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The combination of bevacizumab or ramucirumab with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy, chemotherapy, or immunotherapy for non-small-cell lung cancer (NSCLC) patients with EGFR mutations could have survival benefits. However, no study, to date, has been conducted to compare the efficacy and safety of these two antiangiogenic therapies (AATs). Stage IIIB to IV EGFR-mutated NSCLC patients who received first-line EGFR-TKIs between January 2014 and May 2022 were enrolled. These patients were divided into two groups: those receiving bevacizumab and those receiving ramucirumab as a combination therapy in any line of treatment. Ninety-six patients were enrolled in this study’s final analysis. The progression-free survival (PFS) of patients who received front-line AATs combined with EGFR-TKI therapy was longer than that of patients receiving later-line AATs combined with other therapies (19.6 vs. 10.0 months, p < 0.001). No difference in overall survival (OS) was observed between front-line and later-line therapy (non-reach vs. 44.0 months, p = 0.261). Patients who received these two different AATs did not differ in PFS (24.1 vs. 15.7 months, p = 0.454) and OS (48.6 vs. 43.0 months, p = 0.924). In addition, these two AATs showed similar frequencies of the T790M mutation (43.6% vs. 38.2%; p = 0.645). Multivariate Cox regression analysis indicated several AAT cycles as an independent good prognostic factor in OS. The incidence of some adverse events such as bleeding and hepatitis was higher for bevacizumab than for ramucirumab but it was not significant. Front-line AAT and EGFR-TKI combination therapy improved the PFS of stage IV EGFR-mutated NSCLC patients. The effectiveness and safety of the two AATs were similar.

Background Traditional Chinese medicine (TCM) has potential benefits to prevent multi-viral infection including by modulating the immune system or defending oxidative stress. Artemisia argyi (A. argyi) has been widely used for anti-microbial infection, anti-allergy, anti-diabetes, and anti-inflammation in Eastern Asia. However, it remain unclear whether A. argyi has the potential to reduce the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results Through the docking simulation, eriodictyol and umbelliferone, two phytochemicals existed in Artemisia argyi, have showed their potential to bind to cellular proteins transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2), which are required for the cellular entry of SARS-CoV-2. Our results further found that eriodictyol and umbelliferone suppressed the infection of ACE2-expressed HEK-293T cells with lentiviral-based pseudo-particles expressing wild type and variants of SARS-CoV-2 spike (S) protein via interrupting the interaction between S protein and cellular receptor ACE2 and via reducing ACE2 and TMPRSS2 expressions. Conclusions In summary, Artemisia argyi and its ingredients eriodictyol and umbelliferone are potential agents to reduce SARS-CoV-2 infection.

Targeting protein kinase C (PKC) family was found to repress the migration and resistance of non-small cell lung cancer cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, none of the PKC inhibitors has been approved for anticancer therapy yet due to the limited efficacy in clinical trials, and the underlying mechanisms remain unclear. l-lactic acidosis, a common condition comprising high l-lactate concentration and acidic pH in the tumor microenvironment, has been known to induce tumor metastasis and drug resistance. In this study, l-lactic acid was found to reverse the inhibitory effects of pan-PKC inhibitors GO6983 on PKC activity, cell migration, and EGFR-TKI resistance, but these effects were not affected by the modulators of lactate receptor GPR81. Interestingly, blockade of lactate transporters, monocarboxylate transporter-1 and -4 (MCT1 and MCT4), attenuated the intracellular level of GO6983, and its inhibitory effect on PKC activity, suggesting that lactic acid promotes the resistance to PKC inhibitors by competing for the uptake through these transporters rather than by activating its receptor, GPR81. Our findings explain the underlying mechanisms of the limited response of PKC inhibitors in clinical trials.

Objective: This real-world study evaluated the efficacy of once-daily long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) for improving spirometry in patients with chronic obstructive pulmonary disease (COPD).Methods: We conducted this retrospective study at a single medical center in Taiwan from December 2014 to September 2020. Patients with COPD who were treated with once-daily LABA/LAMA FDCs for 12 months were enrolled. We evaluated their lung function improvement after 12 months treatment with different LABA/LAMA FDCs. Results: A total of 198 patients with COPD who were treated with once-daily LABA/LAMA FDCs were analyzed. A total of 114 patients were treated with umeclidinium/vilanterol (UMEC/VIL); 34 patients were treated with indacaterol/glycopyrronium (IND/GLY) and 50 patients were treated with tiotropium/olodaterol (TIO/OLO). The forced expiratory volume in 1 second (FEV1%) was significantly increased in the patients treated with all three once-daily FDCs (55.2% to 60.9%; Δ = 5.74%, p=0.012 for UMEC/VIL, 58.2% to 63.6%; Δ = 5.37%, p=0.023 for IND/GLY, and 54.1% to 57.7%; Δ = 3.61%, p=0.009 for TIO/OLO). Treatment of COPD patients with TIO/OLO resulted in a significant improvement in both forced vital capacity (FVC%) (71.7% to 77.9%; Δ = 6.16%, p=0.009) and residual volume (RV%) (180.1% to 152.5%; Δ = -27.55%, pConclusions: Patients with COPD who were treated with different once-daily LABA/LAMA FDCs all had pulmonary lung function improvement in FEV1. Patients treated with UMEC/VIL or TIO/OLO showed better improvement in FVC compared to those treated with IND/GLY. On the other hand, those receiving TIO/OLO had better improvement in RV compared to those who received UMEC/VIL or IND/GLY.

Development of acquired resistance to lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor, severely limits the duration of clinical response in advanced HER2‐driven breast cancer patients. Although the compensatory activation of the PI3K/Akt survival signal has been proposed to cause acquired lapatinib resistance, comprehensive molecular mechanisms remain required to develop more efficient strategies to circumvent this therapeutic difficulty. In this study, we found that suppression of HER2 by lapatinib still led to Akt inactivation and elevation of FOX3a protein levels, but failed to induce the expression of their downstream pro‐apoptotic effector p27kip1, a cyclin‐dependent kinase inhibitor. Elevation of miR‐221 was found to contribute to the development of acquired lapatinib resistance by targeting p27kip1 expression. Furthermore, upregulation of miR‐221 was mediated by the lapatinib‐induced Src family tyrosine kinase and subsequent NF‐κB activation. The reversal of miR‐221 upregulation and p27kip1 downregulation by a Src inhibitor, dasatinib, can overcome lapatinib resistance. Our study not only identified miRNA‐221 as a pivotal factor conferring the acquired resistance of HER2‐positive breast cancer cells to lapatinib through negatively regulating p27kip1 expression, but also suggested Src inhibition as a potential strategy to overcome lapatinib resistance., The downregulation of p27kip1 by Src/NF‐κB axis‐induced miR‐221 expression as a novel mechanistic insight into lapatinib resistance. Targeting Src would be a promising strategy to overcome lapatinib resistance.

The tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have been widely used for non-small cell lung cancer (NSCLC) patients, but the development of acquired resistance remains a therapeutic hurdle. The reduction of glucose uptake has been implicated in the anti-tumor activity of EGFR TKIs. In this study, the upregulation of the active sodium/glucose co-transporter 1 (SGLT1) was found to confer the development of acquired EGFR TKI resistance and was correlated with the poorer clinical outcome of the NSCLC patients who received EGFR TKI treatment. Blockade of SGLT1 overcame this resistance in vitro and in vivo by reducing glucose uptake in NSCLC cells. Mechanistically, SGLT1 protein was stabilized through the interaction with PKCδ-phosphorylated (Thr678) EGFR in the TKI-resistant cells. Our findings revealed that PKCδ/EGFR axis-dependent SGLT1 upregulation was a critical mechanism underlying the acquired resistance to EGFR TKIs. We suggest co-targeting PKCδ/SGLT1 as a potential strategy to improve the therapeutic efficacy of EGFR TKIs in NSCLC patients.

Wei-Chun Huang,1,2 Chih-Yu Chen,1 Wei-Chih Liao,1,2 Biing-Ru Wu,1,3,4 Wei-Chun Chen,1,3,4 Chih-Yen Tu,1,2 Chia-Hung Chen,1,2 Wen-Chien Cheng1– 4 1Division of Pulmonary and Critical Care, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; 2School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan; 3Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 4Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, TaiwanCorrespondence: Wen-Chien Cheng; Chia-Hung ChenDivision of Pulmonary and Critical Care, Department of Internal Medicine, China Medical University Hospital, No. 2, Yude Road, North District, Taichung City, 40402, TaiwanEmail wcchengdr@gmail.com; hsnu758@gmail.comObjective: This real world study evaluated the effectiveness of switching to closed triple therapy from mono/dual combination or open triple therapy in patients with chronic obstructive pulmonary disease (COPD).Methods: We conducted this retrospective study at a single medical center from December 2014 to September 2020. Patients with COPD who were stepped up to triple therapy were enrolled. We analyzed the duration from initial COPD management to open or closed triple therapy and identified the clinical predictors of the patients who needed triple therapy early. We also evaluated the effectiveness of triple therapy after switching from initial management, and closed triple therapy after switching from open triple therapy.Results: A total 115 COPD patients who were stepped up to triple therapy from initial treatment were analyzed. The duration from initial treatment to triple therapy was 22.4 months. The baseline peripheral blood eosinophil counts of the patients who switched to triple therapy early (n=63, less than 22 months) and those who switched to triple therapy later (n=52, more than 22 months) were similar (489.6 vs 434.5 cells/uL; p=0.589). After univariate and multivariate analysis, the patients who were older had more acute exacerbations (AEs) in the previous year, asthma and COPD overlap (ACO), and initial dual bronchodilator therapy were stepped up to triple therapy early. The FEV1 of the patients was significantly increased after switching to open triple therapy from mono bronchodilator therapy. In addition, switching from initial or open triple therapy to closed triple therapy significantly reduced the incidence of AEs.Conclusion: COPD patients with high blood eosinophilia, older age, more AEs in the previous year, ACO, and initial dual bronchodilator therapy were stepped up to triple therapy early. Triple therapy showed improvements in lung function of most patients switching from mono bronchodilator therapy. After switching to closed triple therapy further reduced the incidence of AEs.Keywords: COPD, chronic obstructive pulmonary disease, closed triple therapy, open triple therapy, ACO, asthma COPD overlap

Wen-Chien Cheng,1 Te-Chun Hsia,1,2 Chih-Yen Tu,1,2 Hung-Jen Chen1,2 1Division of Pulmonary and Critical Care, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; 2School of Medicine, College of Medicine, China Medical University, Taichung, TaiwanCorrespondence: Hung-Jen ChenDivision of Pulmonary and Critical Care, Department of Internal Medicine, China Medical University Hospital, No. 2, Yude Road, North District, Taichung City 40447, TaiwanEmail redman0127@gmail.comObjective: To utilize liquid biopsy to investigate the potential clinical factors influencing the incidence of the acquired epidermal growth factor receptor (EGFR) T790M mutation, and the impact of EGFR circulating cell-free DNA (CfDNA) on overall survival for patients with advanced EGFR-mutated adenocarcinoma resistant to first-line EGFR-tyrosine kinase inhibitor (TKI).Methods: A retrospective study was conducted to analyze EGFR-mutated stage IIIB-IV adenocarcinoma patients who received an EGFR-TKI (gefitinib, erlotinib, or afatinib) as first-line therapy and then underwent a liquid biopsy exam at disease progression.Results: A total of 135 patients were included, and the T790M mutation was detected in 51 patients (37.7%). The incidence of T790M mutation increased with the number of initial metastatic sites (p = 0.015). Liver metastasis (odds ratio [OR], 3.373; p = 0.017) and other metastasis (OR, 3.063; p = 0.023) were also independently correlated with T790M mutation incidence. T790M mutation was also associated with more than two progressive sites (OR, 3.382; p = 0.006), liver progression (OR, 6.204; p = 0.002), and bone progression (OR, 3.366; p = 0.004). However, central nervous system progression was inversely correlated with T790M mutation (OR, 0.183; p = 0.027). Overall survival was the longest among the patients without CfDNA, followed by those shedding T790M mutation and those shedding Del 19/L858R mutations (p = 0.005).Conclusion: Initial metastasis to the liver and other sites may be independent factors for secondary EGFR T790M mutation. T790M-positive lung adenocarcinoma has specific progression patterns. Moreover, not having EGFR CfDNA, being positive for Del19/L858R mutations, and being positive for T790M mutation have differing impacts on overall survival for patients with advanced EGFR-mutated adenocarcinoma resistant to first-line EGFR-TKI.Keywords: circulating cell-free DNA, EGFR, liquid biopsy, overall survival, T790M

Wen-Chien Cheng,1– 6 Biing-Ru Wu,1,3,5,6 Wei-Chih Liao,1,2,4,7 Chih-Yu Chen,1 Wei-Chun Chen,1,3– 6 Te-Chun Hsia,1,4,8 Chih-Yen Tu,1– 3 Chia-Hung Chen,1,2,7 Wu-Huei Hsu1 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; 2School of Medicine, China Medical University, Taichung, Taiwan; 3Department of Life Science, National Chung Hsing University, Taichung, Taiwan; 4Department of Internal Medicine, Hyperbaric Oxygen Therapy Center, China Medical University Hospital, Taichung, Taiwan; 5Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 6Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan; 7Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; 8Department of Respiratory Therapy, China Medical University, Taichung, TaiwanCorrespondence: Chia-Hung Chen; Chih-Yu ChenDepartment of Internal Medicine, China Medical University Hospital, No. 2, Yude Road, Taichung, TaiwanEmail hsnu758@gmail.com; cychen0808@gmail.comPurpose: Triple therapy versus dual therapy for chronic pulmonary obstructive disease (COPD) can reduce symptoms, limit the risk of acute exacerbations (AEs) as well as improve lung function. Currently, studies that feature clinically important deterioration (CID) as a composite endpoint to assess the need for treatment intensification for patients maintained on dual therapy remained to be scarce.Patients and Methods: This study is a retrospective analysis (January 2014 to January 2018) of COPD patients that presented with moderate to severe AEs during the previous year with blood eosinophil counts ≥ 100 cells/μL. The first line of therapy included a combination of inhaled corticosteroid (ICS) and a long-acting β2 agonist (LABA). Composite CID was used in assessing the response to treatment after 24 weeks of therapy.Results: This study included 110 patients, of which 49 patients reportedly experienced CID. The most common events of CID include a decline in forced expiratory volume in 1 second (FEV1) ≥  100 mL from baseline (25/49, 51%) and an increase in COPD Assessment Test (CAT) scores ≥ 2 (13/49, 26.5%); many of these patients respond to the addition of a long-acting muscarinic antagonist (LAMA). Seven patients (7/110, 6.3%) experienced moderate to severe exacerbations while undergoing treatment with ICS/LABA. Univariate and multivariate analyses have identified low baseline FEV1 (OR = 0.81, p = 0.004), high CAT score (OR = 1.89, p = 0.004), and the frequency of AE (OR = 19.86, p = 0.021) as independent predictors of CID. A baseline FEV1 of ≤ 42%, an initial CAT score ≥ 18, and AE ≥ 2 last year were considered the optimal cut-off values, which were identified via receiver operating characteristics (ROC) curve analysis.Conclusion: Triple therapy (ICS/LABAs/LAMAs) may be considered as first-line treatment in patients experiencing more than 2 times moderate to severe AEs of COPD in the previous year and who have blood eosinophil counts ≥ 100 cells/μL, reduced lung function (FEV1 ≤ 42%), and more symptoms (CAT score ≥ 18).Keywords: inhaled corticosteroid, ICS, long-acting muscarinic antagonist, LAMA, long-acting β2 agonist, LABA, triple therapy, chronic pulmonary obstructive disease, COPD, clinically important deterioration, CID

Smoker patients with non-small cell lung cancer (NSCLC) have poorer prognosis and survival than those without smoking history. However, the mechanisms underlying the low response rate of those patients to EGFR tyrosine kinase inhibitors (TKIs) are not well understood. Here we report that exposure to cigarette smoke extract enhances glycolysis and attenuates AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR; this in turn reduces the sensitivity of NSCLC cells with wild-type EGFR (EGFRWT) to EGFR TKI by repressing expression of liver kinase B1 (LKB1), a master kinase of the AMPK subfamily, via CpG island methylation. In addition, LKB1 expression is correlated positively with sensitivity to TKI in patients with NSCLC. Moreover, combined treatment of EGFR TKI with AMPK activators synergistically increases EGFR TKI sensitivity. Collectively, the current study suggests that LKB1 may serve as a marker to predict EGFR TKI sensitivity in smokers with NSCLC carrying EGFRWT and that the combination of EGFR TKI and AMPK activator may be a potentially effective therapeutic strategy against NSCLC with EGFRWT.

Background Randomized controlled trials had demonstrated local therapy, such as radiotherapy, can improve outcomes of patients with lung cancer with oligometastatic disease (OMD). However, the definition of OMD is not uniform and the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) proposed a new classification in 2020 comprising nine subtypes. Therefore, we aimed to investigate the prognostic significance of this European classification for patients with lung OMD treated with definitive radical radiotherapy. Patients and methods We identified eligible patients via an in-house database. Patient, disease, and treatment characteristics, as well as outcomes, were obtained via chart review plus peer review. Overall and progression-free survival were estimated via the Kaplan-Meier method. Log-rank test was used in univariate analysis and Cox regression in multivariable analyses to investigate the prognostic significance of the subtypes of OMD. Results We identified 35 eligible patients with six different OMD subtypes treated from 2011 to 2019. After a median follow-up of 23 (range=2-88) months, the median progression-free and overall survival were 11 and 38 months, respectively. The prognosis for patients with the subtype 'induced oligoprogression' was statistically worse than for those without in both univariate (p=0.02) and multivariate (adjusted hazard ratio for death=4.8, 95% confidence interval=1.4-16.2, p=0.01) analyses. Conclusion We found the subtype with induced oligoprogression in the European classification to be associated with worse survival. Further studies are needed to confirm our finding.

BACKGROUND For lung cancer (LC) patients with limited brain metastases (LBM), radiosurgery (RS) was the current preferred strategy. We aimed to report our experience regarding an alternative strategy (focal conformal fractionated radiotherapy, FCFRT) for these patients in this cohort study. METHODS We identified LC patients with LBM treated with either FCFRT or RS within 2016-2019 without prior brain local treatment via in-house databases. The characteristics of patients, disease, treatment, and outcome were retrospectively obtained via chart review and peer review. The 1st day of FCFRT or RS was the index date. Overall survival (OS) was calculated from the index date to the last date of contact or death via the Kaplan-Meier method. Log-rank test was used in univariate analyses (UVA) whereas Cox regression method was used in the multivariate analyses (MVA). The incidence of local progression (LP) or distal brain metastases (DBM) was estimated by the competing risk approach with death as the competing risk. RESULTS We identified 23 eligible patients. The median dose/fractionation for FCFRT was 36 Gy/10 fractions. The median dose for RS was 20 Gy. The Lung-molGPA prognostic groups' distribution for these two groups was not statistically different. After a median follow-up of 8 months (range, 1-38 months), the OS was not statistically different in UVA [P value 0.9]. The adjusted hazard ratio of death was 0.96 when FCFRT was compared to RS in MVA (95% CI, 0.21-5.22). There was also no statistical significant difference in LP (P value 0.79) or DBM (P value 0.88). CONCLUSIONS For LC patients with LBM, the OS was not statistically different for definitive FCFRT or RS. There was also no statistical difference in LP or DBM. Further studies should be considered to clarify the indication of FCFRT.

Background This study aimed to evaluate the characteristics of patients with newly diagnosed advanced lung cancer who initially presented with respiratory failure. Methods This was a retrospective study which analyzed patients in the intensive care unit (ICU) with newly diagnosed advanced lung cancer who were placed on mechanical ventilation (MV). We defined newly diagnosed lung cancer as pathological or molecular results for treatment decisions not yet determined when the patient was admitted to ICU. Results During the 14‐year inclusion period, 845 lung cancer patients requiring MV were screened. A total of 56 newly diagnosed extensive lung cancer patients were analyzed. Cancer‐related to central airway obstruction (n = 29, 51.8%) was the leading cause of respiratory failure. The significant etiologies of delay in the diagnosis of lung cancer were diagnostic error, mistaking cancer for tuberculosis, and missed hilar lesions. The six‐month survival rate was only 7.1% (n = 4). The sequential organ failure assessment (SOFA) score was significantly associated with mortality (HR = 1.142, 95% CI = 1.012–1.288, P = 0.031). The six‐month survival rate in patients receiving suitable targeted therapy and accepting chemotherapy and best supportive care was 40% (2/5), 0% (0/7), and 4.5% (2/44), respectively. Conclusions Patients with newly diagnosed advanced lung cancer with acute life‐threatening respiratory failure have poor outcomes. Cancer‐related to central airway obstruction is a leading cause of respiratory failure. Diagnostic errors such as tuberculosis and missed hilar lesions are the two main etiologies of a delay in diagnosis. The SOFA score is correlated with mortality. Targeted therapy can raise the six‐month survival rates in patients with oncogenic mutation adenocarcinoma, who survive after presentation in a critical condition., This was a retrospective study which assessed the etiologies of delayed diagnosis and characteristics of patients with newly diagnosed advanced lung cancer who initially presented with respiratory failure.

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., In this updated nonrandomized study, we found that overall survival of locally advanced lung cancer patients treated with definitive concurrent chemoradiotherapy was not statistically different between those treated with IGRT versus non‐IGRT. The results should be interpreted with caution given the nonrandomized design. Randomized controlled trials are needed to clarify this finding.

The role of adjuvant concurrent chemoradiotherapy (aCCRT) for locally advanced non-small cell lung cancer (LA-NSCLC) treated with radical surgery, with microscopically involved resection margin, has been debated without there being any direct evidence. In this study, we aimed to compare the outcomes between aCCRT and adjuvant chemotherapy (aCT).Eligible patients diagnosed within 2011-2018 with LA-NSCLC were identified via the Taiwan Cancer Registry. We used propensity-score weighting to balance observable potential confounders, and then compared the hazard ratios of death between aCCRT-treated vs. aCT-treated groups. We also performed supplementary analyses using propensityscore matching.Our main study population consisted of 82 patients. The propensity score weight-adjusted hazard ratio of death for the aCCRT group was 0.74 (95% confidence interval=0.35-1.56, p=0.43). There was also no statistically significant difference in survival between groups in the supplementary analyses.For patients treated with radical but R1 resection for LA-NSCLC, there was no significant OS benefit from the addition of concurrent radiotherapy.

To compare the clinical efficacy of cefoperazone-sulbactam with piperacillin-tazobactam in the treatment of severe community-acquired pneumonia (SCAP).The retrospective study was conducted from March 1, 2018 to May 30, 2019. Clinical outcomes were compared for patients who received either cefoperazone-sulbactam or piperacillin-tazobactam in the treatment of SCAP. A total of 815 SCAP patients were enrolled. Among them, 343 received cefoperazone-sulbactam, and 472 received piperacillin-tazobactam. Patients who received cefoperazone-sulbactam presented with higher Charlson Comorbidity Index scores. (6.20 ± 2.77 vs 5.72 ± 2.61; p = 0.009). The clinical cure rates and effectiveness for patients receiving cefoperazone-sulbactam and piperacillin-tazobactam were 84.2% versus 80.3% (p = 0.367) and 85.4% versus 83.3% (p = 0.258), respectively. In addition, the overall mortality rate of the cefoperazone-sulbactam group was 16% (n = 55), which was also comparable to the piperacillin-tazobactam group (17.8%, n = 84, p = 0.572). The primary clinical outcomes for patients receiving cefoperazone-sulbactam were superior compared to those receiving piperacillin-tazobactam after adjusting disease severity status. The clinical efficacy of cefoperazone-sulbactam in the treatment of adult patients with SCAP is comparable to that of piperacillin-tazobactam. After adjusting for disease severity, cefoperazone-sulbactam tended to be superior to piperacillin-tazobactam.

The poor prognosis and chemoresistance of patients with triple-negative breast cancer (TNBC) urge the development of new therapeutic strategies. Snail mucus has shown its ability against inflammation, a process closely related to tumorigenesis, suggesting a potential anti-cancer activity.The effect and mechanisms of snail mucus on cell viability were determined by IncuCyte Live-cell analysis and molecular biological methods. The anti-cancer fractions of snail mucus were isolated and identified by medium pressure liquid chromatography (MPLC) and nuclear magnetic resonance (NMR) spectrometry analysis.Snail mucus significantly decreased the viability of TNBC cells with relatively lower cytotoxicity to normal breast epithelial cells and enhanced their response to chemotherapy through activation of Fas signaling by suppressing nucleolin. Two peptide fractions have been identified as the anti-cancer ingredients of the snail mucus.Snail mucus can induce programmed cell death via the extrinsic apoptotic pathway and has therapeutic potential by achieving a chemo-sensitizing effect in TNBCs.

BackgroundTriple-negative breast cancers (TNBCs) patients showed poor survival outcomes due to chemoresistance, and the development of new therapeutic strategies is urgently needed. The development of cancer is mainly related to chronic inflammation. Therefore, the pharmacological reduction of inflammation by natural extract components may promote anti-cancer activity and increase chemosensitivity. Snail mucus has been reported to possess the ability against inflammation, a process closely related to tumorigenesis, suggesting a potential anti-cancer function. The direct cytotoxic activity of snail mucus in cancer cells was investigated in this study.Methods The effect of snail mucus on cell viability in breast cancer cells and normal epithelial cells were measured by MTT and IncuCyte Live-cell analysis. The active fractions of snail mucus were isolation by performing MPLC and the anti-cancer ingredients were identified by NMR spectrometer analysis.Results Snail mucus significantly decreased the proliferation and viability of TNBC cells with relatively lower cytotoxicity to normal breast epithelial cells and enhanced their response to chemotherapy. Mechanistically, snail mucus induces an extrinsic apoptotic pathway through activation of Fas signaling by suppressing nucleolin. Two possible peptide fractions have also been identified as the anti-cancer ingredients of the snail mucus.ConclusionsIn summary, snail mucus can induce programmed cell death via the extrinsic apoptotic pathway and might have therapeutic potential with chemo-sensitizing effect for TNBCs.

Chia-Hung Chen,1 Chih-Yen Tu,1 Wei-Chih Chen,2 Li-Kuo Kuo,3 Yao-Tung Wang,4 Pin-Kuei Fu,5 Shih-Chi Ku,6 Wen-Feng Fang,7 Chin-Ming Chen,8 Chih-Cheng Lai9 1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; 2Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan; 4Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; 5Department of Critical Care Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; 6Division of Chest Medicine, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 8Department of Intensive Care Medicine, Chi Mei Medical Center, Tainan, Taiwan; 9Department of Internal Medicine, Kaohsiung Veterans General Hospital, Tainan Branch, Tainan, TaiwanCorrespondence: Chih-Cheng Lai Email dtmed141@gmail.comObjective: The aim of this study was to compare the usefulness of cefoperazone-sulbactam and that of piperacillin-tazobactam in the treatment of hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).Methods: This retrospective study included the adult patients receiving cefoperazone-sulbactam or piperacillin-tazobactam against HAP/VAP in nine hospitals in Taiwan from March 1, 2018 to May 30, 2019. Primary outcome was clinical cure rate.Results: A total of 410 patients were enrolled. Among them, 209 patients received cefoperazone-sulbactam and 201 patients received piperacillin-tazobactam. Overall, cefoperazone-sulbactam group had similar distribution of age, sex, or SOFA scores as piperacillin-tazobactam group. However, cefoperazone-sulbactam had higher comorbidity score and disease severity than piperacillin-tazobactam group (Charlson score: 6.5 ± 2.9 vs 5.7 ± 2.7, p < 0.001; APACHE II score: 21.4 ± 6.2 vs 19.3 ± 6.0, p = 0.002). Regarding clinical outcomes, no significant difference in clinical cure and failure rates was observed between cefoperazone-sulbactam and piperacillin-tazobactam group (clinical cure rate: 80.9% vs 80.1% and clinical failure rate: 17.2% vs 18.4%, p = 0.943). Moreover, no significant difference in clinical effectiveness and ineffectiveness rates was observed between cefoperazone-sulbactam and piperacillin-tazobactam group (clinical effective rate: 80.9% vs 80.6% and clinical ineffective rate: 17.7% vs 18.9%, p = 0.711). The all-cause mortality rates of the cefoperazone-sulbactam and piperacillin-tazobactam groups were similar (23.9% vs 20.9%, p = 0.48). After adjustment of Charlson score and APACHE II score, the similarities in these clinical outcomes did not change in overall patients and patients with HAP or VAP.Conclusion: For treating adult patients with nosocomial pneumonia, cefoperazone-sulbactam was as effective as piperacillin-tazobactam.Keywords: cefoperazone-sulbactam, hospital-acquired pneumonia, piperacillin-tazobactam, ventilator-associated pneumonia

Hesperidin (HD) is a common flavanone glycoside isolated from citrus fruits and possesses great potential for cardiovascular protection. Hesperetin (HT) is an aglycone metabolite of HD with high bioavailability. Through the docking simulation, HD and HT have shown their potential to bind to two cellular proteins: transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2), which are required for the cellular entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results further found that HT and HD suppressed the infection of VeroE6 cells using lentiviral-based pseudo-particles with wild types and variants of SARS-CoV-2 with spike (S) proteins, by blocking the interaction between the S protein and cellular receptor ACE2 and reducing ACE2 and TMPRSS2 expression. In summary, hesperidin is a potential TMPRSS2 inhibitor for the reduction of the SARS-CoV-2 infection.

BACKGROUND: According to several phase III studies, tiotropium [a long-acting muscarinic antagonist (LAMA)] is a well-tolerated add-on therapy to inhaled corticosteroids (ICS) for asthmatics with or without the addition of long-acting beta2-agonists (LABAs). However, real-world studies based on clinical phenotypes to predict the long-term need of tiotropium as an add-on therapy for asthmatics are limited. METHODS: This is a retrospective study conducted at a single medical center in Taiwan from July 2016 to July 2018. An asthma control test (ACT) is applied to uncontrolled asthmatics to evaluate the effectiveness of tiotropium as an add-on therapy. Asthmatic subgroups with different clinical phenotypes and needing long-term tiotropium as a maintenance treatment are identified. The effectiveness of tiotropium add-on therapy is defined as an improvement of ACT score ≥3 points 3 months after the treatment (vs. baseline), while the long-term requirement of tiotropium is defined as tiotropium dependency >1 year. RESULTS: The study analyzed a total of 160 uncontrolled asthmatics regardless of low- or medium-to-high-dose ICS plus LABA. One hundred and twelve patients responded well (ACT score increased ≥3 points) to tiotropium. These patients were further divided into two subgroups: one with tiotropium add-on therapy for ≥1 year due to patients’ difficulties in stepping down from tiotropium; the other with tiotropium add-on therapy for 30 kg/m(2) were predictors for asthmatics requiring long-term tiotropium add-on therapy. CONCLUSIONS: Tiotropium add-on therapy is effective for uncontrolled asthmatics. Moreover, patients with ACO, initial FEV1% predicted 30 kg/m(2) require long-term tiotropium add-on therapy for asthma control.

Background and objective In the United States, lung cancer is the leading cause of cancer death. The survival rate could increase by early detection. In recent years, the endobronchial ultrasonography (EBUS) images have been utilized to differentiate between benign and malignant lesions and guide transbronchial needle aspiration because it is real-time, radiation-free and has better performance. However, the diagnosis depends on the subjective judgment from doctors. In some previous studies, which using the grayscale image textures of the EBUS images to classify the lung lesions but it belonged to semi-automated system which still need the experts to select a part of the lesion first. Therefore, the main purpose of this study was to achieve full automation assistance by using convolution neural network. Methods First of all, the EBUS images resized to the input size of convolution neural network (CNN). And then, the training data were rotated and flipped. The parameters of the model trained with ImageNet previously were transferred to the CaffeNet used to classify the lung lesions. And then, the parameter of the CaffeNet was optimized by the EBUS training data. The features with 4096 dimension were extracted from the 7th fully connected layer and the support vector machine (SVM) was utilized to differentiate benign and malignant. This study was validated with 164 cases including 56 benign and 108 malignant. Results According to the experiment results, applying the classification by the features from the CNN with transfer learning had better performance than the conventional method with gray level co-occurrence matrix (GLCM) features. The accuracy, sensitivity, specificity, and the area under ROC achieved 85.4% (140/164), 87.0% (94/108), 82.1% (46/56), and 0.8705, respectively. Conclusions From the experiment results, it has potential ability to diagnose EBUS images with CNN.

BACKGROUND Nosocomial bloodstream infection (BSI) remains a significant cause of mortality and morbidity. We evaluate the trend of the pathogens of nosocomial BSI and investigate the distribution of the pathogens to demonstrate the risk factors of mortality. METHODS In this retrospective study, we collected data from a 2076-bed tertiary referral center that offers a full range of clinical services in central Taiwan during January, 2016 to December, 2017. RESULTS Five hundred and eighty-four patients were identified with nosocomial BSI. Among the comorbidities of nosocomial BSI patients with, the most frequent were hypertension, in 294 patients (50.3%), malignancy, in 279 patients (47.8%); diabetes, in 278 patients (47.6%); chronic kidney disease, in 171 patients (29.3%); and liver cirrhosis, in 132 patients (22.6%). Gram-positive organisms caused 22.9% of these nosocomial BSIs, gram-negative organisms caused 69.2%, and fungi caused 6.8%. The most common organism causing nosocomial BSIs were Klebsiella spp. (14%), E coli. (14%), and Enterococcus spp. (11%). Multivariate analysis of risk factors for mortality displayed that comorbidity with low body weight, liver cirrhosis, and malignancy, high CRP level, high Charlson Comorbidity Index and internal medicine and hematology/oncology distribution were strikingly associated with mortality (P = 0.0222, 0.0352, 0.0008, 0.0122

Background Few large-scale cohort studies have investigated the association between community acquired pneumonia and the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). We aimed to study whether using ACEIs or ARBs had protective effects for community acquired pneumonia. Methods This database cohort study was conducted retrospectively in Taiwan. The hypertensive patients were the target population of this study. Patients with ARB use were defined as our first study cohort. The second study cohort comprised patients who used ACEI. Propensity-score matching at 1:1 was used between ARB users and non-ARB users. We recruited 67 944 participants for the ARB study and 58 062 participants for the ACEI study. The same matching was also performed between ACEI users and non-ACEI users. Cox proportional hazard regression was used to analyze the risk of the outcome of viral pneumonia. Results The hazard ratio of community acquired pneumonia for ARB users relative to non-ARB users was 0.33. The hazard ratio of community acquired pneumonia was 0.71 times in ACEI users compared with ACEI nonusers. In stratification analysis, both ARB and ACEI both exhibited a protective effect for community acquired pneumonia in each age and sex group. In the analysis of the effects of therapy duration, patients using ARB for fewer than 100 days exhibited a greater reduction in the risk of community acquired pneumonia (adjusted HR = 0.58) compared with the non-ARB cohort. For the ACEI study, patients who used ACEI for 121 to 450 days were more likely to exhibit reduced risks of community acquired pneumonia (adjusted HR = 0.5). Conclusion Both ACEI and ARB uses were associated with decreased risk of community acquired pneumonia infection.

Objective Image 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. Methods Patients 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. Results 184 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). Conclusions Type 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.

We report the case of a 24‐year‐old man who presented with chief complaints of shortness of breath and haemoptysis; chest radiography revealed complete collapse of the left lung. Bronchoscopy revealed an endobronchial tumour with complete obstruction of the left main bronchus. Cryosurgical excision was performed; tissue pathology confirmed the diagnosis of metastatic embryonal carcinoma. The patient underwent a right orchiectomy followed by a bleomycin + etoposide + cisplatin (BEP) chemotherapy regimen., In this report, we present a case of endobronchial metastases from a primary embryonal carcinoma.

OBJECTIVES We hypothesized that specific endobronchial ultrasound (EBUS) features may differentiate sarcoidosis from other causes of lymphadenopathy. METHODS We conducted this retrospective observational study from January 2014 to January 2019 to analyze patients with intrathoracic lymphadenopathy who underwent EBUS-guided transbronchial needle aspiration. Ultrasound features, including nodal size, margin, echogenicity, the presence or absence of calcification, a central hilar structure, the coagulation necrosis sign, nodal conglomeration, and the septal vessel sign in the color Doppler mode were recorded and compared between 3 groups. RESULTS Of the 90 included patients, 15 had a diagnosis of tuberculosis; 56 had a diagnosis of sarcoidosis; and 19 had a diagnosis of malignant lymph nodes by EBUS-guided transbronchial needle aspiration. The presence of nodal conglomeration (94.6% versus 60.0% versus 5.3%; P

Both cefoperazone-sulbactam (CFP-SUL) and piperacillin-tazobactam (PIP-TAZ) are β-lactam/β-lactamase inhibitor antibiotics and have a similar antimicrobial spectrum. However, comparative clinical efficacy and safety of CFP-SUL and PIP-TAZ for the treatment of pneumonia remain largely unknown, especially in elderly patients.Based on a multi-centre registry database, patients aged ≥65 years, diagnosed with severe community-acquired pneumonia (SCAP), hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP), and given empirical therapy with CFP-SUL or PIP-TAZ were included in the analysis. The primary outcome of interest was the proportion of patients achieving clinical cure. Multi-variate logistic regression was conducted to compare odds ratios (OR) for the outcome between patients who received CFP-SUL and patients who received PIP-TAZ.In total, 941 elderly patients (624 with SCAP, and 317 with either HAP or VAP) were included in this study. Overall in-hospital mortality for the entire cohort was 19%. Clinical cure was achieved in 81% and 83% of patients with SCAP and HAP/VAP, respectively. Multi-variate logistic regression analysis showed similar odds for clinical cure for patients receiving CFP-SUL or PIP-TAZ among those with SCAP [adjusted OR 1.10, 95% confidence interval (CI) 0.71-1.70] or HAP/VAP (adjusted OR 0.72, 95% CI 0.30-1.76). Regarding safety, both CFP-SUL and PIP-TAZ were generally well tolerated with few reported adverse events.Among elderly patients with SCAP or HAP/VAP, empirical therapy with CFP-SUL is a viable alternative to PIP-TAZ, while considering antibiotic heterogeneity in the antimicrobial stewardship context.

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.

Background: Long-acting muscarinic antagonist (LAMA) tiotropium improved lung function and reduced risks of exacerbation when added on to inhaled corticosteroids (ICS) with or without long-acting B2 agonists (LABAs) in patients with uncontrolled asthma. However, studies predicting the effectiveness of tiotropium based on patients’ clinical characteristics were limited. Methods: We conducted this retrospective study at a single medical center from July 2016 to July 2017, and used asthma control test (ACT) to evaluate the effectiveness of tiotropium add-on therapy in patients with uncontrolled asthma. The effectiveness was shown by an increase in ACT score from baseline of 3 or greater after 3 months of tiotropium add-on therapy. Results: Patients with uncontrolled asthma despite the use of low- or medium- to high-dose of ICS plus LABA (n=160) were analyzed. Among patients having good response (n=112, ACT score increased ≥3 points) to tiotropium (TGR group) and patients having poor response (n=48, ACT increased 30 were predictors of the effectiveness of tiotropium. Patients with high serum total IgE level >430 µg/L and eosinophil count >0.6×10 9 /L had a negative impact on response to tiotropium. Multivariate logistic regression analysis demonstrated that the independent factor of poor response to tiotropium was high serum IgE level >430 µg/L. Conclusions: Tiotropium add-on therapy in patients with uncontrolled asthma was effective. However, patients with serum total IgE level >430 µg/L were less likely to benefit from tiotropium.

Pleuroscopy, also known as medical thoracoscopy (MT), is an important tool for pleural disease management. Removal of foreign body (FB) by MT was reported in a few reports because it can identify the position of a FB in the pleural cavity and can be used for its urgent removal. In this study, we describe the case of a male patient with a ruptured lung abscess and a rare complication of self-expandable metallic stent (SEMS) migration into the pleural cavity via a bronchopleural fistula after the management of obstructive airway disease. An experienced pulmonologist successfully removed the SEMS from the pleural cavity using semi-rigid pleuroscopy under local anesthesia and conscious sedation in a bronchoscopy suite.

// Chih-Yen Tu 1, 2, 3, * , Chuan-Mu Chen 1, * , Wei-Chih Liao 2, 5, 6 , Biing-Ru Wu 2 , Chih-Yu Chen 2, 6 , Wei-Chun Chen 2, 6 , Te-Chun Hsia 2, 4, 5 , Wen-Chien Cheng 2 and Chia-Hung Chen 2, 4, 5, 7 1 Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan 2 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan 3 School of Medicine, China Medical University, Taichung, Taiwan 4 Department of Respiratory Therapy, China Medical University, Taichung, Taiwan 5 Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan 6 Department of Internal Medicine, Hyperbaric Oxygen Therapy Center, China Medical University, Taichung, Taiwan 7 Taiwan Clinical Trial Consortium for Lung Diseases (TCoC), Taichung, Taiwan * These authors contributed equally to this work Correspondence to: Wei-Chih Liao, email: weichih.liao@gmail.com Chia-Hung Chen, email: hsnu758@gmail.com Keywords: EGFR-mutated lung adenocarcinoma; gefitinib; erlotinib; afatinib; progression-free survival Received: August 21, 2017 Accepted: January 25, 2018 Epub: February 04, 2018 Published: May 11, 2018 ABSTRACT Introduction: Patients with advanced lung adenocarcinoma harboring epidermal growth factor receptor (EGFR)-activating mutations have good response rate and longer progression-free survival (PFS) when treated with the tyrosine kinase inhibitors (TKI) compared with platinum-based chemotherapy. However, studies comparing the effectiveness of these drugs as first-line therapy in such patients are limited. Results: We analyzed 422 patients with EGFR-mutated advanced lung adenocarcinoma receiving first-line gefitinib ( n = 195, 46.2%), erlotinib ( n = 123, 29.1%), or afatinib ( n = 104, 24.6%). The PFS of the afatinib group was longer (12.2 months) than that of the gefitinib group (9.8 months) ( p = 0.035) but similar to that of the erlotinib group (11.4 months) ( p = 0.38). In patients without brain metastasis (BM), subgroup analysis showed that the afatinib group had significantly longer PFS (13.1 months) than erlotinib (11.7 months) and gefitinib (9.8 months) groups ( p = 0.010). Patients with exon 19 deletions in the afatinib and erlotinib groups had potentially long PFS ( p = 0.073). Efficacy of afatinib was similar between the 30 mg and 40 mg arms (median PFS 16.1 months vs. 10.3 months; p = 0.923). Conclusions: Afatinib may be the optimal EGFR-TKI for advanced lung adenocarcinoma harboring EGFR-activating mutations, particularly in the absence of BM. Patients with exon 19 deletions taking afatinib had potentially long PFS. An afatinib dose of 30 and 40 mg has similar effect. Methods: We conducted this retrospective study at a single medical center from January 2013 to March 2017 and used PFS to evaluate the effectiveness of gefitinib, erlotinib, and afatinib in patients with advanced lung adenocarcinoma harboring EGFR mutations.

Background Stereotactic ablative radiotherapy (SABR) is a promising option for non-operated early-stage non-small cell lung cancer (NSCLC) compared to conventional fractionated radiotherapy (CFRT). However, results from conclusive randomized controlled trials are not yet available. The aim of our study was to explore the effectiveness of SABR vs. CFRT for non-operated early-stage NSCLC. Patients and methods We used a comprehensive population-based database to identify clinical stage I non-operated NSCLC patients in Taiwan diagnosed from 2007 to 2013 who were treated with either SABR or CFRT. We used inverse probability weighting and the propensity score as the primary form of analysis to address the nonrandomization of treatment. In the supplementary analyses, we constructed subgroups based on propensity score matching to compare survival between patients treated with SABR vs. CFRT. Results We identified 238 patients in our primary analysis. A good balance of covariates was achieved using the propensity score weighting. Overall survival (OS) was not significantly different between those treated with SABR vs. CFRT (SABR vs. CFRT: probability weighting adjusted hazard ratio [HR] 0.586, 95% confidence interval 0.264–1.101, p = 0.102). However, SABR was significantly favored in supplementary analyses. Conclusions In this population-based propensity-score adjusted analysis, we found that OS was not significantly different between those treated with SABR vs. CFRT in the primary analysis, although significance was observed in the supplementary analyses. Our results should be interpreted with caution given the database (i.e., nonrandomized) approach used in our study. Overall, further studies are required to explore these issues.

The increase in incidental discovery of pulmonary nodules has led to more urgent requirement of tissue diagnosis. The peripheral pulmonary nodules are especially challenging for clinicians. There are various modalities for diagnosis and tissue sampling of pulmonary lesions, but most of these modalities have their own limitations. This has led to the development of many advanced technical modalities, which have empowered pulmonologists to reach the periphery of the lung safely and effectively. These techniques include thin/ultrathin bronchoscopes, radial probe endobronchial ultrasound (RP-EBUS), and navigation bronchoscopy—including virtual navigation bronchoscopy (VNB) and electromagnetic navigation bronchoscopy (ENB). Recently, newer technologies—including robotic-assisted bronchoscopy (RAB), cone-beam CT (CBCT), and augmented fluoroscopy (AF)—have been introduced to aid in the navigation to peripheral pulmonary nodules. Technological advances will also enable more precise tissue sampling of smaller peripheral lung nodules for local ablative and other therapies of peripheral lung cancers in the future. However, we still need to overcome the CT-to-body divergence, among other limitations. In this review, our aim is to summarize the recent advances in diagnostic bronchoscopy technology.

Background: Studies have reported an association between asthma and oral diseases, including periodontal diseases. The aim of this retrospective study is to investigate risk of periodontal diseases for patients with asthma.Methods: Using the claims data of National Health Insurance of Taiwan and patients without a history of periodontal diseases, 19,206 asthmatic patients, who were newly diagnosed from 2000 through 2010, were identified. For each case, four comparison individuals without history of asthma and periodontal disease were randomly selected from the general population and frequency matched (categorical matched) by sex, age, and year of diagnosis (n = 76,824). Both cohorts were followed to the end of 2011 to monitor occurrence of periodontal diseases. Adjusted hazard ratios (aHRs) of periodontal disease were estimated using Cox proportional hazards regression analysis.Results: Overall incidence of periodontal diseases was 1.18-fold greater in the asthma cohort than in the comparison cohort (P

Pleural empyema is an important complication of pneumonia. Patients with stroke are at a higher risk developing pneumonia; however, the association between stroke and pleural empyema risk is largely unknown. We used the data from the National Health Insurance Research Database of Taiwan to establish a stroke group consisting of 466,170 patients diagnosed between 2000 and 2010, and a non-stroke group consisting of the same number of individuals matched by the propensity score. Incident pleural empyema was monitored toward the end of 2011. Adjusted hazard ratios (aHRs) of pleural empyema in the stroke group, compared to the non-stroke group, were estimated using the Cox proportional hazards model. We found that the incidence of pleural empyema is 2.69-fold higher in the stroke group than in the non-stroke group (15.2 vs. 5.59/10,000 person-years, p

Acquired resistance occurs in most non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations experiencing a response to EGFR-tyrosine kinase inhibitor (TKI) initially. We investigated EGFR-TKI retreatment in patients who had previously received EGFR-TKI followed by chemotherapy.This was a retrospective multicenter study. Patients with locally advanced or metastatic adenocarcinoma or TTF-1 (+) NSCLC, positive EGFR sensitive mutation, and EGFR-TKI reuse after initial EGFR-TKI followed by chemotherapy were enrolled. The objectives were to assess the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of EGFR TKI switched retreatment.In total, 205 patients were enrolled, with a median age of 61.8 years (range 31.4-92.9). There was a larger proportion of females (62.9%) than males, and more never-smokers (73.2%) than ever-smokers. In the initial EGFR-TKI administration, 57.6% of patients showed a complete response (CR) or partial response (PR), and 34.6% had stable disease (SD); in the second-line chemotherapy, 13.7% had PR, and 58.0% had SD; in the EGFR-TKI retreatment, 7.3% had PR, and 37.1% had SD. The median PFS of first-line EGFR-TKI was 8.0 months (95% CI 7.3-8.2), and retreatment EGFR-TKI was 4.1 months (95% CI 2.7-4.6). The median OS since the start of the first-line EGFR-TKI therapy was 35.9 months (95% CI 28.8-50.9), and since the start of EGFR-TKI retreatment was 12.6 months (95% CI 10.4-20.9). In the univariable and multivariable regression analysis of factors associated with PFS of EGFR-TKI retreatment, time interval between the two EGFR TKIs equal to or more than 7 months was statistically significant (HR=0.62, 95% CI 0.44-0.86; HR=0.6, 95% CI 0.43-0.86), both p0.01. Females with exon 21 mutation also showed a significant difference between the two groups (HR=0.51, 95% CI 0.30-0.86; HR=0.52 (0.31-0.88), both p0.05).EGFR-TKI retreatment was effective in prolonging survival, and was shown to be a worthwhile option for EGFR-mutated NSCLC patients after failure of first-line EGFR-TKI and chemotherapy. The survival benefit was especially pronounced in patients with longer drug holidays from the initial EGFR-TKI and in females with the exon 21 mutation.

Background: We hypothesized that specific sonographic features on endobronchial ultrasonography (EBUS) may differentiate sarcoidosis from other lymph nodes. In current study, the sonographic features of sarcoidosis, lymphoma and tuberculosis lymph nodes were compared. Methods: We conducted a retrospective observational study to analyze the patients with intrathoracic lymphadenopathy who underwent EBUS-guided transbronchial needle aspiration (TBNA). Sonographic features such as nodal size, margin, echogenicity, and presence or absence of calcification, a central hilar structure, coagulation necrosis sign, intranodular vascularity, and nodal conglomeration were recorded and compared in the 3 groups. Results: During the study period, a diagnosis of tuberculosis (n=9), sarcoidosis (n=53), and lymphoma (n=9) was made in 71 patients by EBUS-TBNA. Presence of nodal conglomeration (98.1% versus 88.9% versus 11.1 %, P Conclusions: The presence of nodal conglomeration, and intranodular vascularity, and absence of coagulation necrosis in the lymph nodes on EBUS are predictive of sarcoidosis.