Systemic adjuvant chemotherapy for cholangiocarcinoma surgery: A systematic review and meta-analysis.

BACKGROUND: The role of adjuvant therapy for biliary tract cancer is not clearly defined with conflicting results demonstrated across nonrandomized and randomized studies. We report a systematic review and meta-analysis to delineate the effect of AT on overall survival. METHODS: Eligible studies were identified from MEDLINE, EMBASE, Cochrane and PubMed. Studies comparing adjuvant chemotherapy or chemoradiotherapy after curative-intent surgery with curative surgery only for biliary tract cancer were included. Data pertaining to tumours of the gallbladder and bile ducts were included. The primary outcome assessed was overall survival. Random-effects meta-analysis was performed, as well as pooling of unadjusted Kaplan-Meier curve data. RESULTS: 35 studies involving 42,917 patients were analysed. There was a significant improvement in overall survival with any adjuvant therapy after surgery compared with surgery only (HR 0.74; 95% CI, 0.67 to 0.83; P < 0.001). There was a significant benefit for adjuvant therapy in those with margin positive surgery (RR, 0.83; 95% CI, 0.77 to 0.91; P < 0.001) and node-positive disease (RR 0.82; 95% CI 0.76 to 0.89; P < 0.001) CONCLUSION: Our review advocates the use of adjuvant therapy in bile duct cancer after curative intent resection. Further prospective studies are needed to determine the optimal regime and timing of an adjuvant approach.

Characterization of Drug-Specific Signaling Between Primary Human Hepatocytes and Immune Cells.

It is now apparent that antigen-specific T-cells are activated in certain patients with drug-induced liver injury (DILI). Since cross-talk between hepatocytes and immune cells is likely to be critical in determining the outcome of drug exposure, the aim of this study was to profile the signals released by drug-treated hepatocytes and to characterize the impact of these molecules on dendritic cells. Human hepatocytes were exposed to 3 drugs (flucloxacillin, amoxicillin, and isoniazid) associated with DILI potentially mediated by the adaptive immune system as drug-specific T-cells have been isolated from DILI patients, and the metabolite nitroso-sulfamethoxazole (SMX-NO). Hepatocyte toxicity, cytokine release and activation of oxidative stress pathways were measured. Supernatants were transferred to monocyte-derived dendritic cells and cell phenotype and function were assessed. High-mobility group box 1 protein (HMGB1) and lactate dehydrogenase release as well as adenosine triphosphate depletion occurred in a drug-, time-, and concentration-dependent manner with SMX-NO and flucloxacillin, whereas isoniazid and amoxicillin were nontoxic. Furthermore, drug-induced activation of nuclear factor (erythroid-derived 2)-like 2 marker genes was observed when hepatocytes were exposed to test drugs. The disulfide isoform of HMGB1 stimulated dendritic cell cytokine release and enhanced the priming of naive T-cells. Incubation of dendritic cells with supernatant from drug-treated hepatocytes resulted in 2 distinct cytokine profiles. SMX-NO/flucloxacillin stimulated secretion of TNF-α, IL-6, IL-1α, and IL-1-ß. Isoniazid which did not induce significant hepatocyte toxicity, compared with SMX-NO and flucloxacillin, stimulated the release of a panel of cytokines including the above and IFN-γ, IL-12, IL-17A, IP-10, and IL-10. Collectively, our study identifies drug-specific signaling pathways between hepatocytes and immune cells that could influence whether drug exposure will result in an immune response and tissue injury.