Analysis Of Preoperative Blood Unconjugated Bilirubin And The Prognosis Of Esophageal Squamous Cell Carcinoma

Backgrounds:Esophageal carcinoma is the third most common cancer in China and the sixth most common cause of cancer related deaths worldwide with developing nations making up more than 80%of total cases and deaths.Esophageal squamous cell carcinoma(ESCC)is the most common histological type of esophageal cancer worldwide,which has a higher incidence in the developing nations.Distant metastasis is a mainly cause of treatment failure and mortality in patients with ESCC.So,it is very significant to find the mechanism of ESCC metastasis and identify credible prognostic factors.Free radicals and 'reactive molecules containing oxygen are reactive oxygen species(ROS)related to oxygen metabolism in the organism.A large number of studies have shown that ROS and oxidative stress may promote many biological behaviors of tumors,including proliferation,survival,transformation,radioresistance,chemoresistance,angiogenesis and metastasis.Therefore,reactive oxygen species(ROS)inhibitors play a very important role in the chemoprevention of tumors.Unconjugated bilirubin(UCB)was considered a waste product of the heme catabolism,until the discovery of its antioxidant effects under physical concentrations.At present,more and more studies have suggested that bilirubin plays an important protective role in oxidative stress related diseases,including respiratory disease,carotid artery atherosclerosis,coronary heart disease,stroke and cancer.However,very few studies have addressed the role of bilirubin in tumor metastasis.In this study,we investigated the correlation of preoperative blood UCB level and the prognosis of ESCC patients who underwent esophagectomy.Objective:The aim of our study is to investigate the association between preoperative blood UCB level and the prognosis in ESCC.We hope to find a novel prognostic factor of ESCC.Methods:A total of 336 patients with squamous cell carcinoma of the esophagus underwent resection at Qilu Hospital of Shandong University between January 2007 and December 2010 were included in our study.Baseline bilirubin levels were obtained within 1 week prior to surgery.A total of 181 patients were followed up regularly for 2 years,followed by an outpatient visit every 3 months,followed by every 6 months until death,and the follow-up ended in December 2013.None of the patients received neoadjuvant therapy before surgery.All patients underwent staging of TNM according to the staging guidelines of the American Cancer staging Association(Seventh Edition,2010).We used the receiver operating characteristic(ROC)curve analysis to obtain the most appropriate cut-off point,which will stratify patients with different distant metastasis or local recurrence risk.Chi-square test and Kruskal-Wallis test were used to analyze the relationship between UCB absolute value and clinicopathological features.The use of Kaplan-Meier survival curves and log-rank test on disease free survival(DFS)and overall survival(OS)were analyzed and compared,using Cox proportional hazards models to 181 patients characteristics(such as sex,age,T stage,N stage,TNM stage,treatment modalities and indirect bilirubin levels)for multivariate regression analysis.P<0.05 was statistically significant.All statistical analyses were performed using SPSS21.0 statistical software(version 21.0,SPSS Inc,Chicago,IL).Results:Among the 181 patients included in this study,37(20.1%)were female and 144(79.9%)were male.The median age at diagnosis was 60 years(range 35-82 years).The 5-year OS and DFS of all patients were 47.0%and 52.5%,respectively.The median of UCB level was 8.0 ?M(inter-quartile range:5.9-10.3?M).To find whether there's difference between the UCB levels of males and females,we took Student's t-test to compare the UCB levels of males and females.The mean of UCB for males was 8.05?M,while the mean of UCB for females was 7?M.There is no statistical significance between males and females.The cut-off point of level for survi-val outcomes was determined by ROC curve analyses,and a UCB value of 6.45?M resulted in the most appropriate sensitivity and specificity for DFS.Univariate analysis revealed that a higher UCB level(?6.45?M)was associated with superior DMFS in ESCC(P<0.01).The results of multivariate analysis showed that UCB? 6.45?M was a significantly independent predictor for the favorable DFS[hazard ratio(or HR)= 0.416,95%confidence interval(or 95%CI)= 0.280-0.618;P<0.001)],while UCB>6.45?M was not a significantly independent predictor for the favorable OS(HR =0.715,95%CI= 0.449-1.138;P=0.157).In conclusion,UCB levels were a favorable predictor of DFS in ESCC patients..Conclusion:UCB is a favorable and independent prognostic biomarker correlated with better DFS in ESCC patients,and higher preoperative serum UCB level under physical concentrations is correlated with better DFS.The test of preoperative blood UCB level could predict the metastasis and local recurrence of postoperative ESCC.