title: Cytokine profile and prognostic significance of high neutrophil-lymphocyte ratio in colorectal cancer.
abstract: BACKGROUND
  High circulating neutrophil-lymphocyte ratio (NLR) appears to be prognostic in metastatic colorectal cancer (mCRC). We investigated the relationship of NLR with circulating cytokines and molecular alterations.
  
  
  METHODS
  We performed retrospective analyses on multiple cohorts of CRC patients (metastatic untreated (n=166), refractory metastatic (n=161), hepatectomy (n=198), stage 2/3 (n=274), and molecularly screened (n=342)). High NLR (ratio of absolute neutrophil-to-lymphocyte counts in peripheral blood) was defined as NLR>5. Plasma cytokines were evaluated using multiplex-bead assays. Kaplan-Meier estimates, non-parametric correlation analysis, and hierarchical cluster analyses were used.
  
  
  RESULTS
  High NLR was associated with poor prognosis in mCRC (hazard ratio (HR) 1.73; 95% confidence interval (CI):1.03-2.89; P=0.039) independent of known prognostic factors and molecular alterations (KRAS/NRAS/BRAF/PIK3CA/CIMP). High NLR correlated with increased expression of interleukin 6 (IL-6), IL-8, IL-2Rα, hepatocyte growth factor, macrophage-colony stimulating factor, and vascular epidermal growth factor in exploratory (n=39) and validation (n=166) cohorts. Fourteen additional cytokines correlated with high NLR in the validation cohort. All 20 cytokines fell into three major clusters: inflammatory cytokines, angiogenic cytokines, and epidermal growth factor ligands. In mCRC, composite stratification based on NLR-cytokine score provided enhanced prognostic information (HR 2.09; 95% CI: 1.59-2.76; P<0.001) over and above NLR.
  
  
  CONCLUSIONS
  High NLR is an independent poor prognostic marker in CRC and correlates with a distinct cytokine profile related to key biological processes involved in carcinogenesis. A composite NLR-cytokine stratification has enhanced prognostic value in mCRC.
authors: Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
authors: Z-Y
authors: ZY
authors: Chen
authors: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: K
authors: K
authors: Raghav
authors: Division of Medical Oncology, University of Colorado, Aurora, Colorado, USA.
authors: C H
authors: CH
authors: Lieu
authors: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Z-Q
authors: ZQ
authors: Jiang
authors: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: C
authors: C
authors: Eng
authors: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: J-N
authors: JN
authors: Vauthey
authors: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: G J
authors: GJ
authors: Chang
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: W
authors: W
authors: Qiao
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: J
authors: J
authors: Morris
authors: Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: D
authors: D
authors: Hong
authors: Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Oncologia Clínica, São Paulo, Brazil.
authors: P
authors: P
authors: Hoff
authors: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: H
authors: H
authors: Tran
authors: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: D G
authors: DG
authors: Menter
authors: Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: J
authors: J
authors: Heymach
authors: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: M
authors: M
authors: Overman
authors: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: S
authors: S
authors: Kopetz
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000097:blood* / Q000276:immunology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007958:Leukocyte Count / Q000379:methods; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009504:Neutrophils / Q000276:immunology / Q000473:pathology*; D011379:Prognosis; D012189:Retrospective Studies
chemical_list: D016207:Cytokines