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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

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.

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

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.

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: 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 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

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.

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 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.

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.

Background: Tiotropium is well tolerated and significantly improve lung function and asthma control as add-on therapy to ICS with or without LABA treatment regardless of baseline characteristics from phase III studies. However, real word studies predicting the long-term need of tiotropium add-on therapy according to clinical phenotypes of asthmatics were limited. Methods: This retrospective study was conducted at a single medical center from July 2016 to July 2018, and used asthma control test (ACT) to evaluate the effectiveness of tiotropium as add-on therapy in uncontrolled asthmatics. We try to identify the subgroups of asthmatics who need long-term use of tiotropium as a maintenance treatment. The effectiveness is defined as an increased in ACT score > or =3 from baseline after 3 months of tiotropium as add-on therapy. The long-term need of tiotropium is defined as patients required this maintenance drug > 1 year. Results: A total of 160 uncontrolled asthmatics despite the use of low- or medium - to high-dose of ICS plus LABA were analyzed. There were 112 patients having good response ( ACT score ≧3 points) to tiotropium. Among these patients, subjects were divided into two groups: one was tiotropium adding on therapy > 1 year because patients cannot step down easily; the other was tiotropium adding on therapy 30 were predictors of asthmatics who required long term use of tiotropium. Conclusions: Athmatics with ACO, initial FEV1 30 required long-term use of tiotropium.

Background Transbronchial lung cryobiopsy (TBLC) has emerged as a new bronchoscopic procedure which can improve specimen size and obtain crush artifact-free tissue to increase diagnostic yield in various diffuse parenchymal lung diseases (DPLDs). However, TBLC has been associated with a higher incidence of complications, and variability in diagnostic yield. Radial probe endobronchial ultrasound (R-EBUS) may be able to overcome these problems. We evaluated the safety and feasibility of TBLC in combination with R-EBUS to diagnose DPLDs.Methods We conducted this retrospective study at a single medical center from January 2015 to March 2019. Patients with DPLDs who underwent R-EBUS to locate target lesions and confirm the absence of adjacent vessels, followed by sampling with conventional transbronchial lung forceps biopsy (TBLB) and cryobiopsy (TBLC) were enrolled. TBLC and TBLB samples were sent to the pathology department for diagnostic analysis. The sample size, diagnostic yield and complications after the procedure were recorded.Results A total 30 patients with DPLD were analyzed, of whom 17 had diffuse lung infiltrates and 13 had pulmonary nodules/masses. The overall diagnostic rate was 80% (24/30) and the diagnostic yield increased from 46.7% with the forceps biopsy to 73.3% after adding cryobiopsy (p=0.038). Compared to conventional transbronchial biopsy with forceps, cryobiopsy provided a larger specimen and sample volume (40 mm3 vs 6 mm3; p

Background Previous studies have suggested that mycobacterial infections could trigger autoimmune diseases, including rheumatoid arthritis (RA). Objective To explore the association between previous tuberculosis (TB) and RA. Methods We conducted a case-control study using data obtained from the National Health Insurance (NHI) system of Taiwan. We identified 26 535 adults with RA from 2002 to 2011, with the date of diagnosis as the index date. This number was randomly selected and frequency-matched four times by age, sex and the year of index date from among non-RA individuals. Odds ratios (ORs) of RA were calculated for associations with TB. Results Compared with controls, RA patients had a crude OR of 1.77 for TB (95%CI 1.61-1.94). The strength of the association between RA and TB remained at the same level after controlling for other potential risk factors (adjusted OR 1.73, 95%CI 1.57-1.90), although RA patients tended to have a higher prevalence of hypertension, coronary artery disease and kidney disease. Conclusion TB was much more prevalent in RA patients than in control subjects. Prospective cohort studies are required to establish a causal relationship between previous TB and RA.

The eighth edition of the American Joint Committee on Cancer (AJCC) staging system for lung cancer was introduced in 2017 and included major revisions, especially of stage III. For the subgroup stage IIIA-N2 non-small-cell lung cancer (NSCLC), surgical resection remains controversial due to heterogeneous disease entity. The aim of this study was to evaluate the clinicopathologic features and prognostic factors of patients with completely resected stage IIIA-N2 NSCLC. We retrospectively evaluated 77 consecutive patients with pathologic stage IIIA-N2 NSCLC (AJCC eighth edition) who underwent surgical resection with curative intent in China Medical University Hospital between 2006 and 2014. Survival analysis was conducted, using the Kaplan&ndash, Meier method. Prognostic factors predicting overall survival (OS) and disease-free survival (DFS) were analyzed, using log-rank tests and multivariate Cox proportional hazards models. Of the 77 patients with pathologic stage IIIA-N2 NSCLC examined, 35 (45.5%) were diagnosed before surgery and 42 (54.5%) were diagnosed unexpectedly during surgery. The mean age of patients was 59 years, and the mean length of follow-up was 38.1 months. The overall one-, three-, and five-year OS rates were 91.9%, 61.3%, and 33.5%, respectively. Multivariate analysis showed that tumor size &lt, 3 cm (hazards ratio (HR): 0.373, p = 0.003) and video-assisted thoracoscopic surgery (VATS) approach (HR: 0.383, p = 0.014) were significant predictors for improved OS. For patients with surgically treated, pathologic stage IIIA-N2 NSCLC, tumor size &lt, 3 cm and the VATS approach seemed to be associated with better prognosis.

ObjectiveThoracic infection and pneumonia are prevalent in patients with schizophrenia; however, it is unclear whether patients with schizophrenia are at an increased risk of developing pleural empyema.DesignA retrospective cohort study with propensity-matched cohorts with and without schizophrenia.SettingUsing the National Health Insurance Research Database of Taiwan.ParticipantsWe identified 55 888 patients with schizophrenia newly diagnosed in 2000–2011 and same number of individuals without schizophrenia as the comparison cohort, frequency matched by propensity scores estimated using age, sex, occupation, income, urbanisation, year of diagnosis and comorbidities.Primary outcome measuresWe assessed incident pleural empyema by the end of 2011 and used the Cox proportional hazards model to calculate the schizophrenia cohort to comparison cohort HR of pleural empyema.ResultsThe overall incidence of pleural empyema was 2.44-fold greater in the schizophrenia cohort than in the comparison cohort (4.39vs1.80 per 10 000 person-years), with an adjusted HR of 2.87(95% CI 2.14 to 3.84). Stratified analyses by age, sex, occupation, income, urbanisation and comorbidity revealed significant hazards for pleural empyema associated with schizophrenia in all subgroups.ConclusionsPatients with schizophrenia are at an increased risk of developing pleural empyema and require greater attention and appropriate support.

Background/purpose: It is controversial whether healthcare-associated pneumonia (HCAP) belongs to a unique clinical entity or it shares common characteristics with community-acquired pneumonia (CAP). The impact of prior pulmonary tuberculosis (PTB) in clinical presentation and treatment outcome of ICU-admitted CAP and HCAP patients also remains unknown. Methods: We report a nationwide, multi-center, retrospective study. ICU-admitted CAP and HCAP patients from six medical centers in Taiwan were enrolled for analysis. Patients were defined as either CAP or HCAP cases, and with and without prior PTB, according to the database of Taiwan CDC. The disease severity, microbiologic characteristics, and treatment outcomes between CAP and HCAP patients with or without prior PTB were compared and analyzed. Results: A total of 414 ICU-admitted patients, including 176 CAP cases and 238 HCAP cases were included for analysis during the study period. In both CAP and HCAP subgroups, the pneumonia severities, proportions of organ dysfunction, and microbiologic characteristics were similar between patients with and without prior PTB. In survival analysis, patients with prior PTB had higher 30-day mortality than those without prior PTB (38.9% vs. 16.5%, p = 0.021) in the CAP population. Multivariate analysis revealed that a history of prior PTB was an independent clinical factor associated with higher 30-day mortality rate in CAP patients (HR = 4.45, 95% CI: 1.81–10.98, P = 0.001). Conclusion: History of prior PTB is an independent clinical factor for increased 30-day mortality rate in ICU-admitted CAP patients, but not in ICU-admitted HCAP patients. Keywords: Community-acquired pneumonia, Healthcare-associated pneumonia, Intensive care unit, Mortality, Tuberculosis

Background. The aim of this study was thus to evaluate the feasibility and safety of taking biopsy specimens by cryoprobe from the parietal pleura during semirigid pleuroscope.Methods. In a single-center, observational, prospective study, patients with exudative pleural effusion (EPE) were evaluated with a semirigid pleuroscope between January 2015 and July 2017. Each patient underwent pleural biopsy using flexible forceps and flexible cryoprobe through pleuroscope following diagnostic thoracentesis and closed pleural biopsy (CPB).Results. A total of 92 patients (median age 64 years) were included in the study, most of whom were men (65.2%). Cytological cell block (CCB) and CPB made definitive diagnoses in 32/92 (34.8%) and 25/92 (27.5%), respectively; flexible forceps biopsy (FFB) and cryoprobe biopsy (CB) established definitive diagnoses in 84/92 (91.3%) and 91/92 (98.9%), respectively. The sample obtained by CB (9.4 ± 4.9 mm) was significantly larger than the other two methods: FFB (4.2 ± 2.3 mm) or CPB (1.9 ± 1.0 mm) (P<0.0001). The immunohistochemical (IHC) staining was more easily performed with CB (98.9%) compared to either FFB (87.0%) or CPB (13.0%). There were no significant complications or procedure-related deaths.Conclusions. Based on these results, CB during semirigid pleuroscope has a high diagnostic yield, differentiating EPE of unknown etiology with satisfactory effectiveness and safety.

Study objectives Previous literature lacks the analysis of non-apnea sleep disorder (NASD) and peripheral arterial disease (PAD). The aim of this study was to evaluate the association between NASD and risk of developing PAD using retrospective data from a national database in Taiwan. Design, setting, and participants We identified 46,064 patients with NASD using the catastrophic illness registry of the Taiwan National Health Insurance Research Database (NHIRD) from 1996 to 2010. We also selected a comparison cohort of 92,128 subjects who were randomly frequency-matched by age, sex, and entry year of the NASD cohort from the same database. Interventions non-apnea sleep disorders. Main outcome and measurements The study followed up all subjects from their entry date to the occurrence of PAD. We evaluated the risks of PAD using Cox proportional hazards regression models. The survival function for PAD was assessed using the Kaplan–Meier method. Results The risk of PAD was 1.49-fold in patients with NASD compared with patients without NASD after adjusting for age, sex, and comorbidities. Patients with NASD and diabetes or with NASD and hyperlipidemia had an increased risk of PAD compared to those without NASD and diabetes or hyperlipidemia. Conclusions We demonstrated the significantly increased risk of PAD in NASD patients through a nationwide population-based retrospective cohort study.

// Yu-Tang Tung 1, * , Pin-Wu Huang 1, * , Yu-Ching Chou 1 , Cheng-Wei Lai 1 , Hsiu-Po Wang 1 , Heng-Chien Ho 2 , Chih-Ching Yen 1, 3 , Chih-Yen Tu 1, 3 , Tung-Chou Tsai 1 , Dah-Cherng Yeh 4 , Jiun-Long Wang 1, 5 , Kowit-Yu Chong 6, 7 , Chuan-Mu Chen 1, 8 1 Department of Life Sciences, and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan 2 Department of Medicine, China Medical University Hospital, Taichung 404, Taiwan 3 Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan 4 Department of General Surgery and Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan 5 Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan 6 Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan 7 Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan 8 Rong-Hsing Translational Medicine Center and iEGG Center, National Chung Hsing University, Taichung 402, Taiwan * These authors have contributed equally to this work Correspondence to: Chuan-Mu Chen, e-mail: chchen1@dragon.nchu.edu.tw Keywords: VEGF, transgenic mice, pulmonary tumorigenesis, magnetic resonance imaging (MRI), miRNA therapy Received: November 03, 2014 Accepted: April 10, 2015 Published: April 22, 2015 ABSTRACT Many studies have shown that vascular endothelial growth factor (VEGF), especially the human VEGF-A 165 (hVEGF-A 165 ) isoform, is a key proangiogenic factor that is overexpressed in lung cancer. We generated transgenic mice that overexpresses hVEGF-A 165 in lung-specific Clara cells to investigate the development of pulmonary adenocarcinoma. In this study, three transgenic mouse strains were produced by pronuclear microinjection, and Southern blot analysis indicated similar patterns of the foreign gene within the genomes of the transgenic founder mice and their offspring. Accordingly, hVegf-A 165 mRNA was expressed specifically in the lung tissue of the transgenic mice. Histopathological examination of the lung tissues of the transgenic mice showed that hVEGF-A 165 overexpression induced bronchial inflammation, fibrosis, cysts, and adenoma. Pathological section and magnetic resonance imaging (MRI) analyses demonstrated a positive correlation between the development of pulmonary cancer and hVEGF expression levels, which were determined by immunohistochemistry, qRT-PCR, and western blot analyses. Gene expression profiling by cDNA microarray revealed a set of up-regulated genes ( hvegf-A 165 , cyclin b1 , cdc2 , egfr , mmp9 , nrp-1 , and kdr ) in VEGF tumors compared with wild-type lung tissues. In addition, overexpressing hVEGF-A 165 in Clara cells increases CD105, fibrogenic genes ( collagen α1 , α-SMA , TGF-β1 , and TIMP1 ), and inflammatory cytokines (IL-1, IL-6, and TNF- α ) in the lungs of hVEGF-A 165 -overexpressing transgenic mice as compared to wild-type mice. We further demonstrated that the intranasal administration of microRNA-16 (miR-16) inhibited lung tumor growth by suppressing VEGF expression via the intrinsic and extrinsic apoptotic pathways. In conclusion, hVEGF-A 165 transgenic mice exhibited complex alterations in gene expression and tumorigenesis and may be a relevant model for studying VEGF-targeted therapies in lung adenocarcinoma.

BACKGROUND Tuberculosis (TB) is an infectious disease involving multiple organs, including the eyes. We examined the risk of cataract among patients with TB using population data. METHOD Using data from the National Health Insurance (NHI) system of Taiwan, we established a TB cohort with 6994 patients newly diagnosed between 2000 and 2010. For each TB patient, four subjects without TB were randomly selected for the non-TB cohort, frequency matched by age, sex and diagnosis years. The incidence of cataract was measured by the end of 2011. The hazard ratio (HR) of cataract was estimated using Cox proportional hazards regression analysis. RESULTS The overall incidence rate of cataract was 21% greater in the TB cohort than in the non-TB cohort (22.9 vs. 18.8/1000 person-years, P < 0.001), with an adjusted HR (aHR) of 1.26 (95%CI 1.16-1.37). Cataract incidence increased with age, and was higher in men than women and much higher for those with comorbidity. The hazard of cataract was higher in the first 6 months after TB diagnosis. CONCLUSION TB patients are at elevated risk of developing cataract. Although the incidence decreased with time, the aHR remains statistically significant through the follow-up years.

Background There is some evidence that the prevalence of depression in patients with tuberculosis (TB) is higher than those in the general population. However, the incidence of depression after Mycobacterium tuberculosis infection remains unknown. Our aim was to assess the association between TB and the subsequent risk of depression. Methods We conducted a retrospective cohort study using data from the National Health Insurance (NHI) system of Taiwan. The TB cohort included 9020 patients who were newly diagnosed and recruited between 2000 and 2010. Each patient was randomly frequency-matched for age, sex and the year of index date with four people without TB from the general population. The newly diagnosed depression was followed up until the end of 2011. The relative risks of depression were estimated using Cox proportional hazard models after adjusting for age, sex, index year and comorbidities. Results The overall incidence rate of depression was 1.54-fold higher in the TB cohort as compared with the controlled cohort (8.15 vs. 5.29 per 1000 person-years, 95% confidence interval [CI] = 1.45–1.64). Stratified analyses by gender, age group, monthly income and comorbidities revealed that the adjusted hazard ratio (HR) of depression was higher in males as well as individuals older than 65 years with a low monthly income and comorbidities. Conclusion People who have been diagnosed with TB have a significantly higher risk of developing depression compared with those in the general population. We should pay more attention to this group of individuals and ensure that they are offered appropriate support.

Background: Surgical resection of stage IIIA-N2 disease in non-small cell lung cancer (NSCLC) remains controversial with heterogeneous disease entity that consists of different subgroups: patients diagnosed in the preoperative period (suspected N2) and patients diagnosed unexpectedly during resection surgery (unsuspected N2). There is only limited evidence to support the current guidelines for unsuspected N2 disease. Aim: To compare clinicopathological characters and long-term prognosis of the patients with unsuspected N2 disease with that of the patients with suspected N2 disease. Methods: We performed a retrospective analysis of consecutive patients who underwent surgical resection of stage IIIA-pN2 NSCLC between 2006 and 2014 at a single institution. Patients were grouped based on the diagnosis of N2 disease (suspected or unsuspected). Clinical features were recorded and Kaplan-Meier method was used to investigate the effect of N2 disease subgroups on survival. Results: Of 105 patients, 48 patients belonged to suspected N2 disease and 57 patients belonged to unsuspected N2 disease. The only factor associated with unsuspected N2 disease was better (well/moderately differentiated) tumor differentiation (OR 2.93, 95% CI 1.11-7.73, p=0.029). Compared to suspected N2 disease, unsuspected N2 disease did not result in significantly poorer survival (HR 1.09, 95% CI 0.65-1.82, p=0.738). Gender, performance status, histologic type, tumor differentiation and lymphovascular invasion were significantly associated with survival. Conclusion: In the setting of unsuspected N2 disease, continuation of surgical resection can be employed without compromising survival.

Purpose Radiomics, which extract large amount of quantification image features from diagnostic medical images had been widely used for prognostication, treatment response prediction and cancer detection. The treatment options for lung nodules depend on their diagnosis, benign or malignant. Conventionally, lung nodule diagnosis is based on invasive biopsy. Recently, radiomics features, a non-invasive method based on clinical images, have shown high potential in lesion classification, treatment outcome prediction. Methods Lung nodule classification using radiomics based on Computed Tomography (CT) image data was investigated and a 4-feature signature was introduced for lung nodule classification. Retrospectively, 72 patients with 75 pulmonary nodules were collected. Radiomics feature extraction was performed on non-enhanced CT images with contours which were delineated by an experienced radiation oncologist. Result Among the 750 image features in each case, 76 features were found to have significant differences between benign and malignant lesions. A radiomics signature was composed of the best 4 features which included Laws_LSL_min, Laws_SLL_energy, Laws_SSL_skewness and Laws_EEL_uniformity. The accuracy using the signature in benign or malignant classification was 84% with the sensitivity of 92.85% and the specificity of 72.73%. Conclusion The classification signature based on radiomics features demonstrated very good accuracy and high potential in clinical application.

Background With the release of the National Lung Screening Trial results, the detection of peripheral pulmonary lesions (PPLs) is likely to increase. Computed tomography (CT)-guided percutaneous transthoracic needle biopsy (PTNB) and radial probe endobronchial ultrasound (r-EBUS)-guided transbronchial lung biopsy (TBLB) are recommended for tissue diagnosis of PPLs. Methods A systematic review of published literature evaluating the accuracy of r-EBUS-TBLB and CT-PTNB for the diagnosis of PPLs was performed to determine point sensitivity and specificity, and to construct a summary receiver-operating characteristic curve. Results This review included 31 publications dealing with EBUS-TBLB and 14 publications dealing with CT-PTNB for the diagnosis of PPLs. EBUS-TBLB had point sensitivity of 0.69 (95% CI: 0.67-0.71) for the diagnosis of peripheral lung cancer (PLC), which was lower than the sensitivity of CT-PTNB (0.94, 95% CI: 0.94-0.95). However, the complication rates observed with EBUS-TBLB were lower than those reported for CT-PTNB. Conclusions This meta-analysis showed that EBUS-TBLB is a safe and relatively accurate tool in the investigation of PLC. Although the yield remains lower than that of CT-PTNB, the procedural risks are lower.

Background: The role of autoimmune pathology in development and progression of chronic obstructive pulmonary disease (COPD) is becoming increasingly popular. Our aim was to assess the association between patients with rheumatoid arthritis (RA) and subsequent COPD risk in a nationwide population. Method: We conducted a retrospective cohort study using data from the National Health Insurance system of Taiwan. The RA cohort included patients who were newly diagnosed and recruited between 1998 and 2008. Each patient was randomly frequency-matched for age, sex and the year of index date with people without RA from the general population. The newly diagnosed COPD was followed up until the end of 2010. The relative risks of COPD were estimated using Cox proportional hazard models after adjusting for age, sex, index year and comorbidities. Result: The overall incidence rate of COPD was 1.74-fold higher in the RA cohort than in the non-RA cohort (5.25 vs. 3.01 per 1000 person-years, 95% confidence interval (CI) = 1.68–1.81). Age-related risk analysis showed an increased incidence of COPD with age in both RA and non-RA cohorts. However, adjusted hazard ratio (HR) maximum was witnessed in the age range of 20–34 years (adjusted HR: 7.67, 95% CI=1.94–30.3), whereas adjusted HR minimum was observed in the oldest age group (>65 years). Conclusion: Patients with RA have a significantly higher risk of developing COPD than that of the control population. Further, age-related risk analysis indicated much higher adjusted HR in younger patients although COPD incidence increased with age. It can be hypothesized that in addition to cigarette smoke, RA may be a determining factor for COPD incidence and/or facilitates shortening of the time course for developing COPD. However, further investigation is needed to corroborate this hypothesis.

Objective Sleep disorders are prevalent medical disorders in patients with rheumatoid arthritis (RA). However, whether patients with RA are at an increased risk of developing obstructive sleep apnoea (OSA) is unclear. Design Using population-based retrospective cohort study to examine the risk of OSA in patients with RA. Setting We used claims data of the National Health Insurance Research Database (NHIRD) of Taiwan. Participants We identified a RA cohort with 33 418 patients newly diagnosed in 2000–2010 and a randomly selected non-RA comparison cohort with 33 418 individuals frequency matched by sex, age and diagnosis year. Primary and secondary outcome measures Incident OSA was estimated by the end of 2011. The HRs of OSA were calculated using the Cox proportional hazards regression analysis. Results The overall incidence rate of OSA was 75% greater in the RA cohort than in the non-RA cohort (3.04 vs 1.73/10 000 person-years, p

BACKGROUND: Patients with advanced esophageal cancer and airway involvement have a poor prognosis. Self-expandable metallic stent (SEMS) implantation via bronchoscopy can immediately relieve airway stenosis and improve survival. The purpose of this study was to determine the factors that predict survival in patients with airway involvement due to advanced esophageal cancer after SEMS implantation. METHODS: We conducted this retrospective study from February 2007 to October 2013 at a university hospital. Forty-two patients with advanced esophageal cancer and airway involvement were included. The patients underwent flexible bronchoscopy with electrosurgery and SEMS implantation under bronchoscopic visualization and local anesthesia with no fluoroscopic guidance throughout the procedure. RESULTS: Acute respiratory failure (ARF) occurred in 14 patients (33.3%). After SEMS implantation, 28 patients (66.7%) received additional anti-cancer therapy. The median survival after the procedure was 83 days. A longer survival was seen in the patients who received further anti-cancer therapy [hazard ratio (HR), 0.146; 95% confidence interval (CI), 0.06–0.34; P

Lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) kinase inhibitor, showed clinical benefits in advanced HER2-positive breast cancer patients. Because some triple-negative breast cancers (TNBCs) frequently overexpress EGFR, the antitumor activity of lapatinib in such diseases was also tested. However, the results showed a worse event-free survival rate. It remains unknown whether and how lapatinib elicits the aggressiveness of such cancer cells. In this study, our results demonstrated that lapatinib facilitated axillary and lung metastases of triple-negative MDA-MB-231 breast cancer cells without affecting their viability, leading to worse survival in orthotopic xenograft mice. The lapatinib-increased motility was attributed by the elevation of EGFR through the downregulation of microRNA-7 and by the subsequent overexpression of cyclooxygenase-2 (COX-2). Strikingly, independent of its kinase activity, the elevated EGFR at least partly stabilized COX-2 expression by enhancing the binding of HuR to COX-2 mRNA. Our results suggest that lapatinib may increase the migration and invasion of MDA-MB-231 cells by upregulating EGFR and COX-2 through the downregulation of microRNA-7, providing a potential explanation for the worse clinical outcome of TNBC patients who receive lapatinib-based treatment. These findings also shed new light on the molecular mechanism of COX-2 mRNA stabilization by EGFR in a kinase-independent manner.

Background/Purpose Community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP) may be caused by potential antimicrobial drug-resistant (PADR) microbes. The aims of this study were to evaluate the incidences and risk factors associated with PADR microbes observed in patients with pneumonia occurring outside the hospital setting in Taiwan. Methods We conducted a retrospective study of patients with CAP or HCAP admitted to six medical centers in the northern, central, and southern regions of Taiwan in 2007. The pathogens were evaluated by microbiological specimens within 72 hours after admission. The patients’ comorbidities, pathogens, and outcomes were evaluated. The risk factors of PADR microbes were identified by logistic regression analysis. Results The enrolled patients exhibited HCAP ( n = 713) and CAP ( n = 933). The pathogens associated with HCAP ( n = 383) and CAP ( n = 441) included Pseudomonas spp. (29%vs. 10%, p Klebsiella spp. (24% vs. 25%, p = 0.250), Escherichia coli (6% vs. 8%, p = 0.369), Haemophilus influnezae (3% vs. 7%, p = 0.041), Streptococcus pneumoniae (2% vs. 6%, p = 0.003) and methicillin-resistant Staphylococcus aureus (MRSA) (8% vs. 4%, p = 0.008). The core pathogens of CAP and HCAP differed among the three regions of Taiwan. PADR microbes, including Pseudomonas spp. ( n = 191), Acinetobacter spp. ( n = 41), MRSA ( n = 49) and cefotaxime- or ceftazidime-resistant Enterbacteriaceae ( n = 25), were isolated from 13% of patients with CAP and 23% of patients with HCAP. Previous hospitalization, and neoplastic and neurological diseases were significant risk factors for acquiring PADR microbes. Conclusion PADR microbes were common in patients with HCAP and CAP in Taiwan. Broad-spectrum antibiotics targeting PADR microbes should be administered to patients who have undergone previous hospitalization and who exhibit neurological disorders and/or malignancies.