Yoonki Hong

Risk Factors for Recurrence after Successful Treatment of Mycobacterium avium Complex Lung Disease

ABSTRACT This study analyzed the recurrence rate and risk factors for recurrence of Mycobacterium avium complex (MAC) lung disease in patients successfully treated for this disease. The medical records of 158 patients successfully treated for MAC lung disease at a tertiary referral center in South Korea between March 2000 and December 2009 were retrospectively analyzed. Recurrence was recorded, and factors associated with recurrence were analyzed. The mean age of the 158 patients was 60.7 ± 11.1 years. The etiologic agent was Mycobacterium avium in 77 patients (48.7%) and Mycobacterium intracellulare in 81 patients (51.3%). Radiographic features included nodular bronchiectatic disease in 95 (60.1%), fibrocavitary disease in 49 (31.0%), and an unclassifiable form in 14 (8.9%) patients. Almost all (98.7%, 156/158) patients had been previously treated with a macrolide-containing regimen, and 68 (43.0%) patients had received treatment with an aminoglycoside. During a median follow-up of 43.8 months after completion of therapy, 50 patients (31.6%) experienced recurrence, at a median of 11.9 months after treatment completion. Multivariate analysis showed that only the nodular bronchiectatic form of the disease (hazard ratio, 2.39; 95% confidence interval, 1.19 to 4.81) was independently associated with an increased risk of recurrence. Recurrence after successful treatment is frequent in patients with MAC lung disease. The recurrence rate was significantly higher in patients with the nodular bronchiectatic form than in those with the fibrocavitary form or an unclassifiable form of the disease.

RNA sequencing identifies novel markers of non-small cell lung cancer.

INTRODUCTION The development of reliable gene expression profiling technology increasingly impacts our understanding of lung cancer biology. Here, we used RNA sequencing (RNA-Seq) to compare the transcriptomes of non-small cell lung cancer (NSCLC) and normal lung tissues and to investigate expression in lung cancer tissues. METHODS We enrolled 88 male patients (mean age, 61.2 years) with NSCLC. RNA-Seq was performed on 88 pairs of NSCLC tumor tissue and non-tumor tissue from 54 patients with adenocarcinoma and 34 patients with squamous cell carcinoma. Immunohistochemistry was performed to validate differential candidate gene expression in a different NSCLC group. RESULTS RNA-Seq produced 25.41 × 10(6) (± 8.90 × 10(6)) reads in NSCLC tissues and 24.70×10(6) (± 4.70 × 10(6)) reads in normal lung tissues [mean (± standard deviation)]. Among the genes expressed in both tissues, 335 were upregulated and 728 were downregulated ≥ 2-fold (p < 0.001). Four upregulated genes - CBX3, GJB2, CRABP2, and DSP - not previously reported in lung cancer were studied further. Their altered expression was verified by immunohistochemistry in a different set of NSCLC tissues (n = 154). CBX3 was positive in 90.3% (139 cases) of the samples; GJB2, in 22.7% (35 cases); CRABP2, in 72.1% (111 cases); and DSP, in 17.5% (27 cases). The positive rate of CRABP2 was higher in adenocarcinoma than squamous cell carcinoma (p < 0.01). CONCLUSIONS CBX3 and CRABP2 expression was markedly increased in lung cancer tissues and especially CRABP2 may be promising candidate genes in lung adenocarcinoma.

Association of lung function genes with chronic obstructive pulmonary disease.

AbstractBackgroundSpirometric measurements of pulmonary function are important in diagnosing and determining the severity of chronic obstructive pulmonary disease (COPD). We performed this study to determine whether candidate genes identified in genome-wide association studies of spirometric measurements were associated with COPD and if they interacted with smoking intensity. MethodsThe current analysis included 1,000 COPD subjects and 1,000 controls recruited from 24 hospital-based pulmonary clinics. Thirteen SNPs, chosen based on genome-wide association studies of spirometric measurements in the Korean population cohorts, were genotyped. Genetic association tests were performed, adjusting for age, sex, and smoking intensity, using models including a SNP-by-smoking interaction term. ResultsPID1 and FAM13A were significantly associated with COPD susceptibility. There were also significant interactions between SNPs in ACN9 and FAM13A and smoking pack-years, and an association of ACN9 with COPD in the lowest smoking tertile. The risk allele of FAM13A was associated with increased expression of FAM13A in the lung.ConclusionsWe have validated associations of FAM13A and PID1 with COPD. ACN9 showed significant interaction with smoking and is a potential candidate gene for COPD. Significant associations of genetic variants of FAM13A with gene expression levels suggest that the associated loci may act as genetic regulatory elements for FAM13A gene expression.

Prevalence of Latent Tuberculosis Infection among Health Care Workers in South Korea: A Multicenter Study

Background We investigated the prevalence of latent tuberculosis infection (LTBI) among the health care workers (HCWs) and analyzed its risk factors in South Korea. Methods A standard questionnaire regarding the baseline demographics and risk factors for LTBI was given to each participant and tuberculin skin test (TST), QuantiFERON-TB GOLD In-Tube (QFT-GIT) assay, and chest radiography were performed. Results A total of 493 participants, 152 (30.8%) doctors and 341 (69.2%) nurses were enrolled in eight tertiary referral hospitals. The mean age of the subjects was 30.6 years old, and 383 (77.7%) were female. Of the 152 doctors, 63 (41.4%) and 36 (23.7%) were positive by TST and by QTF-GIT, respectively, and among the 341 nurses, 119 (34.9%) and 49 (14.4%) had positive TST and QFT-GIT results, respectively. Overall, the agreement between the two tests was 0.22 by the chance corrected proportional agreement rate (kappa coefficient) in 493 subjects. Experience of working in tuberculosis (TB)-related departments was significantly associated with positive LTBI test results by QFT-GIT assay, not by TST. In multivariate analysis, only age was independently associated with increased risk of a positive TST result, while age and experience of working in TB-related departments (odds ratio, 2.29; 95% confidence interval, 1.01-5.12) were independently associated with increased risk of a positive QFT-GIT result. Conclusion A high prevalence of LTBI was found among South Korean HCWs. Considering the association between the experience of working in TB-related departments and high risk of LTBI, QFT-GIT may be a better diagnostic test for LTBI than TST in HCWs.

DNA methylation and smoking in Korean adults: epigenome-wide association study.

BackgroundExposure to cigarette smoking can increase the risk of cancers and cardiovascular and pulmonary diseases. However, the underlying mechanisms of how smoking contributes to disease risks are not completely understood. Epigenome-wide association studies (EWASs), mostly in non-Asian populations, have been conducted to identify smoking-associated methylation alterations at individual probes. There are few data on regional methylation changes in relation to smoking. Few data link differential methylation in blood to differential gene expression in lung tissue.ResultsWe identified 108 significant (false discovery rate (FDR) < 0.05) differentially methylated probes (DMPs) and 87 significant differentially methylated regions (DMRs) (multiple-testing corrected p < 0.01) in current compared to never smokers from our EWAS of cotinine-validated smoking in blood DNA from a Korean chronic obstructive pulmonary disease cohort (n = 100 including 31 current, 30 former, and 39 never smokers) using Illumina HumanMethylation450 BeadChip. Of the 108 DMPs (FDR < 0.05), nine CpGs were statistically significant based on Bonferroni correction and 93 were novel including five that mapped to loci previously associated with smoking. Of the 87 DMRs, 66 were mapped to novel loci. Methylation correlated with urine cotinine levels in current smokers at six DMPs, with pack-years in current smokers at six DMPs, and with duration of smoking cessation in former smokers at eight DMPs. Of the 143 genes to which our significant DMPs or DMRs annotated, gene expression levels at 20 genes were associated with pack-years in lung tissue transcriptome data of smokers (Asan Biobank, n = 188).ConclusionsOur study of differential methylation in Koreans confirmed previous findings from non-Asian populations and revealed novel loci in relation to smoking. Smoking-related differential methylation in blood is associated with gene expression in lung tissue, an important target of adverse health effects of smoking, supporting the potential functional importance of methylation in smoking-related disease.

Behavior of Salmonella spp. and natural microbiota on fresh-cut dragon fruits at different storage temperatures

The aim of this study was to determine survival or growth of unadapted, acid-adapted and cold-stressed Salmonella spp., and natural microbiota on fresh-cut dragon fruits at different storage temperatures. Dragon fruits were sliced and spot inoculated with five-strain cocktail of Salmonella spp. at two inoculum levels (2.5 or 5.5 log CFU/g). Inoculated fruits were stored at 28°C for 48h and at 4°C and 12°C for 96 h. Salmonella population significantly increased by 2.4 to 3.0 log CFU/g at low inoculum level, whereas the numbers increased by 0.4 to 0.7 log CFU/g at the high inoculum level on fruits held at 28°C for 48h. Only unadapted and acid-adapted cells grew with 0.7 to 0.9log increase at the low inoculum level at 12°C for 96h. No significant growth was observed at both inoculum levels during storage at 4°C. Overall, acid, starved and cold adaptation of Salmonella spp. did not show significant difference in survival or growth on fresh-cut dragon fruits during storage compared to unadapted control cells. For natural microbiota on the fruit, mesophilic bacterial counts reached to 5-log CFU/g at 28 and 12°C by 9.9 and 52.9h. Similar with Salmonella spp. there was no growth of natural microbiota at 4°C. These results showed that Salmonella spp. could grow on fresh-cut dragon fruits under inappropriate storage conditions, indicating that fresh-cut dragon fruits could be a potential vehicle for salmonellosis. Thus, this study suggests that fresh-cut dragon fruits should be stored at 4°C to ensure the safety as well as to extend the shelf life of fresh-cut dragon fruits.

Study Design and Outcomes of Korean Obstructive Lung Disease (KOLD) Cohort Study

Background The Korean Obstructive Lung Disease (KOLD) Cohort Study is a prospective longitudinal study of patients with chronic obstructive pulmonary disease (COPD), asthma, or other unclassified obstructive lung diseases. It was designed to develop new classification models and biomarkers that predict clinically relevant outcomes for patients with obstructive lung diseases. Methods Patients over 18 years old who have chronic respiratory symptoms and airflow limitations or bronchial hyper-responsiveness were enrolled at 17 centers in South Korea. After a baseline visit, the subjects were followed up every 3 months for various assessments. Results From June 2005 to October 2013, a total of 477 subjects (433 [91%] males; 381 [80%] diagnosed with COPD) were enrolled. Analyses of the KOLD Cohort Study identified distinct phenotypes in patients with COPD, and predictors of therapeutic responses and exacerbations as well as the factors related to pulmonary hypertension in COPD. In addition, several genotypes were associated with radiological phenotypes and therapeutic responses among Korean COPD patients. Conclusion The KOLD Cohort Study is one of the leading long-term prospective longitudinal studies investigating heterogeneity of the COPD and is expected to provide new insights for pathogenesis and the long-term progression of COPD.

Risk factors for 1-year relapse of pulmonary tuberculosis treated with a 6-month daily regimen

BACKGROUND We aimed to identify the 1-year relapse rate and risk factors for patients with pulmonary tuberculosis (TB) treated with a 6-month daily regimen. METHODS A total of 317 patients with pan-susceptible pulmonary TB who completed a 6-month daily course of treatment [2HRZ(E)/4HR(E)] were retrospectively analyzed. RESULTS The mean age was 50.0 ± 16.8 years and men were predominant (61.2%). All of 137 adults tested for HIV were negative. Six (1.9%) cases relapsed within one year. Relapse rate was higher in patients with a positive culture after 2 months of treatment (10.0%, p = 0.049) and in patients with both a positive culture after 2 months of treatment and cavitation on initial chest radiograph (18.2%, p = 0.015), whereas relapse rate in patients with cavitation alone was comparable to that of the total population (2.7%). Among various risk factors known to increase risk of relapse, the combined variable of cavitation and positive culture at 2 months (OR = 15.56, 95% CI 2.56-98.71, p = 0.003) was only associated with increased relapse rate in a multivariate analysis. CONCLUSIONS Even with a 6-month daily treatment regimen throughout the intensive and continuation phases, the relapse rate was unacceptably high in patients with both a positive culture at 2 months of treatment and cavitation on baseline chest radiography. Intensification of treatment, such as an extension of treatment duration, should be considered in this category of patients.

3′-Deoxy-3′-18F-Fluorothymidine PET for the Early Prediction of Response to Leucovorin, 5-Fluorouracil, and Oxaliplatin Therapy in Patients with Metastatic Colorectal Cancer

The aim of this study was to evaluate 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET for early prediction of the standard anatomic response and survival outcomes in patients with metastatic colorectal cancer (mCRC) receiving leucovorin, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX). Methods: The main eligibility criteria included histologically confirmed mCRC, ≥1 extrahepatic measurable lesions, and no prior chemotherapy in a metastatic setting. Chemotherapy consisted of leucovorin on day 1, followed by the continuous infusion of 5-FU on days 1 and 2, and oxaliplatin on day 3. In the second and subsequent cycles of chemotherapy, oxaliplatin was administered simultaneously with leucovorin on day 1. 18F-FLT PET scans were obtained 3 times during the first cycle of chemotherapy: before chemotherapy, 24 h after infusion of 5-FU (day 2), and 48 h after completion of chemotherapy (day 5). The maximum standardized uptake value (SUVMAX) of 18F-FLT was measured. Treatment responses were assessed by CT after 3 cycles of FOLFOX. Results: Eighteen patients were included in the study. The response rate after 3 cycles of FOLFOX was 27.8% (5/18). The SUVMAX was increased in responders (P = 0.043) and nonresponders (P < 0.001) on day 2 and was decreased, compared with baseline values, on day 5 in responders only (P = 0.043). Receiver-operating-characteristic curve analysis indicated that the use of a threshold of an SUVMAX increase on day 2 of ≤45.8% resulted in a sensitivity of 100%, specificity of 69.2%, and relative risk of 2.250 (P = 0.029) for the diagnosis of responders. Use of a threshold of an SUVMAX decrease on day 5 of ≥10.6% resulted in a sensitivity of 100%, specificity of 76.9%, and relative risk of 2.667 (P = 0.007). Patients with low 18F-FLT flare tended to have longer survivals than patients with high flare (2-y overall survival rate, 77.8% vs. 44.4%; P = 0.051). Conclusion: The 18F-FLT flare observed during 5-FU infusion was associated with poor treatment response in patients with mCRC. The degree of 18F-FLT flare might be used to predict the outcome of patients who receive infusional 5-FU–based chemotherapy.

Use of venovenous extracorporeal membrane oxygenation in central airway obstruction to facilitate interventions leading to definitive airway security

PURPOSE Extracorporeal membrane oxygenation (ECMO) is useful for providing hypoxic patients with ventilatory support, but its usefulness in the management of patients with central airway obstruction has rarely been reported. Nineteen cases in one center where venovenous (VV) ECMO was used to support patients with severe central airway obstruction while they underwent lifesaving interventions are reported here. METHODS In total, 113 cases of VV ECMO were performed in Asan Medical Center between January 2009 and June 2012. In 19 cases (18 patients), VV ECMO was used to support patients with severe airway obstruction. RESULTS Of the 18 patients, 13 were male, and their median age was 62.5 (range, 16-82) years. The main reasons for using ECMO to provide airway security were malignant mass removal with a rigid bronchoscope (8 cases) and insertion of a tracheal stent (7 cases). The median ECMO time was 20.9 (range, 2.2-113.4) hours. In 1 case, a patient died of massive bleeding after a malignant mass was removed. Weaning off ECMO therapy occurred successfully in the remaining 18 cases. CONCLUSIONS Venovenous ECMO may be useful in patients with central airway obstruction because it provides short-term airway security while lifesaving procedures are being performed.