Purpose: NF-E2-related factor 2 (Nrf2), a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells. In this study, therefore, the role of Nrf2 in cancer cell proliferation and resistance to anticancer drugs was investigated. Experimental Design: We used three human lung cancer cell lines with different degrees of Nrf2 activation: Nrf2 was highly activated in A549 cells, slightly activated in NCI-H292 cells, and not activated in LC-AI cells under unstimulated conditions. Result: A549 cells showed higher resistance to cisplatin compared with NCI-H292 and LC-AI cells. The resistance to cisplatin was significantly inhibited in A549 but not in NCI-H292 or LC-AI cells by knockdown of Nrf2 with its specific small interfering RNA (Nrf2-siRNA). The cell proliferation was also most prominently inhibited in A549 cells by treatment with Nrf2-siRNA. In A549 cells, the expression of self-defense genes, such as antioxidant enzymes, phase II detoxifying enzymes, and drug efflux pumps, was significantly reduced by Nrf2-siRNA concomitant with a reduction of the cellular glutathione level. The degree of DNA crosslink and apoptosis after treatment with cisplatin was significantly elevated in A549 cells by Nrf2-siRNA. Knockdown of Nrf2 arrested the cell cycle at G 1 phase with a reduction of the phosphorylated form of retinoblastoma protein in A549 and NCI-H292 cells but not in LC-AI cells. Conclusion: These results indicate that the Nrf2 system is essential for both cancer cell proliferation and resistance to anticancer drugs. Thus, Nrf2 might be a potential target to enhance the effect of anticancer drugs.

Abstract. The present retrospective study was performed to evaluate the clinicopathological characteristics associated with distant metastasis from non-small-cell lung cancer (NSCLC). The records of NSCLC patients with metastasis at the time of diagnosis between 1999 and 2012 were reviewed. Of the consecutive 1,542 NSCLC patients diagnosed during the study period, 729 (47.3%) patients presented with distant metastasis. Among those 729 metastatic NSCLC patients, 250 (34.3%), 234 (32.1%), 207 (28.4%), 122 (16.7%), 98 (13.4%) and 69 (9.5%) had bone, lung, brain, adrenal gland, liver and extrathoracic lymph node metastasis, respectively. In a multivariate analysis using the Cox proportional hazards model, liver and adrenal gland metastases were unfavorable prognostic factors. However, brain and bone metastases were not statistically significant prognostic factors. Using a logistic regression analysis, metastasis to the adrenal glands and the presence of pleural and̸or pericardial fluid effusion were correlated with a poor performance status. Therefore, when planning the treatment of NSCLC patients, particularly those with liver and adrenal gland metastases, we should take into consideration information regarding these unfavorable organ metastases.

s. Objectives.  KL‐6 is a specific marker in patients with interstitial lung diseases (ILDs); however, the relationship between elevated levels of KL‐6 and subsequent mortality is not well defined. To determine if elevated serum levels of KL‐6 are associated with increased mortality, and to identify the most suitable cut‐off level of KL‐6 by which to distinguish between good prognosis and poor prognosis, we evaluated the prognostic significance of serum KL‐6 levels in patients with stable‐state ILDs. Methods.  Two hundred and nineteen patients diagnosed with ILDs (152 with idiopathic interstitial pneumonia and 67 with collagen disease‐associated pulmonary fibrosis) at Tsukuba University Hospital from April 1999 to October 2005 were entered in this study. Serum KL‐6 levels in patients with ILDs were measured with a commercially available enzyme immunoassay kit, and these patients were then followed up. Results.  During the follow‐up period, 58 of the 219 patients died of respiratory failure. Patients who died during this period had higher levels of KL‐6 than did those who did not (P = 0.0004). The receiver operating characteristic curve analysis showed 1000 U mL−1 as the most suitable cut‐off level by which to distinguish between the two groups of patients. The 95% specificity serum KL‐6 level with poor outcome was 2750 U mL−1. In univariate and multivariate analysis, elevated serum KL‐6 (>1000 U mL−1) in the stable state indicated poor prognosis (P = 0.0005, log‐rank test; P = 0.0001, Cox proportional hazard model). Conclusions.  Elevated KL‐6 level may provide simple, yet valuable information by which to identify patients with ILDs who are at increased risk for subsequent mortality.

Abstract. The aim of our retrospective study was to evaluate the clinicopathological features associated with distant metastasis from small cell lung cancer (SCLC). We reviewed patients diagnosed with SCLC metastasis at the time of presentation between 1999 and 2010. Among the consecutive 251 SCLC patients diagnosed, 152 (60.6%) patients had distant metastasis, of which 20.3, 18.3, 15.5, 10.0 and 6.0% of patients had liver, bone, brain, lung and adrenal gland metastasis, respectively. In a multivariate analysis using Cox's proportional hazards model, we identified that liver, bone and brain metastasis as well as the presence of pleural and/ or pericardial fluids were unfavorable prognostic factors. However, lung, adrenal gland and extrathoracic lymph node metastasis were not statistically significant prognostic factors. With regard to the treatment of SCLC patients, particularly those with liver, bone and brain metastasis or pleural and/or pericardial fluids, we should take the metastasizing organs into consideration.