cohort study.

BACKGROUND: Gastric cancer remains the fourth leading cause of cancer-related mortality worldwide, with delayed diagnosis contributing to poor prognosis. Current biomarkers lack sensitivity for early detection. Interleukin-8 (IL-8), a pro-inflammatory chemokine implicated in H. pylori-associated gastric carcinogenesis, has not been rigorously evaluated in longitudinal studies for its ability to predict malignant progression in patients with precancerous lesions. AIM: To investigate whether serial serum IL-8 measurements predict progression to gastric cancer among Egyptian patients with H. pylori-associated atrophic gastritis and intestinal metaplasia over 24 months of follow-up. METHODS: a prospective, longitudinal biomarker, multicenter cohort study enrolled 200 participants across 5 Egyptian centers: 50 with atrophic gastritis, 50 with intestinal metaplasia, 25 with H. pylori-positive gastric cancer, 25 with H. pylori-negative gastric cancer, and 50 healthy controls. All underwent baseline clinical assessment, laboratory evaluation (including CEA, CA19-9), H. pylori testing (stool antigen and urea breath test per Maastricht VI), and endoscopy with histopathology (Updated Sydney System). Patients with precancerous lesions were followed for 24 months with serial IL-8 measurements at 0, 6, 12, 18, and 24 months, and repeat endoscopy at study completion. Group-based trajectory modeling was performed blinded to outcome status. Multivariable logistic regression with penalization was used due to low event count. Time-dependent ROC analysis used a cumulative/dynamic approach. RESULTS: Of 100 patients with precancerous lesions, 94 completed follow-up, and 9 progressed to gastric cancer (7 from intestinal metaplasia, 2 from atrophic gastritis). Baseline IL-8 levels demonstrated a progressive increase across groups (controls: 9.7 ± 3.2 pg/mL; atrophic gastritis: 42.1 ± 11.8; intestinal metaplasia: 64.8 ± 14.3; gastric cancer: 107.4 ± 24.6; p < 0.001). IL-8 elevation in gastric cancer was independent of H. pylori status across all stages (p > 0.50 for all stage-stratified comparisons, though these subgroup analyses are limited by small sample sizes and may be considered exploratory). Baseline IL-8 > 52.3 pg/mL was associated with progression risk, AUC 0.84, sensitivity 88.9%, specificity 78.0%, and negative predictive value 98.5%, significantly outperforming CEA (AUC 0.62) and CA19-9 (AUC 0.58). Time-dependent AUC increased to 0.91 at 12 months and 0.94 at 18 months. Trajectory modeling, performed blinded to outcome, identified three patterns: Stable-Low (n = 42), Moderate-Rising (n = 49), and High-Accelerating (n = 9). The acceleration point in the High-Accelerating group preceded clinical cancer diagnosis by a median of 6 months (range 3-12), however, this exploratory finding requires external validation. In multivariable analysis using Firth penalized regression, baseline IL-8 (aOR per 10 pg/mL: 2.31, 95% CI: 1.48-3.61, p < 0.001) and intestinal metaplasia (aOR: 4.22, 95% CI: 1.31-13.61, p = 0.016) were independently associated with progression. CONCLUSIONS: In this prospective longitudinal biomarker study, serial serum IL-8 trajectories were significantly associated with progression from H. pylori-associated precancerous lesions to gastric cancer. Rising IL-8 levels preceded clinical diagnosis by approximately 6-12 months, suggesting potential utility for risk stratification. A Baseline IL-8 > 52.3 pg/mL was independently associated with progression (adjusted HR: 6.94, p < 0.001), but this exploratory trajectory is hypothesis-generating and requires external validation before causal interpretation. However, these findings are exploratory and hypothesis-generating.