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Abstract Background Osimertinib is an irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It is the preferred first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC) compared to first-generation EGFR-TKIs. However, limited research has compared its clinical effectiveness with second-generation (2nd G) EGFR-TKIs. Materials and methods This study recruited patients diagnosed with stage IIIb-IV EGFR-mutated NSCLC who received first-line treatment with either 2nd G EGFR-TKIs (afatinib and dacomitinib) or osimertinib between April 2020 and April 2023. Results The final analysis included 168 patients, of whom 113 received 2nd G EGFR-TKIs (afatinib or dacomitinib) and 55 received osimertinib. The median progression-free survival (PFS) did not differ significantly between 2nd G EGFR-TKIs and osimertinib (del 19: 17.6 months; L858R: 20.0 months vs. 28.3 months, p = 0.081). In patients with the EGFR exon 19 deletion, osimertinib conferred a longer median PFS (28.3 vs. 17.6 months, p = 0.118) and time to treatment failure (30.2 vs. 22.7 months, p = 0.722) than 2nd G EGFR-TKIs. However, the differences were not statistically significant. In patients with with the EGFR exon 19 deletion and central nervous system metastasis, the median PFS did not differ significantly between those treated with osimertinib (14.3 months) and those treated with 2nd G EGFR-TKIs (17.6 months; p = 0.881). Multivariate regression analysis revealed that the NSCLC stage was the only independent negative predictor of PFS. The treatment patterns in the second line also differed significantly between groups (p = 0.008). Conclusions This study found comparable effectiveness between osimertinib and 2nd G EGFR-TKIs as first-line treatment for advanced EGFR-mutated NSCLC, with only the NSCLC stage identified as a negative predictor of PFS. However, whether the different second-line treatments affect overall survival should be examined.

Abstract Introduction The use of stereotactic ablative radiotherapy (SABR) over conventional fractionated radiotherapy (CFRT) for early‐stage non‐small‐cell lung cancer (NSCLC) has been advocated, but is also debated in the literature. Methods In this retrospective cohort study, we adopted a target trial emulation framework to identify eligible patients diagnosed between 2011 and 2021 using the Taiwan Cancer Registry. In the primary analysis, the overall survival (OS) was the primary endpoint, whereas incidences of lung cancer mortality and radiation pulmonary toxicity were the secondary endpoints. Extensive supplementary analyses were also conducted. Results We included 351 patients in the primary analysis and found that the OS was not significantly different between the SABR (n = 290) and CFRT (n = 61) groups. The propensity score weighting adjusted hazard ratio of death was 0.75 (95% confidence interval 0.53–1.07, p = 0.118). The secondary endpoints and supplementary analyses showed no significant differences. Conclusions The OS of patients with early‐stage NSCLC treated with SABR was not significantly different from that of patients treated with CFRT alone. The results of the relevant ongoing clinical trials are eagerly awaited.

PURPOSETissue-based next-generation sequencing (NGS) analysis is highly recommended for patients with advanced/metastatic non–small cell lung cancer (NSCLC). We investigated a specific patient population with NSCLC that required tissue-based NGS analysis.MATERIALS AND METHODSWe enrolled 500 patients with advanced/metastatic (1) epidermal growth factor receptor (EGFR) mutations or anaplastic large-cell lymphoma kinase (ALK) rearrangement–positive NSCLC who had failed at minimum one line of tyrosine kinase inhibitor (TKI) therapy, (2) EGFR-/ALK-negative nonsquamous, and (3) non- or light-smoker patients with squamous NSCLC who were treatment-naïve or had failed at maximum two lines of systemic treatment. These patients were divided into five cohorts. Comprehensive tissue-based NGS testing (ACTOnco+) was conducted.RESULTSCohort 1: EGFR TKI-pretreated EGFR-mutated population (50.0%, n = 250), cohort 2: ALK inhibitor-pretreated ALK-positive population (1.6%, n = 8), cohort 3: treatment-naïve EGFR-/ALK-negative population (28.2%, n = 141), cohort 4: pretreated EGFR-/ALK-negative population (16.8%, n = 84), and cohort 5: squamous cell carcinoma (3.4%, n = 17). In cohort 1, 11.2% (28/250) of the patients had MET amplification, 32.4% (81/250) had been treated with osimertinib, and EGFR C797S was detected in 6.2% (5/81) of these patients. In cohort 2, resistance ALK mutation was detected in 37.5% (3/8) of the patients. In cohorts 3 and 4, targetable genetic alterations, including EGFR mutation (13.3%), ERBB2 mutation (9.3%), MET exon 14 skipping (5.3%), KRAS G12C mutation (4.4%), ROS1 fusion (2.7%), RET fusion (1.8%), and BRAF V600E mutation (1.3%), were detected. In cohort 5, MET exon 14 skipping was detected in 29.4% (5/17) of the patients.CONCLUSIONThis multicenter registration study investigated tissue-based NGS for a specific patient population with NSCLC in Taiwan.

Abstract Background Pneumoconiosis is associated with pulmonary and cardiovascular diseases; however, the link between pneumoconiosis and sleep disorders is not well understood. This study aimed to investigate the connection between pneumoconiosis and subsequent risk of sleep disorders. Methods This population-based retrospective cohort study used data from the National Health Insurance database in Taiwan. The pneumoconiosis cohort consisted of 13,329 patients newly diagnosed between 2000 and 2015. The comparison group included 53,316 age-, sex-, and diagnosis date-matched individuals without pneumoconiosis. The development of sleep disorders was monitored until the end of 2018. Cox proportional hazard regression models were used for risk assessment. Results The incidence of sleep disorders was 1.31 times higher in the pneumoconiosis cohort than in the comparison cohort (22.8 vs. 16.2 per 1000 person-years). After controlling for age, sex, comorbidity, and medication, the adjusted hazard ratio (aHR) was 1.24 (95% confidence interval [CI] = 1.17–1.32). Stratified analyses by age group, sex, and comorbidity status showed significant associations between pneumoconiosis and sleep disorders (aHRs, 1.19–1.64). In addition, patients with pneumoconiosis had a significantly increased risk of developing sleep apnea (aHR = 1.71, 95% CI = 1.31–2.22). Conclusion This study demonstrates that patients with pneumoconiosis are at a higher risk of developing sleep disorders and sleep apnea. Healthcare professionals should pay close attention to sleep quality and disturbances in patients with pneumoconiosis.

Abstract Objectives The irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) afatinib and dacomitinib are approved for first-line treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and dacomitinib in this setting. Materials and methods Between September 2020 and March 2023, we retrospectively recruited patients diagnosed with advanced-stage EGFR-mutant NSCLC who were treated with first-line irreversible EGFR-TKIs. The enrolled patients were assigned to two groups based on whether they received afatinib or dacomitinib. Results A total of 101 patients were enrolled in the study (70 to afatinib and 31 to dacomitinib). The partial response rates (PR) for first-line treatment with afatinib and dacomitinib were 85.7 and 80.6% (p = 0.522). The median progression-free survival (PFS) (18.9 vs. 16.3 months, p = 0.975) and time to treatment failure (TTF) (22.7 vs. 15.9 months, p = 0.324) in patients with afatinib and dacomitinib treatment were similar. There was no significant difference observed in the median PFS (16.1 vs. 18.9 months, p = 0.361) and TTF (32.5 vs. 19.6 months, p = 0.182) between patients receiving the standard dose and those receiving the reduced dose. In terms of side effects, the incidence of diarrhea was higher in the afatinib group (75.8% vs. 35.5%, p

Abstract Background This study aimed to examine the clinical characteristics of bone metastasis (BoM) in patients with non‐small cell lung cancer (NSCLC) who have an epidermal growth factor receptor (EGFR) mutation and to identify the most effective treatment strategy using EGFR–tyrosine kinase inhibitors (TKIs). Methods The study included patients with stage IV EGFR‐mutated NSCLC who were receiving first‐line treatment with EGFR–TKIs between January 2014 and December 2020. These patients were divided into two groups based on the presence or absence of BoM at the time of initial diagnosis. The BoM group was further subdivided based on whether they received denosumab or not. Results The final analysis included 247 patients. Those with BoM at initial diagnosis had shorter progression‐free survival (12.6 vs. 10.5 months, p = 0.002) and overall survival (OS) (49.7 vs. 30.9 months, p = 0.002) compared to those without BoM. There was a difference in the location of metastatic sites between the two groups, with a higher incidence of extrathoracic metastasis in the BoM group (p

Abstract Background The patient population with stage III non-small-cell lung cancer (NSCLC) is heterogeneous, with varying staging characteristics and diverse treatment options. Despite the potential practice-changing implications of randomized controlled trials evaluating the efficacy of perioperative epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), concerns have been raised due to conflicting overall survival (OS) results. Few real-world studies have examined the survival outcomes of patients with resected EGFR-mutant stage III adenocarcinoma receiving perioperative chemotherapy and EGFR–TKIs. Methods In this retrospective observational study, we enrolled patients with resected stage III adenocarcinoma with EGFR mutations between January 2011 and December 2021. Patients were classified into two groups: perioperative chemotherapy and perioperative EGFR–TKIs. Outcomes and prognostic factors were analyzed using Cox proportional hazards regression analysis. Results Eighty-four patients were enrolled in the analysis. Perioperative EGFR-TKIs led to longer progression-free survival (PFS) than chemotherapy (38.6 versus 14.2 months; p = 0.019). However, only pathological risk factors predicted poor PFS in multivariate analysis. Patients receiving perioperative chemotherapy had longer OS than those receiving EGFR-TKIs (111.3 versus 50.2 months; p = 0.052). Multivariate analysis identified perioperative treatment with EGFR-TKIs as an independent predictor of poor OS (HR: 3.76; 95% CI: 1.22–11.54). Conclusion Our study demonstrates that chemotherapy should be considered in the perioperative setting for high-risk patients, when taking pathological risk factors into consideration, and that optimized sequencing of EGFR–TKIs might be the most critical determinant of OS.

Osimertinib has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) in clinical trials. However, real-world data on its effectiveness remain scarce. Taiwanese patients with T790M-positive locally advanced or metastatic NSCLC and progressive disease following treatment with at least one EGFR tyrosine kinase inhibitor (TKI) were enrolled from the osimertinib early access program. Of the 419 patients (mean age, 63 years; female, 67%), 53% were heavily pretreated (≥ third-line [3L]), making osimertinib a fourth-line (4L) intervention. The median progression-free survival (PFS) was 10.5 months (95% confidence interval [CI]: 8.95-11.41); the 18-month PFS rate was 26.5%. The median overall survival (OS) was 19.0 months (95% CI: 16.30-20.95); the 24-month OS rate was 40.9%. The objective response rate was 32.46%, and the disease control rate was 86.38%. The median time to treatment discontinuation of osimertinib monotherapy was 11.9 months (95% CI: 10.49-13.11). Subgroup analyses of median PFS and OS in the chemotherapy combination group vs. the osimertinib monotherapy group yielded no difference. Central nervous system (CNS) metastasis, number of prior lines of therapy, and types of initial EGFR-TKIs did not significantly impact outcomes. The median PFS values were 9.0 (95% CI: 5.18-11.34) and 10.9 (95% CI: 9.18-11.90) months with and without CNS metastasis, respectively, and 10.8 (95% CI: 8.59-12.69), 13.6 (95% CI: 10.89-16.3), and 9.2 (95% CI: 7.8-10.62) months for second-line (2L), 3L, and ≥4L therapy, respectively. In patients who received osimertinib as 2L therapy, the median PFS values in response to prior afatinib, erlotinib and gefitinib treatment were 11.2 (95% CI: 4.85-4.79), 10.5 (95% CI: 8.59-20.26) and 8.7 (95% CI: 7.21-16.79) months, respectively. Overall, real-world data from Taiwan support the clinical benefits of osimertinib in EGFR T790M -positive NSCLC.

Background. The effectiveness of definitive radiotherapy (RT) for patients with clinical stage IIIB or IIIC lung adenocarcinoma and epidermal growth factor receptor (EGFR) mutations who received first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) is unclear. Methods. Taiwan Cancer Registry data were used in this retrospective cohort study to identify adult patients diagnosed with EGFR-mutated stage IIIB or IIIC lung adenocarcinoma between 2011 and 2020. Patients treated with first- or second-generation EGFR TKIs were classified into RT and non-RT groups. Propensity score (PS) weighting was applied to balance covariates between groups. The primary outcome was overall survival (OS), and the incidence of lung cancer mortality (ILCM) was considered as a supplementary outcome. Additional supplementary analyses were conducted to assess the robustness of the findings. Results. Among 270 eligible patients, 41 received RT and 229 did not. After a median follow-up of 46 months, PS-weighted analysis showed the PS-weighted hazard ratio of death for the RT group compared to the non-RT group was 0.94 (95% CI: 0.61–1.45, p=0.78). ILCM rates did not differ significantly between the two groups. Supplementary analyses yielded consistent results. Conclusion. The addition of definitive RT to first- or second-generation EGFR TKI treatment does not significantly improve OS of patients with EGFR-mutated stage IIIB or IIIC lung adenocarcinoma. NCT03521154NCT05167851.

The coronavirus disease (COVID-19) pandemic has resulted in an increasing population that is experiencing a wide range of long-lasting symptoms after recovery from the acute infection. Long COVID refers to this specific condition and is associated with diverse symptoms, such as fatigue, myalgias, dyspnea, headache, cognitive impairment, neurodegenerative symptoms, anxiety, depression, and a sense of despair. The potential of hyperbaric oxygen therapy (HBOT) to improve chronic fatigue, cognitive impairments, and neurological disorders has been established; therefore, the use of HBOT to treat long COVID has also been studied. We conducted a literature search between 1 January 2019 and 30 October 2023, focusing on the clinical efficacy and utility of HBOT for treating long COVID and found ten clinical studies that fit the review topic, including one case report, five one-group pretest-posttest design studies, one safety report from a randomized controlled trial (RCT), and three complete reports of RCTs. Most studies found that HBOT can improve quality of life, fatigue, cognition, neuropsychiatric symptoms, and cardiopulmonary function. Although HBOT has shown some benefits for long COVID symptoms, further rigorous large-scale RCTs are required to establish precise indications, protocols, and post-treatment evaluations.

Abstract Asthma is a chronic airway inflammation disease and the diagnosis and treatment strategies remain difficult. MicroRNAs play important roles in many biological and pathological processes including asthma development. There is no study confirming the contribution of genetic variants in miR-145 to asthma etiology. We hypothesize that single nucleotide polymorphisms (SNPs) in the promoter region of miR-145 may be associated with the risk of asthma in Taiwanese. We used a case–control study to test this hypothesis. In 198 asthma patients and 453 healthy controls, the genotypes of miR-145 rs4705342 and rs4705343 were determined, and the associations of miR-145 genotypes with asthma risk and severity were evaluated. The distribution of miR-145 rs4705342 genotypes between asthma patients and non-asthmatic control groups were significantly different (p = 0.0187). In multivariable logistic regression analysis, compared with the wild-type TT genotype, individuals carrying the variant genotypes had progressively decreased risks of asthma: the odds ratio (OR) for the heterogeneous variant genotype (CT) and homozygous variant genotype (CC) was 0.77 (95% CI 0.55–1.10, p = 0.1788) and 0.41 (95% CI 0.21–0.79, p = 0.0102), respectively (p for trend = 0.0187). In allelic test, the C allele was associated with a 31% reduced risk of asthma (OR = 0.69, 95% CI 0.53–0.90, p = 0.0070). In addition, the rs4705342 variant genotypes were correlated with the symptom severity (p = 3 × 10–5). Furthermore, the variant genotypes correlated with lower miR-145-5p expression level in serum (p = 0.0001). As for rs4705343, there was no differential distribution of genotypes between cases and controls. Our data provide evidence for miR-145 rs4705342 to serve as a novel biomarker for asthma risk prediction.

Abstract Background The addition of anti-angiogenesis drugs to epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) or chemotherapy in patients with EGFR-mutant non–small cell lung cancer (NSCLC) can improve disease control. We conducted a study to evaluate the efficacy of combination therapeutic strategies and identify patients who could benefit from combination therapy. Methods This study enrolled patients with stage IV EGFR-mutant NSCLC treated with first-line EGFR-TKIs between January 2014 and December 2020. We divided patients into three groups: patients who received an anti-angiogenesis drug as first-line combination therapy, those who received an anti-angiogenesis drug as further-line combination therapy, and those with no anti-angiogenesis therapy. Results A total of 204 patients were enrolled in the final analysis. Progression-free survival (PFS) in patients receiving first-line anti-angiogenesis plus EGFR-TKI combination therapy was longer (18.2 months) than those treated with first-line EGFR-TKI monotherapy (10.0 months for both, p

Abstract Background The treatment options for epidermal growth factor receptor (EGFR)‐mutated non‐small cell lung cancer (NSCLC) with brain metastases (BMs) include EGFR‐tyrosine kinase inhibitors (TKIs), stereotactic radiosurgery (SRS), whole‐brain radiotherapy, brain surgery, and antiangiogenesis therapy. As treatment options evolve, redefining optimal treatment strategies to improve survival are crucial. Methods A total of 150 EGFR‐mutant NSCLC patients with BMs who received first‐ or second‐generation EGFR‐TKIs as first‐line treatment between January 2012 and October 2019 were included in this analysis. Results After multivariate analysis, patients with the graded prognostic assessment for lung cancer using molecular markers (Lung‐mol GPA) ≥3 (hazard ratio [HR]: 0.538, 95% confidence interval [CI]: 0.35–0.83), who received afatinib or erlotinib as first‐line treatment (HR: 0.521, 95% CI: 0.33–0.82), underwent SRS therapy (HR: 0.531, 95% CI: 0.32–0.87), or were sequentially treated with osimertinib (HR: 0.400, 95% CI: 0.23–0.71) were associated with improved overall survival (OS). Furthermore, SRS plus EGFR‐TKI provided more OS benefits in patients with Lung‐mol GPA ≥3 compared with EGFR‐TKI alone in our patient cohort (44.9 vs. 26.7 months, p = 0.005). The OS in patients who received sequential osimertinib therapy was significantly longer than those without osimertinib treatment (43.5 vs. 24.3 months, p

Background Asthma is the most common chronic inflammatory airway disease worldwide. Asthma is a complex disease whose exact etiologic mechanisms remain elusive; however, it is increasingly evident that genetic factors play essential roles in the development of asthma. The purpose of this study is to identify novel genetic susceptibility loci for asthma in Taiwanese. We selected a well-studied long non-coding RNA (lncRNA), MEG3, which is involved in multiple cellular functions and whose expression has been associated with asthma. We hypothesize that genetic variants in MEG3 may influence the risk of asthma. Methods We genotyped four single nucleotide polymorphisms (SNPs) in MEG3, rs7158663, rs3087918, rs11160608, and rs4081134, in 198 patients with asthma and 453 healthy controls and measured serum MEG3 expression level in a subset of controls. Results The variant AG and AA genotypes of MEG3 rs7158663 were significantly over-represented in the patients compared to the controls (P = 0.0024). In logistic regression analyses, compared with the wild-type GG genotype, the heterozygous variant genotype (AG) was associated with a 1.62-fold [95% confidence interval (CI) [1.18–2.32], P = 0.0093] increased risk and the homozygous variant genotype (AA) conferred a 2.68-fold (95% CI [1.52–4.83], P = 0.003) increased risk of asthma. The allelic test showed the A allele was associated with a 1.63-fold increased risk of asthma (95% CI [1.25–2.07], P = 0.0004). The AG plus AA genotypes were also associated with severe symptoms (P = 0.0148). Furthermore, the AG and AA genotype carriers had lower serum MEG3 expression level than the GG genotype carriers, consistent with the reported downregulation of MEG3 in asthma patients. Conclusion MEG3 SNP rs7158663 is a genetic susceptibility locus for asthma in Taiwanese. Individuals carrying the variant genotypes have lower serum MEG3 level and are at increased risks of asthma and severe symptoms.

Defects in the non-homologous end-joining (NHEJ) DNA repair pathway lead to genomic instability and carcinogenesis. However, the roles of individual NHEJ genes in nasopharyngeal carcinoma (NPC) etiology are not well-understood. The aim of this study was to assess the contribution of NHEJ genotypes, including XRCC4 (rs6869366, rs3734091, rs28360071, rs28360317, rs1805377), XRCC5 (rs828907, rs11685387, rs9288518), XRCC6 (rs5751129, rs2267437, rs132770, rs132774), XRCC7 rs7003908, and Ligase4 rs1805388, to NPC risk, with 208 NPC patients and 416 controls. Genotype–phenotype correlations were also investigated by measuring mRNA and protein expression in adjacent normal tissues and assessing the NHEJ repair capacity in blood lymphocytes from 43 NPC patients. The results showed significant differences in the distributions of variant genotypes at XRCC4 rs3734091, rs28360071, and XRCC6 rs2267437 between the cases and controls. The variant genotypes of these three polymorphisms were associated with significantly increased NPC risks. NPC patients with the risk genotypes at XRCC6 rs2267437 had significantly reduced expression levels of both mRNA and protein, as well as a lower NHEJ repair capacity, than those with the wild-type genotype. In conclusion, XRCC4 rs3734091, rs28360071, and XRCC6 rs2267437 in the NHEJ pathway were associated with NPC susceptibility. XRCC6 rs2267437 can modulate mRNA and protein expression and the NHEJ repair capacity.

Background/Purpose: There is a lack of data on nivolumab treatment outcomes in Taiwanese patients with advanced or recurrent non-small cell lung cancer (NSCLC) ineligible for radical radiotherapy and resistant to platinum-based chemotherapy. We investigated the safety and efficacy of nivolumab in this population. Methods: In this ongoing, multicenter, open-label, single-arm, phase II study, patients aged ≥20 years with a performance status of 0–1 and stage IIIB/IV or recurrent NSCLC received nivolumab 3 mg/kg every 2 weeks in 6-week cycles. Interim data obtained between 27 January 2016 and 21 May 2017 were analyzed. Safety, based on adverse event (AE) reporting, was the primary endpoint. Efficacy assessment parameters included overall response rate (ORR), overall survival (OS), and progression-free survival (PFS). Results: Among 53 treated patients with advanced NSCLC (median age 61.0 years; 62.3% male), mean treatment duration was 99.7 days. AEs (any grade) and serious AEs were reported by 92.5% and 47.2% of patients, respectively. Adverse drug reactions (ADRs; any) occurred in 58.5% of patients; grade ≥3 ADRs occurred in 13.2% of patients. Five deaths occurred; two cases (neoplasm progression and septic shock) were considered treatment-emergent. Common ADRs were fatigue (17.0%) and rash (13.2%). Common immune-related treatment-emergent AEs were rash (17.0%) and pruritus (13.2%). The centrally assessed ORR was 9.4% (5/53). The median OS and median PFS were 11.5 months and 1.4 months, respectively. Conclusion: Nivolumab appeared to be safe and effective in Taiwanese patients. These interim results suggest that nivolumab is a suitable treatment option for this population. Clinical trial registration: NCT02582125.

BackgroundRespiratory system infections commonly occur among individuals with asthma. However, whether asthma patients have a higher risk of pleural empyema development remains unclear.MethodsThis is a retrospective cohort study based on data from the National Health Insurance Research Database of Taiwan. The asthma cohort consisted of 48,360 newly diagnosed adult individuals from 2000 to 2012. The comparison cohort consisted of the same number of adults who did not have asthma and was matched for age, gender, comorbidity, and the year of diagnosis. The development of pleural empyema was followed up to 2013.ResultsPleural empyema incidence was 2.03-fold higher in the asthma cohort compared to the comparison cohort (8.65 vs. 4.25 per 10,000 person-years), with an adjusted hazard ratio (HR) of 2.12 [95% confidence interval (CI) = 1.76–2.56]. Stratified analyses by age, gender, comorbidity, and corticosteroid use revealed that the crude and adjusted HRs of pleural empyema associated with asthma were all significant. Among patients with asthma, the risk of pleural empyema elevated with increased frequency of annual asthma-related emergency room visits and hospital admissions (≥1 vs.

Objectives: To evaluate the efficacy of prophylactic traditional Chinese medicine (TCM) on skin toxicities in patients with advanced lung adenocarcinoma treated with first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a randomized-controlled trial (RCT). Materials and methods: This pilot study was a prospective, single-center, double-blinded RCT. The study enrolled patients with a new diagnosis of locally advanced and metastatic lung adenocarcinoma harboring EGFR mutations who were treated with first-line afatinib from July 1, 2016 to December 31, 2017. Thirty patients who met the inclusion and exclusion criteria were assigned to the TCM and placebo groups with simple randomization. TCM and placebo were initiated at the same time as afatinib and were administered for 3 months. The survival of each subject was followed until 3 years. Results: There were 36 patients with newly diagnosed lung adenocarcinoma during the study period. After the exclusion of 6 patients, the remaining 30 patients were assigned to the TCM (n = 14) and placebo (n = 16) groups comprising the intention-to-treat population. The time to first skin toxicity was 22.3 days in the TCM group and 17.6 days in the placebo group (P = .510) in the per-protocol population. The analysis of the present pilot study results determined that the difference in time to first skin toxicity between the 2 groups would reach statistical significance with a sample size of 237 based on a power of 0.8. There were significant differences in certain subscales of quality of life between the TCM and placebo groups; however, there was no significant difference in progression-free survival or overall survival between the 2 groups. Conclusions: Integrative TCM may prolong the time to first skin toxicity in patients with advanced lung adenocarcinoma treated with first-line afatinib. Prophylactic TCM could delay skin toxicity of any grade and reduce the incidence of grade 3 skin toxicity. Future large-scale RCTs are warranted to validate these findings. Trial Registration: ClinicalTrials.gov, NCT05204758. Registered on 24 Jan 2022.

Introduction: Patients with stage III NSCLC represent a very heterogenous group that requires different treatment strategies, especially in patients with N2 (2 nearby lymph nodes having cancer)-positive NSCLC and unresectable EGFR-mutant NSCLC. This real-world study may provide more insights into treatment decisions. Methods: The KINDLE study is a large, multinational real-world observational study that assessed different treatment strategies in patients with stage III NSCLC. Progression-free survival (PFS) and overall survival (OS) were estimated and compared using Kaplan-Meier and log-rank testing. Patients were classified on the basis of disease stage, resectability, and treatment modalities. Results: The Taiwan subgroup enrolled 200 patients. The median PFS and OS values were similar among patients with stage IIIA and stage IIIB disease, but were significantly better in patients who were deemed as a resectable disease than in those who were deemed as an unresectable disease. In patients with N2-positive NSCLC, patients who underwent surgery had better PFS, but not OS, than patients administered with chemoradiotherapy (CRT) (PFS 13.4 vs. 7.3 mo, hazard ratio [HR] = 0.18, p < 0.001; OS 32.4 vs. 22.0 mo, HR = 0.64, p = 0.215). Among patients with unresectable EGFR-mutant NSCLC, OS was significantly poorer after upfront EGFR–tyrosine kinase inhibitors (TKI) than after upfront CRT with sequential EGFR-TKI (27.4 vs. 49.0 mo, HR = 3.09, p = 0.03). Conclusions: Our study suggests that surgery could be added as part of therapy for patients with stage III N2-positive NSCLC. Moreover, upfront CRT with sequential EGFR-TKI seems to be appropriate for stage III unresectable EGFR-mutant NSCLC. Further randomized studies are needed to validate these results.

Background Image‐guided radiotherapy (IGRT) is an advanced radiotherapy technique to improve the precision and accuracy of treatment delivery. A recent randomized controlled trial (RCT) for prostate cancer patients treated with radiotherapy via either IGRT or routine care reported statistically significantly worse overall survival (OS) for those patients treated with IGRT. This raised the concern regarding the effectiveness of IGRT in definitive concurrent chemoradiotherapy (dCCRT) for locally advanced lung cancer (LALC). Methods Eligible LALC patients diagnosed between 2011 and 2016 were identified via the Taiwan Cancer Registry. We used propensity score (PS) weighting to balance observable potential confounders between groups. The hazard ratio (HR) of death and other outcomes were compared between IGRT and non‐IGRT. We also evaluated OS in various subgroups. Results Our primary analysis consisted of 797 patients in whom covariates were well balanced after PS weighing. The HR for death when IGRT was compared with non‐IGRT was 0.96 (95% confidence interval 0.79–1.15, P = 0.65). There were also no significant differences for most of the other outcomes or subgroup analyses. Conclusions In this updated nonrandomized study, we found that OS of LALC patients treated with dCCRT was not statistically different between those treated with IGRT versus non‐IGRT. The results should be interpreted with caution given the nonrandomized design. Studies regarding toxicity, local control, or designed as RCT are needed to clarify the role of IGRT. Key points Significant findings of the study The OS of LALC patients treated with dCCRT was not statistically different between those treated with IGRT versus those without IGRT, although the observed HR for death was less than unity (ie, in favor of IGRT). What this study adds In this updated nonrandomized study using real world data with additional potential confounders, our study provided a reasonable tentative evidence in the lack of RCT as suggested in the literature.

Background: Pneumoconiosis has considerable comorbidities, most notably pulmonary and cardiovascular diseases. However, the relationship between pneumoconiosis and chronic kidney disease (CKD) is largely unknown. The present study aimed to use a retrospective cohort study design to further clarify the association between pneumoconiosis and subsequent CKD risk. Methods: This is a nationwide, population-based, retrospective cohort study that used data from Taiwan’s National Health Insurance Database. Between 2008 and 2018, 17,952 newly diagnosed patients were included in the pneumoconiosis cohort, while 71,808 individuals without pneumoconiosis were included in the comparison cohort, with a propensity score matching for age, gender, and date of pneumoconiosis diagnosis. The development of CKD was monitored until the end of 2019. The risk was assessed using Cox proportional hazard regression models. Results: After controlling for age, gender, and comorbidity, the overall incidence of CKD was 1.69-fold higher in the pneumoconiosis cohort than in the comparison cohort (19.71 vs. 11.76 per 1000 person-years, respectively, p < 0.001), with an adjusted hazard ratio of 1.83 (95% confidence interval: 1.73–1.93). Stratified analyses by age group, gender, and presence of comorbidity revealed that the adjusted hazard ratios of CKD associated with pneumoconiosis remained significant (8/9). Furthermore, pneumoconiosis and tri-high (hypertension, hyperglycemia, and hyperlipidemia) interact positively with CKD development (p < 0.001). Conclusion: Patients with pneumoconiosis had a significantly higher risk of developing CKD than those without. Pneumoconiosis combined with hypertension, hyperglycemia, or hyperlipidemia would increase the risk even further. More studies are required to understand the possible pathophysiological mechanisms.

The development of third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) targeting T790M-mutant non-small cell lung cancer (NSCLC) has raised the importance of re-biopsy after EGFR-TKI failure. This study aimed to investigate the feasibility of interventional pulmonology (IP) procedures as re-biopsy methods for identifying the T790M mutation in EGFR-TKI-resistant patients. One hundred and thirty-nine NSCLC patients who underwent IP procedures for re-biopsy as their initial investigation after EGFR-TKI treatment failure were enrolled in this study between January 2020 and August 2022. All patients underwent a first re-biopsy with IP methods, with a diagnostic yield of 81.2% and T790M mutation detection rate of 36%. Thirty patients underwent a second re-biopsy; IP methods were used for 17 (56.6%) patients and non-IP methods for 13 (43.4%) patients; the T790M mutation detection rate was 36.4%. Only six patients underwent a third re-biopsy; no T790M mutation was noted. The T790M mutation detection rate did not differ between IP and non-IP methods (33.6 % vs. 37.5%, p = 0.762). In 11 cases (7.5%), a re-biopsy revealed histologic transformation from lung adenocarcinoma. IP procedures, as first-line re-biopsy methods for NSCLC, are feasible and provide sufficient tissue for identification of the resistance mechanism and target gene T790M mutation.

Background: Patients with chronic kidney disease (CKD) receiving maintenance renal replacement therapy are at higher risk of tuberculosis (TB) infection. The risk of TB infection in CKD patients not receiving dialysis is unknown.Aim: We conduct this study to test the hypothesis that TB infection is negatively correlated to renal function.Design: Non-dialysis CKD stage 1–5 patients, admitted in China Medical University Hospital from January of 2003 to May of 2014, were enrolled in this study and were prospectively followed up to the diagnosis of TB, death, loss to follow-up, or December 2014. The risk factors of TB infection were analyzed using competing-risks regression analysis with time-varying covariates. The initiation of dialysis and patients' death were considered as competing events. Patients' estimated glomerular filtration rate (eGFR) and body mass index (BMI) were recorded at enrollment.Results: They were followed-up for a median duration of 1.4 years. Of the 7221 patients, TB infection was identified in 114 patients. Higher eGFR was associated with lower risk of TB infection (P < 0.01). The adjusted subdistribution hazard ratio (aSHR) was 0.82 [95% confidence interval (CI), 0.72 to 0.94] for every 5 ml/min/1.73 m2 increase in eGFR. In addition, higher BMI (p = 0.01) was associated with a lower risk of TB infection and the aSHR was 0.91 (95% CI, 0.85 to 0.98) for every 1 kg/m2 increase in BMI.Conclusion: Renal function and body mass index are independently associated with the risk of tuberculosis infection in patients with chronic kidney disease not receiving dialysis.

Immune checkpoint inhibitors (ICIs) have been approved to treat patients with various cancer types, including lung cancer, in many countries. This study aims to investigate the effectiveness and safety of ICIs under different treatment conditions of non-small cell lung cancer patients. A population-based retrospective cohort study was conducted using the electronic health records of three medical centers in Taiwan. From January 01, 2016, to November 30, 2018, a total of 91 ICIs and 300 traditional chemotherapy users who had undergone stage III and IV lung cancer treatment were included in the study. We performed the randomized matched pair design by selecting a Chemotherapy subject for each ICI patient in the sample population. All subjects were monitored from the date of taking ICIs or chemotherapy drugs until the event of death, loss to follow-up, or were occurred with any defined adverse events. Kaplan-Meier estimators and cox proportional hazard regression models were used to compute the overall survival, efficacy, and safety of the ICIs group. The median overall survival (OS) in the ICI and Chemo groups after matching was 11.2 months and 10.5 months, respectively. However, the results showed no significant OS differences between ICIs and chemo groups for both before and after matching (HR,1.30; 95%CI, 0.68-2.46; p=0.428 before matching and HR,0.96; 95CI%, 0.64-1.44; p=0.838 after matching). We observed that with the higher amount of PD-L1, the length of the patients’ overall survival was (positive vs. negative PD-L1, HR,0.21; 95%CI, 0.05-0.80; p=0.022). The incidences of serious adverse drug events above grade 3 in the ICIs and traditional chemo groups were 12.7% and 21.5%, respectively. We also found that the number of AEs was less in ICIs than in the Chemo group, and the AEs that occurred after treatments were observed earlier in the ICIs compared to the Chemo group. ICIs drugs were observed to be safer than traditional chemotherapy as they had a lower risk of serious adverse drug events. It is necessary to pay attention to immune-related side effects and provide appropriate treatment. Furthermore, the patient’s physical status and PD-L1 test can be used to evaluate the clinical effectiveness of ICIs.

Background: Carbon monoxide (CO), a colorless and odorless gas, is one of the common causes of poisoning-related deaths worldwide. CO poisoning can result in hypoxic brain damage and death, but intensive care can improve the likely outcome for critically ill patients. However, there is a paucity of clinical data regarding the prognostic factors and association between organ dysfunction and clinical outcome of patients treated for CO poisoning in the intensive care unit (ICU). Methods: We performed a retrospective study of patients admitted to a university affiliated hospital ICU between July 2001 and December 2010 following CO poisoning. Outcomes were survival to ICU discharge and to hospital discharge. Results: Seven hundred and eighty-seven patients were admitted to the university hospital following CO poisoning, of which 140 (17.8%) were admitted to the hospital ICU. The overall mortality rate of the patients admitted to the ICU was 14.3% (20/140). Univariate analysis indicated that non-surviving patients with CO poisoning were more likely to have initial blood carboxyhemoglobin (COHb) level > 30%, shock, acute respiratory failure, Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥ 25, Glasgow coma scale (GCS) score of 3, acute renal failure, dysfunction or failure of more than 3 organs, low blood pH, low HCO3- level, high potassium level, and high glucose level. They were also more likely to have not received hyperbaric oxygen (HBO) intervention. Multivariate logistical regression analysis indicated that the mortality rate of patients treated in the ICU for CO poisoning was higher if their initial APACHE II score was ≥25, GCS was 3, and more than 3 organs were dysfunctional. Moreover, HBO intervention in ICU significantly decreased patients’ risk of mortality due to CO poisoning. Conclusion: In conclusion, we observed that APACHE II score >25, GCS 3, and dysfunction of more than 3 organ systems on admission to emergency department was associated with a significant mortality risk in patients treated in the ICU for CO poisoning. Moreover, HBO therapy could reduce the risk of mortality in patients with CO poisoning in ICU. Keywords: Carbon monoxide poisoning, Intensive care unit, Outcome

Matrix metalloproteinases-2 (MMP2) has been reported to be overexpressed in various types of cancer. However, the contribution of various genotypes of MMP2 to lung cancer is controversial and not yet been examined in Taiwan. Therefore, in the current study, we investigated the association of MMP2 genotypes with lung cancer risk among Taiwanese. In this hospital-based, case–control study, 358 lung cancer patients and 716 age- and gender-matched healthy controls were recruited, and the genotypic distributions of MMP2-1306 and MMP2- 735 were determined. Then, their association with lung cancer was evaluated, and their interaction with personal smoking status was also examined via stratification analysis. The results showed that the percentages of variant CT and TT at MMP2-1306 were 17.3% and 1.7% among the lung cancer patients, respectively, much lower than those of 28.7% and 2.4%, respectively, among the healthy controls (P for trend = 0.0001). The allelic frequency distribution analysis showed that the variant T allele at MMP2-1306 conferred a statistically significantly lower lung cancer risk than the wild-type C allele (adjusted odds ratio = 0.54, 95% confidence interval = 0.41–0.72, P = 0.0001). There was an obvious effect of MMP2-1306 genotype on lung cancer risk among the subpopulations of ever smokers but not nonsmokers. As for the genotypes of MMP2-735, there was no such differential distribution in the aspects of genotypic or allelic frequencies, or combinative effects with smoking status. The genotypes of MMP2-1306 may act as a biomarker in determining personal susceptibility to lung cancer in Taiwan. The contribution of MMP2 genotypes alone and its joint effects with personal cigarette smoking habit on lung cancer susceptibility should be taken into consideration of the clinical practices for early detection and prediction of lung cancer in Taiwan.

Background: The relative importance of predictive factors for advanced non-small cell lung cancer (NSCLC) patients on epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment remains unclear. Materials and methods: We retrospectively enrolled advanced NSCLC patients with single first-generation EGFR-TKI treatment for ⩾5 years (Y) in Taiwan. Clinical data was collected and compared with those of another cohort with single first-line EGFR-TKI treatment for 5 Y group. Results: Overall, 128 and 278 patients were enrolled in the ⩾5 Y and

Introduction: In the phase 3 ASCEND-4 study, ceritinib exhibited improved progression-free survival (PFS) by Blinded Independent Review Committee (BIRC) assessment versus the standard first-line chemotherapy in patients with advanced ALK-rearranged NSCLC. Here, we assessed the efficacy and safety of ceritinib in the subgroup of Asian patients from the ASCEND-4 trial. Methods: Treatment-naive patients with stage IIIB or IV ALK-rearranged nonsquamous NSCLC were randomized in a one-to-one ratio to receive either oral ceritinib 750 mg/day (fasted) daily or intravenous chemotherapy ([cisplatin 75 mg/m2 or carboplatin area under the curve 5–6 plus pemetrexed 500 mg/m2] every three wk, followed by pemetrexed maintenance). The primary end point was PFS by BIRC assessment. Results: Of 376 randomized patients, 158 (42.0%) were Asian (ceritinib arm: N = 76; chemotherapy arm: N = 82). The median time from randomization to the cutoff date (June 24, 2016) was 18.3 months (range = 13.5–34.2) in the Asian subgroup. The median PFS (by BIRC assessment) was 26.3 months (95% confidence interval [CI]: 8.6–not estimable) and 10.6 months (95% CI: 6.7–15.0), with an estimated 34% risk reduction in PFS (hazard ratio = 0.66, 95% CI: 0.41–1.05) in the ceritinib arm versus chemotherapy arm. The most common adverse events of any grade were diarrhea (85.5%), increased alanine aminotransferase and vomiting (73.7% each), and increased aspartate aminotransferase and nausea (69.7% each) in the ceritinib arm, and nausea (49.3%), vomiting (42.7%), and anemia (40.0%) in the chemotherapy arm. Conclusion: Ceritinib was effective and safe in treatment-naive Asian patients with advanced ALK-rearranged NSCLC. The findings were largely consistent with that of the overall study population.

Introduction: The TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets EGFR T790M and common EGFR-activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs. Methods: Patients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). Results: Enrollment was halted when rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to rociletinib (n = 53: 500 mg twice daily; n = 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval [CI]: 2.6–5.4) in the rociletinib 500-mg group and 5.5 months (95% CI: 1.8–8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4–2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with rociletinib (n = 25; 500 mg and 625 mg twice daily) versus chemotherapy (n = 20; 6.8 versus 2.7 mo; hazard ratio = 0.55, 95% CI: 0.28–1.07, p = 0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively). Conclusions: Rociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point.

In Taiwan, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), gefitinib, erlotinib, and afatinib are served as first-line therapy for non-small lung cell cancer (NSCLC) patients with EGFR sensitizing mutations. However, the majority of patients who initially respond to EGFR-TKIs, progress through acquiring EGFR T790M mutations (T790M), which is the most common resistant mechanism. Patients with T790M gain the opportunity of subsequent treatment with third-generation EGFR-TKI, osimertinib. This study aimed to evaluate the association between prior EGFR-TKI therapy and incidence of acquired T790M resistance in lung adenocarcinoma patients who have progressed on first/second-generation EGFR-TKI therapy. This retrospective study included lung adenocarcinoma patients who had a radiographically-confirmed progressive disease under EGFR-TKI treatment and had re-biopsy samples for T790M testing from seven medical centers in Taiwan from June 2013 to December 2018. Patients harboring de novo T790M or using more than one EGFR-TKI were excluded. Of the 407 patients enrolled, the overall T790M acquisition rate was 52.8%. The patients treated with gefitinib, erlotinib or afatinib had a statistically significant difference in the T790M rates (59.9, 45.5, and 52.7%, respectively; p = 0.037) after disease progression. Patients with common baseline EGFR mutations (Del-19 and L858R) (p = 0.005) and longer treatment duration with EGFR-TKIs (p < 0.001) had higher chances of T790M acquisition. Multivariate logistic regression analysis further showed that patients with common baseline EGFR mutations, gefitinib (compared to erlotinib) administration, and longer treatment duration with EGFR-TKIs had higher T790M incidence. There was no significant difference in the incidence of acquired T790M between different re-biopsy tissue samples or complications. In conclusion, this study showed that patients who progressed from gefitinib treatment, bearing common EGFR mutations, and with longer EGFR-TKI treatment duration had increased incidence of T790M acquisition and, therefore, were suitable for subsequent osimertinib treatment.

Background: Respiratory system infections are prevalent in patients with depression. However, it remains unclear if patients with depression are at an increased risk of developing pleural empyema. Methods: We conducted a retrospective cohort study using data from the National Health Insurance Research Database of Taiwan. The depression group included 42,283 newly diagnosed patients between 2000 and 2012. The comparison group included the same number of individuals without depression, frequency matched for age, sex, comorbidities, and the year of diagnosis. The occurrence of pleural empyema was monitored until the end of 2013. Results: The overall incidence of pleural empyema was 1.32-fold higher in the depression group than in the comparison group (3.94 versus 2.97 per 10,000 person-years), with an adjusted hazard ratio of 1.33 (95% confidence interval, 1.27−1.40). Stratified analyses by age, sex, and comorbidity revealed that the crude and adjusted hazard ratios of pleural empyema associated with depression were significant in all subgroups. The 30-day mortality for pleural empyema was higher, but not significantly, in the depression group compared to the comparison group (10.7% versus 6.4%, adjusted odds ratio = 2.23, 95% confidence interval, 0.77−6.49). Conclusion: An association between depression and the development of pleural empyema may exist; however, more evidence is required to support this association. The reviews of this paper are available via the supplemental material section.

ObjectiveImage evaluation strategy for lung cancer patients has difficulty obtaining the appropriate quantity of diffuse lung nodules and bone metastases. The study was to demonstrate whether early variations in the levels of serum 4-tumor markers (4-TMs)(carcinoembryonic antigen [CEA], cancer antigen [CA]125, CA19-9, and CA15-3) after TKI targeted therapy were associated with treatment response in patients with lung adenocarcinoma.MethodsPatients with stage IIIB-IV lung adenocarcinoma taking epidermal growth factor receptor (EGFR) TKIs or anaplastic lymphoma kinase (ALK) inhibitors were enrolled prospectively from June 2012 to February 2015. According to the variations of the percentage of change in 4-TM levels (4-TMpc), we divided patients into ascending (increases in 4-TMpc over the 7th- 14th day) and descending (decreases in 4-TMpc over the 7th- 14th day) groups.Results184 patients were enrolled, and 89% had at least one of the pre-treatment evaluable TMs and were further analyzed. An excellent response to the TKI targeted therapy was accurately predicted in the descending group, as determined using receiver operating characteristic curve analysis (an area under the curve, 0.83). Multivariate Cox hazards model analyses demonstrated that the type of 4-TMpc and mutation status were the strongest predictors of progression-free survival (PFS)(descending versus ascending, hazard ratios [HR] 0.30, 95% confidence interval [CI], 0.19-0.47; sensitive mutation versus wide type, HR 0.30, 95% CI, 0.19-0.48).ConclusionsType of 4-TMpc 14 days after TKI targeted therapy is associated with an image response and PFS, without regarding mutation status, in patients with advanced lung adenocarcinoma.

Abstract Background Tuberculosis (TB) is one of the world’s major communicable infectious diseases, and it still imposes a great health burden in developing countries. The development of drug-resistant TB during the treatment increases the treatment complexity, and the long-term pulmonary complications after completing treatment raise the epidemic health burden. This study intended to investigate the utilization of Chinese medicine (CM) for respiratory symptoms by patients with a medical history of TB in Taiwan. Methods We analyzed a cohort of one million individuals who were randomly selected from the National Health Insurance Research Database in Taiwan. The inclusion criteria of patients (n = 7905) with history of TB (ICD-9-CM codes 010–018 and A02) were: (1) TB diagnosed between January 1, 1997 and December 31, 2010 (2) 18 years old or over (3) Clinical records for at least 2 months with complete demographic information (4) Record of treatment with first-line TB medication prescriptions. CM users for conditions other than respiratory discomforts (n = 3980) were excluded. Finally, a total of 3925 TB patients were categorized as: CM users for respiratory discomforts (n = 2051) and non-CM users (n = 1874). Results Among the 3925 subjects, 2051 (52.25%) were CM users, and 1874 (44.753%) were non-CM users. Female patients and those who were younger (18–39 y/o) and who lived in urbanized areas relatively tended to be CM users (p

Cigarette smoking is one of the leading risks for lung cancer and is associated with the insensitivity of non‐small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, it remains undetermined whether and how cigarette smoke affects the therapeutic efficacy of EGFR TKIs. In this study, our data showed that chronic exposure to cigarette smoke extract (CSE) or tobacco smoke‐derived carcinogen benzo[α]pyrene, B[α]P, but not nicotine‐derived nitrosamine ketone (NNK), reduced the sensitivity of wild‐type EGFR‐expressing NSCLC cells to EGFR TKIs. Treatment with TKIs almost abolished EGFR tyrosine kinase activity but did not show an inhibitory effect on downstream Akt and ERK pathways in B[α]P‐treated NSCLC cells. CSE and B[α]P transcriptionally upregulate c‐MET and activate its downstream Akt pathway, which is not inhibited by EGFR TKIs. Silencing of c‐MET reduces B[α]P‐induced Akt activation. The CSE‐treated NSCLC cells are sensitive to the c‐MET inhibitor crizotinib. These findings suggest that cigarette smoke augments oncogene addiction to c‐MET in NSCLC cells and that MET inhibitors may show clinical benefits for lung cancer patients with a smoking history.

Tetrandrine (TET), a bisbenzylisoquinoline (BBI) alkaloid, is isolated from the plant Stephania tetrandra S. Moore and has a wide range of biological activity, including anticancer properties in vitro and in vivo. At first, we established a luciferase-expressing stable clone that was named GBM 8401/luc2 cells. Herein, the primary results indicated that TET reduced the total cell viability and induced cell apoptosis in GBM 8401/luc2 human glioblastoma cells. However, there is no available information showing that TET suppresses glioblastoma cells in vivo. Thus, we investigated the effects and mechanisms of TET on a GBM 8401/luc2 cell-generated tumor in vivo. After the tumor volume reached 100–120 mm3 in subcutaneously xenografted nude mice, all of the mice were randomly divided into three groups: Group I was treated with phosphate-buffered solution (PBS) containing 0.1% dimethyl sulfoxide, Group II with 25 mg/kg of TET, and Group III with 50 mg/kg of TET. All mice were given the oral treatment of PBS or TET by gavage for 21 days, and the body weight and tumor volumes were recorded every 5 days. After treatment, individual tumors, kidneys, livers, and spleens were isolated from each group. The results showed that TET did not affect the body weights, but it significantly decreased the tumor volumes. The TET treatment at 50 mg/kg had a two-fold decrease in tumor volumes than that at 25 mg/kg when compared to the control. TET decreased the total photon flux, and treatment with TET at 50 mg/kg had a lower total photon flux than that at 25 mg/kg, as measured by a Xenogen IVIS imaging system. Moreover, the higher TET treatment had lower tumor volumes and weights than those of the lower dose. The apoptosis-associated protein expression in the tumor section was examined by immunohistochemical analysis, and the results showed that TET treatment reduced the levels of c-FLIP, MCL-1, and XIAP but increased the signals of cleaved-caspase-3, -8, and -9. Furthermore, the hematoxylin and eosin (H & E) staining of kidney, liver, and spleen tissues showed no significant difference between the TET-treated and control groups. Overall, these observations demonstrated that TET suppressed subcutaneous tumor growth in a nude-mice model via the induction of cell apoptosis.

Chronic inflammation induces autoimmune disorders and chronic diseases. Several natural products activate nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, attenuating inflammatory responses. Ergosta-7,9(11),22-trien-3β-ol (EK100) isolated from Cordyceps militaris showed anti-inflammatory and antioxidative activity, but those mechanisms are still unclear. This study is the first to investigate EK100 on antioxidant Nrf2 relative genes expression in LPS-stimulated macrophage-like cell lines. The results showed that EK100 reduced IL-6 (interleukin-6) and tumor necrosis factor-α production. EK100 also attenuated a mitogen-activated protein kinase/activator protein-1 (MAPK/AP-1) pathway and interleukin-6/Janus kinase/signal transducer and activator of transcription (IL-6/JAK/STAT) pathway in LPS-stimulated cells. Toll-like receptor 4 (TLR4) inhibitor CLI-095 and MAPK inhibitors can synergize the anti-inflammatory response of EK100 in LPS-stimulated cells. Moreover, EK100 activated Nrf2/HO-1 (heme oxygenase-1) signaling in LPS-stimulated murine macrophage-like RAW 264.7 cells, murine microglial BV2 cells, and human monocytic leukemia THP-1 cells. However, Nrf2 small interfering RNA (Nrf2 siRNA) reversed EK100-induced antioxidative proteins expressions. In conclusion, EK100 showed anti-inflammatory responses via activating the antioxidative Nrf2/HO-1 signaling and inhibiting TLR4 related MAPK/AP-1 induced IL-6/JAK/STAT pathways in the LPS-stimulated cells in vitro. The results suggest EK100 acts as a novel antioxidant with multiple therapeutic targets that can potentially be developed to treat chronic inflammation-related diseases.

Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2‐positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase‐dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin‐dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK‐mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor‐induced Akt activation.

Abstract Asthma is an inflammatory disease and interleukin 12 (IL-12) may play a regulatory role in allergen-induced inflammation. The aim of this study was to investigate the association of polymorphisms in IL-12A/IL-12B with asthma. The asthma group included 198 adult patients and the control group included 453 individuals without asthma that were frequency-matched by gender and age. The distribution of genotypic and allelic frequencies of IL-12A rs568408 demonstrated significant differences between case and control groups. Specifically, the percentages of AA genotype of IL-12A rs568408 was significantly higher among asthmatic patients in Taiwan than healthy controls, compared to GG genotype. No significant difference was observed among the IL-12A rs2243115 and IL-12B rs3212227 genotypes between case and control groups. In addition, the A allele at IL-12A rs568408 was associated with more severe symptoms (P = 0.0085) among asthmatic patients. These results suggest that IL-12A rs568408 may contribute to the etiology and symptoms severity of asthma, indicating its usefulness as a predictive and diagnostic biomarker of asthma.

Objectives: The clinical effect of traditional Chinese medicine (TCM) on survival in patients with advanced lung adenocarcinoma treated with first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a major concern and requires more evidence from large-scale clinical studies. Materials and Methods: This population-based cohort study used the Taiwan National Health Insurance Research Database to enroll patients between 2006 and 2012 who had newly diagnosed locally advanced and metastatic lung adenocarcinoma treated with first-line gefitinib or erlotinib. Survival was tracked until 2013. The patients were separated into TCM users and nonusers, and Cox regression models were applied to determine the association between the use of TCM and the survival of patients. Results: A total of 1988 patients receiving first-line gefitinib or erlotinib for the treatment of EGFR-mutated advanced lung adenocarcinoma, with the exclusion of TCM users after tumor progression, were included in this cohort study. Compared with TCM nonuse, TCM use for ≥180 days was associated with a significantly decreased risk of mortality by 68% (adjusted hazard ratio [HR], 0.32 [95% CI, 0.21-0.50], P < .0001). Compared with TCM nonuse, TCM use for ≥180 days was associated with a significantly decreased risk of disease progression by 59% (adjusted HR, 0.41 [95% CI, 0.29-0.58], P < .0001). Conclusion: This cohort study suggests that adjunctive TCM therapy could improve overall survival and progression-free survival in patients with advanced lung adenocarcinoma treated with first-line TKIs. Future randomized, controlled trials are required to validate these findings.

[This corrects the article DOI: 10.1371/journal.pone.0128461.].

Lung cancer screening using low-dose computed tomography (CT) has been reported to reduce lung cancer-specific mortality for smokers at high risk. However, despite different characteristics of lung cancer in Asia, there are few data concerning this specific population for screening. We aim to analyze the performance of lung cancer screening with low-dose CT concurrent with chest radiography in Taiwan, with reference to international experience. Methods: During the 1-year period from January 2012 to December 2012, we conducted a retrospective, single-center population-based screening program for lung cancer in the setting of annual medical examinations. Participants were asymptomatic adults without prior history of any cancer. Low-dose CT and chest radiography were offered to all individuals. Baseline CT evaluations were defined as positive if any noncalcified nodule≥4 mm in diameter, which were then classified as solid, pure ground-glass or partial ground-glass opacity. Results: Of 3339 individuals, we detected 34 cancers, yielding an overall cancer detection rate of 1.02%. There was a particularly high cancer detection rate of 6.2% (8/129) in the high-risk group aged younger than 50 years with a positive family history of all types of cancers in first-degree relatives. Adenocarcinomas accounted for 88% (30/34) of cancers and 99% of them were early-stage (including carcinoma in situ and Stage I). The probability of cancers was significant higher in nodules with interval growth (odds ratio 257.89, p = 0.0002). There was no significant difference in the probability of cancers between ground glass opacity nodules and solid nodules (odds ratio 1.16, p=0.72). Of all screen-detected cancers, 61.76% (21/34) were chest radiographically occult. Conclusion: Low-dose CT is effective to detect early lung cancers. Further establishment of selection criteria for lung cancer screening, specifically for Asian individuals, is definitely warranted.

Casticin was obtained from natural plants, and it has been shown to exert biological functions; however, no report concerns the induction of DNA damage and repair in human lung cancer cells. The objective of this study was to investigate the effects and molecular mechanism of casticin on DNA damage and repair in human lung cancer A549 cells. Cell viability was determined by flow cytometric assay. The DNA damage was evaluated by 4’,6-diamidino-2-phenylindole (DAPI) staining and electrophoresis which included comet assay and DNA gel electrophoresis. The protein levels associated with DNA damage and repair were analyzed by western blotting. The expression and translocation of p-H2A.X were observed by confocal laser microscopy. Casticin reduced total viable cell number and induced DNA condensation, fragmentation, and damage in A549 cells. Furthermore, casticin increased p-ATM at 6 h and increased p-ATR and BRCA1 at 6−24 h treatment but decreased p-ATM at 24−48 h, as well as decreased p-ATR and BRCA1 at 48 h. Furthermore, casticin decreased p-p53 at 6−24 h but increased at 48 h. Casticin increased p-H2A.X and MDC1 at 6−48 h treatment. In addition, casticin increased PARP (cleavage) at 6, 24, and 48 h treatment, DNA-PKcs and MGMT at 48 h in A549 cells. Casticin induced the expressions and nuclear translocation of p-H2AX in A549 cells by confocal laser microscopy. Casticin reduced cell number through DNA damage and condensation in human lung cancer A549 cells.

The apoptotic effects of maslinic acid (MA) at 4, 8, 16, 32 and 64 μmol/L on human lung cancer A549 cells under normoxic and hypoxic conditions were examined. MA at 4–64 and 16–64 μmol/L lowered Bcl-2 expression under normoxic and hypoxic conditions, respectively (p < 0.05). This agent at 4–64 μmol/L decreased Na+-K+-ATPase activity and increased caspase-3 expression under normoxic conditions, but at 8–64 μmol/L it caused these changes under hypoxic conditions (p < 0.05). MA up-regulated caspase-8, cytochrome c and apoptosis-inducing factor expression under normoxic and hypoxic conditions at 8–64 μmol/L and 32–64 μmol/L, respectively (p < 0.05). MA down-regulated hypoxia-inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), survivin and inducible nitric oxide synthase (iNOS) expression under normoxic and hypoxic conditions at 8–64 and 16–64 μmol/L, respectively (p < 0.05). After cells were pre-treated with YC-1, an inhibitor of HIF-1α, MA failed to affect the protein expression of HIF-1α, VEGF, survivin and iNOS (p > 0.05). MA at 8-64 and 32-64 μmol/L reduced reactive oxygen species and nitric oxide levels under both conditions (p < 0.05). These findings suggest that maslinic acid, a pentacyclic triterpenic acid, exerted its cytotoxic activities toward A549 cells by mediating mitochondrial apoptosis and the HIF-1α pathway.

Lung cancer is the leading cause of cancer related death and there is no effective treatment to date. Bufalin has been shown effective in inducing apoptosis and DNA damage in lung cancer cells. However, the genetic mechanisms underlying these actions have not been elucidated yet. Cultured NCI-H460 cells were treated with or without 2 μM of bufalin for 24 h. The total RNA was extracted from each treatment for cDNA synthesis and labeling, microarray hybridization, and then followed by flour-labeled cDNA hybridized on chip. The localized concentrations of fluorescent molecules were detected and quantitated and analyzed by Expression Console software (Affymetrix) with default RMA parameters. The key genes involved and their possible interaction pathways were mapped by GeneGo software. About 165 apoptosis-related genes were affected. CASP9 was up-regulated by 5.51 fold and THAP1 by 2.75-fold while CCAR1 was down-regulated by 2.24 fold. 107 genes related to DNA damage/repair were affected. MDC1 was down-regulated by 2.22-fold, DDIT4 by 2.52 fold while GADD45B up-regulated by 3.72 fold. 201 genes related to cell cycles were affected. CCPG1 was down-regulated by 2.11 fold and CDCA7L by 2.71 fold. Many genes about apoptosis, cell cycle regulation and DNA repair are changed significantly following bufalin treatment in NCI-H460 cells. These changes provide an in depth understanding of cytotoxic mechanism of bufalin in genetic level and also offer many potentially useful biomarkers for diagnosis and treatment of lung cancer in future.

Although global and Asian studies on second-line pemetrexed for the treatment of advanced nonsmall cell lung cancer have confirmed its efficacy and safety, a pivotal postcommitment study to consolidate the evidence regarding the Taiwanese population was warranted. This open-label single-arm study assessed the objective response rate to a tailored dose of single-agent pemetrexed in Taiwanese patients with advanced nonsmall cell lung cancer who had received prior chemotherapy. Methods: Patients with stage IIIB/IV disease were treated with pemetrexed on day 1 of each 21-day cycle. A 500 mg/m² dose was administered in cycle 1. For cycle 2, the dose was increased to 1000 mg/m² (if there was no toxicity above predefined levels) or decreased to 375 mg/m². All patients received standard supplemental therapy. Patient follow-up continued until 18 months after the last patient was enrolled in this study or death. All patients were included in all analyses. Results: Of the 33 patients who were enrolled, 25 (75.8%) received the 1000 mg/m2 dose during cycle 2; 18 patients were dropped from the study, including 17 (51.5%) who had died by the time of analysis. The objective response and disease control rates were 18.2% (95% confidence limits [CI]: 7.0–35.5) and 54.5% (95% CI: 36.4–71.9), respectively. No patients exhibited a complete response. There were two serious drug-related adverse events (neutropenia and leukopenia) and two drug-related adverse events that resulted in removal from the study. Decreased neutrophil/granulocyte counts were the most frequently observed drug-related grade 3/4 events (9 patients, 24 treatment cycles). Conclusion: The objective response rate, disease control rate, and safety and tolerability profile in this population of Taiwanese patients were consistent with the published findings that were conducted using Asian and Western populations. These findings support the use of single-agent, second-line pemetrexed for the treatment of advanced nonsmall cell lung cancer in Taiwanese patients.

BACKGROUND:There is a demonstrated association between asthma and irritable bowel syndrome (IBS). In this study, we examined the bidirectional association between asthma and IBS using a nationwide database. METHODS:We conducted two retrospective cohort studies using data obtained from the National Health Insurance of Taiwan. Study 1 included 29,648 asthma patients newly diagnosed between 2000 and 2010. Study 2 included 29,875 IBS patient newly diagnosed between 2000 and 2010. For each study, four subjects without asthma and IBS were selected, respectively, frequency-matched by sex, age, and the diagnosis date. All four cohorts were followed up until the end of 2011 to estimate incident IBS for Study 1 and incident asthma for study 2. Adjusted hazard ratios (aHRs) were estimated using the Cox proportional hazards model after controlling for sex, age and comorbidities. RESULTS:The incidence of IBS was 1.89 times higher in the asthma cohort than in the comparison cohort (8.26 vs. 4.36 per 1,000 person-years), with an aHR of 1.57 [95% confidence interval (CI) = 1.47-1.68]. The aHRs remained significant in all subgroups measured by sex, age and the presence of comorbidities. In contrast, the incidence of asthma was 1.76 times higher in the IBS cohort than the comparison cohort (7.09 vs. 4.03 per 1,000 person-years), with an aHR of 1.54 (95% CI = 1.44-1.64). Similarly, aHRs remained significant in all subgroups measured by sex, age and the presence of comorbidities. CONCLUSION:The present study suggests a bidirectional association between asthma and IBS. Atopy could be a shared pathophysiology underlying this association, deserving a further investigation.

11-Dehydrosinulariolide, an active compound that is isolated from the cultured soft coral Sinularia flexibilis, has been suggested to show anti-tumor biological characteristics according to previous studies. However, its potential effect on small cell lung cancer (SCLC) remains unknown. The present study investigates the underlying mechanism for the treatment of SCLC in vitro and in vivo. Cell viability was examined using the methyl-thiazol-diphenyl-tetrazolium (MTT) assay. Flow cytometry was applied to evaluate cell cycle distribution and apoptosis. The expression of proteins related to the cell cycle and apoptosis was analyzed by Western blot analysis. Additionally, an in vivo study was performed to determine the anti-SCLC effect on an H1688 subcutaneous tumor in a BALB/c nude mouse model. 11-Dehydrosinulariolide inhibited cell growth, triggered G2/M arrest and induced H1688 cell apoptosis in a dose- and time-dependent manner. Additionally, 11-dehydrosinulariolide caused the accumulation of p53 and Bax, accompanied by the activation of DNA damage-inducing kinases, including ataxia-telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2). Moreover, 11-dehydrosinulariolide increased the activity of caspase-3 and -7, suggesting that caspases are involved in 11-dehydrosinulariolide-induced apoptosis. 11-Dehydrosinulariolide also increased the level of tumor suppressor phosphatase and tensin homolog (PTEN) and inhibited the expression of phosphorylated Akt. In the in vivo study, the intraperitoneal injection of 11-dehydrosinulariolide at a dosage of 10 mg/kg significantly inhibited tumor growth compared with the control treatment. Together, the data indicate that 11-dehydrosinulariolide induces G (2)/M cell cycle arrest and apoptosis through various cellular processes, including the upregulation of p53 and Bax, activation of ATM and Chk2, activation of caspase-3 and -7, and accumulation of PTEN, leading to inhibition of the Akt pathway. These findings suggest that 11-dehydrosinulariolide might serve as a promising chemotherapy drug in the treatment of SCLC.

BackgroundIt is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations.MethodsThis prospective study was a multicenter project conducted in Taiwan for assessment of lung adenocarcinoma genetic tests. Five oncogenic drivers, including EGFR, KRAS, BRAF, HER2 and EML4-ALK fusion mutations, were tested. EGFR, KRAS, BRAF and HER2 mutations were assessed by MALDI-TOF MS (Cohort 1). EML4-ALK translocation was tested by Ventana method in EGFR-wild type patients (Cohort 2).ResultsFrom August 2011 to November 2013, a total of 1772 patients with lung adenocarcinoma were enrolled. In Cohort 1 analysis, EGFR, KRAS, HER2 and BRAF mutations were identified in 987 (55.7%), 93 (5.2%), 36 (2.0%) and 12 (0.7%) patients, respectively. Most of these mutations were mutually exclusive, except for co-mutations in seven patients (3 with EGFR + KRAS, 3 with EGFR + HER2 and 1 with KRAS + BRAF). In Cohort 2 analysis, 29 of 295 EGFR-wild type patients (9.8%) were positive for EML4-ALK translocation. EGFR mutations were more common in female patients and non-smokers and KRAS mutations were more common in male patients and smokers. Gender and smoking status were not correlated significantly with HER2, BRAF and EML4-ALK mutations. EML4-ALK translocation was more common in patients with younger age.ConclusionThis was the first study in Taiwan to explore the incidence of five oncogenic drivers in patients with lung adenocarcinoma and the results could be valuable for physicians in consideration of targeted therapy and inclusion of clinical trials.

The relationship between asthma and ankylosing spondylitis (AS) is controversial. We examined the risk of asthma among AS patients in a nationwide population.We conducted a retrospective cohort study using data from the National Health Insurance (NHI) system of Taiwan. The cohort included 5,974 patients newly diagnosed with AS from 2000 to 2010. The date of diagnosis was defined as the index date. A 4-fold of general population without AS was randomly selected frequency matched by age, gender and the index year. The occurrence and hazard ratio (HR) of asthma were estimated by the end of 2011.The overall incidence of asthma was 1.74 folds greater in the AS cohort than in the non-AS cohort (8.26 versus 4.74 per 1000 person-years) with a multivariable Cox method measured adjusted HR of 1.54 (95% confidence interval (CI), 1.34-1.76). The adjusted HR of asthma associated with AS was higher in women (1.59; 95% CI, 1.33-1.90), those aged 50-64 years (1.66; 95% CI, 1.31-2.09), or those without comorbidities (1.82; 95% CI, 1.54-2.13).Patients with AS are at a higher risk of developing asthma than the general population, regardless of gender and age. The pathophysiology needs further investigation.

BACKGROUND:There are several publications reported that obstructive sleep apnea (OSA) was associated with asthma. However, large-scaled, population-based cohort study has been limited. We aimed to examine the risk of OSA among adult patients with asthma in an Asian population. METHODS:We conducted a retrospective cohort study using data from the National Health Insurance (NHI) of Taiwan. The asthma cohort included 38,840 newly diagnosed patients between 2000 and 2010. The date of diagnosis was defined as the index date. Each patient was randomly matched with four people without asthma according to gender, age, and the index year as the comparison cohort. The occurrence of OSA was followed up until the end of 2011. The risk of OSA was estimated using the Cox proportional hazard model after adjusting for gender, age, and comorbidities. RESULTS:The overall incidence of OSA was 2.51-fold greater in the asthma cohort than in the comparison cohort (12.1 versus 4.84 per 1000 person-years). Compared to non-asthma subjects, the adjusted hazard ratio (aHR) of OSA increased to 1.78 for asthma patients with one or less annual emergency room (ER) visit, and 23.8 for those who visited ER more than once per year. In addition, aHR in patients with inhaled steroid treatment compared to those without steroid treatment was 1.33 (95% CI = 1.01-1.76). CONCLUSION:Patients with asthma have a significantly higher risk of developing OSA than the general population. The results suggest that the risk of OSA is proportional to asthma control and patients with inhaled steroid treatment have a higher risk for OSA than those without steroid treatment.