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Background: Identifying patients with stage I non-small cell lung cancer (NSCLC) at increased risk of tumor recurrence following surgery remains a major challenge. The current study aimed to compare disease-free survival (DFS) rates after surgery between patients with clinically node-positive (cN+) and -negative (cN0) stage I NSCLC., Methods: Patients with pathological stage I resected NSCLC were identified from the lung cancer database of Changhua Christian Hospital in Taiwan. Patients with clinical N status 1 or 2 and pathological N status 0 were identified as the cN+/pN0 cohort, whereas others were identified as the cN0/pN0 cohort. Propensity score matching (PSM) was used to balance the baseline characteristics between both cohorts. Kaplan-Meier method and Cox proportional hazards model were used to evaluate DFS., Results: From January 2010 to July 2019, 754 eligible patients were enrolled into the study, among whom 41 (5.4%) were cN+/pN0. The median follow-up time was 43.4 months. Before PSM, the 5-year DFS rate was 79.0% and 90.3% in cN+/pN0 and cN0/pN0 cohorts (log-rank test, p = 0.009), respectively. After a 1:4 PSM, multivariate analysis showed that the cN+/pN0 cohort still had a poorer DFS compared to the cN0/pN0 cohort in (hazard ratio, 3.17; p = 0.040)., Conclusion: Among patients with stage I resected NSCLC, cN+ patients had a worse DFS compared to cN0 patients. Surgeons should therefore consider more aggressive adjuvant therapy or frequent follow-up in patients with surgically resected stage I NSCLC with cN+ status., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: Pendulone, an isoflavone compound, is known to act against human cancer cells. However, its role in human non-small cell lung cancer (NSCLC) and the exact molecular mechanisms of action have never been reported., Methods: We investigated the effects of pendulone on cell proliferation and apoptosis in human NSCLC H1299 cells. Cell viability was examined using the methyl-thiazol-diphenyl-tetrazolium (MTT) assay. Flow cytometry was employed to evaluate apoptotic indices such as the cell cycle, mitochondrial membrane potential, cytochrome c release, caspase activity, and death receptor expression. The expression of proteins related to the cell cycle and apoptosis were analyzed by Western blot analysis., Results: Pendulone significantly decreased H1299 cell viability by inducing endoplasmic reticulum (ER) stress through the accumulation of reactive oxygen species (ROS). Pendulone induced the expression of ER stress-associated proteins, such as ATF4 and CHOP, which promoted the expression of death receptors. Activation of caspase 8 induced extrinsic pathway apoptosis. Pendulone also caused the loss of mitochondrial membrane potential, inhibited the anti-apoptotic proteins BCL-2 and activated the pro-apoptotic protein BAX, which promoted the release of cytochrome c to activate caspase 9. Antioxidant N-acetylcysteine (NAC), with its ROS-suppressive property, reversed pendulone-induced ER stress and cell apoptosis., Conclusion: Our findings provide evidence that pendulone induces apoptosis by inducing ER stress through ROS accumulation and mitochondrial dysfunction in NSCLC cell lines., (Copyright © 2022. Published by Elsevier Ltd.)

Background/aim: Niclosamide is an antihe-minthic drug that has shown cytotoxic effects on non-small cell lung carcinoma (NSCLC) cells. However, the exact mechanisms underlying the anti-tumour activity of niclosamide in NSCLC cancer cells remains to be defined. The aim of this study was to evaluate the antitumor activity of niclosamide in human A549 and CL1-5 non-small cell lung cancer cells using in vitro and in vivo., Materials and Methods: We investigated the effects of niclosamide on cell viability, apoptosis, the mitochondrial membrane potential (MMP; Δϕm), and autophagy and apoptosis-related protein expression in human A549 and CL1-5 non-small cell lung cancer cells., Results: Niclosamide induced mainly caspase-independent apoptosis through apoptosis-inducible factor (AIF) translocation to the nucleus upon mitochondria damage. Moreover, niclosamide-induced autophagy may act as adaptive response against apoptosis. AMPK/AKT/mTOR pathway were involved in niclosamide-induced cell death and autophagy in response to ATP depletion. Furthermore, niclosamide efficiently suppressed tumor growth and induce autophagy in vivo., Conclusion: Niclosamide induced apoptosis by activating the intrinsic and caspase-independent pathway in human A549 and CL1-5 non-small cell lung cancer cells. Therefore, niclosamide is a potential candidate for anti-NSCLC therapy., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The therapeutic strategies for clinical stage T1-3N2 (cT1-3N2) lung cancer are controversial. For operable tumors, treatment can vary by center, region, and continent. This study aimed to identify the optimal therapeutic method and type of surgical strategy for cT1-3N2 lung cancer., Methods: This retrospective evaluation analyzed the records of 17,954 patients with cT1-3N2 lung cancer treated in 2010 through 2015 from the SEER database. The effects of different therapeutic methods and types of surgical strategies on overall survival (OS) were assessed. Univariate and multivariate analyses were performed using a Cox proportional hazards model., Results: The 5-year OS rates were 27.7% for patients with T1N2 disease, 21.8% for those with T2N2 disease, and 19.9% for T3N2 disease. Neoadjuvant therapy plus operation (OP) plus adjuvant therapy, and OP plus adjuvant therapy, provided better 5-year OS rates than OP alone or concurrent chemoradiotherapy (34.1%, 37.7%, 29.3%, and 16.1%, respectively). In the T1N2, T2N2, and T3N2 groups, lobectomy provided better 5-year OS than pneumonectomy, sublobectomy, and no surgery. Both univariate and multivariate analyses showed that young age, female sex, well-differentiated histologic grade, adenocarcinoma cell type, neoadjuvant and adjuvant therapy, lobectomy, and T1 stage were statistically associated with better 5-year OS rates., Conclusions: In cT1-3N2 lung cancer, multimodal treatments tended to provide better 5-year OS than OP alone or concurrent chemoradiotherapy. In addition, lobectomy was associated with better survival than other operative methods.

Background: There are several studies comparing the difference between adenocarcinoma (AC) and squamous cell carcinoma (SqCC) of lung cancer. However, seldom studies compare the different overall survival (OS) between AC and SqCC at same clinical or pathological stage. The aim of the study was to investigate the 5-year OS between AC and SqCC groups., Methods: Data were obtained from the Taiwan Society of Cancer Registry. There were 48,296 non-small cell lung cancer (NSCLC) patients analyzed between 2009 and 2014 in this retrospective study. We analyzed both the AC and SqCC groups by age, gender, smoking status, Charlson co-morbidity index (CCI) score, clinical TNM stage, pathological stage, tumor location, histologic grade, pleura invasion, performance status, treatment, stage-specific 5-year OS rate in each clinical stage I-IV and causes of death. We used propensity score matching to reduce the bias., Results: The AC and SqCC groups are significantly different in age, gender, smoking status, CCI score, clinical TNM stage, pathological stage, tumor location, histologic grade, pleura invasion, performance status, treatment, stage-specific 5-year OS rate in each clinical stage and causes of death (p < 0.0001). The stage-specific 5-year OS rates between AC and SqCC were 79% vs. 47% in stage I; 50% vs. 32% in stage II; 27% vs. 13% in stage III; 6% vs. 2% in stage IV, respectively (all p values < 0.0001)., Conclusions: AC and SqCC have significantly different outcomes in lung cancer. We suggest that these two different cancers should be analyzed separately to provide more precise outcomes in the future.

Lung cancer remains a highly prevalent disease and a leading cause of cancer-related deaths worldwide. Currently, exploring antitumor drugs derived from herbs used in traditional Chinese medicine is increasingly becoming an attractive area of research. Paclitaxel (PTX), a highly effective chemotherapeutic drug, is widely used for treating different cancers; however, the clinical use of PTX is dose limited because of its adverse side effects. Chemotherapeutic agents are being developed to enhance the anticancer activity of PTX, particularly for use in combination therapy. 5-Demethylnobiletin (5-DMN), a natural, active compound isolated from orange peel, has been reported to induce apoptosis in several cancer cell lines. In this study, we tested the synergistic anticancer antiproliferative effects of combinations of PTX and 5-DMN on CL1-5 lung cancer cells through the MTT and propidium iodide assays. After low-dose combination treatments (PTX and 5-DMN), a reduction in cell viability and a concomitant increase in apoptosis were observed in the CL1-5 cells. We propose that 5-DMN cooperates with PTX to induce apoptosis via the caspase pathway (by modulating caspase-3, caspase-8, and caspase-9 activities). Furthermore, we observed that the combination treatment significantly suppressed tumor growth in the nude mouse xenograft model. The results suggest that the synergistic effects of PTX and 5-DMN in lung cancer cells deserve particular attention and indicate the possibility of developing additional new strategies for treating lung cancer.

Background/aim: Pyrimethamine (PYR), an anti-malarial drug is known to inhibit various types of human cancer cells. The aim of this study was to investigate the anti-tumour effects of pyrimethamine (PYR) and its underlying molecular mechanisms using the human NSCLC cell line A549., Materials and Methods: PYR was dissolved in dimethyl sulfoxide to determine its apoptotic activity on A549 cells. Cell viability was determined by the MTT assay. Cell cycle, mitochondrial membrane potential, and Annexin V-FITC early apoptosis detection were evaluated by flow cytometry. Cyclin-dependent kinase (CDK) and Bcl-2 family protein expression was determined by western blotting., Results: PYR reduced cell viability percentage and induced G 0 /G 1 arrest, which was associated with down-regulation of cyclins D1 and E, CDK4, and CDK2, and up-regulation of p21. PYR induced sub-G 1 accumulation, Annexin-V binding, caspase-9 and -3 activation, poly (ADPribose) polymerase cleavage, and mitochondrial dysfunction in A549 cells. Moreover, PYR effectively inhibited NSCLC tumour growth in an A549 xenograft model., Conclusion: PYR demonstrated anti-tumour effects on NSCLC in vitro and in vivo, indicating its therapeutic potential against human NSCLC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: IFN-γ takes part in immunologic responses to cancer and its interactions with chemotherapy have also been described. Our previous study had showed an association between phytohemagglutinin (PHA)-stimulated IFN-γ (PSIG) response and overall survival in patients with advanced non-small-cell lung cancer (NSCLC). Here, we aimed to evaluate the correlation between PSIG and chemotherapy responses., Materials and Methods: From January 2011 to August 2012, 340 newly diagnosed patients with lung cancer were enrolled in a prospective latent tuberculosis observational study. Patients with advanced NSCLC who were treated with chemotherapy were included in this analysis. An IFN-γ release assay (IGRA) was used to evaluate pre-treatment PSIG levels. Patients were grouped into low and high PHA response groups according to their PSIG levels. Their demographic characteristics, tumor responses, and survival rates were investigated., Results: Eighty-four patients were enrolled. The chemotherapy response rates in the high and low PHA response groups were 45.2% and 35.7% (p=0.190), respectively. The disease control rate in the high PHA response group was 76.2%, versus 52.4% in the low PHA response group (p=0. 023). In multivariate analysis, PHA response was an independent predictor of disease control (odds ratio=3.017, 95% confidence interval=1.115-8.165). The Kaplan-Meier method demonstrated both longer progression-free survival (p=0.008) and overall survival (p=0.003) in the high PHA response group., Conclusions: A higher pre-treatment PSIG response, obtained using the IGRA, was associated with better disease control rate and survival among patients with advanced NSCLC treated with chemotherapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Objectives: Complete surgical resection is recommended for early stage lung cancer, and adjuvant chemotherapy is given for stage IB to IIIA disease. No studies have examined the best timing to administer chemotherapy after surgery in lung cancer. This study was to investigate the optimal timing of adjuvant chemotherapy after surgical resection., Methods: Data collected from the Taiwan National Health Insurance Research Database between January, 2004 and December, 2010 were retrospectively analyzed. Patients with stage IB to IIIA lung cancer underwent complete surgical resection and adjuvant chemotherapy were included. A total of 1522 patients were included. The patients were divided into 4 groups according to the interval between surgery and chemotherapy: group 1, < 30 days; group 2, 30-45 days; group 3, 46-60 days; group 4 > 60 days. Univariate and multivariate regression analyses were used to identify prognostic factors for overall survival., Results: The numbers of patients in groups 1, 2, 3, and 4 were 153, 161, 290, and 818, respectively. The 5-year survival rate was 41% in group 1, 48% in group 2, 50% in group 3, and 35% in group 4 (p<0.001). The median survival time was 44.50 months in group 1, 59.53 months in group 2, 67.33 months in group 3 and 36.33 months in group 4 (p<0.001) Survival rate is the poorest when chemotherapy is delayed beyond 60 days after surgical resection Multivariate analysis also indicated the interval between surgery and first course of chemotherapy more than 60 days after surgery was an independent risk factor for survival., Conclusions: Timing of chemotherapy after surgery is associated with poorer survival in lung cancer patients., Competing Interests: The authors have declared that no competing interests exist.

Background: There is a lack of large, prospective, randomized studies comparing thoracoscopic and open lobectomy in terms of long-term survival in the setting of NSCLC. Additionally, large case series evaluating the issue are limited. Until now, whether thoracoscopic lobectomy entails a long-term survival benefit compared with open lobectomy not been determined., Methods: Data were obtained from the National Health Insurance Research Database published in Taiwan. We included patients treated with open lobectomy or thoracoscopic lobectomy. In this retrospective review, the clinicopathologic characteristics of 5222 patients with lung cancer during the period 2004-2010 were analyzed. Patients were stratified according to clinical stage. Overall survival (OS) was compared between patients treated with open and those treated with thoracoscopic lobectomy and was also compared between patients in the three different clinical stages. Propensity-matching analysis and multivariate analysis were performed., Results: Open lobectomy was performed on 3058 patients (58.6%) and thoracoscopic lobectomy on 2164 (41.4%). Propensity matching produced 1848 patients in each group. The 1-year, 3-year, and 5-year OS rates for propensity-matched patients treated with open lobectomy were 93.4%, 79.3%, and 65.5%, respectively. The 1-year, 3-year, and 5-year OS rates for propensity-matched patients treated with thoracoscopic lobectomy were 94.1%, 80.9%, and 68.7%, respectively. The difference was not statistically significant. In multivariate analysis, surgical resection (open versus thoracoscopic) was not an independent prognostic factor., Conclusions: This propensity-matched study suggests that open and thoracoscopic lobectomy are associated with similar long-term survival in the setting of lung cancer. Thoracoscopic lobectomy is an acceptable surgical treatment of lung cancer., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Interferon-gamma (IFN-γ) has been used to treat various malignant tumors. However, the molecular mechanisms underlying the direct anti-proliferative activity of IFN-γ are poorly understood. In the present study, we examined the in vitro antitumor activity of IFN-γ on two human non-small-cell lung carcinoma (NSCLC) cell lines, H322M and H226. Our findings indicated that IFN-γ treatment caused a time-dependent reduction in cell viability and induced apoptosis through a FADD-mediated caspase-8/tBid/mitochondria-dependent pathway in both cell lines. Notably, we also postulated that IFN-γ increased indoleamine 2,3-dioxygenase (IDO) expression and enzymatic activity in H322M and H226 cells. In addition, inhibition of IDO activity by the IDO inhibitor 1-MT or tryptophan significantly reduced IFN-γ-induced apoptosis and death receptor 5 (DR5) expression, which suggests that IDO enzymatic activity plays an important role in the anti-NSCLC cancer effect of IFN-γ. These results provide new mechanistic insights into interferon-γ antitumor activity and further support IFN-γ as a potential therapeutic adjuvant for the treatment of NCSLC.