SCI 발표논문

2017년 269편

1492017

제1저자 오보람 · 교신저자 송영욱

, , , , , , , , ,
Therapeutic effect of a novel histone deacetylase 6 inhibitor, CKD-L, on collagen-induced arthritis in vivo and regulatory T cells in rheumatoid arthritis in vitro.
Arthritis Res Ther. 2017;19(1):154.

Abstract
BACKGROUND Histone deacetylase (HDAC) inhibitor has recently been reported to have a therapeutic effect as an anti-inflammatory agent in collagen-induced arthritis (CIA). We investigated the therapeutic effect of a new selective HDAC6 inhibitor, CKD-L, compared to ITF 2357 or Tubastatin A on CIA and regulatory T (Treg) cells in patients with rheumatoid arthritis (RA).
METHODS CIA was induced by bovine type II collagen (CII) in DBA/1 J mice. Mice were treated with HDAC inhibitor for 18 days. Arthritis score was assessed and histological analysis was performed by hematoxylin and eosin (H&E) stain. Cytotoxic T-lymphocyte associated protein (CTLA)-4 expression in induced Treg cells was analyzed and suppression assay was analyzed using Treg cells and effector T (Teff) cells isolated from naive C57BL/6 mice by flow cytometry. Cytokines were analyzed in peripheral blood mononuclear cells (PBMC) of five patients with RA by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). Tumor necrosis factor (TNF) was analyzed using PMA- activated THP-1 cells by ELISA. Suppression assay was analyzed using Treg cells and Teff cells isolated from RA patients by flow cytometry.
RESULTS In the CIA model, CKD-L and Tubastatin A significantly decreased the arthritis score. CKD-L increased CTLA-4 expression in Foxp3⁺ T cells and inhibited the proliferation of Teff cells in the suppression assay. In RA PBMC, CKD-L significantly inhibited TNF and interleukin (IL)-1β, and increased IL-10. CKD-L and Tubastatin A inhibited TNF secretion from PMA-activated THP-1 cells. CKD-L and ITF 2357 inhibited the proliferation of Teff cells in RA patients in the suppression assay. Tubastatin A had no effect on inhibition of proliferation.
CONCLUSION CKD-L decreased the arthritis score in CIA, reduced the expression of TNF and IL-1β, and increased the expression of IL-10 in PBMC from RA patients. CKD-L increased CTLA-4 expression and the suppressive function of Treg cells. These results suggest that CKD-L may have a beneficial effect in the treatment of RA.
PubMed IF 5.4 류마티스내과
1482017

제1저자 공성혜, 김정희 · 교신저자 신찬수

, , , ,
Dietary calcium intake and risk of cardiovascular disease, stroke, and fracture in a population with low calcium intake.
Am J Clin Nutr. 2017;106(1):27-34.

Abstract
Background: The role of dietary calcium intake in cardiovascular disease (CVD), stroke, and fracture is controversial. Most previous reports have evaluated populations with high calcium intake.Objective: We aimed to evaluate whether high dietary calcium intake was associated with the risk of CVD, stroke, and fracture in a population with low calcium intake.Design: In a prospective cohort study beginning in 2001 in Ansung-Ansan, Korea, 2158 men and 2153 women aged >50 y were evaluated for all-cause mortality, CVD, stroke, and fractures over a median 9-y follow-up.Results: During follow-up, 242 and 100 deaths, 149 and 150 CVD events, 58 and 82 stroke events, and 211 and 292 incident fractures occurred in men and women, respectively. The first quartiles of energy-adjusted dietary calcium intake were 249 mg/d (IQR: 169 mg/d) in men and 209 mg/d (IQR: 161 mg/d) in women. Both men and women with higher dietary calcium intake tended to have higher fat, protein, sodium, phosphorus, fruit, and vegetable intakes. In men, outcomes were not significantly associated with dietary calcium intake with or without adjustments, and CVD risk tended to increase with increasing energy-adjusted dietary calcium intake, but this was not statistically significant (P = 0.078 and P = 0.093 with and without adjustment, respectively). In women, CVD risk and dietary calcium intake showed a U-shaped association; the HRs (95% CIs) without adjustment relative to the first quartile were 0.71 (0.47, 1.07), 0.57 (0.36, 0.88), and 0.52 (0.33, 0.83) for quartiles 2, 3, and 4, respectively, and the values after adjustment were 0.70 (0.45, 1.07), 0.51 (0.31, 0.81), and 0.49 (0.29, 0.83) for quartiles 2, 3, and 4, respectively.Conclusion: In Korean women, increased dietary calcium intake was associated with a decreased CVD risk, but it did not influence the risk of stroke or fracture.
PubMed IF 6.9 내분비대사내과
1472017

제1저자 김현수, 유수종 · 교신저자 윤정환, 김영수

, , , , , , , , , , , , ,
Prediction of Response to Sorafenib in Hepatocellular Carcinoma: A Putative Marker Panel by Multiple Reaction Monitoring-Mass Spectrometry (MRM-MS).
Mol Cell Proteomics. 2017;16(7):1312-1323.

Abstract
Sorafenib is the only standard treatment for unresectable hepatocellular carcinoma (HCC), but it provides modest survival benefits over placebo, necessitating predictive biomarkers of the response to sorafenib. Serum samples were obtained from 115 consecutive patients with HCC before sorafenib treatment and analyzed by multiple reaction monitoring-mass spectrometry (MRM-MS) and ELISA to quantify candidate biomarkers. We verified a triple-marker panel to be predictive of the response to sorafenib by MRM-MS, comprising CD5 antigen-like (CD5L), immunoglobulin J (IGJ), and galectin-3-binding protein (LGALS3BP), in HCC patients. This panel was a significant predictor (AUROC > 0.950) of the response to sorafenib treatment, having the best cut-off value (0.4) by multivariate analysis. In the training set, patients who exceeded this cut-off value had significantly better overall survival (median, 21.4 months) than those with lower values (median, 8.6 months; p = 0.001). Further, a value that was lower than this cutoff was an independent predictor of poor overall survival [hazard ratio (HR), 2.728; 95% confidence interval (CI), 1.312-5.672; p = 0.007] and remained an independent predictive factor of rapid progression (HR, 2.631; 95% CI, 1.448-4.780; p = 0.002). When applied to the independent validation set, levels of the cut-off value for triple-marker panel maintained their prognostic value for poor clinical outcomes. On the contrast, the triple-marker panel was not a prognostic factor for patients who were treated with transarterial chemoembolization (TACE). The discriminatory signature of a triple-marker panel provides new insights into targeted proteomic biomarkers for individualized sorafenib therapy.
PubMed IF 6.54 소화기내과
1462017

제1저자 최연주 · 교신저자 김진원

, , , , , , , , ,
Systemic inflammation is associated with the density of immune cells in the tumor microenvironment of gastric cancer.
Gastric Cancer. 2017;20(4):602-611.

Abstract
BACKGROUND The neutrophil-lymphocyte ratio (NLR) and the prognostic nutritional index (PNI) are markers of systemic inflammation known to be useful prognostic indicators of malignancy. However, little evidence has defined the influence of inflammation on the tumor microenvironment.
METHODS Two hundred eighty-eight patients who underwent curative surgery for gastric cancer were included. Preoperative peripheral blood samples were used to analyze the NLR and PNI. The optimal cutoff levels for the NLR and PNI were defined by receiver operating characteristic curve analysis for survival (NLR = 2.7, PNI = 47.7). The densities of specific immune cells (CD3⁺, CD4⁺, CD8⁺) within the tumor microenvironment were measured in tumor microarrays by immunohistochemical analysis.
RESULTS Two hundred thirty-five patients (81.6 %) had a low NLR and 53 patients (18.4 %) had a high NLR. One hundred seventeen patients (40.6 %) had a low PNI and 171 patients (59.4 %) had a high PNI. CD3⁺ and CD8⁺ immune cell density were not associated with the NLR and PNI. However, in the high-NLR group compared with the low-NLR group, CD4⁺ immune cell density was significantly decreased (P < 0.001). Similarly, the density of CD4⁺ immune cells was also significantly decreased in the low-PNI group compared with the high-PNI group (P = 0.007). A high NLR and a low PNI were correlated with worse overall survival in multivariate analysis (P = 0.028 and P = 0.002 respectively).
CONCLUSIONS The NLR and PNI are associated with the density of CD4⁺ immune cells in the tumor microenvironment, which leads to prognostic values of systemic inflammation in gastric cancer.
PubMed IF 6.1 혈액종양내과
1452017

제1저자 송지현 · 교신저자 김영선

, , , , , ,
High Salt Intake Is Associated with Atrophic Gastritis with Intestinal Metaplasia.
Cancer Epidemiol Biomarkers Prev. 2017;26(7):1133-1138.

Abstract
Background: Although several studies have investigated excessive salt intake as a risk factor for gastric precancerous lesions, such as atrophic gastritis and intestinal metaplasia, the evidence is insufficient to make a conclusion. We evaluated the association between gastric precancerous lesions and salt intake.Methods: From 2008 to 2015, the medical records of 728 subjects who underwent upper gastrointestinal endoscopy and sodium excretion in 24-hour urine tests were retrospectively reviewed. Sixty-six subjects were excluded due to diuretics use (n = 55), diagnosis with a gastric neoplasm (n = 4), or the cases of intestinal metaplasia in the absence of atrophy (n = 7), so 662 subjects were included. Atrophic gastritis and intestinal metaplasia were diagnosed by endoscopic findings. The subjects were grouped into three levels by tertiles of 24-hour urine sodium excretion.Results: A total of 192 (29.0%) had atrophic gastritis without intestinal metaplasia and 112 (16.9%) had atrophic gastritis with intestinal metaplasia. A total of 276 subjects (61.5%) were infected with Helicobacter pylori (H. pylori). In multivariate analyses, H. pylori infection [OR = 14.17; 95% confidence interval (CI), 7.12-28.22) was associated with atrophic gastritis without intestinal metaplasia. Highest levels of sodium excretion (OR = 2.870; 95% CI, 1.34-6.14), heavy smoking (≥20 pack-years) (OR = 2.75; 95% CI, 1.02-7.39), and H. pylori infection (OR = 3.96; 95% CI, 2.02-7.76) were associated with atrophic gastritis with intestinal metaplasia.Conclusions: Our endoscopy-based study suggested that high salt intake could be associated with an increased risk of atrophic gastritis with intestinal metaplasia.Impact: Low salt diet might be helpful to prevent gastric carcinogenesis. Cancer Epidemiol Biomarkers Prev; 26(7); 1133-8. ©2017 AACR.
PubMed IF 3.7 소화기내과
1442017

제1저자 박혜정 · 교신저자 강혜련

, , , , , , , , , , , ,
Re-exposure to low osmolar iodinated contrast media in patients with prior moderate-to-severe hypersensitivity reactions: A multicentre retrospective cohort study.
Eur Radiol. 2017;27(7):2886-2893.

Abstract
OBJECTIVES To evaluate the outcomes of re-exposure to low-osmolar iodinated contrast medium (LOCM) in patients with a history of moderate-to-severe hypersensitivity reaction (HSR).
METHODS We retrospectively evaluated a cohort comprising all subjects satisfying the following conditions at 11 centres: (1) experienced a moderate-to-severe HSR to LOCM by December 2014, and (2) underwent contrast-enhanced computed tomography after the initial HSR between January 2014 and December 2014.
RESULTS A total of 150 patients with 328 instances of re-exposure were included; the recurrence rate of HSR was 19.5%. Patients with severe initial HSR exhibited a higher recurrence rate of severe HSR compared to patients with moderate initial HSR, despite more intensive premedication. In the multivariate analysis, the independent risk factors for recurrence of HSR were diabetes, chronic urticaria, drug allergy other than to iodinated contrast media (ICM) and severe initial HSR. The risk of recurrent HSR was 67.1% lower in cases where the implicated ICM was changed to another one (odds ratio: 0.329; P = 0.001). However, steroid premedication did not show protective effects against recurrent HSR.
CONCLUSION In high-risk patients who have previously experienced a moderate-to-severe initial HSR to LOCM, we should consider changing the implicated ICM to reduce recurrence risk.
KEY POINTS • In patients with moderate-to-severe HSR, steroid premedication only shows limited effectiveness. • Changing the implicated ICM can reduce the recurrence of HSR to ICM. • Diabetes, chronic urticaria and drug allergies increase the risk of ICM HSR.
PubMed IF 6 알레르기내과
1432017

제1저자 류양 · 교신저자 김인호

, , , , ,
KML001 and doxercalciferol induce synergistic antileukemic effect in acute lymphoid leukemia cells.
Oncol Rep. 2017;38(1):481-487.

Abstract
KML001 (NaAsO2, sodium metaarsenite, KOMINOX), a kind of arsenic compound, that has shown promising efficacy in non-Hodgkin's lymphoma (NHL) both in vitro and in vivo. In our study, the antileukemic effect of KML001 on acute lymphoid leukemia (ALL) and its mechanism of action were investigated. The results showed that KML001 inhibited cell proliferation in two types of ALL cell lines, CCRF-CEM and Molt-4. Exposure of ALL cells to KML001 induced apoptosis in a time-dependent manner. KML001 caused cell cycle arrest at G2/M phase instead of G0/G1 phase shown in other leukemia cells. In addition, we also tested the possibility of synergy of KML001 with doxercalciferol, a vitamin D2 derivative. Also, we found that a combination of KML001 with doxercalciferol showed a synergistic effect on ALL cell lines and this could be due to its different mechanism of action. Overall, our findings demonstrated KML001 could be a promising antileukemic agent especially when it is combined with doxercalciferol in ALL treatment.
PubMed IF 4.7 혈액종양내과
1422017

제1저자 김민주 · 교신저자 최훈성

, , , , , , , ,
Extent of surgery did not affect recurrence during 7-years follow-up in papillary thyroid cancer sized 1-4 cm: Preliminary results.
Clin Endocrinol (Oxf). 2017;87(1):80-86.

Abstract
OBJECTIVE There is debate whether hemithyroidectomy is sufficient for patients with papillary thyroid cancer (PTC) sized 1-4 cm. Therefore, we investigated whether hemithyroidectomy affects recurrence rate compared with thyroidectomy in patients with PTC sized 1-4 cm.
DESIGN Retrospective observational study.
PATIENTS We included 147 patients with 1-4 cm PTC who underwent hemithyroidectomy between 2004 and 2008. They were matched with 298 patients who underwent thyroidectomy, comparing age, sex, tumour size, multiplicity, extrathyroidal extension status and lymph node (LN) metastasis status.
MEASUREMENTS Recurrence-free survival (RFS) was compared between hemithyroidectomy and thyroidectomy groups.
RESULTS Median follow-up length was 7 years, during which there were nine (6.1%) and 17 (5.7%) recurrences in hemithyroidectomy and thyroidectomy groups, respectively. Recurrence-free survival in the hemithyroidectomy group was not different from that in the thyroidectomy group regardless of variant, multifocality, LN metastasis and radioactive iodine treatment. However, in subgroup analysis, hemithyroidectomy significantly increased the risk of recurrence in patients with contralateral nodules on the preoperative imaging.
CONCLUSIONS Recurrence after hemithyroidectomy was not different from that after thyroidectomy during a median follow-up of 7 years. However, because thyroidectomy might be favoured in patients with contralateral nodules at preoperative evaluation, a thorough evaluation of the contralateral thyroid lobe is necessary.
PubMed IF 2.8 내분비대사내과
1412017

제1저자 박경선 · 교신저자 김정희

, , , , , , , , ,
Outcomes analysis of surgical and medical treatments for patients with primary aldosteronism.
Endocr J. 2017;64(6):623-632.

Abstract
Patients with aldosterone-producing adenomas are treated using surgery, and patients with idiopathic hyperaldosteronism receive medical treatment using mineralocorticoid receptor antagonists (MRAs). However, the outcomes of surgical and medical treatment for primary aldosteronism (PA) remain unclear. Therefore, we compared the outcomes of surgical and medical treatment for PA and aimed to identify a specific subgroup that might benefit from medical treatment. We identified 269 patients who were treated for PA (unilateral excess: 221 cases; bilateral excess: 48 cases) during 2000-2015 at the Seoul National University Hospital and two other tertiary centers. The main outcomes were the amelioration of hypertension and hypokalemia. Treatment improved hypertension in the surgical treatment group (78.2%) and the medical treatment group (55.6%) (p = 0.001). At the last follow-up, hypokalemia was normalized in the surgical treatment group (97.1%) and the medical treatment group (93.7%, p = 0.046). Among patients with unilateral aldosterone excess, surgery provided advantages in resolving hypertension without worsening renal function. Among patients who were >60 years old or had impaired renal function, surgical and medical treatment provided similar amelioration of hypokalemia and hypertension. Three patients developed hyperkalemia after surgery, and no patients developed hyperkalemia after initiating medical treatment. The surgical treatment group exhibited a lower postoperative estimated glomerular filtration rate (eGFR) and higher serum potassium levels, compared to the medical treatment group. Surgical treatment provided better hypertension and hypokalemia outcomes among patients with PA, compared to medical treatment. However, MRAs may be appropriate for elderly patients with impaired renal function.
PubMed IF 2.5 내분비대사내과
1402017

제1저자 이재원 · 교신저자 김원, 조남혁

, , , , , , , , , , ,
Immunological dynamics associated with rapid virological response during the early phase of type I interferon therapy in patients with chronic hepatitis C.
PLoS One. 2017;12(6):e0179094.

Abstract
Type I interferons (IFNs) play an important role in antiviral immunity as well as immunopathogenesis of diverse chronic viral infections. However, the precise mechanisms regulating the multifaceted effects of type I IFNs on the immune system and pathological inflammation still remain unclear. In order to assess the immunological dynamics associated with rapid viral clearance in chronic hepatitis C patients during the acute phase of type I IFN therapy, we analyzed multiple parameters of virological and immunological responses in a cohort of 59 Korean hepatitis C patients who received pegylated IFN-α and ribavirin (IFN/RBV). Most of the Korean patients had favorable alleles in the IFN-λ loci for responsiveness to IFN/RBV (i.e., C/C in rs12979860, T/T in rs8099917, and TT/TT in rs368234815). Rapid virological response (RVR) was determined mainly by the hepatitis C virus genotype. Among the cytokines analyzed, higher plasma levels of IL-17A and FGF were observed in non-RVR patients infected with viral genotype 1 and IP-10 was consistently elevated in RVR group infected with genotype 2 during the early phase of antiviral therapy. In addition, these three cytokines were correlated each other, suggesting a functional linkage of the cytokines in antiviral responses during IFN/RBV therapy. A low baseline frequencies of regulatory T cells and γδ T cells, but high level of group 2 innate lymphoid cells, in peripheral bloods were also significantly associated with the RVR group, implicating a potential role of the cellular immunity during the early phase of IFN/RBV therapy. Therefore, the immunological programs established by chronic hepatitis C and rapid disruption of the delicate balance by exogenous type I IFN might be associated with the subsequent virological outcomes in chronic hepatitis C patients.
PubMed IF 2.8 소화기내과
1392017

제1저자 이주명 · 교신저자 구본권, 신은석

, , , , , , , , , ,
Impact of Longitudinal Lesion Geometry on Location of Plaque Rupture and Clinical Presentations.
JACC Cardiovasc Imaging. 2017;10(6):677-688.

Abstract
OBJECTIVES This study sought to investigate the impact of longitudinal lesion geometry on the location of plaque rupture and clinical presentation and its mechanism.
BACKGROUND The relationships among lesion geometry, external hemodynamic forces acting on the plaque, location of plaque rupture, and clinical presentation have not been comprehensively investigated.
METHODS This study enrolled 125 patients with plaque rupture documented by intravascular ultrasound. Longitudinal locations of plaque rupture were identified and categorized by intravascular ultrasound. Patients' clinical presentations and TIMI (Thrombolysis In Myocardial Infarction) flow grade in an initial angiogram were compared according to the location of plaque rupture. Longitudinal lesion asymmetry was quantitatively assessed by the luminal radius change over the segment length (radius gradient [RG]). Lesions with a steeper radius change in the upstream segment compared with the downstream segment (RG_upstream > RG_downstream) were defined as upstream-dominant lesions.
RESULTS On the basis of the site of maximum rupture aperture, 56.0%, 16.0%, and 28.0% of the patients had upstream, minimal lumen area, and downstream rupture, respectively. Patients with upstream rupture more frequently presented with ST-segment elevation myocardial infarction (45.7%, 40.0%, 22.9%; p = 0.030) and with TIMI flow grade <3 (32.9%, 20.0%, 17.1%; p = 0.042). According to the ratio of upstream and downstream RG, 69.5% of lesions were classified as upstream-dominant lesions, and 30.5% were classified as downstream-dominant lesions. Among the 66 upstream-dominant lesions, 65 cases (98.5%) had upstream rupture, and the RG ratio (RG_upstream/RG_downstream) was an independent predictor of upstream rupture (odds ratio: 1.481; 95% confidence interval: 1.035 to 2.120; p = 0.032). Upstream-dominant lesions more frequently manifested with ST-segment elevation myocardial infarction than did downstream-dominant lesions (48.5% vs. 24.1%; p = 0.026).
CONCLUSIONS Both clinical presentation and degree of flow limitation were associated with the location of plaque rupture. Longitudinal lesion asymmetry assessed by RG, which can affect regional distribution of hemodynamic stress, was associated with the location of rupture and with clinical presentation.
PubMed IF 19 순환기내과
1382017

제1저자 조용숙 · 교신저자 이창훈

, , , , ,
Different prevalence and clinical characteristics of asthma-chronic obstructive pulmonary disease overlap syndrome according to accepted criteria.
Ann Allergy Asthma Immunol. 2017;118(6):696-703.e1.

Abstract
BACKGROUND A unified definition of asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is not available, which makes it difficult to evaluate the prevalence and clinical features of patients with ACOS.
OBJECTIVE To investigate the prevalence and clinical characteristics of ACOS according to the updated widely accepted diagnostic criteria.
METHODS Participants were enrolled from a prospective cohort study conducted between April 2013 and November 2016 in South Korea. We adopted 4 criteria of ACOS: modified Spanish, American Thoracic Society (ATS) Roundtable criteria, the Latin American Project for the Investigation of Obstructive Lung Disease (PLATINO), and the Global Initiative for Asthma/Global Initiative for Chronic Obstructive Lung Disease (GINA/GOLD) criteria. The prevalence, clinical characteristics, and exacerbations of ACOS were investigated.
RESULTS Among 301 patients with chronic obstructive pulmonary disease, 31.3%, 11.9%, 48.3%, and 46.15% were diagnosed with ACOS according to the modified Spanish, ATS Roundtable criteria, PLATINO, and GINA/GOLD criteria, respectively. Compared with other criteria, patients with ACOS diagnosed according to the modified Spanish criteria had better exercise capacity and lung function at baseline but higher risk of moderate to severe (adjusted hazard ratio, 1.97; 95% confidence interval, 1.14-3.41; P = .01) and total (adjusted odds ratio, 2.10; 95% confidence interval, 1.33-3.31; P < .01) exacerbations during at least a 1-year follow-up period than patients without ACOS.
CONCLUSION The prevalence of ACOS varied according to the diagnostic criteria. Among the different criteria, the modified Spanish criteria could identify patients with more asthmatic features and higher risk of exacerbation.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02527486.
PubMed IF 7.1 호흡기내과
1372017

제1저자 김미화 · 교신저자 오도연

, , , , ,
Resistance Mechanism against Trastuzumab in HER2-Positive Cancer Cells and Its Negation by Src Inhibition.
Mol Cancer Ther. 2017;16(6):1145-1154.

Abstract
Trastuzumab in combination with chemotherapy is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancers. Several resistance mechanisms against anti-HER2 therapy have been proposed. Src activation has been suggested to be responsible for the resistance of HER2-positive breast cancer. In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from HER2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773). Elevated Src phosphorylation was detected in SNU2670HR and NCI-N87HR cell lines, but not in SNU216HR or SNU2773HR cell lines. In SNU216HR and SNU2773HR cell lines, phospho-FAK (focal adhesion kinase) was elevated. Bosutinib as a Src inhibitor suppressed growth, cell-cycle progression, and migration in both parental and HR cell lines. Specifically, Src interacted with FAK to affect downstream molecules such as AKT, ERK, and STAT3. Bosutinib showed more potent antitumor effects in Src-activated HR cell lines than parental cell lines. Taken together, this study suggests that Src inhibition may be an effective measure to overcome trastuzumab resistance in HER2-positive cancer. Mol Cancer Ther; 16(6); 1145-54. ©2017 AACR.
PubMed IF 6.9 혈액종양내과
1362017

제1저자 김형우 · 교신저자 황진혁

, , , , , , , ,
Adjunctive role of preoperative liver magnetic resonance imaging for potentially resectable pancreatic cancer.
Surgery. 2017;161(6):1579-1587.

Abstract
BACKGROUND The adjunctive role of magnetic resonance imaging of the liver before pancreatic ductal adenocarcinoma has been unclear. We evaluated whether the combination of hepatic magnetic resonance imaging with multidetector computed tomography using a pancreatic protocol (pCT) could help surgeons select appropriate candidates and decrease the risk of early recurrence.
METHODS We retrospectively enrolled 167 patients in whom complete resection was achieved without grossly visible residual tumor; 102 patients underwent pCT alone (CT group) and 65 underwent both hepatic magnetic resonance imaging and pCT (magnetic resonance imaging group).
RESULTS By adding hepatic magnetic resonance imaging during preoperative evaluation, hepatic metastases were newly discovered in 3 of 58 patients (5%) without hepatic lesions on pCT and 17 of 53 patients (32%) with indeterminate hepatic lesions on pCT. Patients with borderline resectability, a tumor size >3 cm, or preoperative carbohydrate antigen 19-9 level >1,000 U/mL had a greater rate of hepatic metastasis on subsequent hepatic magnetic resonance imaging. Among 167 patients in whom R0/R1 resection was achieved, the median overall survival was 18.2 vs 24.7 months (P = .020) and the disease-free survival was 8.5 vs 10.0 months (P = .016) in the CT and magnetic resonance imaging groups, respectively (median follow-up, 18.3 months). Recurrence developed in 82 (80%) and 43 (66%) patients in the CT and magnetic resonance imaging groups, respectively. The cumulative hepatic recurrence rate was greater in the CT group than in the magnetic resonance imaging group (P < .001).
CONCLUSION Preoperative hepatic magnetic resonance imaging should be considered in patients with potentially resectable pancreatic ductal adenocarcinoma, especially those with high tumor burden.
PubMed IF 3.2 소화기내과
1352017

제1저자 김윤기 · 교신저자 서정원

, , , , , , , , , ,
A laboratory association between hemoglobin and VerifyNow P2Y12 reaction unit: A systematic review and meta-analysis.
Am Heart J. 2017;188:53-64.

Abstract
BACKGROUND VerifyNow P2Y12 assay is used widely to evaluate residual platelet reactivity in patients taking P2Y12 receptor antagonists. However, a laboratory association between VerifyNow P2Y12 reaction unit (PRU) and hemoglobin, which might lead to wrong interpretation of the data, is reported. We performed these systematic review and meta-analysis to clearly define the relationship between PRU and hemoglobin and to elucidate whether the relationship, if any, is a true biological association or is just a laboratory error.
METHODS Through a comprehensive electronic and manual search, 10 studies were selected for the cohort level meta-analysis. Among 10 studies, we were able to retrieve the raw data of 5 studies, and a patient-level meta-analysis was performed. Potential publication bias was searched by funnel plot analysis and was actively adjusted, if present, by trim and fill method.
RESULTS The pooled analysis revealed a significant inverse correlation between PRU and hemoglobin (r=-0.349; P<.001; 10 studies with 4,793 patients). VerifyNow P2Y12 base unit, which reflects off-drug platelet reactivity, was also inversely correlated with hemoglobin (r=-0.526; P<.001; 8 studies with 4,395 patients). % Inhibition (r=0.081; P=.059; 6 studies with 3,832 patients) and ΔPRU (r=-0.037; P=.188; 5 studies with 3,521 patients) were not associated with hemoglobin. A significant inverse association between PRU and hemoglobin was also observed in the patient-level meta-analysis (3,533 patients pooled from 5 studies; r=-0.335; P<.001). Light transmission aggregometry (r=0.160; P=.072; 4 studies with 1,144 patients) and multiple electrode platelet aggregometry (r=-0.029; P=.394; 3 studies with 7,645 patients) showed no significant association with hemoglobin.
CONCLUSIONS A significant inverse association was observed between PRU and hemoglobin which is likely to be a laboratory error. Clinicians should be aware that this association might lead to wrong interpretation of the data.
PubMed IF 3.4 순환기내과
1342017

제1저자 박경택, 김학령 · 교신저자 조주희

, , , , , , , ,
Association between reduced arterial stiffness and preserved diastolic function of the left ventricle in middle-aged and elderly patients.
J Clin Hypertens (Greenwich). 2017;19(6):620-626.

Abstract
The aim of this study was to investigate whether arterial stiffness plays a role in retaining normal diastolic function in a middle-aged and elderly Korean population. A total of 267 patients without documented cardiovascular disease, 50 years and older (mean age, 57.3±6.3 years; 69.8% men) were retrospectively analyzed. All patients underwent both transthoracic echocardiography and brachial-ankle pulse wave velocity measurement on the same day. Patients with septal annular peak velocity (e') ≥8 cm/s and left atrial volume index <34 mL/m² were considered as having normal diastolic function. Ninety-eight patients (36.7%) had normal diastolic function. Low brachial-ankle pulse wave velocity (<1314 cm/s) was an independent factor for determining normal diastolic function even after controlling for potential confounders in multiple logistic regression analysis (odds ratio, 2.58; 95% confidence interval, 1.46-4.57; P=.001). Our results suggest that compliant arteries may play an important role in maintaining normal left ventricular diastolic function in middle-aged and elderly patients without documented cardiovascular disease.
PubMed IF 2.9 순환기내과
1332017

제1저자 이진우 · 교신저자 박영식

, , , , , , , ,
The additional role of Xpert MTB/RIF in the diagnosis of intrathoracic tuberculous lymphadenitis.
J Infect Chemother. 2017;23(6):381-384.

Abstract
BACKGROUND Diagnosis of intrathoracic tuberculosis (TB) lymphadenitis remains a challenge because of difficulties in obtaining adequate tissue and the lack of a sensitive test. Recently, Xpert MTB/RIF assay is being used for rapid diagnosis of pulmonary TB, but it has not yet been widely validated in intrathoracic TB lymphadenitis. The aim of this study was to assess the additional role of Xpert MTB/RIF in diagnosing intrathoracic TB lymphadenitis using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) specimen.
METHODS Consecutive patients who underwent Xpert MTB/RIF assay using EBUS-TBNA specimen from January 2012 and November 2013 at a tertiary referral hospital were recruited. Among them, the cases with malignant lymph nodes were excluded.
RESULTS Among 73 patients, 13 (17.8%) cases were diagnosed with intrathoracic TB lymphadenitis. In detail, 10 patients were diagnosed using conventional methods only (histology or AFB culture) and 3 patients were additionally diagnosed when adding Xpert MTB/RIF assay. The median time to diagnosis using Xpert MTB/RIF (1 day) was shorter than conventional methods (3 days for histology, 14 days for AFB culture). Rifampin resistance was not detected in any patients.
CONCLUSION In patients with enlarged intrathoracic lymph nodes and low suspicion of malignancy, combination of conventional diagnostic methods with Xpert MTB/RIF could lead to additional and rapid diagnosis of intrathoracic TB lymphadenitis.
PubMed IF 1.7 호흡기내과
1322017

제1저자 이소령 · 교신저자 최의근

, , , ,
Trends in the incidence and prevalence of atrial fibrillation and estimated thromboembolic risk using the CHA2DS2-VASc score in the entire Korean population.
Int J Cardiol. 2017;236:226-231.

Abstract
BACKGROUND Data on the epidemiology of atrial fibrillation (AF) and temporal trends are not well established in the Korean population. We aimed to estimate the incidence and prevalence of AF in Korea between 2008 and 2015.
METHODS Using the National Health Insurance Service database, we analyzed as a nationwide cohort the entire Korean adult population from 2008 to 2015 (n=41,505,679 in 2015). AF was identified by using diagnostic codes.
RESULTS During an 8-year period representing 314,311,360 person-years of follow-up, 496,341 individuals were newly diagnosed with AF. The incidence of AF increased to >1.12-fold as follows: from 15.34 to 17.14 per 10,000 person-years (p<0.001). We also found a 1.68-fold increase in the prevalence of AF, from 0.46% in 2008 to 0.67% in 2015 (p<0.001). The incidence and prevalence of AF increased with advancing age. The median age of the AF patients increased from 68 to 71years (p<0.001). The prevalence of diabetes and heart failure in AF subjects increased (p<0.001). The percentage of patients with a CHA₂DS₂-VASc score of ≥2, who were strongly recommended for anticoagulation treatment, increased from 80.2% to 86.8% (p<0.001).
CONCLUSION The incidence and prevalence of AF gradually increased from 2008 to 2015. The proportion of AF patients who were candidates for anticoagulation therapy also significantly increased owing to population aging and increasing comorbidities (i.e., heart failure and diabetes). These findings may provide a framework to understand the actual disease burden and establish the optimal management strategy for AF.
PubMed IF 3.3 순환기내과
1312017

제1저자 박석우 · 교신저자 이정표, 김영훈

, , , , , , , , , , , , ,
Metabolic Acidosis and Long-Term Clinical Outcomes in Kidney Transplant Recipients.
J Am Soc Nephrol. 2017;28(6):1886-1897.

Abstract
Metabolic acidosis (MA), indicated by low serum total CO₂ (TCO₂) concentration, is a risk factor for mortality and progressive renal dysfunction in CKD. However, the long-term effects of MA on kidney transplant recipients (KTRs) are unclear. We conducted a multicenter retrospective cohort study of 2318 adult KTRs, from January 1, 1997 to March 31, 2015, to evaluate the prevalence of MA and the relationships between TCO₂ concentration and clinical outcomes. The prevalence of low TCO₂ concentration (<22 mmol/L) began to increase in KTRs with eGFR<60 ml/min per 1.73 m² and ranged from approximately 30% to 70% in KTRs with eGFR<30 ml/min per 1.73 m² Multivariable Cox proportional hazards models revealed that low TCO₂ concentration 3 months after transplant associated with increased risk of graft loss (hazard ratio [HR], 1.74%; 95% confidence interval [95% CI], 1.26 to 2.42) and death-censored graft failure (DCGF) (HR, 1.66; 95% CI, 1.14 to 2.42). Cox regression models using time-varying TCO₂ concentration additionally demonstrated significant associations between low TCO₂ concentration and graft loss (HR, 3.48; 95% CI, 2.47 to 4.90), mortality (HR, 3.16; 95% CI, 1.77 to 5.62), and DCGF (HR, 3.17; 95% CI, 2.12 to 4.73). Marginal structural Cox models adjusted for time-varying eGFR further verified significant hazards of low TCO₂ concentration for graft loss, mortality, and DCGF. In conclusion, MA was frequent in KTRs despite relatively preserved renal function and may be a significant risk factor for graft failure and patient mortality, even after adjusting for eGFR.
PubMed IF 9.7 신장내과
1302017

제1저자 곽민선 · 교신저자 김동희

, , , ,
The preventive effect of sustained physical activity on incident nonalcoholic fatty liver disease.
Liver Int. 2017;37(6):919-926.

Abstract
BACKGROUND & AIMS Physical activity (PA) is inversely associated with nonalcoholic fatty liver disease (NAFLD) prevalence. However, few studies evaluated the effect of PA on NAFLD incidence in regard to visceral adipose tissue (VAT) and insulin resistance (IR). We investigated whether PA at baseline and change in PA during follow-up have any effect on incident NAFLD.
METHODS We enrolled subjects who underwent health screenings between 2007 and 2008 and participated in voluntary follow-up between 2011 and 2013 (median 4.42 years). Incident NAFLD was defined as NAFLD absence at baseline and presence at follow-up by ultrasonography. PA was measured using a detailed questionnaire-based metabolic equivalent at baseline and follow-up; the difference during follow-up was calculated.
RESULTS Of the 1373 subjects enrolled, 288 (21.0%) developed NAFLD. Both total and leisure-time PA at baseline were inversely associated with incident NAFLD (P for trend=.005 and .003 respectively). Decreased PA at follow-up was associated with increased incident NAFLD risk after adjusting for age, gender, body mass index, smoking, hypertension, diabetes and diet [hazard ratio (HR) 1.45, 95% confidence interval (CI) 1.04-2.02, 4th (most decreased PA) vs 1st quartile (increased PA), P=.028]. This relationship was attenuated but remained statistically significant after adjustment for VAT(HR 1.48, 95% CI 1.06-2.06, 4th vs 1st quartile) and IR(HR 1.59, 95% CI 1.11-2.27, 4th vs 1st quartile).
CONCLUSIONS This study shows an independent protective effect of PA at baseline on incident NAFLD after 4-year follow-up. Furthermore, sustained or increased PA had a preventive effect on incident NAFLD independent of VAT and IR.
PubMed IF 6.2 소화기내과
1292017

제1저자 김유림 · 교신저자 이연주

, , , , , , , , , , , , ,
Effectiveness Analysis of a Part-Time Rapid Response System During Operation Versus Nonoperation.
Crit Care Med. 2017;45(6):e592-e599.

Abstract
OBJECTIVES To evaluate the effect of a part-time rapid response system on the occurrence rate of cardiopulmonary arrest by comparing the times of rapid response system operation versus nonoperation.
DESIGN Retrospective cohort study.
SETTING A 1,360-bed tertiary care hospital.
PATIENTS Adult patients admitted to the general ward were screened. Data were collected over 36 months from rapid response system implementation (October 2012 to September 2015) and more than 45 months before rapid response system implementation (January 2009 to September 2012).
INTERVENTIONS None.
MEASUREMENTS AND MAIN RESULTS The rapid response system operates from 7 AM to 10 PM on weekdays and from 7 AM to 12 PM on Saturdays. Primary outcomes were the difference of cardiopulmonary arrest incidence between pre-rapid response system and post-rapid response system periods and whether the rapid response system operating time affects the cardiopulmonary arrest incidence. The overall cardiopulmonary arrest incidence (per 1,000 admissions) was 1.43. Although the number of admissions per month and case-mix index were increased (3,555.18 vs 4,564.72, p < 0.001; 1.09 vs 1.13, p = 0.001, respectively), the cardiopulmonary arrest incidence was significantly decreased after rapid response system (1.60 vs 1.23; p = 0.021), and mortality (%) was unchanged (1.38 vs 1.33; p = 0.322). After rapid response system implementation, the cardiopulmonary arrest incidence significantly decreased by 40% during rapid response system operating times (0.82 vs 0.49/1,000 admissions; p = 0.001) but remained similar during rapid response system nonoperating times (0.77 vs 0.73/1,000 admissions; p = 0.729).
CONCLUSIONS The implementation of a part-time rapid response system reduced the cardiopulmonary arrest incidence based on the reduction of cardiopulmonary arrest during rapid response system operating times. Further analysis of the cost effectiveness of part-time rapid response system is needed.
PubMed IF 7.5 호흡기내과
1282017

제1저자 장민정 · 교신저자 박종선, 이재호

, , , , , , , , , , , ,
Population pharmacokinetics of moxifloxacin, cycloserine, p-aminosalicylic acid and kanamycin for the treatment of multi-drug-resistant tuberculosis.
Int J Antimicrob Agents. 2017;49(6):677-687.

Abstract
Control of multi-drug-resistant tuberculosis (MDR-TB) requires extensive, supervised chemotherapy because second-line anti-TB drugs have a narrower therapeutic range than first-line drugs. This study aimed to develop population pharmacokinetic (PK) models for second-line drugs in patients with MDR-TB, evaluate the recommended dosage regimens and, if necessary, suggest new dosage regimens. A prospective, single-centre PK study was performed on second-line anti-TB drugs in patients with MDR-TB. Moxifloxacin, cycloserine, p-aminosalicylic acid (PAS), kanamycin and other second-line drugs were administered to the patients. Plasma concentrations were analysed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Population PK models were developed using non-linear mixed effect modelling (NONMEM, Version 7.30; ICON Development Solutions, Ellicott City, MD, USA). Simulations were performed using the calculated PK parameters. The respective absorption rate constant, apparent clearance and apparent volume of distribution values were as follows: 0.305/h, 9.37 L/h and 56.7 L for moxifloxacin; 0.135/h, 1.38 L/h and 10.5 L for cycloserine; 0.510/h, 30.8 L/h and 79.4 L for PAS; and 1.67/h, 3.75 L/h and 15.2 L for kanamycin. The simulations showed that the following dosage regimens were more likely to be within the recommended concentration ranges than the raw data in this study: 200 mg of moxifloxacin once daily (QD) (patient weight <50 kg) and 400 mg of moxifloxacin QD (patient weight ≥50 kg), 500-750 mg of cycloserine QD, 4.95-6.6 g of PAS twice daily and 750-1000 mg of intramuscular kanamycin QD. These findings indicate that the recommended doses should be revised to improve the clinical outcomes of MDR-TB treatment.
PubMed IF 5 호흡기내과
1272017

제1저자 백우현 · 교신저자 박도현

, , , , , , , , , ,
Conversion of external percutaneous transhepatic biliary drainage to endoscopic ultrasound-guided hepaticogastrostomy after failed standard internal stenting for malignant biliary obstruction.
Endoscopy. 2017;49(6):544-548.

Abstract
Background and study aim Percutaneous transhepatic biliary drainage (PTBD) is a rescue procedure after a failed endoscopic retrograde cholangiopancreatography. As PTBD causes patient discomfort, conversion of the PTBD to internal biliary stenting (PTBDS) may be required; however, PTBDS is sometimes difficult because of the tight stricture. We evaluated the efficacy and safety of conversion of external PTBD to endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) after failed PTBDS. Patients and methods A total of 16 patients with malignant distal biliary obstruction who underwent conversion of external PTBD to EUS-HGS after failed PTBDS were enrolled from two institutions in Korea and Japan. Data were analyzed retrospectively. Results The technical and clinical success rates were 100 % and 81 %, respectively. Early adverse events developed in two patients: proximal stent migration (n = 1), and cholecystitis (n = 1). Stents were occluded or migrated distally in five patients. The mean duration of stent patency was 402 days. Conclusions Conversion of external PTBD to EUS-HGS may be a good rescue option after failed PTBDS.
PubMed IF 11.8 소화기내과
1262017

제1저자 이은봉 · 교신저자 이은봉

, , , , , , ,
Disease-Drug Interaction of Sarilumab and Simvastatin in Patients with Rheumatoid Arthritis.
Clin Pharmacokinet. 2017;56(6):607-615.

Abstract
INTRODUCTION Elevated interleukin (IL)-6 occurs in patients with active rheumatoid arthritis (RA), which has been shown to lead to a decrease in cytochrome P450 (CYP) enzyme activity and alterations in drug concentrations metabolized by CYP. IL-6 signaling blockade by IL-6 receptor (IL-6R) antagonists may reverse this effect of IL-6 and restore CYP activity. This study evaluated the pharmacokinetic profile of simvastatin (a CYP3A4 substrate) before and 1 week after a single dose of sarilumab (a human monoclonal antibody [mAb] blocking the IL-6Rα) in patients with RA, to assess potential interaction.
METHODS Nineteen patients with active RA received oral simvastatin 40 mg 1 day before and 7 days after subcutaneous injection of sarilumab 200 mg. The pharmacokinetic parameters of simvastatin and its primary metabolite, β-hydroxy-simvastatin acid, were calculated using noncompartmental analysis.
RESULTS Compared with simvastatin alone, single-dose simvastatin administration 7 days after single-dose sarilumab administration in patients with RA resulted in reduced simvastatin and β-hydroxy-simvastatin acid exposure in plasma. Mean effect ratios (90 % confidence interval) for simvastatin peak plasma concentration (C _max) and area under the concentration-time curve extrapolated to infinity (AUC_∞) were 54.1 % (42.2-69.4 %) and 54.7 % (47.2-63.3 %), respectively. No changes occurred in time to C _max or half-life for either simvastatin or β-hydroxy-simvastatin acid after sarilumab administration.
CONCLUSIONS Sarilumab treatment resulted in a reduction in exposure of simvastatin, consistent with reversal of IL-6-mediated CYP3A4 suppression in patients with active RA, as was reported for tocilizumab with simvastatin and for sirukumab with midazolam.
CLINICAL TRIAL REGISTRATION NUMBER NCT02017639.
PubMed IF 4 류마티스내과
1252017

제1저자 박성열 · 교신저자 오도연

, , , , , , ,
Prospective Evaluation of Changes in Tumor Size and Tumor Metabolism in Patients with Advanced Gastric Cancer Undergoing Chemotherapy: Association and Clinical Implication.
J Nucl Med. 2017;58(6):899-904.

Abstract
A change in tumor size is a well-validated and commonly used value for evaluating response to chemotherapy in cancer. Metabolic changes induced by chemotherapy are related to prognosis in several tumor types. However, the clinical implication of metabolic changes in patients with advanced gastric cancer (AGC) undergoing chemotherapy remains unclear. We aimed to evaluate response of tumor size and metabolism in AGC during chemotherapy and to reveal the relationship between them in view of their impact on patient survival. Methods: We prospectively enrolled patients with AGC before the initiation of first-line palliative chemotherapy. Using baseline and follow-up contrast-enhanced CT and ¹⁸F-FDG PET, we assessed the tumor diameter, SUV_max, and total lesion glycolysis in each lesion and their changes during chemotherapy at the same time. We included all lesions with the maximal longest diameters over 1 cm on CT, and each lesion was evaluated by matched ¹⁸F-FDG PET. We analyzed the association between changes in tumor metabolism and tumor size and performed outcome analysis on overall survival (OS) and progression-free survival (PFS). Results: Seventy-four patients were enrolled, and the number of all lesions included in this study was 620. Compared with adenocarcinomas, poorly cohesive carcinomas demonstrated lower SUV_max irrespective of tumor size (P < 0.001). Human epidermal growth factor receptor 2 (HER2)-positive tumors showed higher SUV_max than HER2-negative tumors (P = 0.002). The changes in SUV_max due to chemotherapy had a linear correlation with the changes in tumor size of each lesion, and a 30% tumor size reduction was associated with a 50% SUV_max reduction (P < 0.001). Total lesion glycolysis changes also correlated with tumor size changes (P < 0.001). Better OS and PFS were obtained in patients with both tumor size and SUV_max reduction than in patients with either size or SUV_max reduction only (OS, P = 0.003; PFS, P = 0.038). Conclusion: Changes in tumor metabolism induced by chemotherapy correlated with changes in tumor size in AGC. Considering both changes in metabolism and size could help predict a more accurate prognosis for AGC patients undergoing chemotherapy.
PubMed IF 9.6 혈액종양내과
1242017

제1저자 이현우 · 교신저자 이창훈

, ,
The impact of olodaterol on the risk of mortality and serious adverse events: a systematic review and meta-analysis.
Br J Clin Pharmacol. 2017;83(6):1166-1175.

Abstract
AIMS Olodaterol is a novel inhaled long-acting β₂ -agonist (LABA) that showed efficacy as a bronchodilator for patients with chronic obstructive pulmonary disease (COPD) and asthma. However, it is unclear whether olodaterol reduces mortality; the safety issues of olodaterol have not been fully evaluated.
METHODS Randomized controlled trials comparing olodaterol with placebo for patients with COPD or asthma, which evaluated mortality or serious adverse events, were included. Eighteen trials reporting mortality and 26 trials reporting nonfatal serious adverse events were included.
RESULTS Inhaled olodaterol did not reduce the risk of mortality (Peto fixed OR 1.31; 95% CI 0.90-1.89) and had no significant impacts on nonfatal serious adverse events (Peto fixed OR 1.03; 95% CI 0.91-1.15).
CONCLUSIONS Inhaled olodaterol has no impact on mortality risk in clinical trials conducted on patients with COPD and asthma. However, the interpretation is limited by a high OR (1.31) and a wide CI that includes the hazardous effect. We could not find any relationship between inhaled olodaterol use and nonfatal serious adverse events.
PubMed IF 3 호흡기내과
1232017

제1저자 김정현 · 교신저자 이창훈

, , , , , , , , , , , , , , ,
Which bronchodilator reversibility criteria can predict severe acute exacerbation in chronic obstructive pulmonary disease patients?
Respir Res. 2017;18(1):107.

Abstract
BACKGROUND It is unclear whether various bronchodilator reversibility (BDR) criteria affect the prognosis of chronic obstructive pulmonary disease (COPD). The aim of this study is to evaluate the impact of positive BDR defined according to various BDR criteria on the risk of severe acute exacerbation (AE) in COPD patients.
METHODS Patients from four prospective COPD cohorts in South Korea who underwent follow-up for at least 1 year were enrolled in this study. The assessed BDR criteria included the Global Initiative for Chronic Obstructive Lung Disease (GOLD), American Thoracic Society (ATS), American College of Chest Physicians, (ACCP), major criteria of the Spanish definition of asthma-COPD overlap syndrome (ACOS), criteria compatible with ACOS in the Global Initiative for Asthma (GINA), and European Respiratory Society (ERS). The rate of patients with severe AE who required hospitalization within 1 year due to BDR results according to each set of criteria was analyzed using logistic regression models.
RESULTS Among a total of 854 patients, the BDR-positive cases varied according to the criteria used. There was a 3.5% positive BDR rate according to GINA and a 29.9% rate according to the ATS criteria. Positive BDR according to the GOLD criteria was significantly associated with a decreased risk of severe AE (adjusted odds ratio (aOR) = 0.38; 95% Confidence interval (CI) = 0.15-0.93). This result remained statistically significant even in a sensitivity analysis that included only participants with a smoking history of at least 10 pack-years and in the analysis for the propensity score-matched participants.
CONCLUSIONS Among different criteria for positive BDR, the use of the GOLD ones was significantly associated with a decreased risk of severe AE in COPD patients. Increase use of ICS/LABA may have affected this relationship.
PubMed IF 5.7 호흡기내과
1222017

제1저자 박미영 · 교신저자 이춘택

, , , , , , , , , , , ,
Generation of lung cancer cell lines harboring EGFR T790M mutation by CRISPR/Cas9-mediated genome editing.
Oncotarget. 2017;8(22):36331-36338.

Abstract
Tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib are effective against lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) mutations. However, cancer cells can develop resistance to these agents with prolonged exposure; in over 50% of cases, this is attributable to the EGFR T790M mutation. Moreover, additional resistance mutations can arise with the use of new drugs. Cancer cell lines with specific mutations can enable the study of resistance mechanisms. In this study, we introduced the EGFR T790M mutation into the PC9 human lung cancer cell line-which has a deletion in exon 19 of the EGFR gene-by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas)9-mediated genome editing. EGFR pyrosequencing and peptide nucleic acid clamping revealed that PC9 cells with EGFR T790M generated by CRISPR/Cas 9 had a higher T790M mutation rate than those with the same mutation generated by long-term exposure to gefitinib (PC9-G); moreover, resistance to gefitinib in these clones was higher than that in PC9-G cells. The clones were also highly sensitive to the 3rd-generation EGFR TKI AZD9291, which is cytotoxic to lung cancer cells with EGFR T790M. The CRISPR/Cas9 programmable nuclease system can be used to generate various cancer cell lines with specific mutations that can facilitate studies on resistance mechanisms and drug efficacy.
PubMed IF 5.008 호흡기내과
1212017

제1저자 김정주 · 교신저자 유철규

, , , , , , , , , , , ,
Inhaled indacaterol for the treatment of COPD patients with destroyed lung by tuberculosis and moderate-to-severe airflow limitation: results from the randomized INFINITY study.
Int J Chron Obstruct Pulmon Dis. 2017;12:1589-1596.

Abstract
BACKGROUND AND OBJECTIVE Pulmonary tuberculosis (TB) is a risk factor for chronic obstructive pulmonary disease (COPD); however, few clinical studies have investigated treatment effectiveness in COPD patients with destroyed lung by TB. The Indacaterol effectiveness in COPD patients with Tuberculosis history (INFINITY) study assessed the efficacy and safety of once-daily inhaled indacaterol 150 µg for the treatment of Korean COPD patients with destroyed lung by TB and moderate-to-severe airflow limitation.
METHODS This was a multicenter, double-blind, parallel-group study, in which eligible patients were randomized (1:1) to receive either once-daily indacaterol 150 µg or placebo for 8 weeks. The primary efficacy endpoint was change from baseline in trough forced expiratory volume in 1 s at Week 8; the secondary endpoints included changes in transition dyspnea index score and St George's Respiratory Questionnaire for COPD score at Week 8. Safety was evaluated over 8 weeks.
RESULTS Of the 136 patients randomized, 119 (87.5%) completed the study treatment. At Week 8, indacaterol significantly improved trough forced expiratory volume in 1 s versus placebo (treatment difference [TD] 140 mL, P<0.001). Statistically significant improvement in transition dyspnea index score (TD =0.78, P<0.05) and numerical improvement in St George's Respiratory Questionnaire for COPD score (TD =-2.36, P=0.3563) were observed with indacaterol versus placebo at Week 8. Incidence of adverse events was comparable between the treatment groups.
CONCLUSION Indacaterol provided significantly superior bronchodilation, significant improvement in breathlessness and improved health status with comparable safety versus placebo in Korean COPD patients with destroyed lung by TB and moderate-to-severe airflow limitation.
PubMed IF 4.1 호흡기내과
1202017

제1저자 최지민 · 교신저자 김상균

, , , , , , , , ,
Clinical implications of pre-existing adenoma in endoscopically resected early gastric cancers.
PLoS One. 2017;12(5):e0178419.

Abstract
BACKGROUND Although gastric adenoma is widely accepted as a precursor of gastric cancer, pre-existing adenoma is not always detected in gastric cancer patients.
OBJECTIVE To investigate the clinical characteristics of early gastric cancer (EGC) arising from adenoma, compared with those of EGC without pre-existing adenoma.
METHODS Patients who underwent endoscopic resection for EGC at a single tertiary hospital were divided into two groups based on the presence (ex-adenoma group) or absence (de novo group) of pre-existing adenoma on pathologic specimens. Clinicopathologic characteristics, endoscopic features and long-term outcomes were analyzed.
RESULTS Of 1,509 patients, 236 (15.6%) were included in the ex-adenoma group. Mean age (P = 0.003) and Helicobacter pylori infection rate (P = 0.040) were significantly higher in the ex-adenoma than in the de novo group. Mean endoscopic size was significantly larger, elevated lesions were more prevalent (both P < 0.001), and carcinomas were more differentiated in the ex-adenoma group than in the de novo group (P = 0.037). The degree of atrophy (P = 0.025) or intestinal metaplasia (P < 0.001) was more advanced in the ex-adenoma group. Synchronous gastric neoplasia was significantly more prevalent in the ex-adenoma group (P < 0.001), whereas metachronous cancer recurrence rate was not significantly different between the two groups.
CONCLUSIONS EGCs with pre-existing adenoma show a greater association with H. pylori-related chronic inflammation than those without, which could explain the differences in the characteristics between groups. Potential differences in carcinogenic mechanisms between the groups were explored.
PubMed IF 2.8 소화기내과

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