Sang Haak Lee

Catholic University of Korea, Sŏul, Seoul, South Korea

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Publications (41)49.46 Total impact

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    ABSTRACT: Purpose: Cigarette smoking increases chronic airway inflammation, oxidative stress, and epithelial mesenchymal transition (EMT), which may result in chronic obstructive pulmonary disease (COPD) and tumor growth in the lung. Phosphodiesterase 4 (PDE4) inhibitors are known to reduce inflammation, and they have recently been introduced for the treatment of COPD. We assessed the impact of rolipram, a selective PDE4 inhibitor, on chemoprevention in benzo(a)pyrene-induced lung cancer in mice. Materials and Methods: Female A/J mice were given a single dose of benzo(a)pyrene. Intraperitoneal administration of rolipram began 2 weeks post-carcinogen treatment and continued tri-weekly for 28 weeks. Tumor load was determined by averaging the total tumor volume in each group. Results: Benzo(a)pyrene induced an average tumor size of 10.4 ± 1.7 tumors per mouse, with an average tumor load of 25.9 ± 3.8 mm3. Rolipram significantly decreased tumor number, by 45.1%, and tumor load, by 52.9%, compared with the benzo(a)pyrene group. Ki67 staining was reduced in rolipram-treated mice compared with benzo(a)pyrene-treated mice. The increased expression of EMT markers caused by benzo(a)pyrene was inhibited by rolipram. Rolipram significantly attenuated NF-κB and Nrf2 expression in benzo(a)pyrene-induced lung cancer tissues. Conclusions: In vivo experiments in the benzo(a)pyrene-induced model of lung cancer show that PDE4 inhibition significant inhibits lung carcinogenesis. Our results provide evidence that PDE4 inhibitors may be suitable for the prevention of the lung cancer in high-risk groups, for example, heavy smokers and patients with COPD.
    Experimental Lung Research 10/2014; · 1.47 Impact Factor
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    ABSTRACT: Takotsubo cardiomyopathy (TTC) is defined as a reversible, acute ventricular dysfunction without any evidence of coronary artery obstruction. There have been reports of TTC caused by emotional or physical stress, drug use, hormone imbalance, or medical conditions such as pulmonary disease, sepsis, and trauma, but a relationship between TTC and pulmonary tuberculosis has not previously been reported. From our knowledge, this is the first report of TTC caused by pulmonary tuberculosis.
    Tuberculosis and Respiratory Diseases 07/2014; 77(1):24-7.
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    ABSTRACT: Background Simultaneous genotyping has advantages in turnaround time and detecting the real mutational prevalence in unresectable non-small-cell lung cancer (NSCLC), a group not previously genetically characterized.Methods We developed simultaneous panel of screening EGFR and KRAS mutations by direct sequencing or PNA clamping, and ALK rearrangement by fluorescent in situ hybridization (FISH) in multicenter manner.ResultsOf 510 NSCLC Korean patients, simultaneous genotyping identified mutations of EGFR (29.0%) and KRAS (8.6%) and rearrangement of ALK (9.2%). Seven patients had overlaps in mutations. Although several well-known associations between genotypes and clinical characteristics were identified, we found no relationship between ALK rearrangement and sex or smoking history. Unlike the other genotype mutations, ALK rearrangement was associated with advanced disease. Among the ALK-negative group, patients with 10–15% of ALK FISH split shared characteristics, such as younger age and advanced stage disease, more with the ALK-positive group (>15% ALK FISH split) than <10% ALK FISH split group.Conclusions Simultaneous panel genotyping revealed more prevalent ALK rearrangements than reported in previous studies and their strong association with advanced stage irrespective of sex or smoking history. ALK rearrangement seems to be a marker for aggressive tumor biology and should be assessed in advanced disease. J. Surg. Oncol. © 2014 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 05/2014; · 2.64 Impact Factor
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    ABSTRACT: Obstructive sleep apnea is becoming more important in gastroesophageal reflux disease (GERD) patients. This study investigated the prevalence of high risk for obstructive sleep apnea in GERD patients in comparison with that in healthy controls using the Berlin Questionnaire. We also investigated the risk factors for obstructive sleep apnea in GERD patients.
    Journal of neurogastroenterology and motility 04/2014; 20(2):197-204.
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    ABSTRACT: Spontaneous pneumomediastinum is an uncommon disorder, and usually affects young men and has a benign course. Common triggers are asthma, the smoking of illicit drugs, the Valsalva maneuver, and respiratory infections. Most cases are usually due to alveolar rupture into the pulmonary interstitium caused by excess pressure. The air dissects to the hilum along the peribronchovascular sheaths and spreads into the mediastinum. However, pneumomediastinum following pharyngeal perforation is very rare, and has only been reported in relation to dental procedures, head and neck surgery, or trauma. We report a case of pneumomediastinum that developed in a 43-year-old patient with pharyngeal perforation after shouting. His course was complicated by mediastinitis and parapneumonic effusions.
    Yonsei medical journal 01/2014; 55(1):270-2. · 0.77 Impact Factor
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    ABSTRACT: Conventional biomarkers cannot always establish the cause of pleural effusions; thus, alternative tests permitting rapid and accurate diagnosis are required. The primary aim of this study is to assess the ability of pentraxin-3 (PTX3) in order to diagnose the cause of pleural effusion and compare its efficacy to that of other previously identified biomarkers. We studied 118 patients with pleural effusion, classified as transudates and exudates including malignant, tuberculous, and parapneumonic effusions (MPE, TPE, and PPE). The levels of PTX3, C-reactive protein (CRP), procalcitonin (PCT) and lactate in the pleural fluid were assessed. The levels of pleural fluid PTX3 were significantly higher in patients with PPE than in those with MPE or TPE. PTX3 yielded the most favorable discriminating ability to predict PPE from MPE or TPE by providing the following: area under the curve, 0.74 (95% confidence interval, 0.63-0.84), sensitivity, 62.07%; and specificity, 81.08% with a cut-off point of 25.00 ng/mL. Our data suggests that PTX3 may allow improved differentiation of PPE from MPE or TPE compared to the previously identified biomarkers CRP and PCT.
    Tuberculosis and Respiratory Diseases 12/2013; 75(6):244-9.
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    ABSTRACT: Reexpansion pulmonary edema (REPE) is known as a rare and fatal complication after tube thoracostomy.Objectives: We investigated the risk factors for the development of REPE in patients with spontaneous pneumothorax. We selected patients who were diagnosed with spontaneous pneumothorax and were initially treated with tube thoracostomy between August 1, 2003 and December 31, 2011. The patients' electronic medical records, including operative notes and chest x-ray and computed tomography scans, were reviewed. REPE developed in 49 of the 306 patients (16.0%). REPE was more common in patients with diabetes (14.3% vs 3.9%, P = 0.004) or tension pneumothorax (46.8% vs 16.2%, P = 0.000). The pneumothorax was larger in patients with REPE than without REPE (57.0 +/- 16.0% vs 34.2 +/- 17.6%, P = 0.000), and the incidence of REPE increased with the size of pneumothorax. On multivariate analysis, diabetes mellitus [(odds ratio (OR) = 9.93, P = 0.003), and the size of pneumothorax (OR = 1.07, P = 0.000) were independent risk factors of REPE. The presence of diabetes increases the risk of REPE development in patients with spontaneous pneumothorax. The risk of REPE also increases significantly with the size of pneumothorax.
    Journal of Cardiothoracic Surgery 07/2013; 8(1):164. · 0.90 Impact Factor
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    ABSTRACT: Neutrophil recovery has been implicated in deterioration of oxygenation and exacerbation of preexisting acute lung injury (ALI). The aim of this study was to investigate whether imatinib or nilotinib are effective on lipopolysaccharide (LPS)-induced ALI during neutropenia recovery in mice. Mice were rendered neutropenic with cyclophosphamide prior to the intra-tracheal instillation of LPS. Imatinib or nilotinib was administrated by oral gavage during neutropenia recovery. In order to study the effects of the drugs, mice were killed on day 5 and blood, bronchoalveolar lavage (BAL) fluid and lung tissue samples were obtained. The lung wet/dry weight ratio and protein levels in the BAL fluid or lung tissue were determined. Treatment with imatinib or nilotinib significantly attenuated the LPS-induced pulmonary edema, and this result was supported by the histopathological examination. The concentrations of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and myeloperoxidase in BAL fluid were significantly inhibited by imatinib or nilotinib in mice with ALI during neutropenia recovery. The mRNA expressions of platelet-derived growth factor receptor-beta and c-KIT in the imatinib or nilotinib group were significantly lower than LPS group. Our data indicated that imatinib or nilotinib effectively attenuated LPS-induced ALI during neutropenia recovery. These results provide evidence for the therapeutic potential of imatinib and nilotinib in patients with ALI during neutropenia recovery.
    Critical care (London, England) 06/2013; 17(3):R114. · 4.72 Impact Factor
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    ABSTRACT: Peptide nucleic acid (PNA)-mediated real-time PCR clamping has higher sensitivity than conventional direct sequencing for detecting mutations. Pleural effusion and serum may provide good samples in which to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients. We studied 37 NSCLC patients with malignant pleural effusion. EGFR mutations were assessed by PNA clamping and direct sequencing using tumor tissues, cell blocks, pleural effusion, and serum. Concordance between PNA clamping and direct sequencing results, and the diagnostic performance of pleural effusion were investigated. The κ coefficients for the two methods were 0.68 (p=0.0007), 0.91 (p<0.0001), 0.75 (p<0.0001) and -0.01 (p=0.8639) for tissues, cell blocks, pleural effusion, and serum, respectively. The diagnostic performance of pleural effusion compared with the combination of tumor tissue and cell blocks showed 89% sensitivity, 100% specificity, positive predictive value of 100%, and negative predictive value of 95% by PNA clamping, and 67% sensitivity, 90% specificity, positive predictive value of 75%, and negative predictive value of 86% by directing sequencing. A patient in whom an EGFR mutation was identified in pleural effusion only by PNA clamping showed a significant response to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. In contrast to the limited role of serum samples, pleural effusion had a diagnostic performance for the detection of EGFR mutations in NSCLC that was comparable to that of tumor tissues and cell blocks. The diagnostic performance of PNA clamping was good compared with that of direct sequencing. A more sensitive and accurate detection of EGFR mutations would benefit patients by allowing a better prediction of the response to EGFR-TKI treatment.
    Lung cancer (Amsterdam, Netherlands) 05/2013; · 3.14 Impact Factor
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    ABSTRACT: ABSTRACT Although neutropenia recovery is associated with deterioration of preexisting acute lung injury (ALI), there are few reports of the preventive strategies. Statins have been found to attenuate inflammatory responses in murine models of lipopolysaccharide (LPS)-induced ALI. The aim of this study was to determine whether pravastatin could attenuate ALI during neutropenia recovery in mice. Cyclophosphamide was administered to mice to induce neutropenia. Mice were given intratracheal LPS 7 days after cyclophosphamide administration, after which pravastatin was administered by intraperitoneal injection. In order to study the effects of pravastatin, mice were killed on day 5. Pravastatin attenuated the pulmonary edema and histopathological changes of LPS-induced lung injury. The accumulation of neutrophils and the concentrations of TNF-α, IL-1β, IL-6, and MPO in BAL fluids were also effectively inhibited by pravastatin. The expression levels of Toll-like receptor 4, nuclear factor kappa B, tumor growth factor-β and matrix metalloproteinase-9 were significantly reduced by pravastatin. Taken together, pravastatin significantly attenuated LPS-induced ALI during neutropenia recovery. These results provide evidence for the potential of pravastatin in the treatment of ALI during neutropenia recovery.
    Experimental Lung Research 01/2013; · 1.47 Impact Factor
  • Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 01/2013; 8(1):126-7. · 4.55 Impact Factor
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    ABSTRACT: BACKGROUND: Aberrant DNA hypermethylation has been implicated as a component of an epigenetic mechanism that silences genes in cancers. METHODS: We performed a genome-wide search to identify differentially methylated loci between 26 tumor and adjacent non-tumor paired tissues from same lung cancer patients using restriction landmark genomic scanning (RLGS) analysis. Among 229 loci which were hypermethylated in lung tumors as compared to adjacent non-tumor tissues, solute carrier family 5, member 8 (SLC5A8) was one of the hypermethylated genes, and known as a tumor suppressor gene which is silenced by epigenetic changes in various tumors. We investigated the significance of DNA methylation in SLC5A8 expression in lung cancer cell lines, and 23 paired tumor and adjacent non-tumor lung tissues by reverse transcription-PCR (RT-PCR), quantitative methylation specific PCR (QMSP) and bisulfite modified DNA sequencing analyses. RESULTS: Reduced or lost expression of SLC5A8 was observed in 39.1% (9/23) of the tumor tissues as compared with paired adjacent non-tumor tissues. Bisulfite sequencing results of lung cancer cell lines and tissues which did not express SLC5A8 showed a densely methylated promoter region of SLC5A8. SLC5A8 was reactivated by treatment with DNA methyltransferase inhibitor, 5-Aza and/or HDAC inhibitor, trichostatin A (TSA) in lung cancer cell lines, which did not express SLC5A8. Hypermethylation was detected at the promoter region of SLC5A8 in primary lung tumor tissues as compared with adjacent non-tumor tissues (14/23, 60.9%). CONCLUSION: These results suggest that DNA methylation in the SLC5A8 promoter region may suppress the expression of SLC5A8 in lung tumor.
    Lung cancer (Amsterdam, Netherlands) 12/2012; · 3.14 Impact Factor
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    ABSTRACT: A 47-year old man visited our hospital because of purulent sputum for 3 months. Chest X-ray showed destruction of both the upper lungs, and bronchoscopy revealed inflammatory change with whitish plaque on the left main bronchus through upper division of the left upper lobe. Tracheobronchial aspergillosis (TBA) was finally diagnosed as a result of histologic and microbiologic examination. However, he went abroad without medication before the diagnosis was made and visited again 10 months later. Follow-up bronchoscopy showed complete regression of the previously noted endobronchial lesion. We describe this case to consider the role of antifungal treatment in immunocompetent hosts, as well as to discuss a rare condition; TBA resolved spontaneously.
    Tuberculosis and Respiratory Diseases 11/2012; 73(5):278-81.
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    ABSTRACT: Typhlitis is a necrotizing colitis that usually occurs in neutropenic patients and develops most often in patients with hematologic malignancies such as leukemia and lymphoma. Typhlitis may proceed to bowel perforation, peritonitis and sepsis, which requires immediate treatment. Irinotecan is a semisynthetic analogue of the natural alkaloid camptothecin which prevents DNA from unwinding by inhibition of topoisomerase I. It is mainly used in colon cancer and small cell lung carcinoma (SCLC), of which the most common adverse effects are gastrointestinal toxicities. To the best of our knowledge, no case of typhlitis after chemotherapy with a standard dose of irinotecan in a solid tumor has been reported in the literature. We, herein, report the first case of typhlitis developed after chemotherapy combining irinotecan and cisplatin in a patient with SCLC.
    Tuberculosis and Respiratory Diseases 11/2012; 73(5):288-91.
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    ABSTRACT: This post hoc analysis evaluated the efficacy of indacaterol, a novel inhaled once-daily long-acting β(2)-agonist, by disease severity (GOLD 2005) in patients with moderate-to-severe COPD from six Asian countries/areas (Hong Kong, India, Japan, Korea, Singapore, Taiwan). Data from a 12-week, double-blind, placebo-controlled, parallel-group study in patients randomized to indacaterol 150 μg, indacaterol 300 μg or placebo once daily were analyzed based on baseline disease severity (moderate or severe). Endpoints were: trough FEV(1) (average of 23 h 10 min and 23 h 45 min post-dose values), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) at Week 12. Safety data were collected. Of 347 patients randomized, 59.7% had moderate, and 40.3% had severe COPD. Least squares means (LSMs) indacaterol-placebo differences in trough FEV(1) at Week 12 exceeded the pre-specified minimal clinically important difference (MCID) of 0.12L and were statistically superior (p < 0.001) for indacaterol (150 μg, 300 μg) versus placebo in the two subgroups [0.19L, 0.20L (moderate); 0.15L, 0.19L (severe) respectively]. LSM TDI scores for both indacaterol doses versus placebo in both subgroups were statistically superior (p < 0.05) and clinically meaningful (≥1 unit). Both indacaterol doses showed improvements in LSM SGRQ total scores at Week 12 which exceeded the MCID (4 units) versus placebo in both subgroups, with indacaterol 300 μg-placebo difference in the severe subgroup being statistically significant (p < 0.01). Overall incidence of adverse events was lower with indacaterol than with placebo across both subgroups. Indacaterol demonstrated clinically relevant improvements versus placebo in lung function, dyspnea and health status in Asian COPD patients irrespective of disease severity. CLINICAL TRIALS IDENTIFIER: NCT00794157.
    Respiratory medicine 10/2012; 106(12):1715-21. · 2.33 Impact Factor
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    ABSTRACT: Recent evidence suggests that acetylcholine acting through muscarinic receptors may play an inhibitory role in the mechanisms that drive the structural changes in the airways called airway remodeling. The novel anticholinergic drug tiotropium bromide, which selectively antagonizes muscarinic receptors, especially the M3 subtype, and is long acting, could be beneficial in attenuating airway remodeling in chronic asthma. To investigate the effect of tiotropium bromide on parameters of airway remodeling, including smooth muscle hypertrophy and peribronchial thickening, in a mouse model of chronic asthma. To develop the murine models of acute and chronic asthma, BALB/c mice were sensitized and challenged to ovalbumin for 1 and 3 months, respectively. The effect of tiotropium bromide (0.1mM in 50 μL of phosphate-buffered saline) on pulmonary inflammation and remodeling was evaluated. The expression of muscarinic receptors M2 and M3 was analyzed. In the chronic asthma model, the tiotropium-treated group significantly decreased smooth muscle thickening and peribronchial collagen deposition. As for pulmonary inflammation, the chronic asthma model had a reduction of inflammatory cells and T(H)2 cytokines by tiotropium bromide, but the effects in the asthma acute model were reversed. In the chronic asthma model, expression of the M3 receptor was inhibited and that of the M2 receptor was elevated by the administration of tiotropium bromide. This study suggests that tiotropium bromide might have an inhibitory effect on airway remodeling in a murine model of chronic asthma. Differential effects on muscarinic receptor subtypes may explain why tiotropium bromide has different effects on acute and chronic asthma.
    Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 07/2012; 109(1):29-35. · 3.45 Impact Factor
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    ABSTRACT: The aim of this study was to analyze clinical situations requiring rigid bronchoscopy and evaluate usefulness of rigid bronchoscopic intervention in benign or malignant airway disorders. We retrospectively reviewed 29 patients who underwent rigid bronchoscopy from November 2007 to February 2011 at St. Paul's Hospital, The Catholic University of Korea School of Medicine. Of the 29 patients, the most frequent underlying etiology was benign stenosis of trachea (n=20). Of those 20 patients, 16 had post-intubation tracheal stenosis (PITS), 2 had tracheal stenosis due to inhalation burn (IBTS) and other 2 had obstructive fibrinous tracheal pseudomembrane (OFTP). Other etiologies were airway malignancy (n=6), endobronchial stenosis due to tuberculosis (n=2), and foreign body (n=1). For treatment, silicone stent insertion was done in 16 cases of PITS and IBTS and mechanical removal was performed in 2 cases of OFTP. In 6 cases of malignant airway obstruction mechanical debulking was performed and silicone stents were inserted additionally in 2 cases. Balloon dilatation and electrocautery were used in 2 cases of endobronchial stenosis due to tuberculosis. In all cases of stent, airway obstructive symptom improved immediately. Granulation tissue formation was the most common complication. Tracheal stenosis was most common indication and silicone stenting was most common procedure of rigid bronchoscopy in our center. Rigid bronchoscopic procedures, at least tracheal silicone stenting, should be included in pulmonary medicine fellowship programs because it is a very effective and indispensable method to relieve critical airway obstruction which needs training to learn.
    Tuberculosis and respiratory diseases. 06/2012; 72(6):486-92.
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    ABSTRACT: Endobronchial metastasis from thyroid follicular carcinoma is a rare manifestation. We describe a case of 62-year-old woman who underwent total thyroidectomy due to thyroid follicular carcinoma 19 years previously. Computerized tomography and bronchoscopy suggested an endobronchial enhancing nodule in the right bronchus intermedius, resulting in right middle lobe (RML) and right lower lobe (RLL) collapse. A biopsy specimen showed thyroid follicular carcinoma identical to that taken from a specimen previously. She underwent metastectomy and high-dose radioactive iodine ablation therapy. To our knowledge, this patient represents the first case of endobronchial metastasis with a long past history of thyroid follicular carcinoma.
    Internal Medicine 01/2012; 51(4):401-3. · 0.97 Impact Factor
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    ABSTRACT: The efficacy and safety of indacaterol, a novel inhaled once daily ultra long-acting β(2) -agonist was evaluated in COPD patients in six Asian countries/areas. This study was primarily designed to obtain the regulatory approval of indacaterol in Japan. Moderate-to-severe COPD patients were randomized to indacaterol 150 µg, indacaterol 300 µg or placebo once daily. Efficacy variables: trough FEV(1) (average of 23 h 10 min and 23 h 45 min post-dose values), health status (St. George's Respiratory Questionnaire) and transition dyspnoea index at week 12. Safety/tolerability was evaluated. A total of 347 patients were randomized (96.5% male, mean (SD) age 66.7 (8.38) years, post-bronchodilator FEV(1) % predicted: 53.7 (12.50)); 88.8% completed. The least squares means (LSM) trough FEV(1) at week 12 for indacaterol 150 µg, indacaterol 300 µg and placebo were 1.34 L, 1.37 L and 1.17 L, respectively, with differences versus placebo exceeding the prespecified minimal clinically important difference of 0.12 L (0.17 L and 0.20 L for indacaterol 150 µg and 300 µg, respectively, both P < 0.001). The week 12 LSM transition dyspnoea index score was statistically superior for both indacaterol doses versus placebo (differences of 1.30 and 1.26, P < 0.001; both exceeding the minimal clinically important difference of 1). At week 12, both indacaterol doses provided statistically significant (P ≤ 0.005) and clinically meaningful (≥4 units) improvements in LSM St. George's Respiratory Questionnaire total score versus placebo (differences: -4.8 and -5.7 units). Adverse events for indacaterol (49.1%, both doses) were lower than placebo (59.0%) and were mostly mild/moderate in severity; no deaths were reported. Indacaterol provided clinically significant bronchodilation and improvements in dyspnoea and health status in Asian COPD patients.
    Respirology 11/2011; 17(2):379-89. · 2.78 Impact Factor
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    ABSTRACT: The active metabolite (1, 25-dihydroxycholecalciferol) of vitamin D (25-hydroxycholecalciferol) leads to activation of macrophages and deficiency of vitamin D seems to be involved in the risk of tuberculosis. The effects of vitamin D are exerted by interaction with the vitamin D receptor (VDR) and may be influenced by polymorphism in the VDR gene. In this study, variation in the VDR gene was investigated in Korean population with tuberculosis. We typed three VDR polymorphisms of restriction endonuclease sites for TaqI, BsmI and FokI in 155 patients with tuberculosis and 105 healthy volunteers. The frequencies of FokI genotypes determined from TB patients were 29.13% for FF, 56.31% for Ff, and 14.56% for ff. We observed 1.4-fold increased prevalence of the Ff genotype in TB patients compared with normal healthy groups (p=0.0857). However, there was no significant association between the genotype groups, TB patient and normal control, for FokI polymorphism. There was also no significant association between VDR gene and tuberculosis in another polymorphism (BsmI and TaqI). Three polymorphisms (TaqI, BsmI and FokI) in the VDR gene do not appear to be responsible for host susceptibility to human tuberculosis in Korean population.
    Immune Network 10/2011; 11(5):253-7.