No abstract

No abstract

BACKGROUND:Predicting survival is uniquely difficult in patients with pancreatic cancer who receive chemotherapy. The authors developed a systemic inflammation response index (SIRI) based on peripheral neutrophil, monocyte, and lymphocyte counts and evaluated the ability of the SIRI to predict the survival of patients with pancreatic cancer who received chemotherapy. METHODS: The SIRI was developed in a training set of 177 patients who had advanced pancreatic cancer and received palliative chemotherapy. The ability of the SIRI to predict a patient's survival after chemotherapy was validated in 2 independent cohorts (n 5 397). RESULTS: Compared with patients who had an SIRI <1.8, patients in the training cohort who had an SIRI 1.8 had a shorter time to progression (TTP) (hazard ratio [HR], 2.348; 95% confidence interval, 1.559-3.535; P 5 .003) and shorter overall survival (OS) (HR, 2.789; 95% confidence interval, 1.897-4.121; P < .001). Comparable TTP and OS findings were observed in 2 independent validation cohorts. Multivariate analysis confirmed that the SIRI was an independent prognostic factor for both TTP and OS. In addition, compared with no change, an increase in the SIRI at week 8 was associated with poor TTP and OS, whereas a decrease in the SIRI was associated with improved outcomes. In addition, high SIRI scores were correlated with higher serum levels of interleukin 10, C-C motif chemokine ligand 17 (CCL17), CCL18, and CCL22 and with a shortened TTP. CONCLUSIONS: The SIRI can be used to predict the survival of patients with pancreatic adenocarcinomas who receive chemotherapy, potentially allowing clinicians to improve treatment outcomes by identifying candidates for aggressive therapy. Cancer 2016;122:2158-67.

Objective To investigate the molecular mechanisms of CCL13/monocyte chemoattractant protein 4 (MCP‐4) chemokine expression through proinflammatory cytokines in different primary human fibroblasts and the contribution of CCL13 to monocyte migration. Methods Using RNase protection assays and enzyme‐linked immunosorbent assays, we quantified the expression of CCL13 compared with that of CCL2/MCP‐1 in primary human fibroblasts. Boyden chamber assays were performed to determine the importance of CCL13 for migration of primary monocytes. Pharmacologic inhibitors as well as small interfering RNA knockdown approaches were used to investigate the signaling pathways regulating CCL13 expression. Results The interleukin‐6 (IL‐6)–type cytokine oncostatin M (OSM) was a powerful inducer of CCL13 expression in primary synovial fibroblasts from patients with rheumatoid arthritis (RA) as well as those from healthy control subjects but not in other types of fibroblasts. Neither IL‐6 nor tumor necrosis factor α could stimulate the expression of CCL13 in synovial fibroblasts; IL‐1β was a very weak inducer. Synovial fibroblasts from patients with RA constitutively produced low amounts of CCL13, which was partially dependent on constitutive production of OSM. By investigating the underlying molecular mechanism, we identified STAT‐5, ERK‐1/2, and p38 as critical factors involved in OSM‐dependent transcription and messenger RNA stabilization of CCL13. Conclusion In contrast to other prominent cytokines involved in the pathogenesis of RA, OSM can strongly up‐regulate the expression of CCL13, a chemokine recently identified in the synovial fluid of patients with RA. Despite potent OSM‐induced signal transduction in all types of fibroblasts analyzed, only synovial fibroblasts secreted CCL13, which might be indicative of tissue‐specific imprinting of different fibroblasts during development.