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|1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago
Patients with MIC 1 levels in the upper quartile showed reduced survival (median days; 95 CI 157 when compared with patients with MIC 1 levels in the lower three quartiles (median days; 95 CI 259 P but MIC 1 was not an independent prognostic indicator.
Conclusions: There is no independent link between plasma MIC 1 levels and depleted nutritional status or survival in OGC.
Keywords: macrophage inhibitory cytokine 1; oesophageal cancer; gastric cancer; cachexia; survival; nutrition
Systemic inflammation has been linked with adverse survival in a variety of cancer types (Falconer et al, 1995; Scott et al, 2002; Hefler et al, 2008). This association could be explained by a variety of tumour related phenomena, including enhanced tumour progression (Hefler et al, 2008), angiogenesis (Krzystek Korpacka et al, 2008), and metastasis (Weinstein et al, 1984). However, the presence of systemic inflammation has also been linked with both hypermetabolism (Falconer et al, 1994) and reduced food intake (Fearon et al, 2006), two key components of the cachexia syndrome that is known to result in shortened survival in patients with advanced malignancy (Fearon et al, 2006). The mechanisms by which systemic inflammation arises in cancer patients are not established clearly. One hypothesis is that interaction between host and tumour cells within the tumour mass results in activation of peripheral blood mononuclear cells (PBMCs) (O et al, 1999). The latter circulate to distant target organs in which enhanced cytokine production results in the generation of a systemic inflammatory response. We have shown previously increased pro inflammatory cytokine release by PBMCs in patients with elevated plasma CRP concentrations (O et al, 1999). The ability of such PBMCs to induce acute phase protein production from co cultured human hepatocytes seemed to be IL 6 dependent (O et al, 1999). In patients with oesophago gastric cancer (OGC; in which systemic inflammation is associated with weight loss and shortened survival), we have previously shown that tumour IL 1 overexpression and chronic inflammatory cell infiltrate are independent factors influencing systemic inflammation (Deans et al, 2006). However, the precise role of various pro inflammatory cytokines within human tumours in the generation of a systemic response is still incompletely understood.
Macrophage inhibitory cytokine 1 (MIC 1) is a divergent member of the transforming growth factor superfamily that is produced by macrophages in response to activation (Bootcov et al, 1997). MIC 1 is not expressed Converse Trainers UK in most human tissues at basal conditions (except the placenta) but is expressed at high concentrations during inflammation and injury (Fairlie et al, 1999; Schober et al, 2001). MIC 1 is overexpressed by malignant melanoma cells and is associated with tumourigenicity (Boyle et al, Converse Trainers UK 2009). High serum concentrations of MIC 1 have been observed in patients with pancreatic (Koopmann et al, 2004, 2006), gastric (Baek et al, 2009), and breast cancer (Welsh et al, 2003), and have been associated with adverse survival in colorectal cancer (Brown et al, 2003) and glioblastoma (Shnaper et al, 2009). In prostate cancer, high patient serum levels of MIC 1 have been associated with increased disease stage (Selander et al, 2007), docetaxel resistance (Zhao et al, 2009), and adverse survival (Brown et al, 2009). In prostate cancer bone metastases, MIC 1 induced osteoclast activation (Wakchoure et al, 2009). In mice bearing human prostate cancer xenografts, elevated MIC 1 concentrations were associated with marked weight, fat, and lean tissue loss that was mediated by decreased food intake and was reversed by an antibody to MIC 1 (Johnen et al, 2007). In addition, normal mice administered systemic MIC 1, and transgenic mice overexpressing MIC 1, showed hypophagia and reduced body weight (Johnen et al, 2007). In a small group of cachectic prostate cancer patients (n serum MIC 1 concentrations were significantly associated with weight loss and weakly correlated with serum IL 6 (Johnen et al, 2007).
To determine whether MIC 1 is associated with inflammatory and nutritional status, we aimed to measure circulating concentrations of MIC 1 in a large cohort (n of patients with OGC, a disease strongly associated with cachexia, and to analyse the relationships between MIC 1, systemic inflammation, nutritional status, and survival.
Top of pageMaterials and methodsBackground: Methods: Results: Conclusions: Materials and methods Results Discussion References Acknowledgements Figures and TablesPatients and controlsAll patients provided written, informed consent, and the study was approved by the Lothian Research Ethics Committee. Patients with a new histological diagnosis of OGC were recruited (n 198 males and 95 females). Whole blood was taken at diagnosis for plasma analysis of MIC 1 and CRP concentration. Staging was carried out according to the AJCC system (Sobin and Wittekind, 2002). The majority of patients (n were followed up until death. A healthy control cohort (n 25 males, 10 females, median age 29 range 24 composed of laboratory and hospital staff (n and hospital patients undergoing minor operative procedures for benign conditions (n was recruited for comparative MIC 1 analysis.
Nutritional assessmentAt recruitment, pre illness stable weight was self reported by patients and percentage weight loss was calculated (Deans et al, 2009). Height was measured using a wall mounted stadiometer with the patient standing erect without shoes. Patients were weighed on spring balance scales without shoes and wearing light clothing. Mid arm circumference (MAC) was measured at the mid point between the acromion and olecranon processes. Triceps Converse UK Sale skinfold thickness (TSF) was measured with Harpenden skin callipers (Holtain, Crymych, UK). As surrogates of dietary intake, dysphagia score (normal swallowing dysphagia to solids dysphagia to softened foods dysphagia to liquids and total dysphagia and subjective diet score (normal dietary intake reduced dietary intake and poor dietary intake were assessed in a subset of patients (n Cachexia was defined as weight loss of 10 when compared with pre morbid weight. Control subjects did not undergo nutritional assessment beyond confirmation of weight stability.
Total plasma MIC 1 concentration determinationSamples were examined in duplicate using a well established sandwich ELISA as previously described (Moore et al, 2000). In brief, the mouse MAb 26G6H6 was used for antigen capture; and the sheep PAb 233 P was used for detection (Moore et al, 2000; Fairlie et al, 2001; Brown et al, 2002). The hMIC 1 plasma concentration was determined by reference to a standard curve constructed using recombinant hMIC 1 as the standard.
Assessment of systemic inflammationSystemic inflammation was determined in two ways. In a subset of patients (n plasma albumin concentration was determined, and thus calculation of a systemic inflammation based score, the modified Glasgow Prognostic Score (mGPS) (McMillan, 2009), was performed. Plasma CRP and albumin concentrations were assayed using automated methods on Olympus AU 2700 and Olympus 640 analysers, respectively (Olympus Diagnostica GmbH (Irish Branch), Lismeehan, Ireland), in the Department of Clinical Chemistry, Royal Infirmary of Edinburgh (fully accredited by Clinical Pathology Accreditation (UK) Ltd).
Statistical analysisAll statistical analyses were performed using Statistical Package for Social Services version 13.0 (SPSS 13.0; Chicago, IL, USA). Plasma MIC 1 data are presented as box plots. Mild outliers (MIC 1 concentration more than 1.5 times the interquartile range (IQR) above the third quartile) are represented as circles and extreme outliers (MIC 1 concentration more than 3 times the IQR above the third quartile) are presented as stars. For visual clarity, the y axes are limited to a maximum MIC 1 concentration of 5000 or 8000 pg Differences between the distribution functions of data for three or more subject groups were determined using Kruskal test (shown in text and figure legends). Subsequent analysis for determining differences between any two groups was determined using Mann U test (shown in figures). All quoted P values are two tailed. Correlation analysis was performed using non parametric Spearman's rank correlation coefficient. Linear regression was used for analysing the relationship between CRP and MIC 1. Significance levels for the explanatory variables of interest were 0.10 to enter stepwise into the model. Survival analyses were performed on those patients followed until death using Kaplan plots and Cox's proportional hazards models. For construction of the latter model, treatment regimen was defined as either surgery with curative intent, radical chemo with curative intent, chemo with palliative intent, or nil. Statistical significance was set at P level. Furthermore, median BMI, MAMC, and TSF measures were lower than those reported in healthy elderly populations (Corish and Kennedy, 2003). Of the assessed patients, 29.9 (59 out of 197) had a mGPS of 1, and 13.7 (27 out of 197) had a mGPS of 2. Plasma MIC 1 concentration also increased with worsening disease stage (Figure 4) and increasing mGPS (Figure 5).