A Study Of Clinical Characteristics And Molecular Markers For Brain Metastases In Non-small Cell Lung Cancer

Part I:A systematic review of risk factors for brain metastases and value of prophylactic cranial irradiation in non-small cell lung cancerPurpose:The incidence of brain metastases (BM) varies in patients with non-small cell lung cancer (NSCLC), which calls into question the value of prophylactic cranial irradiation (PCI). It is possible that clinicopathologic characteristics are associated with the development of BM, but the characteristics have not been identified. Thus, we conducted this meta-analysis on risk factors for BM and the value of PCI in patients with NSCLC.Materials and methods:Eligible data were extracted and the risk factors for BM and the value of PCI in patients with NSCLC were analyzed by calculating the pooled odds ratio (OR). Heterogeneity was detected using Q and I-squared statistics, and publication bias was tested by funnel plots and Egger’s test.Results:Six randomized controlled trials with a focus on the value of PCI and13eligible studies with a focus on risk factors for BM were included. PCI significantly reduced the incidence of BM in patients with NSCLC (p=0.000, pooled OR=0.34,95%confidence interval=0.23-0.50). Compared with non-squamous cell carcinoma, squamous cell carcinoma was associated with a low incidence of BM in patients with NSCLC (p=0.000, pooled OR=0.47,95%confidence interval=0.37-0.59). The funnel plot and Egger’s test suggested that there was no publication bias in the current meta-analysis. Conclusions:This meta-analysis provides statistical evidence that compared with non-squamous cell carcinoma, squamous cell carcinoma can be used as a predictor for BM in patients with NSCLC, and PCI might reduce the incidence of BM in patients with NSCLC, but does not provide a survival benefit. Part II:Predictive value and mechanisms of miRNA-328and miRNA-378for brain metastases in operable and advanced non-small cell lung cancerPurpose:Brain metastases (BM) are the most important factor influencing patient survival in non-small cell lung cancer(NSCLC). Prophylactic cranial irradiation (PCI) might reduce the incidence of BM in patients with NSCLC, but the incidence of BM varies greatly in patients with NSCLC, so we can not confirm the indication of PCI. Molecular marks are considered to predict BM in NSCLC. So in this study, we will identify the predictive value of miRNA-328and miRNA-378for BM in NSCLC, as well as the mechanisms.Materials and methods:According to our inclusion and exclusion criteria, we screened the patients who received curable operation for their lung cancer between1st January,2010and31th October,2011. And then the patients were followed-up periodically and the survival data were recorded. Finally, the data were analyzed, and the formalin-fixed paraffin-embedded(FFPE) samples of the patients were used to detect the expressions of miRNA-328and miRNA-378with realtime-PCR (RT-PCR), and furthermore the expressions of N-cadherin, E-cadherin, VEGF, PRKCA and S100B were investigated with immunohistochemical staining to explore the mechanisms.Results: In all, eighty-six patients were screened and the time of following-up was no less than2years. During the period of follow-up, sixty-three patients were diagnosed with recurrence or distant metastases including twenty-three patients with BM and forty-seven patients died of progression disease. The2-year and3-year overall survival (OS) were58%and43%, respectively, and the2-year and3-year disease-free survival (DFS) were37%and27%, respectively. And DFS and OS between BM group and non-BM group were significantly different(χ2=15.173、P=0.000and χ2=4.288、P=0.038, respectively). For the patients with and without BM, the expressions of miRNA-328and miRNA-378in the FFPE samples were both significantly different (p=0.0000and0.000, respectively). For the patients with BM, the expressions of miRNA-328and miRNA-378in the tumor tissues and para-carcinoma tissues were also significantly different (p=0.0000and0.000, respectively). The expressions of PRKCA in tumor tissues were significantly different between patients with BM and patients without BM (p=0.010). However the expressions of VEGF, S100B, N-cadherin and E-cadherin in tumor tissues showed no difference between patients with and without BM (p=0.510,1.000,0.890,0.200, respectively). For the patients with BM, the association between miRNA-328and PRKCA was significant (r=0.591, p=0.003), but the association between miRNA-378and PRKCA was not significant (r=0.259, p=0.232). Finally, logistic regression analysis showed the expressions of miRNA-328and miRNA-378in tumor tissues were associated with BM in NSCLC (p=0.013,0.007, respectively).Conclusions:The expressions of miRNA-328and miRNA-378in tumor tissues are associated with future BM in NSCLC and they can be used to predict BM in patients with NSCLC. And miRNA-328promotes BM in NSCLC by regulating the expression of PRKCA, and the mechanism of miRNA-378promoting BM in NSCLC should be studied accordingly in the future.