| The incidence and mortality of lung cancer increased year by year throughout the world. Lung cancer is the leading cause of cancer-related mortality in the world for both men and women.In our country, the lung cancer mortality rates from 7.17/100000 in the 1970 s has rose to 26.7/100000 at the beginning of the 21 st century and has became a major disease threatening people’s life and health.Histologically, non-small cell lung cancer(NSCLC) accounts for approximately 80-90% of all lung cancer cases.The main treatments of lung cancer are surgery, radiotherapy, chemotherapy and molecular targeted therapy. To date, surgery is still the curable treatment option for NSCLC, like the most other human malignancies; however, such a cornerstone of curative treatment is only available to the early-stage NSCLC patients and the 5-year survival of patients with stage IA NSCLC after curative surgery can reach to 67%. Furthermore, approximately 40% NSCLC patients after curable surgery still face recurrences. The treatment of advanced lung cancer is given priority to with radiation and chemotherapy but median survival time is about 8 to 10 months and 5-year survival rate is less than 15%.Chemotherapy has an irreplaceable role as a systemic treatments, however, it is faced to many problems and challenges in clinical practice. Accompanied by a series of large and Ⅲperiod clinical research results published, the value of postoperative adjuvant chemotherapy in NSCLC have be improved. At present, the basic consensus of postoperative adjuvant chemotherapy is that platinum- based chemotherapy can improve the survival rate in radically-resected NSCLC whereas patients with early-stage benefit less. That is to say, on the basis of the results of the evidence-based medicine, adjuvant chemotherapy is reasonable, but only on the basis of pathological types and clinical stage has limitations obviously. Today we have not found reliable indicators of molecular biology predicting patients who can benefit from adjuvant chemotherapy.Platinum-based combinations with newer agents have been widely accepted as first-line options in the treatment of local advanced and advanced NSCLC. The third generation of antitumor drugs have improved the effect of chemotherapy significantly, but the response rate of first-line options is only 30% ~ 40%. Currently relevant biomarkers still lack predictive power in order to be used for response to first-line chemotherapy and significance of prognosis.The development of malignant tumors is controlled by a complex biologic system that depends on genetic abnormalities as well as the interplay between tumor cells, stromal cells, and host inflammatory cells. Altered inflammation and immune responses play a key role in tumor development and progression. Accumulating data demonstrate that tumor associated immune responses are more likely to contribute to tumor growth, progression, and immunosuppression than effective antitumor responses, depending on the differences of the tumor microenvironment(TME).Currently, the tumor, lymph node, metastasis(TNM) staging system is one of the best means to predict survival of NSCLC patients. Molecularly, different biological factors are involved in NSCLC development and progression; thus, they may serve as biomarkers for prediction of prognosis or treatment responses.Based on above reasons, We should fully understand the local immune state of patients with NSCLC and the relationship with prognosis, recurrence of high-risk population and the beneficiaries of chemotherapy and to improve the curative effect of chemotherapy.The literatures related prognostic significance of some factors in NSCLC is much, but it is not common in the immune related factors for the prognosis of NSCLC and the effect of adjuvant chemotherapy for such a large scale and a systematically studies, and we are the first time to explore immune molecular predictions of response to chemotherapy and prognosis in Patients with stage IV NSCLC.Part 1 Analysis of Clinical Pathological Characteristics and Prognosis Related Factors in Radically Resected Non-small Cell Lung Cancer Materials and methods1.129 cases of radically resected NSCLC cases from January 2004 to January 2007 were collected, the clinical pathologic data were complete and follow-up results were clear.2.The clinical pathological features and the relation with overall survival(OS) and disease free survival(DFS)in 129 cases were retrospectively analyzed.3.The clinical pathological features and the relation with OS and DFS in 92 patients who accepted adjuvant chemotherapy were retrospectively analyzed.4.Statistical analysis: All statistical analyses were performed using Statistical Package for the Social Sciences(SPSS version12.0). The correlations between subsets of variables and the clinicopathological features listed were analyzed by Spearman’s test. For the comparison of individual variables, χ2 tests and Fisher’s exact tests were carried out as appropriate. Survival curves were estimated by the Kaplan–Meier method, and differences in overall survival between groups were determined using the Log-rank test. Cox proportional hazards regression analysis was used to measure the association of clinicopathologic variables to overall survival. In all tests, a P value < 0.05 was considered significant. Results1.The median follow-up time was 36 months(range 6-109 months). To follow-up ending time on March 31, 2013, 82 cases(63.6%) of 129 were died and 47 cases(36.4%) were still survival. The median survival of these patients was 34.0 months and median DFS was 17.0 months. Single factor analysis showed that age, gender, Smoking statues, and whether adjuvant chemotherapy had nothing to do with DFS and OS(P>0.05). Adenocarcinoma, earlier p T stage, p N stage and TNM stage presented better OS and PFS(P<0.01). Multiple factors analysis showed that the pathological types(P=0.006), p T stage(P=0.000) and the p N stage(P=0.018) were independent prognostic factors for OS; whereas tumor pathological type(P=0.002) and p T stage(P=0.006) were independent predictors for DFS in radically resected NSCLC.2. In 92 radically resected patients who accepted postoperative adjuvant chemotherapy, 61 cases(66.3%) were died and 31 cases(33.7%) of this group were still survival. The median survival of these patients was 34.0 months and median DFS was 17.0 months. Single factor analysis showed that age and smoking statues had nothing to do with DFS and OS(P>0.05). Earlier p T stage, p N stage and TNM stage presented better OS and PFS(P<0.01). Different pathological type had different OS between the groups(P<0.05); Multiple factors analysis showed that the pathologic types(P=0.032), p T stage(P=0.006) were independent prognostic factors for OS; while p T stage(P=0.006), p N stage(P=0.018), and TNM staging(P=0.005) were independent prognostic factors for DFS.Part 2 Prognostic Significance of the tumor microenvironmentimmune molecules expression in Radically-resected NSCLC Materials and methods1.129 cases of non-small cell lung cancer radical surgery tissue samples were selected, of which clinical pathologic features as described earlier. Immunohistochemical method were used to detect CD3、CD4、CD8、IL-2、IL-6、TGF-β1、TNF-α、APRIL、COX-2 and Survivin expression.2.The expression of the related immune index and the relationship with clinical pathological characteristics and with OS and DFS were retrospectively analyzed. And its clinical characteristics and survival were analyzed in patients who accepted postoperative adjuvant chemotherapy in the same way.3.Statistical analysis:Median value was selected as cutoff and Immunohistochemical score > median score as high expression group while that ≤ the median score as low expression group. All statistical analyses were performed using Statistical Package for the Social Sciences(SPSS version 12.0). The correlations between subsets of variables and the clinicopathological features listed were analyzed by Spearman’s test. For the comparison of individual variables, χ2 tests and Fisher’s exact tests were carried out as appropriate. Survival curves were estimated by the Kaplan–Meier method, and differences in overall survival between groups were determined using the Log-rank test. Cox proportional hazards regression analysis was used to measure the association of clinicopathologic variables to overall survival. In all tests, a P value < 0.05 was considered significant. Results1.For radically resected patients, higher level of CD3(P=0.002) and IL- 2(P= 0.000) whereas lower level of CD4(P=0.000) and CD8(P=0.000) were associated with better OS; while lower level of CD8(P=0.002) and TNF-α(P=0.035) had longer DFS than higher level of that. Multiple factors analysis showed that CD3(P=0.000), CD4(P=0.019) and CD8(P=0.000) levels were independent predictors for OS whereas expression of CD8(P=0.011) was independent predictors for DFS in radically resected NSCLC.2.For 92 patients who accepted postoperative adjuvant chemotherapy, lower level of CD4(P=0.003), CD8(P=0.022) and Survivin(P=0.045) whereas higher level of CD3(P=0.017) and IL-2(P=0.002) were associated with better OS. And lower level of CD8(P=0.002) and Survivin(P=0.05) had longer DFS than higher level of that. COX regression analysis showed that CD3(P=0.002), CD8(P=0.009) and Survivin(P=0.030) levels were independent predictors for OS while CD8(P=0.002) and Survivin(P= 0.036) levels were independent predictors for DFS in postoperative NSCLC who received adjuvant chemotherapy.Part 3 T lymphocyte and IL–2 Prediction Response to First-line Chemotherapy and Survival in Patients with Stage IV Non-small Cell Lung Cancer Materials and methods1.169 cases of Stage IV NSCLC from January 2004 to March 2007 were collected. All cases were confirmed by cytological and/or histologic examination and the clinical pathologic data were complete and follow-up results were clear.2.An immunohistochemical study were performed to identify Tumor infiltrating lymphocytes(TIL) Interleukin- 2(IL-2) expression in biopsy specimens.3.For correlations between TIL and IL-2 and clinical pathological characteristics, response to the first-line chemotherapy and survival were retrospectively analyzed.4.Statistical analysis:The correlations between subsets of TILs and IL-2 and the clinicopathological features were analyzed by Spearman’s test. For the comparison of individual variables, χ2 tests and Fisher’s exact tests were carried out as appropriate. A multivariate logistic regression model was done to analyze the independent factors associated with response to chemotherapy.Survival curves were estimated by the Kaplan–Meier method, and differences in overall survival between groups were determined using the Log-rank test. Cox proportional hazards regression analysis was used to measure the association of clinico- path- ologic variables to overall survival. In all tests, a P value < 0.05 was considered significant. Results1.Expression of CD4(P=0.006) and CD8(P=0.001) were significantly lower whereas IL-2(P=0.030) was higher in the group with better clinical benefit rate for firstline chemotherapy.2.Univariate analysis showed that patients with female(P=0.012), earlier c T stage(P=0.000)and c N stage(P=0.004) and less number of metastasis organs(P= 0.000) had better OS, whereas COX regression analysis showed that c T stage(P= 0.006) and gender(P=0.002)were independent predictors for stage IV NSCLC.3.For expression of immunes parameters, high level IL-2(P=0.001) whereas low level CD4(P=0.000) had better OS. COX regression analysis showed that CD4(P=0.001) and IL-2(P=0.031) levels were independent predictors for stage ⅣNSCLC. Conclusion1. The pathological types, p T stage and the p N stage were independent prognostic factors for OS in radically resected NSCLC whereas the pathological types and p T stage were independent prognostic factors for OS in patients who accepted postoperative adjuvant chemotherapy.2.The expression of CD3, CD4 and CD8 in tumor local tissue were independent prognostic factors of OS in radically-resected NSCLC while the expression of CD3, CD8 and Survivin were independent prognostic factors of OS in patients with postoperative adjuvant chemotherapy.3.CT stage and gender were independent prognostic factors of OS in stage ⅣNSCLC patients.Lower expression of CD4 and CD8 were priority to higher expression for clinical benefit rate to first-line chemotherapy, whereas lower IL–2 was inferior to higher expression for clinical benefit rate to firstline chemotherapy. Higher IL-2 and lower CD4 level were independent predictors for OS in stage ⅣNSCLC in COX regression model.4.In addition to the traditional TNM staging, The immune state of tumor microenvironment was correlated with prognosis of NSCLC closely. Evaluation of immune related molecules in tumor tissues was helpful in predicting prognosis and predictive of response to first-line chemotherapy in stage Ⅳ NSCLC. |
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