Kuo-Tung Huang

Levels of Circulating Microparticles in Lung Cancer Patients and Possible Prognostic Value

Background. Endothelial-derived microparticles (EDMPs) and platelet-derived microparticles (PDMPs) have been reported to be increasing in various diseases including malignant diseases. Here, we investigated whether these MPs may be useful biomarkers for predicting lung cancer (LC) disease status, cell type, or metastasis. Methods and Results. One hundred and thirty LC patients were prospectively enrolled into the study between April 2011 and February 2012. Flow cytometric analysis demonstrated that the circulating levels of platelet-derived activated MPs (PDAc-MPs), platelet-derived apoptotic MPs (PDAp-MPs), endothelial-derived activated MPs (EDAc-MPs), and endothelial-derived apoptotic MPs (EDAp-MPs) were significantly higher in LC patients than in 30 age- and gender-matched normal control subjects (all P < 0.05). Additionally, circulating level of PDAc-MPs was significantly lower (P = 0.031), whereas the circulating levels of the other three biomarkers did not differ (all P > 0.1) in early stage versus late stage LC patients. Furthermore, the circulating levels of the four types of MPs did not differ among patients with different disease statuses (i.e., disease controlled, disease progression, and disease without treatment, i.e., fresh case) (all P > 0.2) or between patients with or without LC metastasis (all P > 0.5). Moreover, only the circulating level of EDAp-MPs was significantly associated with the different cell types (i.e., squamous cell carcinoma, adenocarcinoma, and small cell carcinoma) of LC (P = 0.045). Conclusion. Circulating MP levels are significantly increased in LC patients as compared with normal subjects. Among the MPs, only an increased level of EDAp-MPs was significantly associated with different LC cell types.

Inspiratory muscle training in bronchiectasis patients: a prospective randomized controlled study:

Objective: To investigate the efficacy and feasibility of home-based inspiratory muscle training in patients with bronchiectasis. Design: A prospective, single-blind, randomized, controlled study. Setting: Outpatient clinic of a tertiary care medical centre. Methods: Twenty-six patients with bronchiectasis were randomly divided into inspiratory muscle training and control groups. In the inspiratory muscle training group (n = 13), the training programme started with an intensity of 30% maximal inspiratory pressure (MIP), which was increased by 2 cmH2O each week, for 30 minutes daily, 5 days a week for eight weeks. The control group (n = 13) did not receive inspiratory muscle training. Main outcome measures included spirometry, resting oxyhaemoglobin saturation by pulse oximetry (SpO2), lowest SpO2 and Borg Scale during 6-minute walking tests, 6-minute walking distance (6MWD), 6-minute walking work (6Mwork), MIP, maximal expiratory pressure (MEP) and St George’s Respiratory Questionnaire. Results: There were significant differences in change from baseline in 6MWD (411.9 (133.5) vs. 473.2 (117.2) m, P = 0.021), 6Mwork (21 051.0 (8286.7) vs. 23 915.5 (8343.0) kg-m, P = 0.022), MIP (60.8 (21.8) vs. 84.6 (29.0) cmH2O, P = 0.004), and MEP (72.3 (31.1) vs. 104.2 (35.7) cmH2O, P = 0.004) in the inspiratory muscle training group. Significant improvements in both MIP (23.8 (25.3) vs. 2.3 (16.4) cmH2O, adjusted P-value = 0.005) and MEP (31.9 (30.8) vs. 11.5 (20.8) cmH2O, adjusted P-value = 0.038) levels after adjusting for age by linear regression analysis were observed between groups. Conclusions: An eight-week home-based inspiratory muscle training is feasible and effective in improving both inspiratory and expiratory muscle strength, but has no effect on respiratory function and quality of life in patients with bronchiectasis.

Risk Factors for Mortality in Patients with Nosocomial Stenotrophomonas maltophilia Pneumonia

OBJECTIVE The aim of this study was to determine potential risk factors for mortality in patients with nosocomial Stenotrophomonas maltophilia pneumonia. DESIGN A retrospective, single-center, observational study. SETTING A 2400-bed tertiary teaching hospital in southern Taiwan. PATIENTS AND METHODS This retrospective study evaluated patients (age, at least 18 years) with nosocomial pneumonia (S. maltophilia isolated from respiratory culture) who were seen at Kaohsiung Chang Gung Memorial Hospital over a 3-year period. A total of 406 patients (64% male, mean age +/- standard deviation, 69.6 +/- 14.93 years; mean duration of hospital +/- standard deviation, 57.5 +/- 39.47 days) were included. RESULTS Most index isolates (53.9%) were from the first sample cultured. Polymicrobial isolates were cultured from samples from 177 (43.6%) of the 406 study patients. The most common copathogen was Pseudomonas aeruginosa (53.11% of isolates). The all-cause hospital mortality rate was 42.6% (173 deaths among 406 patients). Survivors had a shorter time from admission to a positive index culture result than did nonsurvivors (26.1 vs 31.7 days; P = .04). Mortality was significantly higher among patients with malignancy (adjusted odds ratio [AOR], 2.48; 95% confidence interval [CI], 1.52-4.07; P < .001), renal disease (AOR, 2.6; 95% CI, 1.51-4.47; P = .001), intensive care unit stay (AOR, 1.72; 95% CI, 1.1-2.7; P = .018), and inadequate initial empirical antibiotic therapy (AOR, 2.17; 95% CI, 1.4-3.38; P = .001). CONCLUSIONS S. maltophilia pneumonia is associated with a high mortality rate and is commonly associated with concomitant polymicrobial colonization or infection. Underlying comorbidities and inadequate initial empirical antibiotic therapy substantially account for increased mortality rates.

Baseline and Trend of Lymphocyte-to-Monocyte Ratio as Prognostic Factors in Epidermal Growth Factor Receptor Mutant Non-Small Cell Lung Cancer Patients Treated with First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

Background Patients with early-stage lung cancer who have a high baseline lymphocyte-to-monocyte ratio (LMR) have a favorable prognosis. However, the prognostic significance of LMR in patients with advanced-stage EGFR-mutant non-small cell lung cancer (NSCLC) receiving first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has not been established. We conducted a retrospective analysis to investigate the influence of LMR on clinical outcomes including progression-free survival (PFS) and overall survival (OS) in EGFR-mutant patients with NSCLC. Materials and Methods Of 1310 lung cancer patients diagnosed between January 2011 and October 2013, 253 patients receiving first-line EGFR-TKIs for EGFR-mutant NSCLC were included. The cut-off values for baseline and the 1-month-to-baseline ratio of LMR (MBR), determined by using receiver operating characteristic curves, were 3.29 and 0.63, respectively. Patients were divided into 3 prognostic groups: high LMR and MBR, high LMR or MBR, and low LMR and MBR. Results The mean patient age was 65.2 years, and 41% were men. The median PFS and OS were 10.3 and 22.0 months, respectively. The PFS in patients with high LMR and MBR, high LMR or MBR, and low LMR and MBR were 15.4, 7.1, and 2.0 months, respectively (p < 0.001), whereas the OS were 32.6, 13.7, and 5.1 months, respectively (p < 0.001). Conclusion A combination of baseline and trend of LMR can be used to identify patients with a high mortality risk in EGFR-mutant NSCLC patients receiving first-line EGFR-TKIs.

Whole Genome DNA Methylation Analysis of Obstructive Sleep Apnea: IL1R2, NPR2, AR, SP140 Methylation and Clinical Phenotype.

STUDY OBJECTIVES We hypothesized that DNA methylation patterns may contribute to disease severity or the development of hypertension and excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea (OSA). METHODS Illuminas (San Diego, CA, USA) DNA methylation 27-K assay was used to identify differentially methylated loci (DML). DNA methylation levels were validated by pyrosequencing. A discovery cohort of 15 patients with OSA and 6 healthy subjects, and a validation cohort of 72 patients with sleep disordered breathing (SDB). RESULTS Microarray analysis identified 636 DMLs in patients with OSA versus healthy subjects, and 327 DMLs in patients with OSA and hypertension versus those without hypertension. In the validation cohort, no significant difference in DNA methylation levels of six selected genes was found between the primary snoring subjects and OSA patients (primary outcome). However, a secondary outcome analysis showed that interleukin-1 receptor 2 (IL1R2) promoter methylation (-114 cytosine followed by guanine dinucleotide sequence [CpG] site) was decreased and IL1R2 protein levels were increased in the patients with SDB with an oxygen desaturation index > 30. Androgen receptor (AR) promoter methylation (-531 CpG site) and AR protein levels were both increased in the patients with SDB with an oxygen desaturation index > 30. Natriuretic peptide receptor 2 (NPR2) promoter methylation (-608/-618 CpG sites) were decreased, whereas levels of both NPR2 and serum C type natriuretic peptide protein were increased in the SDB patients with EDS. Speckled protein 140 (SP140) promoter methylation (-194 CpG site) was increased, and SP140 protein levels were decreased in the patients with SDB and EDS. CONCLUSIONS IL1R2 hypomethylation and AR hypermethylation may constitute an important determinant of disease severity, whereas NPR2 hypomethylation and SP140 hypermethylation may provide a biomarker for vulnerability to EDS in OSA. COMMENTARY A commentary on this article appears in this issue on page 723.

Factors Predicting Ventilator Dependence in Patients with Ventilator-Associated Pneumonia

Objectives. To determine risk factors associated with ventilator dependence in patients with ventilator-associated pneumonia (VAP). Study Design. A retrospective study was conducted at Chang Gung Memorial Hospital, Kaohsiung, from January 1, 2007 to January 31, 2008. Methods. This study evaluated 163 adult patients (aged ≥18 years). Eligibility was evaluated according to the criterion for VAP, Sequential Organ Failure Assessment (SOFA) score, Acute Physiological Assessment and Chronic Health Evaluation II (APACHE II) score. Oxygenation index, underlying comorbidities, septic shock status, previous tracheostomy status, and factors related to pneumonia were collected for analysis. Results. Of the 163 VAP patients in the study, 90 patients survived, yielding a mortality rate of 44.8%. Among the 90 surviving patients, only 36 (40%) had been weaned off ventilators at the time of discharge. Multivariate logistic regression analysis was used to identify underlying factors such as congestive cardiac failure (P = 0.009), initial high oxygenation index value (P = 0.04), increased SOFA scores (P = 0.01), and increased APACHE II scores (P = 0.02) as independent predictors of ventilator dependence. Results from the Kaplan-Meier method indicate that initial therapy with antibiotics could increase the ventilator weaning rate (log Rank test, P < 0.001). Conclusions. Preexisting cardiopulmonary function, high APACHE II and SOFA scores, and high oxygenation index were the strongest predictors of ventilator dependence. Initial empiric antibiotic treatment can improve ventilator weaning rates at the time of discharge.

Antacid Use and De Novo Brain Metastases in Patients with Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Who Were Treated Using First-Line First-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Background Antacid treatments decrease the serum concentrations of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), although it is unknown whether antacids affect clinical outcomes. As cerebrospinal fluid concentrations of TKIs are much lower than serum concentrations, we hypothesized that this drug-drug interaction might affect the prognosis of patients with de novo brain metastases. Materials and Methods This retrospective study evaluated 269 patients with EGFR-mutant non-small cell lung cancer (NSCLC) who had been diagnosed between December 2010 and December 2013, and had been treated using first-line first-generation EGFR-TKIs. Among these patients, we identified patients who concurrently used H2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) as antacids. Patients who exhibited >30% overlap between the use of TKIs and antacids were considered antacid users. Results Fifty-seven patients (57/269, 21.2%) were antacid users, and antacid use did not significantly affect progression-free survival (PFS; no antacids: 11.2 months, H2RAs: 9.4 months, PPIs: 6.7 months; p = 0.234). However, antacid use significantly reduced overall survival (OS; no antacids: 25.0 months, H2RAs: 15.5 months, PPIs: 11.3 months; p = 0.002). Antacid use did not affect PFS for various metastasis sites, although antacid users with de novo brain metastases exhibited significantly shorter OS, compared to non-users (11.8 vs. 16.3 months, respectively; p = 0.041). Antacid use did not significantly affect OS in patients with bone, liver, or pleural metastases. Conclusion Antacid use reduced OS among patients with EGFR-mutant NSCLC who were treated using first-line first-generation EGFR-TKIs, and especially among patients with de novo brain metastases.

Inhaled corticosteroids can reduce osteoporosis in female patients with COPD

Background Whether the use of inhaled corticosteroids (ICSs) in patients with COPD can protect from osteoporosis remains undetermined. The aim of this study is to assess the incidence of osteoporosis in patients with COPD with ICS use and without. Patients and methods This is a retrospective cohort and population-based study in which we extracted newly diagnosed female patients with COPD between 1997 and 2009 from Taiwan’s National Health Insurance (TNHI) database between 1996 and 2011 (International Classification of Diseases, Ninth Revision – Clinical Modification [ICD-9-CM] 491, 492, 496). The patients with COPD were defined by the presence of two or more diagnostic codes for COPD within 12 months on either inpatient or outpatient service claims submitted to TNHI. Patients were excluded if they were younger than 40 years or if osteoporosis had been diagnosed prior to the diagnosis of COPD and cases of asthma (ICD-9 CM code 493.X) before the index date. These enrolled patients were followed up till 2011, and the incidence of osteoporosis was determined. The Cox proportional hazards regression model was also used to estimate hazard ratios (HRs) for incidences of lung cancer. Results Totally, 10,723 patients with COPD, including ICS users (n=812) and nonusers (n=9,911), were enrolled. The incidence rate of osteoporosis per 100,000 person years is 4,395 in nonusers and 2,709 in ICS users (HR: 0.73, 95% confidence interval [CI]: 0.63–084). The higher ICS dose is associated with lower risk of osteoporosis (0 mg to ≤20 mg, HR: 0.84, 95% CI: 0.69–1.04; >20 mg to ≤60 mg, HR: 0.78, 95% CI: 0.59–1.04; and >60 mg, HR: 0.72, 95% CI: 0.55–0.96; P for trend =0.0023) after adjusting for age, income, and medications. The cumulative osteoporosis probability significantly decreased among the ICS users when compared with the nonusers (P<0.001). Conclusion Female patients with COPD using ICS have a dose–response protective effect for osteoporosis.

Chest radiographic presentation in patients with scrub typhus

We conducted a retrospective study of the adult patients (age ≥18 years) with serologically confirmed scrub typhus admitted between January 1998 and December 2009 at Kaohsiung Chang Gung Memorial Hospital. There were 63 adult scrub typhus patients with chest radiographic examinations. A total of 147 chest radiographs were obtained and reviewed. The most frequent abnormal findings in this study were parenchymal infiltration with bilateral and lower lung predilection. The distribution of abnormal chest radiographs was observed more than 50% during the first week. Furthermore, the progressive change was frequently observed during the first week. There is a significant correlation among laboratory findings, clinical course, and outcome. Chest radiography may be a complementary tool to evaluate the clinical course of scrub typhus and chest radiographic examinations should be taken during the first week after the onset of illness.

Baseline, Trend, and Normalization of Carcinoembryonic Antigen as Prognostic Factors in Epidermal Growth Factor Receptor-Mutant Nonsmall Cell Lung Cancer Patients Treated With First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.

AbstractAmong epidermal growth factor receptor (EGFR) mutation status unknown nonsmall cell lung cancer (NSCLC) patients, those with higher carcinoembryonic antigen (CEA) level are more likely to response to EGFR-tyrosine kinase inhibitors (TKIs) because they tend to have mutant epidermal growth factor receptor (EGFR). However, patients with higher CEA also have more tumor burden. With the above paradoxical evidence, it is prudent to understand the prognostic significance of baseline CEA in patients with EGFR-mutant NSCLC treated with first-line EGFR-TKIs. The clinical significance of the trend in CEA after treatment and the impact of CEA normalization during EGFR-TKI therapy are also unknown and potentially important.A total of 241 patients who received first-line EGFR-TKIs were included. As to baseline CEA, patients were divided into normal, low, and high baseline CEA by cut point determined by receiver operating characteristic curves. As to CEA responses, patients were divided into 3 groups accordingly to their amount of CEA change after taking TKIs. In group A, 1-month follow-up CEA level decreased more than 35% with nadir CEA normalization; in group B, 1-month follow-up CEA level decreased more than 35% without nadir CEA normalization; and in group C, 1-month follow-up CEA level decreased less than 35% or increased.Patients with higher baseline CEA levels had shorter progression-free survival (PFS) and overall survival (OS) (CEA > 32 vs 5–32 vs <5 ng/mL, PFS = 8.8 vs 11.3 vs 14.4 months, respectively, P < 0.001; OS = 17.8 vs 22.0 vs 27.9 months, respectively, P = 0.01). For trend and CEA normalization in groups A, B, and C, PFS was 14.3, 10.6, and 7.1 months, respectively (P < 0.001); OS was 29.7, 20.0, and 16.2 months, respectively (P < 0.001).Baseline, trend, and normalization of CEA levels are potential prognostic markers for patients with EGFR-mutant advanced NSCLC treated with first line EGFR-TKIs.