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1.  The Impact of Sequence of Chemotherapy and EGFR-TKI Treatment on Different EGFR Mutation Lung Adenocarcinoma 
BioMed Research International  2015;2015:948267.
Objectives. Chemotherapy as first-/second-line treatment in different epidermal growth factor receptor (EGFR) mutation lung adenocarcinoma remains controversial. Methods. Consecutive patients were collected between 2009 and 2012. Patients were divided into two groups (1st-line chemotherapy: n = 56 and 2nd-line chemotherapy: n = 55). Their outcomes profiles were analyzed. Results. The overall survival (OS) of all patients (390 versus 662 days, p < 0.0001), as well as both progression-free survival (PFS, 151 versus 252 days, p = 0.0001) and OS (308 versus 704 days, p = 0.0001) of patients with L858R mutation (n = 63), who received 2nd-line chemotherapy, was significantly poor. By univariate and multivariate analysis, 2nd-line chemotherapy, and L858R mutation were significantly related to poor PFS and OS. Conclusion. In advanced lung adenocarcinoma, L858R mutation and 2nd-line chemotherapy caused a poor outcome. It is a consideration to choice of 1st-line chemotherapy in these subjects. A prospective design is warranted to confirm this finding.
PMCID: PMC4644829  PMID: 26609535
2.  Associated bone mineral density and obstructive sleep apnea in chronic obstructive pulmonary disease 
Osteoporosis is an important issue for patients with chronic obstructive pulmonary disease (COPD). Worse systemic inflammation and reduced exercise capacity have been reported in COPD patients with obstructive sleep apnea (OSA), implying that OSA may be an independent factor for osteoporosis in COPD patients.
A total of 66 patients with bone mineral density (BMD) and polysomnography results from a previous COPD cohort (January 2008 to January 2013) were retrospectively enrolled. Clinical characteristics such as medication, pulmonary function, BMD, and results of polysomnography were analyzed.
The BMD in those with OSA was significantly lower than in those without OSA (−1.99±1.63 versus −1.27±1.14, P=0.045). In univariate analysis, body mass index, forced expiratory volume in 1 second, percentage of predicted value, incremental shuttle walk test, apnea–hypopnea index, and oxygen desaturation index (ODI) were significantly associated with BMD. After multivariate linear regression analysis, the ODI was still an independent factor for BMD. In addition, smaller total lung capacity is significantly associated with higher ODI and lower BMD, which implies that lower BMD might cause severer OSA via decreased total lung capacity.
OSA may be an independent factor for BMD in patients with COPD, which implies a possible vicious cycle takes place in these patients.
PMCID: PMC4321657  PMID: 25673983
chronic obstructive pulmonary disease; osteoporosis; total lung capacity
3.  The safety and efficacy of alfentanil-based induction in bronchoscopy sedation 
Medicine  2016;95(43):e5101.
Alfentanil in combination with propofol produces a synergistic sedative effect in patients undergoing flexible bronchoscopy (FB). However, the use of this combination is controversial due to the risk of cardiopulmonary depression. The aim of this study was to evaluate the proper induction regimen of alfentanil in propofol target-controlled infusion for FB sedation.
One hundred seventy-three patients were assigned randomly into 5 regimens: Group 1 and 2, alfentanil 2.5 and 5 μg/kg, respectively, immediately before propofol administration; Group 3 and 4, alfentanil 2.5 and 5 μg/kg, respectively, 2 minutes before propofol administration; and Group 5, propofol administration alone to achieve the observer assessment of alertness and sedation scale 3∼2. The bronchoscopists, physicians in charge of sedation, and patients were blind to the regimens. Adverse events, drug dose, induction, procedure and recovery time, cough severity, and propofol injection related pain were recorded.
The patients in groups 2 and 4 required a lower dose of propofol (P = 0.031 and 0.019, respectively) and shorter time (P = 0.035 and 0.010) than group 5 for induction. Patients in group 2 experienced more hypoxemia than those in group 5 during induction (P = 0.031). The physician in charge of sedation scored a lower severity of cough in the patients in group 4 than in groups 3 and 5. There were no differences in terms of propofol injection related pain among the groups.
Alfentanil 5 μg/kg given immediately before propofol infusion cannot be recommended. Further study is required to define conclusions about alfentanil 2.5 and 5 μg/kg because of the low power rating of subgroup in the present study.
PMCID: PMC5089092  PMID: 27787363
alfentanil; bronchoscopy; hypotension; hypoxemia; propofol
4.  Pulmonary rehabilitation coupled with negative pressure ventilation decreases decline in lung function, hospitalizations, and medical cost in COPD 
Medicine  2016;95(41):e5119.
Supplemental Digital Content is available in the text
Pulmonary rehabilitation (PR) brings benefits to patients with chronic obstructive pulmonary disease (COPD). Negative pressure ventilation (NPV) increases ventilation and decreases hyperinflation as well as breathing work in COPD. We evaluated the long-term effects of a hospital-based PR program coupled with NPV support in patients with COPD on clinical outcomes.
One hundred twenty-nine patients with COPD were followed up for more than 5 years, with the NPV group (n = 63) receiving the support of NPV (20–30 cm H2O delivery pressure for 60 min) and unsupervised home exercise program of 20 to 30 min daily walk, while the control group (n = 6) only received unsupervised home exercise program. Pulmonary function tests and 6 min walk tests (6MWT) were performed every 3 to 6 months. Emergency room (ER) visits and hospitalization with medical costs were recorded.
A significant time-by-group interaction in the yearly decline of forced expiratory volume in 1 s in the control group analyzed by mixed-model repeated-measure analysis was found (P = 0.048). The 6MWT distance of the NPV group was significantly increased during the first 4 years, with the interaction of time and group (P = 0.003), the time alone (P = 0.014), and the quadratic time (P < 0.001) being significant between the 2 groups. ER exacerbations and hospitalizations decreased by 66% (P < 0.0001) and 54% (P < 0.0001) in the NPV group, respectively. Patients on PR program coupled with NPV had a significant reduction of annual medical costs (P = 0.022).
Our hospital-based multidisciplinary PR coupled with NPV reduced yearly decline of lung function, exacerbations, and hospitalization rates, and improved walking distance and medical costs in patients with COPD during a 5-year observation
PMCID: PMC5072959  PMID: 27741132
6 min walk test; chronic obstructive pulmonary disease; hospitalization; lung function; negative pressure ventilation; pulmonary rehabilitation
5.  Circulating Angiopopietin-1 Correlates With the Clinical Course of Multiple Organ Dysfunction Syndrome and Mortality in Patients With Severe Sepsis 
Medicine  2015;94(20):e878.
To determine plasma concentrations of angiopoietin (Ang)-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) in patients with sepsis-induced multiple organ dysfunction syndrome (MODS) and determine their association with mortality.
The study prospectively recruited 96 consecutive patients with severe sepsis in a l intensive care unit of a tertiary hospital. Plasma Ang-1, Ang-2, Tie-2, and VEGF levels and MODS were determined in patients on days 1, 3, and 7 of sepsis. Univariate and Cox proportional hazards analysis were performed to develop a prognostic model.
Days 1, 3, and 7 plasma Ang-1 concentrations were persistently decreased in MODS patients than in non-MODS patients (day1: 4.0 ± 0.5 vs 8.0 ± 0.5 ng/mL, P < 0.0001; day 3, 3.2 ± 0.6 vs 7.3 ± 0.5 ng/mL, P < 0.0001, day 7, 2.8 ± 0.6 vs 10.4 ± 0.7 ng/mL, P < 0.0001). In patients with resolved MODS on day 7 of sepsis, Ang-1 levels were increased from day 1 (4.7 ± 0.6 ng/mL vs 9.1 ± 1.4 ng/mL, n = 43, P = 0.004). Plasma Ang-1 levels were lower in nonsurvivors than in survivors on days 1 (4.0 ± 0.5 vs 7.1 ± 0.5 ng/mL, P < 0.0001), 3 (3.8 ± 0.6 vs 7.1 ± 0.5 ng/mL, P < 0.0001), and 7 (4.7 ± 0.7 vs 11.0 ± 0.8 ng/mL, P < 0.0001) of severe sepsis. In contrast, plasma Ang-2 levels were higher in nonsurvivors than in survivors only on day 1 (15.8 ± 2.0 vs 9.5 ± 1.2 ng/mL, P = 0.035). VEGF and Tie-2 levels were not associated with MODS and mortality. Ang-1 level less than the median value was the only independent predictor of mortality (hazard ratio, 2.57; 95% CI 1.12–5.90, P = 0.025).
Persistently decreased Ang-1 levels are associated with MODS and subsequently, mortality in patients with sepsis.
PMCID: PMC4602874  PMID: 25997069
6.  Mid-arm and calf circumferences are stronger mortality predictors than body mass index for patients with chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is currently the third most common cause of death in the world. Patients with COPD experience airflow obstruction, weight loss, skeletal muscle dysfunction, and comorbidities. Anthropometric indicators are risk factors for mortality in geriatric assessment.
This study examined and compared the associations of anthropometric indicators, such as low body mass index (BMI), low mid-arm circumference (MAC), and low calf circumference (CC), with the prediction of a 3-year follow-up mortality risk in patients with COPD.
We recruited nonhospitalized patients with COPD without acute conditions from a general hospital in Taiwan. The BMI, MAC, and CC of all patients were measured, and they were followed for 3 years through telephone interviews and chart reviews. The Kaplan–Meier survival curves stratified by BMI, MAC, and CC were analyzed. Variables univariately associated with survival were entered into a multivariate Cox regression model. The Bayesian information criterion was used to compare the predictive ability of the three anthropometric indicators to predict mortality rate.
In total, 104 patients were included (mean ± standard deviation age, 74.2±6.9 years; forced expiratory volume in 1 second [%], 58.4±20.4 predicted; males, 94.2%); 22 patients (21.2%) died during the 36-month follow-up. During this long-term follow-up, the three anthropometric indicators could predict mortality risk in patients with COPD (low BMI [<21 kg/m2], hazard ratio [HR] =2.78, 95% confidence interval [CI] =1.10–7.10; low MAC [<23.5 cm], HR =3.09, 95% CI =1.30–7.38; low CC [<30 cm], HR =4.40, 95% CI =1.82–10.63). CC showed the strongest potential in predicting the mortality risk, followed by MAC and BMI.
Among the three anthropometric variables examined, CC can be considered a strong predictor of mortality risk in patients with COPD.
PMCID: PMC5012597  PMID: 27621613
anthropometric indicator; BMI; calf circumference; COPD; mid-arm circumference; mortality
7.  CD14+S100A9+ Monocytic Myeloid-derived Suppressor Cells and Their Clinical Relevance in Non–Small Cell Lung Cancer 
Rationale: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T-cell immunity in tumor-bearing hosts. Their clinical relevance remains unclear.
Objectives: To identify subtypes of myeloid-derived suppressor cells in patients with non–small cell lung cancer (NSCLC) and their clinical relevance.
Methods: CD11b+CD14− and CD11b+CD14+ cells, determined and phenotyped by fluorescence-activated cell sorter analysis, in the peripheral blood mononuclear cells (PBMCs) of treatment-naive patients with advanced NSCLC were correlated with clinical data. T-cell activation in response to CD3/CD28 costimulation was determined by carboxy-fluorescein diacetate succinimidyl ester (CFSE) staining and ELISA analysis of IFN-γ. The percentage of CD11b+CD14+S100A9+ cells in PBMCs was correlated with and tested as a predictor for treatment response in a cohort of patients prospectively receiving first-line cisplatin-based chemotherapy.
Measurements and Main Results: Patients with NSCLC had a significantly higher ratio of CD11b+CD14+ cells than healthy subjects, which was correlated with poor performance status and poor response to chemotherapy. The depletion of these cells in the PBMC reversed the suppression of CD8+ and CD4+ T cells. Isolated CD11b+CD14+ cells suppressed CD8+ T-cell proliferation and IFN-γ production, and the former effect was attenuated by the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine hydrochloride, arginase inhibitor N-hydroxy-nor-l-arginine (nor-NOHA), and blocking antibodies for IL-4Rα+ and IL-10. CD11b+CD14+ cells were monocyte-like, expressing CD33+, CD15−/low, IL-4Rα+, and S100A9+ and producing iNOS, arginase, and several cytokines. The ratio of S100A9+ cells positively correlated with the suppressive ability of the CD11b+CD14+ cells, was associated with poor response to chemotherapy, and predicted shorter progression-free survival.
Conclusions: CD14+S100A9+ inflammatory monocytes in patients with NSCLC are a distinct subset of MDSCs, which suppress T cells by arginase, iNOS, and the IL-13/IL-4Rα axis. The amount of these inflammatory monocytes is associated with poor response to chemotherapy.
Clinical trial registered with (NCT 01204307).
PMCID: PMC4132576  PMID: 22955317
non–small cell lung cancer; myeloid-derived suppressor cell; S100A9; cancer immunity
8.  Characteristics of stable chronic obstructive pulmonary disease patients in the pulmonology clinics of seven Asian cities 
Background and objectives
Chronic obstructive pulmonary disease (COPD) is responsible for significant morbidity and mortality worldwide. We evaluated the characteristics of stable COPD patients in the pulmonology clinics of seven Asian cities and also evaluated whether the exposure to biomass fuels and dusty jobs were related to respiratory symptoms, airflow limitation, and quality of life in the COPD patients.
This cross-sectional observational study recruited 922 COPD patients from seven cities of Asia. The patients underwent spirometry and were administered questionnaires about their exposure to cigarette smoking, biomass fuels, and dusty jobs in addition to respiratory symptoms and health related quality of life.
Of the patients, there appeared to be variations from city to city in the history of exposure to biomass fuels and dusty jobs and also in respiratory symptoms of cough, phlegm, wheeze, and dyspnea. These symptoms were more frequent in those COPD patients with a history of exposure to biomass fuels than without and those with a history of exposure to dusty jobs than without (P < 0.01 for all comparisons). Airflow limitation was more severe in those COPD patients with a history of exposure to biomass fuels than without (52.2% predicted versus 55.9% of post-bronchodilator forced expiratory volume in 1 second [FEV1], P = 0.009); quality of life was poorer in those with exposure to biomass fuels than without (40.4 versus 36.2 of the St George’s Respiratory Questionnaire [SGRQ] total score, P = 0.001). Airflow limitation was more severe in those COPD patients with a history of exposure to dusty jobs than without (51.2% predicted versus 57.3% of post-bronchodilator FEV1, P < 0.001); quality of life was poorer in those with dusty jobs than without (41.0 versus 34.6 of SGRQ score, P = 0.006).
In Asian cities, the characteristics of COPD patients vary and the history of exposure to biomass fuels or dusty jobs was related to frequency of symptoms, severe airflow limitation, and poor quality of life.
PMCID: PMC3553655  PMID: 23378753
COPD; Asia; biomass; dust
9.  Exercise-Induced Changes in Exhaled NO Differentiates Asthma With or Without Fixed Airway Obstruction From COPD With Dynamic Hyperinflation 
Medicine  2016;95(15):e3400.
Asthmatic patients with fixed airway obstruction (FAO) and patients with chronic obstructive pulmonary disease (COPD) share similarities in terms of irreversible pulmonary function impairment. Exhaled nitric oxide (eNO) has been documented as a marker of airway inflammation in asthma, but not in COPD.
To examine whether the basal eNO level and the change after exercise may differentiate asthmatics with FAO from COPD, 27 normal subjects, 60 stable asthmatics, and 62 stable COPD patients were studied. Asthmatics with FAO (n = 29) were defined as showing a postbronchodilator FEV1/forced vital capacity (FVC) ≤70% and FEV1 less than 80% predicted after inhaled salbutamol (400 μg). COPD with dynamic hyperinflation (n = 31) was defined as a decrease in inspiratory capacity (ΔIC%) after a 6 minute walk test (6MWT).
Basal levels of eNO were significantly higher in asthmatics and COPD patients compared to normal subjects. The changes in eNO after 6MWT were negatively correlated with the percent change in IC (r = −0.380, n = 29, P = 0.042) in asthmatics with FAO. Their levels of basal eNO correlated with the maximum mid-expiratory flow (MMEF % predicted) before and after 6MWT. In COPD patients with air-trapping, the percent change of eNO was positively correlated to ΔIC% (rs = 0.404, n = 31, P = 0.024).
We conclude that asthma with FAO may represent residual inflammation in the airways, while dynamic hyperinflation in COPD may retain NO in the distal airspace. eNO changes after 6MWT may differentiate the subgroups of asthma or COPD patients and will help toward delivery of individualized therapy for airflow obstruction.
PMCID: PMC4839859  PMID: 27082615
10.  Efficacy of omalizumab (Xolair®) in patients with moderate to severe predominately chronic oral steroid dependent asthma in Taiwan: a retrospective, population-based database cohort study 
Omalizumab (Xolair®), a recombinant monoclonal anti-IgE antibody, has demonstrated efficacy in clinical trials conducted in patients with moderate to severe persistent allergic asthma. We aimed to investigate the efficacy, discontinuation and medical resource utilization of omalizumab in the real-life setting in Taiwan.
This study was a retrospective, population-based database cohort study using the Taiwan NHIRD from 2007 to 2011 assessing the efficacy of omalizumab therapy over 4 months on changes in asthma medication, asthma control, frequency of exacerbations and hospitalization rates at baseline and after omalizumab discontinuation.
There was a reduction in asthma medication post omalizumab therapy and severe exacerbations and hospitalizations from baseline (31.2 %, n = 282) to the end of follow-up (11.8 %, n = 144, p < 0.001). Nearly all the patients received chronic oral corticosteroids at baseline (92.4 %). The number of ER visits decreased from 1.13 ± 2.04 to 0.29 ± 0.83, and the mean number of admissions decreased from 5.93 ± 16.16 to 2.75 ± 12.02 from baseline to the end of follow-up (p < 0.001). After discontinuation of omalizumab, the cost of ER medical expenses decreased from New Taiwan dollars (NTD) 3934 at 2 months to NTD 2860 at 12 months.
Patients who received omalizumab therapy for over 4 months were more likely to reduce the use of other asthma medications and less likely to experience an asthma exacerbation, ER visits, and hospitalization, even after the discontinuation of omalizumab. These data suggest that omalizumab has efficacy in improving health outcomes in patients with moderate to severe predominately chronic oral steroid dependent asthma in the real-life setting in Taiwan.
PMCID: PMC4706688  PMID: 26747278
Omalizumab; Asthma; Population-based database; Cohort study; Real-life setting
11.  Bronchoscopic debulking for endobronchial malignancy: Predictors of recanalization and recurrence 
Thoracic Cancer  2015;6(6):722-730.
Central airway obstruction related to endobronchial malignancy is one of the most difficult oncological complications and requires efficient palliative intervention.
Fifty-three consecutive patients with unresectable endobronchial malignancy receiving bronchoscopic cryotherapy as palliative treatment were retrospectively reviewed. Efficiency was evaluated by the improvement of performance status (PS), and the best achievement of tumor removal was assessed as complete or partial removal.
Patients’ PS after cryotherapeutic tumor removal improved from the baseline PS (P = 0.006). In multivariate logistic regression analysis, the compression part of the tumor (odds ratio [OR] 0.42; 95% confidence interval [CI] 0.23∼0.75, P = 0.004) and the thin tumor stalk (OR 87.86; 95% CI 2.31∼3337.37, P = 0.016) were independent predictors of complete tumor removal. Tumors larger than 9.3 cm, including compression and invasion parts, had the highest odds of being only partially removed (positive predictive value [PPV]: 88.2%, likelihood ratio [LR]+: 10.49); tumors smaller than 9.3 cm were likely to be completely removed (negative predictive value [NPV]: 80.6%, LR−: 0.34). After cryotherapy, re-obstruction was significantly associated with non-squamous cell carcinoma (65.7 vs. 16.7%, P = 0.001) and patients who had longer overall survival (11.7 vs. 1.5 months, P < 0.001). Odds of tumor re-obstruction increased 2.28-fold (PPV: 81.6%, LR+: 2.28) beyond two months; the odds decreased by 81% (NPV: 73.3%, LR−: 0.19) within two months.
Debulking of a tumor using cryotherapy is a useful palliative treatment for endobronchial obstruction secondary to a variety of malignancies.
PMCID: PMC4632924  PMID: 26557910
Bronchoscopic; cryotherapy; endobronchial; malignancy
12.  A real-world evaluation of indacaterol and other bronchodilators in COPD: the INFLOW study 
INFLOW (INdacaterol eFfectiveness and utiLizatiOn in COPD: real World evaluation) was a prospective, noninterventional study assessing the effectiveness and safety of long-acting bronchodilators in patients with chronic obstructive pulmonary disease (COPD) from the Middle East, Asia, and South Africa.
Patients newly prescribed or switched to indacaterol or other long-acting β2-agonist (LABA), or tiotropium (monotherapy or in combination) were evaluated over 6 months. The primary endpoint was the clinical COPD questionnaire overall score at the end of the study.
Data were analyzed from 1,710 patients (mean postbronchodilator forced expiratory volume in 1 second, 59% predicted) who received indacaterol (n=1,179), other LABA (n=68), tiotropium (n=271), indacaterol plus tiotropium (n=167), or other LABA plus tiotropium (n=25). Across treatments, clinical COPD questionnaire overall score improved from baseline by 0.81–1.26 points (all P<0.0001), 63%–84% of patients were satisfied/very satisfied, and physicians rated effectiveness as good/very good in 63%–80% of cases. The indacaterol inhaler was rated easy/very easy to use by the majority of patients, and physicians considered its use clearly understood by most patients. All treatments had acceptable tolerability.
In real life clinical practice across a diverse region, indacaterol and other long-acting bronchodilators improved health status and were well regarded by patients and physicians.
PMCID: PMC4599566  PMID: 26491281
long-acting bronchodilator; indacaterol; chronic obstructive pulmonary disease; noninterventional study; Middle East; Asia
13.  The relationship between anthropometric indicators and walking distance in patients with chronic obstructive pulmonary disease 
Exercise intolerance is a major issue affecting many people with COPD. Six-minute walking distance (6MWD) is a widely used indicator of exercise capacity in patients with COPD. The process is strenuous and time-consuming, especially for patients who have muscle wasting. Anthropometric indicators that reflect body lean mass, such as body mass index (BMI), mid-arm circumference (MAC), and calf circumference (CC), may have value in predicting exercise intolerance.
This study attempted to determine the abilities of simple anthropometric indicators including BMI, MAC, and CC in reflecting the exercise intolerance of COPD patients.
We recruited 136 nonhospitalized ambulatory COPD patients without acute conditions from a general hospital in Taiwan. Each subject’s BMI, MAC, and CC were measured, and they were examined with pulmonary function tests and a 6-minute walk test.
Among the three anthropometric indicators examined, CC showed the strongest correlation with the 6MWD, followed by MAC and BMI. CC was also strongly associated with functional capacity, followed by MAC, according to the receiver operating characteristic curves. CC and MAC, but not BMI, were significantly associated with exercise intolerance according to logistic regression models that controlled for potential confounders.
Among the three variables examined, CC and walking distance may have the strongest association in COPD patients. CC may have value in serving as an adjunct to 6MWD in evaluating exercise intolerance of patients with COPD.
PMCID: PMC4572723  PMID: 26392760
6-minute walk distance; BMI; calf circumference; COPD; mid-arm circumference
14.  Low bone mineral density in COPD patients with osteoporosis is related to low daily physical activity and high COPD assessment test scores 
COPD patients have an increased prevalence of osteoporosis (OP) compared with healthy people. Physical inactivity in COPD patients is a crucial risk factor for OP; the COPD assessment test (CAT) is the newest assessment tool for the health status and daily activities of COPD patients. This study investigated the relationship among daily physical activity (DPA), CAT scores, and bone mineral density (BMD) in COPD patients with or without OP. This study included 30 participants. Ambulatory DPA was measured using actigraphy and oxygen saturation by using a pulse oximeter. BMD was measured using dual-energy X-ray absorptiometry. OP was defined as a T-score (standard deviations from a young, sex-specific reference mean BMD) less than or equal to −2.5 SD for the lumbar spine, total hip, and femoral neck. We quantified oxygen desaturation during DPA by using a desaturation index and recorded all DPA, except during sleep. COPD patients with OP had lower DPA and higher CAT scores than those of patients without OP. DPA was significantly positively correlated with (lumbar spine, total hip, and femoral neck) BMD (r=0.399, 0.602, 0.438, respectively, all P<0.05) and T-score (r=0.471, 0.531, 0.459, respectively, all P<0.05), whereas CAT scores were significantly negatively correlated with (total hip and femoral neck) BMD (r=−0.412, −0.552, respectively, P<0.05) and (lumbar spine, total hip, and femoral neck) T-score (r=−0.389, −0.429, −0.543, respectively, P<0.05). Low femoral neck BMD in COPD patients was related to high CAT scores. Our results show no significant difference in desaturation index, low SpO2, and inflammatory markers (IL-6, TNF-α, IL-8/CXCL8, CRP, and 8-isoprostane) between the two groups. Chest physicians should be aware that COPD patients with OP have low DPA and high CAT scores.
PMCID: PMC4562728  PMID: 26366066
chronic obstructive pulmonary disease; osteoporosis; daily physical activity; COPD assessment test; bone mineral density
15.  Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis 
Idiopathic pulmonary fibrosis is a progressive diffuse parenchymal lung disorder of unknown etiology. Mesenchymal stem cell (MSC)-based therapy is a novel approach with great therapeutic potential for the treatment of lung diseases. Despite demonstration of MSC grafting, the populations of engrafted MSCs have been shown to decrease dramatically 24 hours post-transplantation due to exposure to harsh microenvironments. Hypoxia is known to induce expression of cytoprotective genes and also secretion of anti-inflammatory, anti-apoptotic and anti-fibrotic factors. Hypoxic preconditioning is thought to enhance the therapeutic potency and duration of survival of engrafted MSCs. In this work, we aimed to prolong the duration of survival of engrafted MSCs and to enhance the effectiveness of idiopathic pulmonary fibrosis transplantation therapy by the use of hypoxia-preconditioned MSCs.
Hypoxic preconditioning was achieved in MSCs under an optimal hypoxic environment. The expression levels of cytoprotective factors and their biological effects on damaged alveolar epithelial cells or transforming growth factor-beta 1-treated fibroblast cells were studied in co-culture experiments in vitro. Furthermore, hypoxia-preconditioned MSCs (HP-MSCs) were intratracheally instilled into bleomycin-induced pulmonary fibrosis mice at day 3, and lung functions, cellular, molecular and pathological changes were assessed at 7 and 21 days after bleomycin administration.
The expression of genes for pro-survival, anti-apoptotic, anti-oxidant and growth factors was upregulated in MSCs under hypoxic conditions. In transforming growth factor-beta 1-treated MRC-5 fibroblast cells, hypoxia-preconditioned MSCs attenuated extracellular matrix production through paracrine effects. The pulmonary respiratory functions significantly improved for up to 18 days of hypoxia-preconditioned MSC treatment. Expression of inflammatory factors and fibrotic factor were all downregulated in the lung tissues of the hypoxia-preconditioned MSC-treated mice. Histopathologic examination observed a significant amelioration of the lung fibrosis. Several LacZ-labeled MSCs were observed within the lungs in the hypoxia-preconditioned MSC treatment groups at day 21, but no signals were detected in the normoxic MSC group. Our data further demonstrated that upregulation of hepatocyte growth factor possibly played an important role in mediating the therapeutic effects of transplanted hypoxia-preconditioned MSCs.
Transplantation of hypoxia-preconditioned MSCs exerted better therapeutic effects in bleomycin-induced pulmonary fibrotic mice and enhanced the survival rate of engrafted MSCs, partially due to the upregulation of hepatocyte growth factor.
PMCID: PMC4487587  PMID: 25986930
16.  Flexible Bronchoscopy with Multiple Modalities for Foreign Body Removal in Adults 
PLoS ONE  2015;10(3):e0118993.
Aspiration of the lower airways due to foreign body is rare in adults. This study aimed to determine the outcome of patients who received flexible bronchoscopy with different modalities for foreign body removal in the lower airways.
Patients and Methods
Between January 2003 and January 2014, 94 patients diagnosed with foreign body in the lower airways underwent flexible bronchoscopy with different modalities, which included forceps, loop, basket, knife, electromagnet, and cryotherapy. The clinical presentation, foreign body location and characteristics, and applications of flexible bronchoscopy were analyzed.
Forty (43%) patients had acute aspiration, which developed within one week of foreign body entry and 54 (57%) had chronic aspiration. The most common foreign bodies were teeth or bone. More patients with chronic aspiration than those with acute aspiration were referred from the out-patient clinic (48% vs. 28%), but more patients with acute aspiration were referred from the emergency room (35% vs. 6%) and intensive care unit (18% vs. 2%). Flexible bronchoscopy with different modalities was used to remove the foreign bodies (85/94, 90%). Electromagnet or cryotherapy was used in nine patients to eliminate the surrounding granulation tissue before foreign body removal. In the nine patients with failed flexible bronchoscopy, eight underwent rigid bronchoscopy instead and one had right lower lung lobectomy for lung abscess.
Flexible bronchoscopy with multiple modalities is effective for diagnosing and removing foreign bodies in the lower respiratory airways in adults, with a high success rate (90%) and no difference between acute and chronic aspirations.
PMCID: PMC4358882  PMID: 25768933
17.  Mobile-phone-based home exercise training program decreases systemic inflammation in COPD: a pilot study 
BMC Pulmonary Medicine  2014;14:142.
Moderate-intensity exercise training improves skeletal muscle aerobic capacity and increased oxidative enzyme activity, as well as exercise tolerance in COPD patients.
To investigate whether the home-based exercise training program can reduce inflammatory biomarkers in patients with COPD, twelve patients using mobile phone assistance and 14 with free walk were assessed by incremental shuttle walk test (ISWT), spirometry, strength of limb muscles, and serum C-reactive protein (CRP) and inflammatory cytokines.
Patients in the mobile phone group improved their ISWT walking distance, with decrease in serum CRP after 2 months, and sustained at 6 months. Patients in the control group had no improvement. Serum IL-8 in the mobile phone group was significantly reduced at 2, 3 and 6 months after doing home exercise training compared to baseline. IL-6 and TNF-α were significantly elevated at 3 and 6 months in control group, while there were no changes in mobile phone group. The strength of limb muscles was significantly greater compared to baseline at 3 and 6 months in the mobile phone group.
A mobile-phone-based system can provide an efficient home endurance exercise training program with improved exercise capacity, strength of limb muscles and a decrease in serum CRP and IL-8 in COPD patients. Decreased systemic inflammation may contribute to these clinical benefits. (Clinical trial registration No.: NCT01631019)
PMCID: PMC4236722  PMID: 25175787
Chronic obstructive pulmonary disease; Pulmonary rehabilitation; Mobile phone; Biomarker; Interleukin-8
18.  NF-κB repressing factor downregulates basal expression and mycobacterium tuberculosis induced IP-10 and IL-8 synthesis via interference with NF-κB in monocytes 
Our previous study showed NF-κB repressing factor (NKRF) downregulates IP-10 and IL-8 synthesis in the peripheral blood mononuclear cells and alveolar macrophages of TB patients with high bacterial loads. However, the mechanism underlying the repressive effect of NKRF is not fully understood.
The levels of IP-10, IL-8 and NKRF were significantly up-regulated in THP-1 cells treated with heated mycobacterium tuberculosis (H. TB). NKRF inhibited NF-κB-mediated IP-10 and IL-8 synthesis and release induced by H. TB. The repressive effect of NKRF is mediated via interference with NF-κB (p65) binding and RNA polymerase II recruitment to promoter sites of IP-10 and IL-8.
We have elucidated that direct contact with MTb induces IP-10, IL-8 and a concomitant increase in NKRF in THP-1 cells. The up-regulated NKRF serves as an endogenous repressor for IP-10 and IL-8 synthesis to hinder host from robust response to MTb infection.
PMCID: PMC4237804  PMID: 25135111
Tuberculosis; IP-10; IL-8; NF-κB repressing factor
19.  Comparison of the efficacy of ciclesonide with that of budesonide in mild to moderate asthma patients after step-down therapy: a randomised parallel-group study 
Inhaled corticosteroids (ICSs) are widely used in asthma control. Ciclesonide (CIC) is an ICS with on-site lung activation for potent anti-inflammatory activity.
This study aimed to compare the clinical benefit of CIC with budesonide (BUD) in step-down therapy.
A total of 150 patients with mild-to-moderate asthma well controlled by a combination of ICS and long-acting β2-agonist were randomised to receive either CIC 320 μg (n=75) once daily or 2 inhalations of BUD 200 μg (n=75) twice daily for 12 weeks. The forced expiratory volume in 1s (FEV1), maximum mid-expiratory flow (MMEF) and asthma control test (ACT) scores were measured. Ranked stratification of patients and physicians was assessed.
Drug adherence was significantly higher in the CIC group than in the BUD group (76.0% vs. 58.7%, P=0.03). The FEV1 and MMEF remained stable throughout the 12-week CIC treatment. In the BUD group, FEV1 significantly decreased at weeks 4 and 12. MMEF had a higher value in the CIC group than in the BUD group. Both patients and physicians ranked CIC over BUD.
CIC is more effective and has better drug adherence than BUD as step-down treatment when asthma is well controlled by combination therapy.
PMCID: PMC4373304  PMID: 24841163
20.  Clinical Characteristics and Treatment Outcomes of Patients with Low- and High-Concentration Isoniazid-Monoresistant Tuberculosis 
PLoS ONE  2014;9(1):e86316.
Isoniazid (INH) resistance is now the most common type of tuberculosis (TB) infection resistance worldwide. The aim of this study was to evaluate the clinical characteristics and treatment outcomes of patients with low- and high-concentration INH-monoresistant TB.
One hundred and thirty-four patients with culture-confirmed INH-monoresistant TB during 2006 January to 2007 December were retrospectively enrolled. INH resistance was classified as either low-concentration or high-concentration resistance according to the critical concentrations of 0.2 µg/mL or 1 µg/mL of INH, respectively. The patients’ clinical outcomes, treatment regimens, and treatment duration were analyzed.
The treatment success rates between low- and high-concentration INH-resistant TB were similar (81.8% vs. 86.7%). The treatment regimens and treatment duration were similar between both groups. Only a minor percentage of the patients in both groups received 6-month treatment regimens (low vs. high concentration resistance, 9.1% vs. 13.3%; respectively, p = 0.447) The most common reason for treatment duration longer than 6 months was pyrazinamide given for less than 6 months, followed by a delay in clinical response to treatment. Multivariable analysis showed that prior tuberculosis treatment (Odds ratio, 2.82, 95% C.I., 1.02–7.77, p = 0.045) was the only independent risk factor for unsuccessful treatment outcome.
Different levels of INH resistance did not affect the treatment outcomes of patients with INH-monoresistant tuberculosis. Prolonged Rifampin-containing regimens may achieve those good outcomes in patients with low- and high-concentration INH-monoresistant TB.
PMCID: PMC3899226  PMID: 24466020
21.  Chronic cough and obstructive sleep apnoea in a sleep laboratory-based pulmonary practice 
Obstructive sleep apnoea (OSA) has recently been identified as a possible aetiology for chronic cough. The aim of this study was to compare the incidence of chronic cough between patients with and without OSA and the impact of continuous positive airway pressure (CPAP) treatment in resolving chronic cough.
Patients referred to the sleep laboratory from January 2012 to June 2012 were retrospectively enrolled. Clinical data, treatment course and resolution of chronic cough were analysed. Specifically, gastro-oesophageal reflux (GERD), upper airway cough syndrome, asthma, apnoea-hypopnoea index and the impact of CPAP treatment on chronic cough were assessed.
A total of 131 patients were reviewed. The incidence of chronic cough in the OSA group was significantly higher than the non-OSA group (39/99 (39.4%) vs. 4/32 (12.5%), p = 0.005). Both GERD and apnoea-hypopnoea index were significantly associated with chronic cough in univariate analysis. After multivariate logistic regression, GERD was the only independent factor for chronic cough. Moreover, the resolution of chronic cough was more significant in the OSA patients with CPAP treatment compared with those not receiving CPAP treatment (12/18 (66.7%) vs. 2/21 (9.5%), p = 0.010).
The incidence of chronic cough was significantly higher in the OSA patients. In addition, CPAP treatment significantly improved chronic cough. Therefore, OSA may be a contributory factor to chronic cough.
PMCID: PMC4176501  PMID: 24188336
Chronic cough; Obstructive sleep apnoea; Continuous positive airway pressure
22.  NF-κB Repressing Factor Inhibits Chemokine Synthesis by Peripheral Blood Mononuclear Cells and Alveolar Macrophages in Active Pulmonary Tuberculosis 
PLoS ONE  2013;8(11):e77789.
NF-κB repressing factor (NRF) is a transcriptional silencer implicated in the basal silencing of specific NF-κB targeting genes, including iNOS, IFN-β and IL-8/CXCL8. IP-10/CXCL10 and IL-8/CXCL8 are involved in neutrophil and lymphocyte recruitment against M. tuberculosis (MTb) and disease progression of pulmonary tuberculosis (TB). Alveolar macrophages (AM) and peripheral blood mononuclear cells (PBMC) were used to study the regulatory role of NRF in pulmonary TB. AM and PBMC were purified from 19 TB patients and 15 normal subjects. To study the underlying mechanism, PBMC were exposed to heated TB bacilli. The regulation role of NRF in IP-10/CXCL10 and IL-8/CXCL8 was determined by NRF knock-down or over-expression. NRF binding capabilities in promoter sites were measured by chromatin immunoprecipitation (ChIP) assay. The levels of IP-10/CXCL10, IL-8/CXCL8 and NRF were significantly higher in AM and PBMC in patients with active TB. NRF played an inhibitory role in IP-10/CXCL10 and IL-8/CXCL8 inductions. We delineate the role of NRF in pulmonary TB, which inhibits the expressions of IP-10/CXCL10 and IL-8/CXCL8 in AM and PBMC of patients with high bacterial load. NRF may serve as an endogenous repressor to prevent robust increase in IP-10/CXCL10 and IL-8/CXCL8 when TB bacterial load is high.
PMCID: PMC3817197  PMID: 24223729
23.  Nocturnal CPAP improves walking capacity in COPD patients with obstructive sleep apnoea 
Respiratory Research  2013;14(1):66.
Exercise limitation is an important issue in patients with chronic obstructive pulmonary disease (COPD), and it often co-exists with obstructive sleep apnoea (overlap syndrome). This study examined the effects of nocturnal continuous positive airway pressure (CPAP) treatment on walking capacity in COPD patients with or without obstructive sleep apnoea.
Forty-four stable moderate-to-severe COPD patients were recruited and completed this study. They all underwent polysomnography, CPAP titration, accommodation, and treatment with adequate pressure. The incremental shuttle walking test was used to measure walking capacity at baseline and after two nights of CPAP treatment. Urinary catecholamine and heart rate variability were measured before and after CPAP treatment.
After two nights of CPAP treatment, the apnoea-hypopnoea index and oxygen desaturation index significantly improved in both overlap syndrome and COPD patients, however these changes were significantly greater in the overlap syndrome than in the COPD group. Sleep architecture and autonomic dysfunction significantly improved in the overlap syndrome group but not in the COPD group. CPAP treatment was associated with an increased walking capacity from baseline from 226.4 ± 95.3 m to 288.6 ± 94.6 m (P < 0.05), and decreased urinary catecholamine levels, pre-exercise heart rate, oxygenation, and Borg scale in the overlap syndrome group. An improvement in the apnoea-hypopnoea index was an independent factor associated with the increase in walking distance (r = 0.564).
Nocturnal CPAP may improve walking capacity in COPD patients with overlap syndrome.
Trial registration
PMCID: PMC3689615  PMID: 23782492
Chronic obstructive pulmonary disease; Obstructive sleep apnoea; Walking capacity; Autonomic dysfunction; Continuous positive airway pressure
24.  Matrix Metalloproteinase-1 Polymorphism (-1607G) and Disease Severity in Non-Cystic Fibrosis Bronchiectasis in Taiwan 
PLoS ONE  2013;8(6):e66265.
Bronchiectasis is characterized by an irreversible dilatation of bronchi and is associated with lung fibrosis. MMP-1 polymorphism may alter its transcriptional activity, and differentially modulate bronchial destruction and lung fibrosis.
To investigate the association of MMP-1 polymorphisms with disease severity in non-cystic fibrosis (CF) bronchiectasis patients, 51 normal subjects and 113 patients with bronchiectasis were studied. The associations between MMP-1 polymorphisms, lung function, and disease severity evaluated by high resolution computed tomography (HRCT) were analyzed.
The frequency of MMP-1(-1607G) allele was significantly higher in patients with bronchiectasis than normal subjects (70.8% vs 45.1%, p<0.01). Forced expiratory volume in 1 second (FEV1) was decreased in bronchiectasis patients with 1G/1G (1.2±0.1 L, n = 14) and 1G/2G (1.3±0.1 L, n = 66) genotypes compared to the 2G/2G genotype (1.7±0.1 L, n = 33, p<0.01). Six minute walking distance was decreased in bronchiectasis patients with 1G/1G and 1G/2G compared to that of 2G/2G genotype. Disease severity evaluated by HRCT score significantly increased in bronchiectasis patients with 1G/1G and 1G/2G genotypes compared to that of 2G/2G genotype. Bronchiectasis patients with at least one MMP-1 (-1607G) allele showed increased tendency for hospitalization. Serum levels of pro-MMP-1, active MMP-1 and TGF-β1 were significantly increased in patients with bronchiectasis with 1G/1G and 1G/2G genotype compared with 2G/2G genotype or normal subjects. Under IL-1β stimulation, peripheral blood monocytes from subjects with 1G/2G or 1G/1G genotype secreted higher levels of TGF-β1compared to subjects with 2G/2G genotype.
This is the first report to address the influence of MMP-1 polymorphisms on lung function and airway destruction in non-CF bronchiectasis patients. Bronchiectasis patients with MMP-1(-1607G) polymorphism may be more vulnerable to permanent lung fibrosis or airway destruction due to the enhanced MMP-1 and TGF-β1 activity. Upregulated MMP-1 activity results in proteolytic destruction of matrix, and leads to subsequent fibrosis.
PMCID: PMC3679085  PMID: 23776649
25.  The Potential Regimen of Target-Controlled Infusion of Propofol in Flexible Bronchoscopy Sedation: A Randomized Controlled Trial 
PLoS ONE  2013;8(4):e62744.
Target-controlled infusion (TCI) provides precise pharmacokinetic control of propofol concentration in the effect-site (Ce), eg. brain. This pilot study aims to evaluate the feasibility and optimal TCI regimen for flexible bronchoscopy (FB) sedation.
After alfentanil bolus, initial induction Ce of propofol was targeted at 2 μg/ml. Patients were randomized into three titration groups (i.e., by 0.5, 0.2 and 0.1 μg/ml, respectively) to maintain stable sedation levels and vital signs. Adverse events, frequency of adjustments, drug doses, and induction and recovery times were recorded.
The study was closed early due to significantly severe hypoxemia events (oxyhemoglobin saturation <70%) in the group titrated at 0.5 μg/ml. Forty-nine, 49 and 46 patients were enrolled into the 3 respective groups before study closure. The proportion of patients with hypoxemia events differed significantly between groups (67.3 vs. 46.9 vs. 41.3%, p = 0.027). Hypotension events, induction and recovery time and propofol doses were not different. The Ce of induction differed significantly between groups (2.4±0.5 vs. 2.1±0.4 vs. 2.1±0.3 μg/ml, p = 0.005) and the Ce of procedures was higher at 0.5 μg/ml titration (2.4±0.5 vs. 2.1±0.4 vs. 2.2±0.3 μg/ml, p = 0.006). The adjustment frequency tended to be higher for titration at 0.1 μg/ml but was not statistically significant (2 (0∼6) vs. 3 (0∼6) vs. 3 (0∼11)). Subgroup analysis revealed 14% of all patients required no further adjustment during the whole sedation. Comparing patients requiring at least one adjustment with those who did not, they were observed to have a shorter induction time (87.6±34.9 vs. 226.9±147.9 sec, p<0.001), a smaller induction dose and Ce (32.5±4.1 vs. 56.8±22.7 mg, p<0.001; 1.76±0.17 vs. 2.28 ±0.41, p<0.001, respectively), and less hypoxemia and hypotension (15.8 vs.56.9%, p = 0.001; 0 vs. 24.1%, p = 0.008, respectively).
Titration at 0.5 μg/ml is risky for FB sedation. A subgroup of patients required no more TCI adjustment with fewer complications. Further studies are warranted to determine the optimal regimen of TCI for FB sedation.
Trial Registration NCT01101477
PMCID: PMC3634750  PMID: 23638141

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