High baseline levels of interleukin-8 in leukocytes and urine predict tumor recurrence in non-muscle invasive bladder cancer patients receiving bacillus Calmette–Guerin therapy: A long-term survival analysis

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Abstract
Bacillus Calmette–Guerin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC) can significantly reduce the risk of recurrence and progression. However, BCG therapy may fail in up to a half of treated patients and may also cause toxicities. Biomarkers to predict the effectiveness of BCG therapy are desired to pre-select patients for BCG therapy to maximize efficacy while avoid unnecessary toxicity. Twelve cytokines were measured in 100 blood and 112 urine samples using cytokine antibody array and correlated with recurrence-free survival in overall and BCG-treated NMIBC patients. Of the 12 cytokines, interleukin (IL) -2, IL-8, IL-10, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)-γ were measurable in more than 30% of peripheral blood leukocyte (PBL) samples. Only IL-8 in PBL was found to be significantly associated with tumor recurrence, especially in those who receiving BCG therapy (hazard ratio [HR] = 4.24; 95% confidence interval [95%CI] = 1.65–10.88; p = 0.003). The median recurrence-free survival time for BCG-treated patients with high baseline IL-8 levels were much shorter than those with low IL-8 levels (7.9 vs. >78.4 mo, p = 0.004). Furthermore, consistent associations between urinary IL-8 levels and tumor recurrence in patients receiving BCG therapy were observed in 58 pre-BCG and 54 long-term post-BCG-treated urine samples (both p ≤ 0.005). High urinary baseline IL-8 level also predicted shorter time to tumor recurrence in NMIBC patients (both p ≤ 0.004). By using antibody array-based technology in two separate cohorts of NMIBC patients, we found that PBL and urinary baseline IL-8 levels were significantly associated with tumor recurrence after BCG therapy.

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