title: How relevant are cytokines in colorectal cancer wasting?
abstract: OBJECTIVE
  The purpose of this article was to investigate the influence of inflammatory cytokines, pro-cachectic (interleukin [IL]-1 receptor agonist [IL-1ra], IL-6, and tumor necrosis factor-alpha [TNF-alpha]), immunomodulatory (IL-10 and interferon-gamma [IFN-gamma]), and pro-angiogenic (vascular endothelial growth factor [VEGF]), on resting energy expenditure (REE), weight, and nutritional intake and to explore potential interactions between their circulating concentrations and colorectal cancer stage/histologic differentiation and response to radiotherapy (RT).
  
  
  METHODS
  This was a prospective longitudinal study in 101 patients evaluated before and after neoadjuvant RT, including REE (indirect calorimetry), percent weight loss, usual/current diet (diet history and 24-hour recall), serum concentrations of cytokines (enzyme-linked immunosorbent assay), and RT response.
  
  
  RESULTS
  Stages III/IV were often associated with histologic grades 2/3 (P < 0.01), albeit both characteristics independently were associated with higher concentrations of IL-1ra (P </= 0.05), IL-6 (P </= 0.02), TNF-alpha (P </= 0.05), IFN-gamma (P </= 0.05), and VEGF (P < 0.03). Before and after RT, higher REE, weight loss >/=5%, and intake reduction >/=25% were associated with advanced stage, histologic grades 2/3, higher IL-1ra, IL-6, TNF-alpha, IFN-gamma, and VEGF, and nonresponse to RT (P = 0.003). A general linear model analysis showed that stages III/IV, histologic grades 2/3, and higher IL-1ra, IL-6, TNF-alpha, IFN-gamma, and VEGF were major determinants of REE increase, weight loss, and intake reduction. In predictive value analyses, higher baseline pro-cachectic cytokines (IL-1ra + IL-6 + TNF-alpha) by themselves predicted increased REE (hazard ratio [HR]: 8.25; 95% CI: 2.74-26.47; P < 0.002), greater weight loss (HR: 8.15; 95% CI: 2.22-25.40; P < 0.002), and intake reductions (HR: 7.15; 95% CI: 2.25-16.11; P < 0.004) after RT.
  
  
  CONCLUSIONS
  This study confirms the fact that wasting in colorectal cancer is correlated with tumor burden and histologic aggressiveness and suggests that both characteristics lead to overproduction of IFN-gamma, VEGF, and pro-cachectic cytokines, all of which may cause higher metabolic rates, poor intake, and nonresponse to RT.
authors.affiliation: Unidade de Nutrição e Metabolismo, Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisbon, Portugal. p.ravasco@fm.ul.pt
authors.forename: Paula
authors.initials: P
authors.lastname: Ravasco
authors.forename: Isabel
authors.initials: I
authors.lastname: Monteiro-Grillo
authors.forename: Maria
authors.initials: M
authors.lastname: Camilo
mesh_terms: D002100:Cachexia / Q000209:etiology* / Q000503:physiopathology; D015179:Colorectal Neoplasms / Q000150:complications* / Q000503:physiopathology / Q000532:radiotherapy; D016207:Cytokines / Q000097:blood / Q000502:physiology*; D002149:Energy Intake; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008137:Longitudinal Studies; D009752:Nutritional Status; D010865:Pilot Projects; D011446:Prospective Studies
chemical_list: D016207:Cytokines