Publications by authors named "Han-Pin Kuo"

133 Publications

Profiles of Peripheral Immune Cells of Uncomplicated COVID-19 Cases with Distinct Viral RNA Shedding Periods.

Viruses 2021 03 19;13(3). Epub 2021 Mar 19.

Pulmonary Research Center, Wanfang Hospital, Taipei Medical University, Taipei 116, Taiwan.

The heterogeneity of immune response to COVID-19 has been reported to correlate with disease severity and prognosis. While so, how the immune response progress along the period of viral RNA-shedding (VRS), which determines the infectiousness of disease, is yet to be elucidated. We aim to exhaustively evaluate the peripheral immune cells to expose the interplay of the immune system in uncomplicated COVID-19 cases with different VRS periods and dynamic changes of the immune cell profile in the prolonged cases. We prospectively recruited four uncomplicated COVID-19 patients and four healthy controls (HCs) and evaluated the immune cell profile throughout the disease course. Peripheral blood mononuclear cells (PBMCs) were collected and submitted to a multi-panel flowcytometric assay. CD19-B cells were upregulated, while CD4, CD8, and NK cells were downregulated in prolonged VRS patients. Additionally, the pro-inflammatory-Th1 population showed downregulation, followed by improvement along the disease course, while the immunoregulatory cells showed upregulation with subsequent decline. COVID-19 patients with longer VRS expressed an immune profile comparable to those with severe disease, although they remained clinically stable. Further studies of immune signature in a larger cohort are warranted.
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http://dx.doi.org/10.3390/v13030514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003740PMC
March 2021

Alveolar epithelial inter-alpha-trypsin inhibitor heavy chain 4 deficiency associated with senescence-regulated apoptosis by air pollution.

Environ Pollut 2021 Jun 9;278:116863. Epub 2021 Mar 9.

School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address:

Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is a type II acute-phase protein; however, the role of pulmonary ITIH4 after exposure to air pollution remains unclear. In this study, we investigated the role of ITIH4 in the lungs in response to air pollution. ITIH4 expression in bronchoalveolar lavage fluid (BAL) of 47 healthy human subjects and of Sprague-Dawley rats whole-body exposed to air pollution was determined, and the underlying antiapoptotic and matrix-stabilizing pathways in alveolar epithelial A549 cells induced by diesel exhaust particles (DEPs) as well as ITIH4-knockdown were investigated. We found that an interquartile range (IQR) increase in PM was associated with a decrease of 2.673 ng/mL in ITIH4, an increase of 1.104 pg/mL of 8-isoprostane, and an increase of 6.918 pg/mL of interleukin (IL)-6 in human BAL. In rats, increases in 8-isoprostane, IL-6, and p53 and a decrease in sirtuin-1 (Sirt1) in the lungs and decreases in ITIH4 in the BAL, lungs, and serum were observed after PM and gaseous exposure. ITIH4 levels in lung lysates were correlated with levels in BAL samples (r = 0.377, p < 0.01), whereas ITIH4 levels in BAL were correlated with IL-6 levels (r = -0.420, p < 0.01). ITIH4 expression was significantly reduced in alveolar epithelial A549 cells by DEP in a dose-dependent manner. A decrease in Sirt1 and increases in phosphorylated extracellular signal-regulated kinase (p-ERK) and caspase-3 were observed after DEP exposure and ITIH4-knockdown. In conclusion, air pollution decreased ITIH4 expression in the lungs, which was associated with alveolar epithelial cell senescence and apoptosis. ITIH4 could be a vital protein in regulating alveolar cell destruction and its inhibition after exposure to air pollution.
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http://dx.doi.org/10.1016/j.envpol.2021.116863DOI Listing
June 2021

Impact of Annual Exposure to Polycyclic Aromatic Hydrocarbons on Acute Exacerbation Frequency in Asthmatic Patients.

J Asthma Allergy 2021 29;14:81-90. Epub 2021 Jan 29.

Pulmonary Medicine Research Center, Taipei Medical University, Taipei, Taiwan.

Purpose: Exposure to polycyclic aromatic hydrocarbons (PAHs) associated with ambient air particulate matter (PM) poses significant health concerns. Increased acute exacerbation (AE) frequency in asthmatic patients has been associated with ambient PAHs, but which subgroup of patients are particularly susceptible to ambient PAHs is uncertain. We developed a new model to simulate grid-scale PM-PAH levels in order to evaluate whether the severity of asthma as measured by the Global Initiative of Asthma (GINA) levels of treatment is related to cumulative exposure of ambient PAHs.

Methods: Patients with asthma residing in the northern Taiwan were reviewed retrospectively from 2014 to 2017. PM were sampled and analysed for PAHs twice a month over a 72-hour period, in addition to collecting the routinely monitored air pollutant data from an established air quality monitoring network. In combination with correlation analysis and principal component analysis, multivariate linear regression models were performed to simulate hourly grid-scale PM-PAH concentrations (ng/m). A geographic information system mapping approach with ordinary kriging interpolation method was used to calculate the annual exposure of PAHs (ng/m).

Results: Among the 387 patients with asthma aged 18 to 93 (median 62), 97 subjects were treated as GINA step 5 (24%). Asthmatics in GINA 5 subgroup with high annual PAHs exposure were likely to have a higher annual frequency of any AE (1 (0-12), p<0.0001). Annual PAHs exposure was correlated with the annual frequency of any exacerbation (r=0.11, p=0.02). This was more significant in the GINA 5 subgroup (r=0.29, p=0.005) and in the GINA 5 subgroup with severe acute exacerbations (r=0.51, p=0.002). Annual PAHs exposure, severe acute exacerbation and GINA steps were independent variables that predict annual frequency of any exacerbation.

Conclusion: Asthmatic patients in the GINA 5 subgroup with acute exacerbations were more susceptible to the effect of environmental PAHs on their exacerbation frequency. Reducing environmental levels of PAHs will have the greatest impact on the more severe asthma patients.
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http://dx.doi.org/10.2147/JAA.S288052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853411PMC
January 2021

Life course body mass index through childhood and young adulthood and risks of asthma and pulmonary function impairment.

Pediatr Pulmonol 2021 May 27;56(5):849-857. Epub 2021 Jan 27.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC.

Background: Adiposity is a key risk factor for asthma and impaired pulmonary function.

Objectives: We aimed to identify the critical period of life course adiposity for asthma in childhood and young adulthood, and to determine whether associations of adiposity and asthma vary across ages.

Methods: Birth weight and body mass index (BMI) from birth to 17 years of age were assessed in 6130 children from the Taiwan Children Health Study. Logistic regression for asthma outcome and linear regression for pulmonary function outcome were used to investigate associations of adiposity with asthma. Seventeen BMI-related single-nucleotide polymorphisms were used to obtain genetic instrumental variables for adiposity to perform Mendelian randomization (MR) analysis.

Results: Using both regression model and MR analyses, we confirmed that the critical period of adiposity in predicting childhood asthma would be before age 6 years. Further, we discovered that the sensitive period of adiposity gain related to young adulthood asthma was the prepubertal stage. Risks of asthma at age 17 per unit increase in z-score of the BMI increased from 0.94 (95% CI: 0.79-1.11) at birth, and became greater than 1.00 between age 11 and 12, then increased to 1.08 (95% CI: 0.95-1.22) at age 17. The associations of life course BMI with asthma and pulmonary function impairment at age 12 and with asthma at age 17 increased with age. The aforementioned association was most prominent among central obesity indicators.

Conclusions: To prevent asthma in childhood and young adulthood, we should aim at promoting healthy growth at the toddler period and prepubertal stage.
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http://dx.doi.org/10.1002/ppul.25197DOI Listing
May 2021

Effectiveness of Low-Dose Itraconazole in Fungal-Associated Severe Asthma: A Retrospective Study.

J Asthma Allergy 2020 8;13:453-461. Epub 2020 Oct 8.

College of Medicine, Taipei Medical University, Taipei, Taiwan.

Background: The efficacy of antifungal therapy in fungal-associated severe asthma remains controversial.

Objective: We aimed to evaluate the differences in the clinical presentation and response to antifungal therapy between severe asthmatics with fungal sensitization and positive fungal isolates.

Methods: This retrospective study included 73 patients with severe asthma from January 2004 to December 2017. We examined the presentation, medication, exacerbations, pulmonary function, serum IgE, blood eosinophils, and sputum culture results. Follow-up care was provided to each patient for minimum 3 years.

Results: We classified the patients into four groups: group 1, neither fungal sensitization nor fungal isolates in the sputum (n=16); group 2, positive fungal sensitization (n=16); group 3, positive fungal isolates (n=31); and group 4, concomitant positive fungal sensitization and positive fungal isolates (n=10). There were four participants in group 2, 15 in group 3, and 6 in group 4 had received itraconazole therapy for 3 months. Patients in group 3 presented with lower serum IgE level than those in groups 2 and 4. Antifungal therapy significantly improved ACT score during the first year in groups 3 (from 18 [15-22] to 24 [23-24], p=0.0004) and resulted in a long-lasting ACT improvement till the third year in group 3 (from 18 [15-22] to 24 [22-24], p=0.0013).

Conclusion: Antifungal therapy could effectively control the symptoms in patients with severe asthma with positive fungal isolates, contrary to those with merely fungal sensitization; therefore, highlighting the need for a more precise treatment strategy in future for fungal-associated severe asthma.
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http://dx.doi.org/10.2147/JAA.S276289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549880PMC
October 2020

Alteration in angiotensin-converting enzyme 2 by PM during the development of emphysema in rats.

ERJ Open Res 2020 Oct 5;6(4). Epub 2020 Oct 5.

Division of Pulmonary Medicine, Dept of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan.

Introduction: Angiotensin-converting enzyme 2 (ACE2) provides an adhesion site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with COPD could have severe outcomes after SARS-CoV-2 infection. The objective of this study was to investigate ACE2 regulation by air pollution during the development of COPD.

Methods: Sprague Dawley rats were exposed to unconcentrated traffic-related air pollution for 3 and 6 months. We examined lung injury markers, oxidative stress, inflammation, emphysema, ACE2 and angiotensin II receptor type 1 (AT1) and 2 (AT2) in the lungs after exposure.

Results: Lung injury occurred due to an increase in permeability and lactate dehydrogenase cytotoxicity was observed after 6 months of exposure to fine particulate matter of <1 μm in aerodynamic diameter (PM). An α-antitrypsin deficiency and neutrophil elastase production with emphysema development were observed after 6 months of PM exposure. 8-isoprostane and interleukin-6 were increased after 3 and 6 months of PM exposure. Caspase-3 was increased after exposure to PM for 6 months. Upregulation of ACE2 was found after 3 months of PM exposure; however, ACE2 had decreased by 6 months of PM exposure. AT1 and AT2 had significantly decreased after exposure to PM for 6 months. Furthermore, smooth muscle hypertrophy had occurred after 6 months of PM exposure.

Conclusions: In conclusion, short-term exposure to PM increased the ACE2 overexpression in lungs. Long-term exposure to PM decreased the ACE2 overexpression in emphysema. Air pollution may be a risk for SARS-CoV-2 adhesion during the development of COPD.
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http://dx.doi.org/10.1183/23120541.00174-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533376PMC
October 2020

Hypoventilation patterns during bronchoscopic sedation and their clinical relevance based on capnographic and respiratory impedance analysis.

J Clin Monit Comput 2020 Feb 6;34(1):171-179. Epub 2019 Feb 6.

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, 199 Tun-Hwa N. Rd., Taipei, Taiwan.

Capnography involves the measurement of end-tidal CO (EtCO) values to detect hypoventilation in patients undergoing sedation. In a previous study, we reported that initiating a flexible bronchoscopy (FB) examination only after detecting signs of hypoventilation could reduce the risk of hypoxemia without compromising the tolerance of the patient for this type of intervention. We hypothesize that hypoventilation status could be determined with greater precision by combining thoracic impedance-based respiratory signals, RESP, and EtCO signals obtained from a nasal-oral cannula. Retrospective analysis was conducted on RESP and EtCO waveforms obtained from patients during the induction of sedation using propofol for bronchoscopic examination in a previous study. EtCO waveforms associated with hypoventilation were then compared with RESP patterns, patient variables, and sedation outcomes. Signals suitable for analysis were obtained from 44 subjects, 42 of whom presented indications of hypoventilation, as determined by EtCO waveforms. Two subtypes of hypoventilation were identified by RESP: central-predominant (n = 22, flat line RESP pattern) and non-central-predominant (n = 20, RESP pattern indicative of respiratory effort with upper airway collapse). Compared to cases of non-central-predominant hypoventilation, those presenting central-predominant hypoventilation during induction were associated with a lower propofol dose (40.2 ± 18.3 vs. 60.8 ± 26.1 mg, p = 0.009), a lower effect site concentration of propofol (2.02 ± 0.33 vs. 2.38 ± 0.44 µg/ml, p = 0.01), more rapid induction (146.1 ± 105.5 vs. 260.9 ± 156.2 s, p = 0.01), and lower total propofol dosage (96.6 ± 41.7 vs. 130.6 ± 53.4 mg, p = 0.04). Hypoventilation status (as revealed by EtCO levels) could be further classified by RESP into central-predominant or non-central-predominant types. It appears that patients with central-predominant hypoventilation are more sensitive to propofol during the induction of sedation. RESP values could be used to tailor sedation management specifically to individual patients.
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http://dx.doi.org/10.1007/s10877-019-00269-0DOI Listing
February 2020

Targeting PKCδ as a Therapeutic Strategy against Heterogeneous Mechanisms of EGFR Inhibitor Resistance in EGFR-Mutant Lung Cancer.

Cancer Cell 2018 12;34(6):954-969.e4

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Multiple mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of nuclear protein kinase Cδ (PKCδ) as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation. Moreover, the level of nuclear PKCδ is associated with TKI response in patients. The combined inhibition of PKCδ and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations.
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http://dx.doi.org/10.1016/j.ccell.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886126PMC
December 2018

Endotypes of severe allergic asthma patients who clinically benefit from anti-IgE therapy.

Clin Exp Allergy 2019 01 11;49(1):44-53. Epub 2018 Sep 11.

College of Medicine, Taipei Medical University, Taipei, Taiwan.

Background: Omalizumab, a recombinant monoclonal anti-IgE antibody, was developed for the treatment of severe allergic asthma. Not all these patients respond to omalizumab.

Objective: This study aimed to evaluate whether the proinflammatory cytokine profiles in the severe allergic asthma patients were different between who responded and nonresponded to omalizumab therapy.

Methods: A prospective study was conducted to examine type 2 cytokines and epithelium-derived cytokines in the bronchial tissues by immunohistochemistry, Western blot and PCR analysis among patients with severe allergic asthma before and after omalizumab therapy.

Results: Fourteen of 23 patients with unstable severe allergic asthma improved their asthma control after 4 months of omalizumab treatment (Responders), while nine failed to improve (Non-Responders). Most of Responders were type 2-high endotype (12/14) with upregulated expression of IL-33, IL-25 and TSLP in their bronchial tissues, while most of Non-Responders were type 2-low endotype (8/9). Repeated bronchoscopic biopsy was done in nine responders after omalizumab treatment and showed a decline in IL-13, IL-33, IL-25 and TSLP expression in the bronchial tissues. Among 14 Responders who continued omalizuamb treatments to a total 12 months, six patients achieved a well control of asthma (ACT ≥ 23), while eight patients required additional treatment for asthma symptoms and had more rhinosinusitis comorbidities and a mixed eosinophilic and neutrophilic inflammation in their bronchial tissues.

Conclusion: Most of the severe allergic asthma patients who benefited from omalizumab treatment were IL-33, IL-25 and TSLP aggravated type 2-high endotype. Rhinosinusitis or with a mixed eosinophilic and neutrophilic airway inflammation should be evaluated in patients who partially responded to omalizumab treatment.
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http://dx.doi.org/10.1111/cea.13248DOI Listing
January 2019

Differences between COPD patients and their families regarding willingness toward life-sustaining treatments.

J Formos Med Assoc 2019 Jan 18;118(1 Pt 3):414-419. Epub 2018 Jul 18.

College of Medicine, Taipei Medical University, Taiwan.

Background/purpose: Patients with chronic obstructive pulmonary disease (COPD) receive more life-sustaining treatments (LSTs) than those with other diseases. The aims of this study were to explore the willingness of COPD patients and their families to consent to LSTs and compare the differences between their levels of willingness.

Methods: A cross-sectional survey was conducted, and structured questionnaires were used for data collection.

Results: A total of 219 valid samples were collected, including 109 patients and 110 families. Sixty percent of family members indicated that they did not know the intentions of the patient. Families were significantly more willing for patients to receive LSTs than the patients themselves. The level of willingness of patients and families varied according to the situation and LST interventions. When patients were in a vegetative state or medical treatments were futile, the willingness of COPD patients and their families to receive LSTs significantly decreased. Endotracheal intubation and external defibrillation were the least likely to be requested, whereas the willingness to receive medication injections and noninvasive ventilation was greatest.

Conclusion: Communication between families and patients on the issue of LST should be facilitated. Adequate information on the patient's condition and possible LSTs should be provided to avoid COPD patients receiving inappropriate LSTs.
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http://dx.doi.org/10.1016/j.jfma.2018.06.020DOI Listing
January 2019

Increased matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio in smokers with airway hyperresponsiveness and accelerated lung function decline.

Int J Chron Obstruct Pulmon Dis 2018;13:1135-1144. Epub 2018 Apr 11.

Department of Thoracic Medicine, Chang Gung Medical Foundation, College of Medicine, Chang Gung University, Taipei, Taiwan.

Background: Airway hyperresponsiveness (AHR) is associated with airway inflammation and a rapid decline in lung function and is a predictor of future risk of COPD among smokers. Alveolar macrophages (AMs) from patients with COPD release a greater amount of matrix metalloproteinase (MMP)-9. We hypothesized that the imbalance between MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) is related to AHR in smokers.

Patients And Methods: Healthy smokers with AHR (AHR + S) or smokers without AHR (AHR - S; divided according to a methacholine challenge test) and nonsmokers without AHR (AHR - NS) were enrolled. Spirometry was performed during enrollment and repeated after 5 years. Initially, AMs recovered from bronchoalveolar lavage (BAL) fluid were cultured in the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), MAPK kinase (MEK) 1/2 (the MEK of extracellular signal-regulated kinase [ERK] inhibitor, PD98059), or medium alone for 24 h. The release of MMP-9 and TIMP-1 in culture supernatants was measured by enzyme-linked immunosorbent assay.

Results: A greater reduction in forced expiratory volume in 1 s (FEV)/forced vital capacity (FVC), FEV (as a percentage of the predicted value [%pred]), and maximal mid-expiratory flow (MMEF) was observed among AHR + S in the 5-year period. There was a higher proportion of neutrophils and a lower proportion of AMs in BAL fluid recovered from AHR + S. Compared to AMs from AHR - NS and AHR - S, AMs from nonsmokers with AHR (AHR + NS) released more MMP-9 and less TIMP-1, with an increase in MMP-9/TIMP-1 ratios. The MMP-9/TIMP-1 ratio in smokers was positively correlated with the annual decline in FEV%pred, FVC%pred, and MMEF%pred. Both SB203580 and PD98059 significantly reduced MMP-9, but not TIMP-1, from AMs of smokers.

Conclusion: AMs of AHR + NS produce excessive MMP-9 over TIMP-1, which may be a predictor of the development of airway obstruction. Inhibition of p38 MAPK and ERK suppresses the generation of MMP-9 by AMs from smokers.
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http://dx.doi.org/10.2147/COPD.S161257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903494PMC
October 2018

Diesel exhaust particles up-regulate interleukin-17A expression via ROS/NF-κB in airway epithelium.

Biochem Pharmacol 2018 05 27;151:1-8. Epub 2018 Feb 27.

Department of Medicine, Taipei Medical University College of Medicine, Taipei, Taiwan. Electronic address:

IL-17A is implicated in many aspects of pathogenesis of severe asthma, including inducing neutrophilic inflammation, airway hyperresponsiveness, steroid insensitivity and airway remodeling. Diesel exhaust particles (DEP) emission from vehicles has been shown to expand Th17 cells to increase IL-17A release that contributes to DEP-mediated exacerbation of asthma severity. It is not known whether non-immune cells in airways may also release IL-17A in response to DEP exposure. In this study, We found IL-17A expression was upregulated in the epithelium of severe allergic asthma patients from high road traffic pollution areas compared to those in low. Furthermore, we found DEP concentration-dependently increased IL-17A synthesis and release by 122.3 ± 15.72% and 235.5 ± 18.37%, respectively in primary bronchial epithelial cells (PBEC), accompanied with increased ROS production. Pretreatment of ROS scavenger (NAC) significantly inhibited DEP-induced IL-17A mRNA expression. DEP-induced IκBα degradation can be inhibited by NAC. We also found DEP increased p65 and RelB subunits expression, and pretreatment of NF-κB inhibitor (SN50) also inhibited DEP-induced IL-17A expression. We further found DEP increased NF-κB subunit RelB recruitment to IL-17A promoter in PBEC and airway tissue of severe allergic asthma patients from high road traffic pollution areas. These results indicate DEP stimulates IL-17A expression in airway epithelium through ROS/NF-κB pathway, and provide a possible link between traffic pollution exposure and IL-17A-related responses in severe allergic asthma patients.
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http://dx.doi.org/10.1016/j.bcp.2018.02.028DOI Listing
May 2018

Reduced suppressive effect of β-adrenoceptor agonist on fibrocyte function in severe asthma.

Respir Res 2017 Nov 21;18(1):194. Epub 2017 Nov 21.

Airway Disease Section, National Heart and Lung Institute, Imperial College London and Biomedical Research Unit, Royal Brompton Hospital, London, UK.

Background: Patients with severe asthma have increased airway remodelling and elevated numbers of circulating fibrocytes with enhanced myofibroblastic differentiation capacity, despite being treated with high doses of corticosteroids, and long acting β-adrenergic receptor (AR) agonists (LABAs). We determined the effect of β-AR agonists, alone or in combination with corticosteroids, on fibrocyte function.

Methods: Non-adherent non-T cells from peripheral blood mononuclear cells isolated from healthy subjects and patients with non-severe or severe asthma were treated with the β-AR agonist, salmeterol, in the presence or absence of the corticosteroid dexamethasone. The number of fibrocytes (collagen I/CD45 cells) and differentiating fibrocytes (α-smooth muscle actin cells), and the expression of CC chemokine receptor 7 and of β-AR were determined using flow cytometry. The role of cyclic adenosine monophosphate (cAMP) was elucidated using the cAMP analogue 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) and the phosphodiesterase type IV (PDE4) inhibitor, rolipram.

Results: Salmeterol reduced the proliferation, myofibroblastic differentiation and CCR7 expression of fibrocytes from healthy subjects and non-severe asthma patients. Fibrocytes from severe asthma patients had a lower baseline surface β-AR expression and were relatively insensitive to salmeterol but not to 8-Br-cAMP or rolipram. Dexamethasone increased β-AR expression and enhanced the inhibitory effect of salmeterol on severe asthma fibrocyte differentiation.

Conclusions: Fibrocytes from patients with severe asthma are relatively insensitive to the inhibitory effects of salmeterol, an effect which is reversed by combination with corticosteroids.
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http://dx.doi.org/10.1186/s12931-017-0678-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697384PMC
November 2017

Capnography monitoring the hypoventilation during the induction of bronchoscopic sedation: A randomized controlled trial.

Sci Rep 2017 08 17;7(1):8685. Epub 2017 Aug 17.

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taipei, Taiwan.

We hypothesize that capnography could detect hypoventilation during induction of bronchoscopic sedation and starting bronchoscopy following hypoventilation, may decrease hypoxemia. Patients were randomized to: starting bronchoscopy when hypoventilation (hypopnea, two successive breaths of at least 50% reduction of the peak wave compared to baseline or apnea, no wave for 10 seconds) (Study group, n = 55), or when the Observer Assessment of Alertness and Sedation scale (OAAS) was less than 4 (Control group, n = 59). Propofol infusion was titrated to maintain stable vital signs and sedative levels. The hypoventilation during induction in the control group and the sedative outcome were recorded. The patient characteristics and procedures performed were similar. Hypoventilation was observed in 74.6% of the patients before achieving OAAS < 4 in the control group. Apnea occurred more than hypopnea (p < 0.0001). Hypoventilation preceded OAAS < 4 by 96.5 ± 88.1 seconds. In the study group, the induction time was shorter (p = 0.03) and subjects with any two events of hypoxemia during sedation, maintenance or recovery were less than the control group (1.8 vs. 18.6%, p < 0.01). Patient tolerance, wakefulness during sedation, and cooperation were similar in both groups. Significant hypoventilation occurred during the induction and start bronchoscopy following hypoventilation may decrease hypoxemia without compromising patient tolerance.
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http://dx.doi.org/10.1038/s41598-017-09082-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561208PMC
August 2017

Effects of a Web-based Health Education Program on Quality of Life and Symptom Distress of Initially Diagnosed Advanced Non-Small Cell Lung Cancer Patients: A Randomized Controlled Trial.

J Cancer Educ 2019 02;34(1):41-49

Department of Nursing, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Advanced non-small cell lung cancer (NSCLC) patients treated with chemotherapy experience functional decline and decreased quality of life. The purpose of this study was to evaluate the effects of a web-based health education program on global quality of life, quality of life-related functional dimensions, and symptom distress of initially diagnosed advanced non-small cell lung cancer patients. This study used a randomized, pre- and post-repeated measures design. A total of 55 participants were randomly assigned to an experimental group (n = 27) and a control group (n = 28). The experimental group participated in a web-based health education program, and the control group received usual care. Patients were assessed at 4 time points: baseline assessment (T0), and then 1, 2, and 3 months (T1, T2, and T3) after participating in the web-based health education program or receiving usual care. Patients in the experimental group had significantly greater global quality of life and emotional function, and significantly less top ten significant symptom distresses compared to those in the control group. There were no differences between the groups and within groups with respect to physical function, role function, cognitive function, and social function. The web-based health education can improve global quality of life, emotional function, and top ten significant symptom distresses in patients receiving chemotherapy during the first 3 months after initial diagnosis of advanced NSCLC. Web-based health education can improve quality of life and lessen distress of initially diagnosed NSCLC patients treated with chemotherapy.
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http://dx.doi.org/10.1007/s13187-017-1263-yDOI Listing
February 2019

Different perceptions of narrative medicine between Western and Chinese medicine students.

BMC Med Educ 2017 May 10;17(1):85. Epub 2017 May 10.

Neurosurgery, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taipei, Taiwan.

Background: Western medicine is an evidence-based science, whereas Chinese medicine is more of a healing art. To date, there has been no research that has examined whether students of Western and Chinese medicine differentially engage in, or benefit from, educational activities for narrative medicine. This study fills a gap in current literature with the aim of evaluating and comparing Western and Chinese Medicine students' perceptions of narrative medicine as an approach to learning empathy and professionalism.

Methods: An initial 10-item questionnaire with a 5-point Likert scale was developed to assess fifth-year Western medical (MS) and traditional Chinese medical (TCMS) students' perceptions of a 4-activity narrative medicine program during a 13-week internal medicine clerkship. Exploratory factor analysis was undertaken.

Results: The response rate was 88.6% (412/465), including 270 (65.5%) MSs and 142 (34.5%) TCMSs, with a large reliability (Cronbach alpha = 0.934). Three factors were extracted from 9 items: personal attitude, self-development/reflection, and emotional benefit, more favorable in terms of enhancement of self-development/reflection. The perceptions of narrative medicine by scores between the two groups were significantly higher in TCMSs than MSs in all 9-item questionnaire and 3 extracted factors.

Conclusions: Given the different learning cultures of medical education in which these student groups engage, this suggests that undertaking a course in Chinese medicine might enhance one's acceptance to, and benefit from, a medical humanities course. Alternatively, Chinese medicine programmes might attract more humanities-focused students.
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http://dx.doi.org/10.1186/s12909-017-0925-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424351PMC
May 2017

Heat shock protein70 is implicated in modulating NF-κB activation in alveolar macrophages of patients with active pulmonary tuberculosis.

Sci Rep 2017 04 27;7(1):1214. Epub 2017 Apr 27.

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.

Heat shock proteins (HSPs) have been shown to modulate NF-κB activation. It is unknown whether HSP70 plays a role in modulating NF-κB-mediated pro-inflammatory cytokines released from alveolar macrophage (AM) of patients with active pulmonary tuberculosis (TB). Peripheral blood monocytes (PBMs) and AM were sampled from nineteen active TB patients and 14 healthy individuals. HSP70 expression was 3-fold higher in AMs of active TB patients than normal subjects, and declined after receiving 3-month anti-TB treatment. Overexpression of HSP70 by transfection with HSP70 plasmid decreased p-IκBα and p65 NF-κB activities. Inhibition of NF-κB activation using NF-κB or MAPK inhibitors increased HSP70 expression in AM of TB patients. Blocking p38- or ERK-MAPK decreased NF-κB and IκB activities, leading to up-regulated HSP70 expression. Overexpression of HSP70 alone or with p38 or ERK inhibitors decreased TNF-α (57%, 83% and 74%, respectively) and IL-6 (53%, 70%, and 67%, respectively) release from macrophages of TB patients. In conclusion, HSP70 modulates NF-κB activation in AM of TB patients, through inhibiting IκB-α phosphorylation or acting as a chaperon molecule to prevent NF-κB binding to the target genes by facilitating degradation. The upregulated HSP70 may suppress the release of pro-inflammatory cytokines during active PTB infection, and prevent overwhelming tissue damage.
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http://dx.doi.org/10.1038/s41598-017-01405-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430681PMC
April 2017

Obstructive sleep apnoea accelerates FEV decline in asthmatic patients.

BMC Pulm Med 2017 03 21;17(1):55. Epub 2017 Mar 21.

Pulmonary Disease Research Centre, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, 199 Tun-Hwa N. Rd., Taipei, Taiwan.

Background: Although the prevalence of both obstructive sleep apnoea (OSA) and asthma are both increasing, little is known about the impact of OSA on the natural history of lung function in asthmatic patients.

Methods: A total of 466 patients from our sleep laboratory were retrospectively enrolled. Of them, 77 patients (16.5%) had asthma with regular follow-up for more than 5 years. Their clinical characteristics, pulmonary function, emergency room visits, and results of polysomnography results were analysed.

Results: The patients were divided into three groups according to the severity of the apnoea-hypopnea index (AHI). The decline in FEV among asthma patients with severe OSA (AHI > 30/h) was 72.4 ± 61.7 ml/year (N = 34), as compared to 41.9 ± 45.3 ml/year (N = 33, P = 0.020) in those with mild to moderate OSA (5 < AHI ≤ 30) and 24.3 ± 27.5 ml/year (N = 10, P = 0.016) in those without OSA (AHI ≤ 5). For those patients with severe OSA, the decline of FEV significantly decreased after continuous positive airway pressure (CPAP) treatment. After multivariate stepwise linear regression analysis, only AHI was remained independent factor for the decline of FEV decline.

Conclusions: Asthmatic patients with OSA had substantially greater declines in FEV than those without OSA. Moreover, CPAP treatment alleviated the decline of FEV in asthma patients with severe OSA.
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http://dx.doi.org/10.1186/s12890-017-0398-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361857PMC
March 2017

Oncostatin M-Preconditioned Mesenchymal Stem Cells Alleviate Bleomycin-Induced Pulmonary Fibrosis Through Paracrine Effects of the Hepatocyte Growth Factor.

Stem Cells Transl Med 2017 03 18;6(3):1006-1017. Epub 2016 Oct 18.

Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China.

Mesenchymal stem cells (MSCs) are widely considered for treatment of pulmonary fibrosis based on the anti-inflammatory, antifibrotic, antiapoptotic, and regenerative properties of the cells. Recently, elevated levels of oncostatin M (OSM) have been reported in the bronchoalveolar lavage fluid of a pulmonary fibrosis animal model and in patients. In this work, we aimed to prolong engrafted MSC survival and to enhance the effectiveness of pulmonary fibrosis transplantation therapy by using OSM-preconditioned MSCs. OSM-preconditioned MSCs were shown to overexpress type 2 OSM receptor (gp130/OSMRβ) and exhibited high susceptibility to OSM, resulting in upregulation of the paracrine factor, hepatocyte growth factor (HGF). Moreover, OSM-preconditioned MSCs enhanced cell proliferation and migration, attenuated transforming growth factor-β1- or OSM-induced extracellular matrix production in MRC-5 fibroblasts through paracrine effects. In bleomycin-induced lung fibrotic mice, transplantation of OSM-preconditioned MSCs significantly improved pulmonary respiratory functions and downregulated expression of inflammatory factors and fibrotic factors in the lung tissues. Histopathologic examination indicated remarkable amelioration of the lung fibrosis. LacZ-tagged MSCs were detected in the lung tissues of the OSM-preconditioned MSC-treated mice 18 days after post-transplantation. Taken together, our data further demonstrated that HGF upregulation played an important role in mediating the therapeutic effects of transplanted OSM-preconditioned MSCs in alleviating lung fibrosis in the mice. Stem Cells Translational Medicine 2017;6:1006-1017.
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http://dx.doi.org/10.5966/sctm.2016-0054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442768PMC
March 2017

Early management of sepsis with emphasis on early goal directed therapy: AME evidence series 002.

J Thorac Dis 2017 Feb;9(2):392-405

Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.

Severe sepsis and septic shock are major causes of morbidity and mortality in patients entering the emergency department (ED) or intensive care unit (ICU). Despite substantial efforts to improve patient outcome, treatment of sepsis remains challenging to clinicians. In this context, early goal directed therapy (EGDT) represents an important concept emphasizing both early recognition of sepsis and prompt initiation of a structured treatment algorithm. As part of the AME evidence series on sepsis, we conducted a systematic review of all randomized controlled EGDT trials. Focus was laid on the setting (emergency department versus ICU) where EGDT was carried out. Early recognition of sepsis, through clinical or automated systems for early alert, together with well-timed initiation of the recommended therapy bundles may improve patients' outcome. However, the original "EGDT" protocol by Rivers and coworkers has been largely modified in subsequent trials. Currently, many investigators opt for an "expanded" EGDT (as suggested by the Surviving Sepsis Campaign). Evidence is also presented on the effectiveness of automated systems for early sepsis alert. Early recognition of sepsis and well-timed initiation of the SSC bundle may improve patient outcome.
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http://dx.doi.org/10.21037/jtd.2017.02.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334094PMC
February 2017

Impact of chronic rhinosinusitis on severe asthma patients.

PLoS One 2017 15;12(2):e0171047. Epub 2017 Feb 15.

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.

Coexistence of chronic rhinosinusitis (CRS) with asthma appears to impair asthma control. Type-2 innate lymphoid cells (ILC2s) respond to the cytokines of thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 and IL-33, thus contributing to airway diseases such as CRS and asthma. We investigate whether the augmented Th2-cytokines in CRS might be related to sinonasal tract ILC2s corresponding to enhanced IL-25, IL-33 and TSLP release in severe asthmatics, and be involved in asthma control. Twenty-eight asthmatics (12 non-severe and 16 severe) with CRS receiving nasal surgery were enrolled. The predicted FEV1 inversely associated with CRS severity of CT or endoscopy scores. Higher expression of Th2-driven cytokines (IL-4, IL-5, IL-9, and IL-13), TSLP, IL-25 and IL-33 in nasal tissues was observed in severe asthma. Severe asthmatics had higher ILC2 cell counts in their nasal tissues. ILC2 counts were positively correlated with Th2-cytokines. Nasal surgery significantly improved asthma control and lung function decline in severe asthma and CRS. The higher expression of IL-33/ILC2 axis-directed type 2 immune responses in nasal tissue of CRS brought the greater decline of lung function in severe asthma. ILC2-induced the upregulated activity of Th2-related cytokines in asthmatics with CRS may contribute to a recalcitrant status of asthma control.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171047PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5310870PMC
August 2017

The safety and efficacy of alfentanil-based induction in bronchoscopy sedation: A randomized, double-blind, controlled trial.

Medicine (Baltimore) 2016 Oct;95(43):e5101

Department of Thoracic Medicine, Chang Gung Memorial Hospital Linkou Branch Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University Healthcare Center, Chang Gung Memorial Hospital, Taoyuan Department of Thoracic Medicine, Ton-Yen General Hospital, Hsinchu County, Taiwan.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1097/MD.0000000000005101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089092PMC
October 2016

Pulmonary rehabilitation coupled with negative pressure ventilation decreases decline in lung function, hospitalizations, and medical cost in COPD: A 5-year study.

Medicine (Baltimore) 2016 Oct;95(41):e5119

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taipei Biostatistics Unit, Clinical Trial Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

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.
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http://dx.doi.org/10.1097/MD.0000000000005119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072959PMC
October 2016

Mid-arm and calf circumferences are stronger mortality predictors than body mass index for patients with chronic obstructive pulmonary disease.

Int J Chron Obstruct Pulmon Dis 2016 31;11:2075-80. Epub 2016 Aug 31.

Department of Nursing, Yuanpei University of Medical Technology, Hsinchu City, Taiwan.

Background: 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.

Purpose: 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.

Methods: 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.

Results: 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/m(2)], 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.

Conclusion: Among the three anthropometric variables examined, CC can be considered a strong predictor of mortality risk in patients with COPD.
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http://dx.doi.org/10.2147/COPD.S107326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012597PMC
August 2017

Exercise-Induced Changes in Exhaled NO Differentiates Asthma With or Without Fixed Airway Obstruction From COPD With Dynamic Hyperinflation.

Medicine (Baltimore) 2016 Apr;95(15):e3400

From the Department of Thoracic Medicine, Chang Gung Memorial Hospital, Cha-Yi (S-YH); Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan (P-CC, T-YW, Y-LL, W-CJ, L-FC, T-FS, C-HW, H-PK); and Experimental Studies, National Heart and Lung Institute, Imperial College, London, UK (KFC).

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.
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http://dx.doi.org/10.1097/MD.0000000000003400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839859PMC
April 2016

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.

BMC Pulm Med 2016 Jan 8;16. Epub 2016 Jan 8.

Department of Thoracic Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taipei, Taiwan.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1186/s12890-015-0156-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706688PMC
January 2016

The Impact of Sequence of Chemotherapy and EGFR-TKI Treatment on Different EGFR Mutation Lung Adenocarcinoma.

Biomed Res Int 2015 2;2015:948267. Epub 2015 Nov 2.

Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, College of Medicine, Taipei 10507, Taiwan ; Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, College of Medicine, Taipei 10507, Taiwan.

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.
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http://dx.doi.org/10.1155/2015/948267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644829PMC
September 2016

Bronchoscopic debulking for endobronchial malignancy: Predictors of recanalization and recurrence.

Thorac Cancer 2015 Nov 16;6(6):722-30. Epub 2015 Mar 16.

Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University School of Medicine Taipei, Taiwan ; Department of Thoracic Medicine, Division of Airway Diseases, Chang Gung Memorial Hospital Taipei, Taiwan.

Background: Central airway obstruction related to endobronchial malignancy is one of the most difficult oncological complications and requires efficient palliative intervention.

Methods: 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.

Result: 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.

Conclusion: Debulking of a tumor using cryotherapy is a useful palliative treatment for endobronchial obstruction secondary to a variety of malignancies.
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http://dx.doi.org/10.1111/1759-7714.12248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632924PMC
November 2015

A real-world evaluation of indacaterol and other bronchodilators in COPD: the INFLOW study.

Int J Chron Obstruct Pulmon Dis 2015 5;10:2109-20. Epub 2015 Oct 5.

Novartis Pharma AG, Basel, Switzerland.

Aim: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.2147/COPD.S83071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599566PMC
July 2016

The relationship between anthropometric indicators and walking distance in patients with chronic obstructive pulmonary disease.

Int J Chron Obstruct Pulmon Dis 2015 8;10:1857-62. Epub 2015 Sep 8.

School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Background: 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.

Purpose: This study attempted to determine the abilities of simple anthropometric indicators including BMI, MAC, and CC in reflecting the exercise intolerance of COPD patients.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.2147/COPD.S87714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572723PMC
June 2016