| 1 Background and ObjectiveEsophageal cancer is a high invasive,poorly prognostic digestive tract malignant tumor,ranked 9th in the world,the world's most common cause of cancer death ranked 6th.About 70%of the world's esophageal cancer occurs in China,with esophageal squamous cell carcinoma(ESCC)accounting for about 90%.Although a variety of treatments,including multidisciplinary treatment,have been developed in recent decades to improve the level of treatment for patients with esophageal cancer,the overall survival rate of patients with esophageal cancer remains low,with a 5-year survival rate of only 20%percent in Europe,the United States and some parts of China.Therefore,the use of pretreatment period indicators rather than surgical and pathological diagnosis to predict clinical prognosis is extremely important for improving prognosis and providing the best treatment strategy.Nutritional,immunity and inflammatory status of the body have been considered to be closely related to the development of tumors,and some scholars have found that immune resistance is considered to play an important role in the invasive behavior of many malignant tumors,including ESCC.There is growing evidence in recent years that systemic nutritional,immunity,inflammatory responses are associated with the prognosis of various malignant tumors,and that Some new predictive indicators,such as the Prognostic Nutrition Index(PNI),the Neutrophil to Lymphocyte Ratio(NLR),the Platelet to Lymphocyte Ratio(PLR),the Lymphocyte to Monocyte Ratio(LMR),Systemic immune Inflammatory index(SII)are prognostic factors that are thought to be likely to be a variety of malignant tumors,including esophageal cancer.The interaction between the host and the tumor is a complex,multilayered interaction between competing factors,and the balance between the tumor and the anti-tumor factors ultimately affects the survival of the patient.Tumor cells may express different molecules that can induce an immune response,which may eliminate the progression and metastasis of these tumor cells or interfere with the tumor;However,tumor cells may also express different molecules that may block or interfere with the activation and proliferation of immune cells,thus avoiding the development of immune responses that destroy tumors,Causes the tumor to escape the immune response.T-Cell Immunoglobulin Mucin-3(TIM-3)and CD27 can be detected on a variety of tumor cells and tumor starter cells,and are involved in tumor initiation and tumor promotion activities.TIM-3 expressed in tumor cells and tumor invasive immune cells,may be a key sentinel cell,in the tumor microenvironment,the damage of tumor immune monitoring and tumor hyperplasia,TIM-3 abnormal expression may mark the depletion of CD8+T lymphocytes.CD27,which affects the immune response by combining with its ligand CD70,plays a role in inhibiting or promoting the occurrence and development of tumor,and its mechanism is not clear.At present,there are few reports on the relationship between the expression of TIM-3and CD27 in ESCC patients and the clinicopathologic features and prognosis of patients,and the related reports are still very controversial.The purpose of this study was to study the relationship between the clinical features of markers based on nutritional immunity,such as PNI,PLR,NLR,LMR,SII and ESCC,and to explore the value of these indexes in the prognosis of patients after ESCC surgery.At the same time,150 cases of ESCC and its corresponding cancerous tissue chip were customized in this paper,and immunohistochemical methods were used to observe the distribution of TIM-3 and CD27 in cancerous tissues and adjacent cancers.The aim was to investigate the relationship between the expression level of TIM-3 and CD27 in cancer tissue and the clinicopathological characteristics of patients with ESCC and its prognostic value.2 Materials and methods2.1 Evaluation value of preoperative PNI,NLR,PLR,LMR and SII on postoperative prognosis of patients with ESCC2.1.1 Research ObjectsIn this study,the general data,clinicopathological information,clinical diagnosis and treatment,blood routine examination results,liver function examination results and follow-up results of 452 cases of ESCC were derived from the database of clinical information and biological samples of 500,000 cases of esophageal and cardiac carcinoma in the key open laboratory of esophageal carcinoma in Henan province.Among them,281 were males,the average diagnosis age was 59.4±8.2years,171 women,the average diagnosis age was 61.8±8.4 years.2.1.2 Research MethodsThe clinical data of 452 patients with esophageal cancer treated by radical resection of esophageal carcinoma in Anyang cancer Hospital of Henan Province were analyzed retrospectively,including general data(age,sex)and clinicopathological information(length of tumor,degree of differentiation,postoperative cutting margin,depth of tumor infiltration,lymph node metastasis,Distant organ metastasis and TNM staging),blood routine examination results during the first 1 weeks(lymphocyte count,neutrophils count,platelet count,mononuclear cell count),liver function examination results(albumin content)and follow-up results,all patients were diagnosed by postoperative pathology as ESCC.According to the formula PNI=10×serum albumin(g/dl)+0.005×lymphocyte count(mm~3),the PNI value was obtained,SII=platelet count×neutrophils count/lymphocyte count,and the SII value was obtained.Using IBM SPSS21.0 to analyze the data,the Receiver Operating Characteristic Curve(ROC Curve)is used to select the best cut-off values of PNI,NLR,PLR,LMR and SII,and the patients are grouped by cut-off values,and the relationship between the grouping variables is tested by Chi square test,and the survival time is measured in years.The survival rate of 1,3 and 5 years was calculated by the life table method,Univariate Survival Analysis was carried out by Kaplan-Meier method and Log-rank method,and Multivariate Survival Analysis was carried out by Cox proportional risk regression model.2.2 Expression of TIM-3 and CD27 in Esophageal Squamous Cell Carcinoma and Their Clinical Significance2.2.1 Research ObjectsThe wax blocks of 150 cases of esophageal cancer and its corresponding cancerous side tissue were randomly selected from June 2003 to December 2011,and the key open experiment of esophageal carcinoma in Henan Province was archived.Among them,85 were males,the average diagnosis age was 59.3±8.6 years,65women,the average diagnosis age was 62.4±7.5 years.2.2.2 Study methodThe 150 cases of tissue specimen wax block were selected,the tissue chip was customized and the immunohistochemical staining experiment was carried out to detect the expression intensity of TIM-3 and CD27,and the statistical analysis was carried out by IBM SPSS21.0.The relationship between the expression intensity and clinical characteristics of TIM-3 and CD27 in esophageal cancer tissues was compared by using Chi square test and Fish accurate test.The survival time is measured in years,the survival rate of 1,3 and 5 years is calculated by the life table method,and Survival Analysis is carried out by Kaplan-Meier method,Log-rank method and Cox proportional risk regression model.3 Results3.1 Evaluation value of preoperative PNI,NLR,PLR,LMR and SII on postoperative prognosis of patients with ESCC3.1.1 Determine the cut-off values of preoperative PNI,NLR,PLR,LMR,and SII and group themAccording to the Youden index(sensitivity+specificity-1),the best truncation values of preoperative PNI,NLR,PLR,LMR and SII were 50,2.2,138.3,4.2 and504.7,respectively,based on the five-year survival of this group of data to produce the ROC curve of each biological index.According to this,452 cases of ESCC patients were divided into PNI?50 Group(265 cases)and PNI<50 Group(187cases);NLR<2.2(220 cases)and NLR?2.2(232 cases)group;PLR<138.3 Group(245 cases)and PLR?138.3 Group(207 cases)group;LMR?4.2 Group(162 cases)and LMR<4.2 group(290 cases);SII<502.7 Group(230 cases)and SII?502.7Group(222 cases).3.1.2 Relationship between Clinicopathologic features of Preoperative PNI,NLR,PLR,LMR,SII and ESCC patientsIn different PNI subgroups,there were significant statistical differences in the distribution of diagnostic age(P=0.010)and long diameter of tumor(P=0.006),and found in different NLR groups,tumor long diameter(P<0.001),There were significant statistical differences in the distribution of Tumor infiltration degree(P=0.006),and in different LMR groups,there were significant statistical differences in the distribution of sex(P=0.006)and long diameter of tumor(P=0.004),and found in different SII groups,tumor long diameter(P<0.001),There were significant statistical differences in the distribution of Differentiation degree(P=0.020)and tumor Infiltration degree(P<0.001),and there was no statistical difference.3.1.3 Preoperative survival comparison of PNI,NLR,PLR,LMR,SII and Univariate analysis of influencing overall survival of ESCC patientsThe results of Kaplan-Meier survival analysis showed that the diagnosis of age,long diameter of tumor,degree of infiltration,lymph node metastasis,TNM staging,PNI,NLR,PLR,LMR and SII were the factors affecting the survival of ESCC patients.The overall survival rate of ESCC patients in PNI?50 group was significantly better than that of PNI<50 Group(?~2=8.991,P=0.003),and the cumulative survival rate of PNI?50 group in 1,3 and 5 years was 93.2%,68.3%and55.1%,PNI<50 group were 87.2%and 56.1%,32.1%,respectively;The overall survival rate of ESCC patients in NLR<2.2 group was significantly better than that of NLR?2.2 Group(?~2=7.510,P=0.006),and the cumulative survival rate of NLR<2.2 group in 1,3 and 5 years was 94.1%,67.3%and 56.4%,NLR?2.2 group were87.5%59.5%,35.3%,respectively.;The overall survival rate of ESCC patients in PLR<138.3 group was significantly better than that of PLR?138.3 group(?~2=6.409,P=0.011),and the cumulative survival rate of PLR<138.3 group in 1,3 and 5years was 91.8%,69.4%and 55.9%respectively.The PLR?138.3 group was 89.4%,56%,33.3%,respectively;The overall survival rate of ESCC patients in LMR?4.2group was significantly better than that of LMR<4.2 group(?~2=6.131,P=0.013),and the cumulative survival rate of LMR?4.2 group in 1,3 and 5 years was 93.8%,69.1%and 55.6%,LMR<4.2 group was 89%,60%,40%,respectively;The overall survival rate of ESCC patients in SII<504.7 group was significantly better than that of SII?504.7 Group(?~2=5.819,P=0.016),and the cumulative survival rate of SII<504.7 group in 1,3 and 5 years was 92.6%,68.3%and 54.3%,respectively.The SII?504.7 group was 88.7%,58.1%,36.5%,respectively.3.1.4 COX analysis of the effects of PNI,NLR,PLR,LMR and SII on the survival of ESCC patientsCOX regression screening Independent prognostic factors showed:TNM staging(HR=1.774,95%CI:1.527~2.016,P<0.001),PNI(HR=1.359,95%CI:1.090~1.696,P=0.006)and PLR(HR=1.269,95%CI:1.019~1.580,P=0.033)were independent influencing factors of postoperative prognosis in ESCC patients.3.2 Expression of TIM-3 and CD27 in ESCC and its clinical significance3.2.1 Relationship between the expression intensity of TIM-3 and CD27 in ESCC tissue and the clinicopathologic features of patientsIn ESCC patients with high expression group of TIM-3 protein in cancer tissue,the number of lymph node metastasis was higher than that in the expression group,and the difference was statistically significant(?~2=9.024,P=0.026),which was related to the age,sex,long diameter of tumor,differentiation degree,tumor infiltration depth,There was no statistically significant difference in TNM staging(P>0.05),and in patients with ESCC in CD27 High expression group,the depth of tumor infiltration was shallow in the control group,and the difference was statistically significant(?~2=10.959,P=0.012),the age,sex,long diameter of tumor,degree of differentiation,number of lymph node metastasis,There was no statistically significant difference in TNM staging(P>0.05).3.2.2 TIM-3,CD27 expression intensity and univariate survival analysis of ESCC patientsUsing Kaplan-Meier and Log-rank test results showed that the overall survival rate of patients with TIM-3 low expression group ESCC in cancer tissue was significantly better than that of high expression group,and the difference was statistically significant(?~2=7.936,P=0.005).The survival rates of 1,3 and 5 years in patients with TIM-3 low expression group were 93.0%,84.5%,64.8%respectively,and those of patients with high expression of TIM-3 were 91.1%,53.2%and 34.2%respectively.The overall survival rate of patients with CD27 high expression group was significantly better than that of low expression group,and the difference was statistically significant(?~2=5.469,P=0.019).The survival rates of 1,3 and 5 years in patients with CD27 high expression group were96.4%,80.4%,64.3%respectively,and those of patients with low expression of CD27 were 89.4%,60.6%and 39.4%respectively.3.2.3 Analysis of TIM-3,CD27 expression intensity and multi-factor survival in patients with ESCCIn the survival analysis of COX proportional risk regression,it is found that TIM-3 expression intensity(HR=1.682,95%CI:1.099~2.574,P=0.017)is an independent influencing factor of postoperative prognosis of ESCC patients.4 Conclusion1)The optimum truncation values of preoperative PNI,NLR,PLR,LMR and SII were 50,2.2,138.3,4.2 and 504.7,respectively.2)The diagnosis age and long diameter of tumor were less than PNI<50 group in patients with preoperative PNI?50 group ESCC,and the long diameter of tumor was less than that in patients with preoperative NLR<2.2 group ESCC.The depth of tumor infiltration was less than that in NLR?2.2 group,the proportion of female patients in LMR?4.2 group before operation was more than that in LMR<4.2 group,and the length of tumor was smaller,and the long diameter of tumor in SII<504.7group was smaller than that in ESCC group,and the depth of tumor was shallower.3)Preoperative PNI,NLR,PLR,LMR and SII were the factors affecting postoperative prognosis of ESCC patients,and preoperative PNI and PLR were independent factors influencing postoperative prognosis of ESCC patients.4)The number of lymph node metastasis was relatively high in TIM-3,which was highly expressed in cancerous tissues,and the degree of tumor infiltration was deeper in the low expression of CD27.5)The expression intensity of TIM-3 and CD27 respectively is the factors that affect the prognosis of ESCC patients,and the intensity of TIM-3 expression is an independent influencing factor of patients'prognosis. |
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