Search

Background: The development of chemo-resistance in non-small lung cancer is a major obstacle in treating patients. Hypoxia is a commonly faced microenvironment in solid tumor and suggested to be related to both autophagy and chemo-resistance. Methods: In this study, we investigated the role of hypoxia-induced autophagy in acquiring chemo-resistance in both cancer cell (A549) and human cancer tissue Results: Hypoxic exposure (1 % O2) of A549 cell stimulated autophagic induction in cancer cells, shown by increase of LC3BI to LC3BII conversion and decrease of p62/sequestosome1 in Western blot, increased GFP-LC puncta in confocal microscopy, and increased number of double-membrane autophagic vacuoles in electron micrographs. Hypoxic exposure also induced resistance of cancer cells to cisplatin, and LC3B siRNA restored the sensitivity of cancer cells to chemotherapy. Furthermore, Human lung cancer tissues that experienced chemotherapy showed increase of LC3BI to LC3BII conversion and decrease of p62/sequestosome1 compared with chemo-naïve cancer tissue in Western blot. Conclusion: Autophagy may play an important role in acquiring resistance to chemotherapy in lung cancer and hypoxia related pathway seems to be involved in autophagy induction. [ABSTRACT FROM AUTHOR]

Background: Although overall survival for non-small cell lung cancer (NSCLC) has increased, survival rate for pathologically staged T2aN0M0 stage IB NSCLC remains low. Adjuvant chemotherapy is not a standard treatment for stage IB NSCLC. Our purpose was to determine the efficacy of platinum-based adjuvant chemotherapy in stage IB NSCLC. Methods: We retrospectively reviewed the medical records of 119 stage IB patients who underwent lobectomy and mediastinal lymph node dissection. Among these, 60 patients underwent platinum-based adjuvant chemotherapy (adjuvant group) and 59 did not receive chemotherapy (observation group). Results: Participants had a mean age of 62.12 ± 11.51 years and 73 (61.3%) were male. The median follow-up period was 49.04 months. Mean age was higher in the observation group whereas patients in the adjuvant group had larger tumors, more dissected lymph nodes, and better performance status. The 5-year overall survival was 64.7% in the observation group and 88.2% in the adjuvant group (p = 0.010). The 5-year disease-free survival was 51.3% in the observation group and 74.0% in the adjuvant group (p = 0.011). In multivariate analysis, only platinum-based adjuvant chemotherapy was a risk factor for overall survival [hazard ratio (HR) = 0.428, p = 0.049] and disease-free survival (HR = 0.57, p = 0.043). In subset analysis, patients with a larger tumor (greater than 3.2 cm), moderate to poor differentiation, and good performance status (Eastern Cooperative Oncology Group, 0) benefitted from platinum-based adjuvant chemotherapy. Conclusions: Platinum-based adjuvant chemotherapy for surgically treated stage IB NSCLC might offer better survival than observation alone. A large-scale randomized clinical trial is needed to validate these findings. [ABSTRACT FROM AUTHOR]

Background: The role of tumor matrix metalloproteinase-9 (MMP-9) expression in non-small cell lung cancer (NSCLC) remains controversial. In this study, we investigated the prognostic value of tumor MMP-9 expression and other clinicopathologic factors in patients with completely resected NSCLC. Methods: This retrospective study included patients who underwent complete resection of pathological stage I-IIIA NSCLC at Severance Hospital, Seoul, Korea, between 1998 and 2009. Tumor samples of 417 patients were stained by immunohistochemistry, and the expression of MMP-9 in tumor cells was evaluated, using the median immunohistochemical score of 10 (range, 0-300) as the cut-off. Results: Tumor MMP-9 expression was observed in 161 (38.6%) of 417 patients. Log-rank analysis showed a significant association of tumor MMP-9 expression with shortened disease-free survival (p = 0.01) but not with overall survival (p = 0.109). Multivariate analysis demonstrated that tumor MMP-9 expression was not an independent prognostic factor of recurrence (p = 0.142) or survival (p = 0.807). However, among patients with adenocarcinoma, tumor MMP-9 expression was associated with relapse (p = 0.003) and poor survival (p = 0.033). Furthermore, tumor MMP-9 expression was an independent prognostic indicator of relapse in patients with adenocarcinoma (p = 0.035). Conclusions: Among patients with NSCLC, tumor MMP-9 expression was associated with poor outcomes in those with adenocarcinoma, but not in those with squamous cell carcinoma. In addition, MMP-9 expression was identified as an independent predictor of relapse of completely resected lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background Lung adenocarcinoma is a highly heterogeneous disease with various etiologies, prognoses, and responses to therapy. Although genome-scale characterization of lung adenocarcinoma has been performed, a comprehensive somatic mutation analysis of EGFR/KRAS/ALKnegative lung adenocarcinoma in never-smokers has not been conducted. Methods We analyzed whole exome sequencing data from 16 EGFR/KRAS/ALK-negative lung adenocarcinomas and additional 54 tumors in two expansion cohort sets. Candidate loci were validated by target capture and Sanger sequencing. Gene set analysis was performed using Ingenuity Pathway Analysis (IPA). Results We identified 27 genes potentially implicated in the pathogenesis of lung adenocarcinoma. These included targetable genes involved in PI3K/mTOR signaling (TSC1, PIK3CA, AKT2) and receptor tyrosine kinase signaling (ERBB4) and genes not previously highlighted in lung adenocarcinomas, such as SETD2 and PBRM1 (chromatin remodeling), CHEK2 and CDC27 (cell cycle), CUL3 and SOD2 (oxidative stress), and CSMD3 and TFG (immune response). In the expansion cohort (N = 70), TP53 was the most frequently altered gene (11%), followed by SETD2 (6%), CSMD3 (6%), ERBB2 (6%), and CDH10 (4%). In pathway analysis, the majority of altered genes were involved in cell cycle/DNA repair (P < 0.001) and cAMPdependent protein kinase signaling (P < 0.001). Conclusions The genomic makeup of EGFR/KRAS/ALK-negative lung adenocarcinomas in never-smokers is remarkably diverse. Genes involved in cell cycle regulation/DNA repair are implicated in tumorigenesis and represent potential therapeutic targets. [ABSTRACT FROM AUTHOR]