Role of nutritional status and intervention in oesophageal cancer treated with definitive chemoradiotherapy:outcomes from SCOPE1

BACKGROUND: Malnutrition is common in oesophageal cancer. We aimed to identify nutritional prognostic factors and survival outcomes associated with nutritional intervention in the SCOPE1 (Study of Chemoradiotherapy in OesoPhageal Cancer with or without Erbitux) trial. METHODS: Two hundred and fifty eight patients were randomly allocated to definitive chemoradiotherapy (dCRT) +/− cetuximab. Nutritional Risk Index (NRI) scores were calculated; NRI<100 identified patients at risk of malnutrition. Nutritional intervention included dietary advice, oral supplementation or major intervention (enteral feeding/tube placement). Univariable and multivariable analyses using Cox proportional hazard modelling were conducted. RESULTS: At baseline NRI<100 strongly predicted for reduced overall survival (hazard ratio (HR) 12.45, 95% CI 5.24–29.57; P<0.001). Nutritional intervention improved survival if provided at baseline (dietary advice (HR 0.12, P=0.004), oral supplementation (HR 0.13, P<0.001) or major intervention (HR 0.13, P=0.003)), but not if provided later in the treatment course. Cetuximab patients receiving major nutritional intervention had worse outcomes compared with controls (13 vs 28 months, P=0.003). CONCLUSIONS: Pre-treatment assessment and correction of malnutrition may improve survival outcomes in oesophageal cancer patients treated with dCRT. Nutritional Risk Index is a simple and objective screening tool to identify patients at risk of malnutrition

AUF1 Isoform-Specific Regulation of Anti-inflammatory IL10 Expression in Monocytes

IL-10 is an immunomodulatory cytokine that regulates inflammatory responses of mononuclear phagocytes (monocytes and macrophages). Mononuclear cells exposed to microbes or microbial products secrete a host of proinflammatory cytokines followed by delayed onset of anti-inflammatory IL-10. IL-10 suppresses immune responses by inhibiting cytokine production by mononuclear phagocytes. Using THP-1, a human promonocytic leukemia cell line, we show that endotoxin/lipopolysaccharide (LPS) exposure induces IL10 expression while IFN-γ blocks this LPS-mediated effect. IFN-γ is an important modulator of IL-10 production during infectious diseases. We show that LPS and IFN-γ regulate IL10 expression in THP-1 cells in part through posttranscriptional mechanisms. Our results demonstrate that 3′-untranslated region (3′-UTR) AU-rich elements (AREs) decrease expression of a chimeric luciferase reporter gene in THP-1 cells. The ARE-binding protein AUF1 binds the IL10 3′-UTR. Depletion of AUF1 by RNAi suppresses LPS-mediated induction of IL10 mRNA and protein without affecting LPS-mediated stabilization of IL10 mRNA. Upon complementation with either RNAi-refractory p37 or p40 AUF1 plasmids, only p40 restores LPS-mediated induction of IL10 mRNA and protein to near normal levels. Thus, the p40 AUF1 isoform selectively plays a critical, positive role in IL10 expression upon LPS exposure