SCI 발표논문

1. 1792017

   제1저자 이주명 · 교신저자 구본권

   Lee JM, Koo BK, Shin ES, Nam CW, Doh JH, Hu X, Ye F, Chen S, Yang J, Chen J, Tanaka N, Yokoi H, Matsuo H, Takashima H, Shiono Y, Hwang D, Park J, Kim KJ, Akasaka T, Wang J

   Clinical Outcomes of Deferred Lesions With Angiographically Insignificant Stenosis But Low Fractional Flow Reserve.

   J Am Heart Assoc. 2017;6(8):JAHA.117.006071.

   Abstract

   BACKGROUND Data are limited regarding outcomes of deferred lesions in patients with angiographically insignificant stenosis but low fractional flow reserve (FFR). We investigated the natural history of angiographically insignificant stenosis with low FFR among patients who underwent routine 3-vessel FFR measurement.

   METHODS AND RESULTS From December 2011 to March 2014, 1136 patients with 3298 vessels underwent routine 3-vessel FFR measurement (3V FFR-FRIENDS study, ClinicalTrials.gov identifier NCT01621438), and this study analyzed the 2-year clinical outcomes of 1024 patients with 2124 lesions with angiographically insignificant stenosis (percentage of diameter stenosis <50%), in which revascularization was deferred. All lesions were classified according to FFR values, using a cutoff of 0.80 (high FFR >0.80 versus low FFR ≤0.80). The primary end point was outcome of major adverse cardiovascular events (a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization) at 2 years. Mean angiographic percentage of diameter stenosis and FFR of total lesions were 32.5±10.3% and 0.91±0.08%, respectively. Among the total lesions with angiographically insignificant stenosis, 8.7% showed low FFR (185 lesions). The incidence of lesions with low FFR was 2.5%, 3.8%, 9.0%, and 15.1% in categories of percentage of diameter stenosis <20%, 20% to 30%, 30% to 40%, and 40% to 50%, respectively. At 2-year follow-up, the low-FFR group showed a significantly higher risk of major adverse cardiovascular events compared with the high FFR group (3.3% versus 1.2%, hazard ratio: 3.371; 95% CI, 1.346-8.442; P=0.009). In multivariable analysis, low FFR was the most powerful independent predictor of future MACE in deferred lesions with angiographically insignificant stenosis (adjusted hazard ratio: 2.617; 95% CI, 1.026-6.679; P=0.044).

   CONCLUSIONS In deferred angiographically insignificant stenosis, lesions with low FFR showed significantly higher event rates than those with high FFR. FFR was an independent predictor of future major adverse cardiovascular events in lesions with angiographically insignificant stenosis.

   CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01621438.

   PubMed IF 6 순환기내과
2. 1782017

   제1저자 장동기 · 교신저자 이상협

   Jang DK, Lee SH, Lee JK, Paik WH, Chung KH, Lee BS, Son JH, Lee JW, Ryu JK, Kim YT, Lee KB

   Comparison of cytological and histological preparations in the diagnosis of pancreatic malignancies using endoscopic ultrasound-guided fine needle aspiration.

   Hepatobiliary Pancreat Dis Int. 2017;16(4):418-423.

   Abstract

   BACKGROUND Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has become a crucial diagnostic technique for pancreatic malignancies. The specimen obtained by EUS-FNA can be prepared for either cytological or histological examinations. This study was to compare diagnostic performance of cytological and histological preparations using EUS-FNA in the same lesions when pancreatic malignancies were suspected.

   METHODS One hundred and eighteen patients who underwent EUS-FNA for suspected pancreatic malignancies were consecutively enrolled. All procedures were conducted by a single echoendoscopist under the same conditions. Four adequate preparations were obtained by 22-gauge needles with 20 to-and-fro movements for each pass. The 4 preparations included 2 cytological and 2 histological specimens. The pathologic reviews of all specimens were conducted independently by a single experienced cytopathologist. Sensitivity, specificity, and accuracy of the 2 preparations were compared.

   RESULTS The enrolled patients consisted of 62 males (52.5%), with the mean age of 64.6±10.5 years. Surgery was performed in 23 (19.5%) patients. One hundred and sixteen (98.3%) lesions were classified as malignant, while 2 (1.7%) were benign. Sensitivity of cytology and histology were 87.9% and 81.9%, respectively, with no significant difference (P=0.190). Accuracy was also not significantly different. Cytological preparation was more sensitive when the size of lesion was <3 cm (86.7% vs 68.9%, P=0.033).

   CONCLUSIONS Our results suggested that the diagnostic performances of cytological and histological preparations are not significantly different for the diagnosis of pancreatic malignancies. However, cytological preparation might be more sensitive for pancreatic lesions <3 cm.

   PubMed IF 3.9 소화기내과
3. 1772017

   제1저자 강민구 · 교신저자 김광일

   Kang MG, Kim SW, Yoon SJ, Choi JY, Kim KI, Kim CH

   Association between Frailty and Hypertension Prevalence, Treatment, and Control in the Elderly Korean Population.

   Sci Rep. 2017;7(1):7542.

   Abstract

   Frailty is a common geriatric syndrome characterized by increased risk of disability, hospitalization, and mortality. Hypertension (HTN) is one of the most common chronic medical conditions in the elderly. However, there have been few studies regarding the association between frailty and HTN prevalence, treatment, and control rates. We analyzed data of 4,352 older adults (age ≥ 65 years) from the fifth Korea National Health and Nutrition Examination Survey. We constructed a frailty index based on 42 items and classified participants as robust, pre-frail, or frail. Of the subjects, 2,697 (62.0%) had HTN and 926 (21.3%) had pre-HTN. Regarding frailty status, 721 (16.6%), 1,707 (39.2%), and 1,924 (44.2%) individuals were classified as robust, pre-frail and frail, respectively. HTN prevalence was higher in frail elderly (67.8%) than pre-frail (60.8%) or robust elderly (49.2%) (P < 0.001). Among hypertensive patients, frail elderly were more likely to be treated than pre-frail or robust elderly (P < 0.001), but the proportion of patients whose blood pressure was under control ( < 150/90 mmHg) was lower in frail elderly (P = 0.005). Considering the adverse cardiovascular outcomes associated with frailty, more attention should be paid to the blood pressure control of the frail elderly.

   PubMed IF 4.9 순환기내과
4. 1762017

   제1저자 안창호 · 교신저자 임수

   Ahn CH, Min SH, Lee DH, Oh TJ, Kim KM, Moon JH, Choi SH, Park KS, Jang HC, Ha J, Sherman AS, Lim S

   Hemoglobin Glycation Index Is Associated With Cardiovascular Diseases in People With Impaired Glucose Metabolism.

   J Clin Endocrinol Metab. 2017;102(8):2905-2913.

   Abstract

   CONTEXT There is a substantial interindividual variation in the association between glycated hemoglobin (HbA1c) and plasma glucose concentrations. Its impact on cardiovascular disease (CVD) has not been comprehensively evaluated.

   OBJECTIVE We examined associations between interindividual variations in HbA1c, which was estimated as the hemoglobin glycation index (HGI), and CVD.

   DESIGN, SETTING, AND PARTICIPANTS We performed a cross-sectional analysis with 1248 treatment-naïve subjects with prediabetes or diabetes. The HGI was defined as the measured HbA1c minus predicted HbA1c, which was calculated from the linear relationship between HbA1c and fasting plasma glucose levels.

   MAIN OUTCOME MEASURES The prevalence of composite and individual CVDs including coronary artery disease (CAD), stroke, and peripheral artery disease (PAD).

   RESULTS The overall prevalence of composite CVD was 10.3% and individual prevalences of CAD, stroke, and PAD were 5.7%, 5.1%, and 1.3%, respectively. All prevalences significantly increased from the first to third tertile of HGI. In multivariate analysis, the highest HGI tertile was independently associated with composite CVD [odds ratio (95% confidence interval): 2.81 (1.59-4.98)], and individual CAD [2.30 (1.12-4.73)], stroke [3.40 (1.50-7.73)], and PAD [6.37 (1.18-34.33)] after adjustment for other CVD risk factors including HbA1c levels. Two consecutive measurements of HGI obtained on different days showed good correlation (r = 0.651, P < 0.001) and high concordance rate in the tertile classification (69.1%).

   CONCLUSIONS High HGI was independently associated with overall and individual CVDs. This result suggests that discrepancy between HbA1c and fasting glucose levels can reflect vascular health in subjects with impaired glucose metabolism.

   PubMed IF 5.4 내분비대사내과
5. 1752017

   제1저자 김민정 · 교신저자 김형관

   Kim MJ, Kim HK, Jung JH, Yoon YE, Kim HL, Park JB, Lee SP, Kim YJ, Cho GY, Sohn DW, Oh JK

   Echocardiographic diagnosis of total or left congenital pericardial absence with positional change.

   Heart. 2017;103(15):1203-1209.

   Abstract

   OBJECTIVES Congenital absence of the pericardium (CAP) is often confused with other conditions presenting with right ventricular dilatation and usually warrants CT or cardiac MR (CMR) to confirm. It would be desirable to have more specific echocardiographic criteria to provide a conclusive diagnosis.

   METHODS 11 patients who were diagnosed with CAP (four patients with total CAP) based on CT/CMR were consecutively enrolled. Thirteen patients with atrial septal defect (ASD) and 16 normal subjects served as controls. To investigate spatial changes of heart in the thoracic cavity in CAP, following echocardiographic measurements were made in the left and right decubitus positions: the angle between the ultrasound beam and the left ventricular posterior wall (Angle-_PW) in end-diastole at the parasternal long axis, and the distance between the chest wall and the most distal part of the left ventricular posterior wall (Distance-_PW) at the parasternal mid-ventricular short axis.

   RESULTS Angle-_PW in patients with CAP were significantly greater than in those with ASD (100.1±12.5° vs 74.5±8.6°, p<0.017) or in normal subjects (100.1±12.5° vs 69.9±7.6°, p<0.017) at the left decubitus, and the difference in Angle-_PW according to posture (left vs right) was significantly greater in CAP compared with the other groups (CAP 20.7±12.7°, ASD 0.31±1.80°, normal 0.31±1.40°, all p<0.017). The differences in Distance-_PW according to patient position (CAP 2.43±0.77°, ASD 0.42±0.45°, normal 0.26±0.55°) or cardiac cycle in each position (left: CAP 1.60±0.76°, ASD 0.41±0.27°, normal 0.17±0.12°; right: CAP 0.70±0.32°, ASD 0.22±0.19°, normal 0.22±0.13°) were significantly higher in the CAP group than in the other groups (all p<0.017).

   CONCLUSIONS Patients with CAP have dynamic alteration in cardiac position depending on posture, which is not observed in ASD or in normal controls. Hence, total or left-sided CAP can be reliably diagnosed with positional changes during routine echocardiography.

   PubMed IF 4.4 순환기내과
6. 1742017

   제1저자 김정희 · 교신저자 김용휘

   Kim JH, Hur KY, Lee JH, Lee JH, Se YB, Kim HI, Lee SH, Nam DH, Kim SY, Kim KW, Kong DS, Kim YH

   Outcome of Endoscopic Transsphenoidal Surgery for Acromegaly.

   World Neurosurg. 2017;104:272-278.

   Abstract

   OBJECTIVE Endoscopic transsphenoidal surgery has recently been introduced in pituitary surgery. We investigated outcomes and complications of endoscopic surgery in 2 referral centers in Korea.

   METHODS We enrolled 134 patients with acromegaly (microadenomas, n = 15; macroadenomas, n = 119) who underwent endoscopic transsphenoidal surgery at Seoul National University Hospital (n = 74) and Samsung Medical Center (n = 60) between January 2009 and March 2016. Remission was defined as having a normal insulin-like growth factor-1 and a suppressed growth hormone (GH) <1 ng/mL during an oral glucose tolerance test.

   RESULTS Remission was achieved in 73.1% of patients, including 13 of 15 microadenoma patients (86.7%) and 86 of 119 macroadenoma patients (72.3%). A multivariate analysis to determine a predictor of biochemical remission demonstrated that absence of cavernous sinus invasion and immediate postoperative GH levels <2.5 ng/dL were significant predictors of remission (adjusted odds ratio [OR], 5.14; 95% confidence interval [CI], 1.52-17.3 and OR, 9.60; 95% CI, 3.41-26.9, respectively). After surgery, normal pituitary function was maintained in 34 patients (25.4%). Sixty-four patients (47.7%) presented complete (n = 59, 44.0%) or incomplete (n = 5, 3.7%) recovery of pituitary function. Hypopituitarism persisted in 20 patients (14.9%) and worsened in 16 patients (11.9%). Postoperatively, transient diabetes insipidus was reported in 52 patients (38.8%) but only persisted in 2 patients (1.5%). Other postoperative complications were epistaxis (n = 2), cerebral fluid leakage (n = 4), infection (n = 1), and intracerebral hemorrhage (n = 1).

   CONCLUSIONS Endoscopic transsphenoidal surgery for acromegaly presented high remission rates and a low incidence of endocrine deficits and complications. Regardless of surgical techniques, invasive pituitary tumors were associated with poor outcome.

   PubMed IF 2 내분비대사내과
7. 1732017

   제1저자 서경진 · 교신저자 이정옥, 김인호

   Suh KJ, Lee JY, Shin DY, Koh Y, Bang SM, Yoon SS, Park S, Kim I, Lee JO

   Analysis of adverse events associated with dasatinib and nilotinib treatments in chronic-phase chronic myeloid leukemia patients outside clinical trials.

   Int J Hematol. 2017;106(2):229-239.

   Abstract

   We analyzed adverse events (AEs) in 201 chronic phase CML patients treated with nilotinib (n = 120) or dasatinib (n = 81) as first- or second-line therapy. The dasatinib group had significantly higher grade 3-4 AEs compared to the nilotinib group (22 vs. 54%, p < 0.001), and had more frequent dose reduction, interruption, and discontinuation (p < 0.001, p = 0.004, and p = 0.006, respectively). Of 59 patients who discontinued treatment, 47 (80%) discontinued treatment due to AEs; 50% of the AEs causing drug discontinuation were of grade 2 severity. Compared to the second-line setting, discontinuation occurred more rapidly in the first-line setting (2.9 vs. 15.6 months, p = 0.015). Pleural effusion occurred in 35% (28/81) of the patients with dasatinib and led to dasatinib discontinuation in 14 patients (grade 2 of 79%). Pulmonary artery hypertension occurred in one patient with dasatinib. Stroke, acute coronary syndrome, and peripheral artery occlusive disease occurred in 5% (6/120) of the patients treated with nilotinib. The dasatinib group had shorter event-free survival than nilotinib group (first-line, p = 0.051; second-line, p = 0.025). In the clinical practice setting, nilotinib or dasatinib use was more frequently interrupted than recommended by guidelines in association with less severe AEs. We believe this phenomenon is attributable to the availability of other TKIs.

   PubMed IF 1.9 혈액종양내과
8. 1722017

   제1저자 박세훈 · 교신저자 김진원, 김혜령

   Park S, Kim JW, Kim H, Kim JW, Kim YJ, Lee KW, Kim JH, Kim JH, Hwang JH, Choi YR, Cho JY, Yoon YS, Han HS

   Prognostic value of p21-activated kinase 4 in resected pancreatic cancer.

   APMIS. 2017;125(8):699-707.

   Abstract

   Resectable pancreatic cancer has a high recurrence rate after curative surgery. Biomarkers are needed for distinguishing patients who may benefit from curative resection. In this study, we sought to analyze the prognostic value of p21-activated kinase 1 (PAK1), p21-activated kinase 4 (PAK4), human equilibrative nucleoside transporter 1 (hENT1), and thymidylate synthase (TS) in surgically resected pancreatic ductal adenocarcinomas. A total of 160 pancreatic cancer patients who underwent surgery with curative intent were retrospectively reviewed. Tissue microarrays were constructed and immunohistochemical stains were performed for PAK1, PAK4, hENT1, and TS. The absence of PAK4 expression in pancreatic adenocarcinomas was associated with poorer histologic differentiation (p < 0.001), shorter overall survival [hazard ratio (HR) = 2.86, 95% confidence interval (CI) 1.43-5.71; p = 0.003], and disease-free survival (HR = 2.29, 95% CI: 1.11-4.74; p = 0.025) on univariate analyses. In addition, more frequent venous invasion and lymph node metastases were seen in PAK4-negative tumors although not statistically significant. PAK1, hENT1, and TS expression status did not have significant influences on patient survival. In conclusion, PAK4 of the markers tested in this study may be a potential prognostic biomarker for pancreatic adenocarcinomas.

   PubMed IF 2.2 혈액종양내과
9. 1712017

   제1저자 정선회 · 교신저자 이해영

   Jung SH, Lee OS, Kim HS, Park CS, Lee HJ, Kwon KH, Lee HY

   Medication Adherence Improvement By Using Administration Timing Simplification Protocol (ATSP) in Cardiovascular Disease Patients.

   J Atheroscler Thromb. 2017;24(8):841-852.

   Abstract

   AIMS In chronic diseases, keeping adherence to medication is very difficult. The objective of this study was to evaluate the impact of administration timing simplification protocol (ATSP) on medication adherence and clinical parameters of cardiovascular diseases.

   METHODS 210 out-patients with cardiovascular disease, who were taking two or more pills of any type of medication per day for more than one year, were enrolled and randomized. The intervention group followed the simplified administration schedule of ATSP with two main strategies: 1) moving medication from "pc" (30 minute after meal) to "stat. pc" (immediately after meal); and 2) moving medication time from "at evening" to "at morning." In contrast, the control group maintained the same medication schedule. Both patient groups were equally educated about the names and effects of the medication.

   RESULTS The intervention group had more pills than the control group with marginal statistical significance (5.1±2.3 vs 4.6±1.8, p=0.05). The total frequency of administration was significantly higher in the intervention group than that of the control group (2.9±1.0 vs 2.6±0.9, p=0.03) at the baseline. In the intervention group, the frequency was significantly decreased to 1.5±0.6 times per day after following ATSP application (p＜0.01). In both patient groups, knowledge about the medication was significantly improved by education. However, medication adherence was only improved in the intervention group. Interestingly, total cholesterol was significantly decreased in the intervention group (p＜0.01). The decrease in serum cholesterol concentration was significantly correlated with the improvement in medication adherence evaluated with Morisky Medication Adherence Scale (MMAS)-8 items (r=0.507, p＜0.01).

   CONCLUSION ATSP was shown to be an effective strategy to improve medication adherence in chronic cardiovascular disease patients.

   PubMed IF 3.4 순환기내과
10. 1702017

    제1저자 이현정 · 교신저자 최의근, 이성환

    Lee H, Choi EK, Lee SH, Han KD, Rhee TM, Park CS, Lee SR, Choe WS, Lim WH, Kang SH, Cha MJ, Oh S

    Atrial fibrillation risk in metabolically healthy obesity: A nationwide population-based study.

    Int J Cardiol. 2017;240:221-227.

    Abstract

    BACKGROUND Metabolically healthy obese (MHO) individuals are reported to have a marginal increase in cardiovascular risk; however, their atrial fibrillation (AF) risk is unclear. We aimed to assess AF risk in MHO individuals and identify whether AF development is associated with obesity or influenced by metabolic comorbidities.

    METHODS A retrospective cohort of 389,321 individuals (age, 45.6±14.5years; male, 52.1%) was extracted from the Korean National Health Insurance sample database between 2004 and 2006 and followed-up for new-onset AF until 2013. Subjects with diabetes mellitus, hypertension, and/or dyslipidemia were classified as "metabolically unhealthy." The cohort was stratified into four groups according to obesity and metabolic healthiness: metabolically healthy non-obese (MHNO), metabolically unhealthy non-obese (MUNO), MHO, and metabolically unhealthy obese (MUO).

    RESULTS AF was newly diagnosed in 5106 (1.3%) individuals during a mean follow-up of 7.5±1.5years. The AF incidence rates for the MHNO, MUNO, MHO, and MUO groups were 0.76, 2.66, 1.10, and 2.88 per 1000 person-years, respectively. Compared with the MHNO group, the MHO group had increased AF risk (adjusted hazard ratio, 1.30; 95% CI, 1.14-1.48) on multivariate analysis. One fourth of the MHO cohort became metabolically unhealthy, contributing to increased AF risk. Obesity was an independent risk factor for AF, and increased AF risk by 20%. Metabolic unhealthiness increased AF risk by around 40%, and of its components, hypertension contributed the most.

    CONCLUSIONS MHO individuals are at increased risk for AF development, and obesity was independently associated with elevated AF risk.

    PubMed IF 3.3 순환기내과
11. 1692017

    제1저자 백선하 · 교신저자 나기영

    Baek SH, Cha RH, Kang SW, Park CW, Cha DR, Kim SG, Yoon SA, Kim S, Han SY, Park JH, Chang JH, Lim CS, Kim YS, Na KY

    Higher Serum Levels of Osteoglycin Are Associated with All-Cause Mortality and Cardiovascular and Cerebrovascular Events in Patients with Advanced Chronic Kidney Disease.

    Tohoku J Exp Med. 2017;242(4):281-290.

    Abstract

    Patients with chronic kidney disease (CKD) have markedly increased rates of major adverse cardiovascular and cerebrovascular events (MACCEs) and mortality. Therefore, identifying early biomarkers predicting clinical outcomes in patients with CKD is critical. We aimed to determine whether osteoglycin, a basic component of the vascular extracellular matrix, was associated with MACCEs or all-cause mortality, using data from a prospective randomized controlled study, K-STAR (Kremezin STudy Against Renal disease progression in Korea: NCT 00860431). A total of 383 patients (mean age: 56.4 years, men/women = 252/131) with CKD stage 3 to 4 from the original trial were enrolled in the present study. We measured serum osteoglycin level and examined the impact of osteoglycin on clinical outcomes. The mean value of osteoglycin levels was 13.3 ± 9.4 ng/mL (healthy control: 5.3 ± 2.1 ng/mL). In multivariable analysis, lower levels of proteinuria and hemoglobin and higher levels of C-reactive protein were significantly associated with higher osteoglycin levels. Estimated glomerular filtration rate was not related to osteoglycin level. During a mean follow-up period of 56 months, 25 deaths, 61 MACCEs, and 76 composite outcomes (all-cause mortality or MACCEs) occurred. In the non-diabetic group, each 1-ng/mL increase in serum osteoglycin was associated with all-cause mortality and composite outcome (hazard ratio [HR] = 1.058, P = 0.031; HR = 1.041, P = 0.036). However, osteoglycin levels were not associated with mortality, MACCEs, or composite outcome in the diabetic group. Our results indicate that serum osteoglycin is a potential predictor of adverse outcomes in patients with CKD.

    PubMed IF 1.5 신장내과
12. 1682017

    제1저자 김동완 · 교신저자 김동완

    Kim DW, Tiseo M, Ahn MJ, Reckamp KL, Hansen KH, Kim SW, Huber RM, West HL, Groen HJM, Hochmair MJ, Leighl NB, Gettinger SN, Langer CJ, Paz-Ares Rodríguez LG, Smit EF, Kim ES, Reichmann W, Haluska FG, Kerstein D, Camidge DR

    Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial.

    J Clin Oncol. 2017;35(22):2490-2498.

    Abstract

    Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC) eventually experience disease progression. We evaluated two regimens of brigatinib, an investigational next-generation ALK inhibitor, in crizotinib-refractory ALK-positive NSCLC. Patients and Methods Patients were stratified by brain metastases and best response to crizotinib. They were randomly assigned (1:1) to oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). Investigator-assessed confirmed objective response rate (ORR) was the primary end point. Results Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 (74%) had received prior chemotherapy. With 8.0-month median follow-up, investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months (95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review committee-assessed intracranial ORR in patients with measurable brain metastases at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events with early onset (median onset: day 2) occurred in 14 of 219 treated patients (all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival; 180 mg (with lead-in) showed consistently better efficacy than 90 mg, with acceptable safety.

    PubMed IF 44.7 혈액종양내과
13. 1672017

    제1저자 조재민 · 교신저자 오도연

    Jo J, Kwon HW, Park S, Oh DY, Cheon GJ, Bang YJ

    Prospective Evaluation of the Clinical Implications of the Tumor Metabolism and Chemotherapy-Related Changes in Advanced Biliary Tract Cancer.

    J Nucl Med. 2017;58(8):1255-1261.

    Abstract

    Tumor metabolism measured by ¹⁸F-FDG PET has a diagnostic and prognostic role in several cancers. The clinical implication of tumor metabolism in biliary tract cancer (BTC) has not been studied well. Therefore, we evaluated the prognostic value of tumor metabolism and chemotherapy-related changes in advanced BTC patients. Methods: We prospectively enrolled advanced BTC patients before the initiation of palliative chemotherapy. Using ¹⁸F-FDG PET, we assessed the baseline SUV_max and monitored the changes in SUV_max during chemotherapy. We analyzed the associations between SUV_max, and clinicopathologic factors and clinical outcomes. Results: Seventy-five patients were enrolled. All patients received gemcitabine/cisplatin as first-line chemotherapy. Primary tumor site, histologic differentiation, molecular characteristics, laboratory findings, and disease extent were associated with the metabolic characteristics. The high-metabolism group showed worse survival outcome (hazard ratio [HR] = 4.09, P = 0.001 for progression-free survival; HR = 2.61, P = 0.019 for overall survival [OS]) than the low-metabolism group. The lesser reduction of SUV_max was also associated with worse outcome (HR = 3.35, P = 0.002 for progression-free survival; HR = 1.96, P = 0.082 for OS). When both baseline tumor metabolism and its chemotherapy-related changes were considered, patients with a low metabolism and more reduction in metabolism obtained the best OS (20.7 vs. 6.2 mo, P = 0.013). Conclusion: Tumor metabolic activity and the chemotherapy-related changes in the metabolism are associated with prognosis in advanced BTC patients.

    PubMed IF 9.6 혈액종양내과
14. 1662017

    제1저자 김지연, 박건재, 황주연 · 교신저자 김원, 김원호

    Kim JY, Park KJ, Hwang JY, Kim GH, Lee D, Lee YJ, Song EH, Yoo MG, Kim BJ, Suh YH, Roh GS, Gao B, Kim W, Kim WH

    Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis.

    J Hepatol. 2017;67(2):349-359.

    Abstract

    BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with β-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development.

    METHODS Zucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants.

    RESULTS ATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration.

    CONCLUSIONS Increased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D.

    LAY SUMMARY Hepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for predicting the progression of NAFLD and the development of T2D. Furthermore, given the significant association between hepatic ATF3 expression and both hepatic steatosis and impaired glucose homeostasis, in vivo ATF3 silencing may be a potential central strategy for preventing and managing NAFLD and T2D.

    PubMed IF 40.1 소화기내과
15. 1652017

    제1저자 김정희 · 교신저자 최성희

    Kim JH, Lim S, Park KS, Jang HC, Choi SH

    Total and differential WBC counts are related with coronary artery atherosclerosis and increase the risk for cardiovascular disease in Koreans.

    PLoS One. 2017;12(7):e0180332.

    Abstract

    OBJECTIVE Inflammation is a key mechanism of atherosclerosis. White blood cells (WBCs) play a pivotal role in the inflammatory process. We investigated the relationships between total and differential WBC counts and multi-detector cardiac computed tomography (MDCT) findings, as well as the risk of cardiovascular disease in asymptomatic patients in Korea.

    MATERIALS AND METHODS We recruited asymptomatic men (n = 7274) and women (n = 5478) aged ≥30 years who were free of known coronary heart disease. All patients underwent MDCT during a routine health check-up in the Seoul National University Bundang Hospital between 2006 and 2007, and were followed-up for 5.6 years. We reviewed medical records for cardiovascular diseases (CVDs) and covariates.

    RESULTS In covariate-adjusted logistic regression models for MDCT findings, subjects within the third tertile of all WBC subtypes had a higher risk for significant stenosis and noncalcified plaques compared with the first tertile of each subtype. In Cox proportional hazard regression models for the risk of CVDs, subjects within the third tertiles of lymphocytes and monocytes were at an increased risk of CVDs (total WBC, HR = 1.22 [1.02-1.44]; lymphocyte, HR = 1.47 [1.25-1.74]; monocytes, HR = 1.26 [1.02-1.35]) even after further adjustment for covariates and coronary artery stenosis.

    CONCLUSIONS Total WBC counts were related with the severity of coronary artery disease, and higher WBC counts increased the risk of CVDs in asymptomatic Koreans mainly by virtue of monocytes.

    PubMed IF 2.8 내분비대사내과
16. 1642017

    제1저자 박주경, 백우현 · 교신저자 류지곤

    Park JK, Paik WH, Lee K, Ryu JK, Lee SH, Kim YT

    DAXX/ATRX and MEN1 genes are strong prognostic markers in pancreatic neuroendocrine tumors.

    Oncotarget. 2017;8(30):49796-49806.

    Abstract

    BACKGROUND PanNETs shows heterogeneous biological behaviors. The aim was to investigate prognostic markers based on most frequently mutated genes in PanNETs.

    RESULTS There was a total of 76 patients (M: 39, F: 37) with pathologically proven PanNETs. ATRX/DAXX and MEN1 protein expression was detected in 16 (21%) and 31 (41%) patients, respectively. The mean OS of the total study patients was 16 years, and DFS was 17 years among the 68 patients with curative resections. PanNETs presented with distant metastasis or loss of ATRX/DAXX protein expression was the independent prognostic factors associated with poor OS. In curative resected PanNETs, there was no significant difference in the mean DFS according to ATRX/DAXX or MEN1 protein. However, there was statistically significant difference in survival after the recurrence according to the expression of ATRX/DAXX protein; Y/N: 10 vs. 15 years, p < 0.001. In metastatic PanNETs, we could find out OS was significantly longer in negative protein expression of ATRX/DAXX and MEN1 groups; 7 vs. 1 years, p < 0.001, 6 vs. 2 years, p = 0.02, respectively.

    MATERIALS AND METHODS The histologically proven PanNETs were enrolled and the clinicopathologic and genetic alterations were evaluated.

    CONCLUSIONS Protein expression of MEN1 and DAXX/ATRX can be prognostic markers for PanNETs. Further investigation in genetic alterations of PanNETs may give us insights understanding the behavior of PanNETs.

    PubMed IF 5.168 소화기내과
17. 1632017

    제1저자 강지훈 · 교신저자 김효수

    Kang J, Han JK, Yang HM, Park KW, Kang HJ, Koo BK, Kim HS

    Bioresorbable Vascular Scaffolds - Are We Facing a Time of Crisis or One of Breakthrough?

    Circ J. 2017;81(8):1065-1074.

    Abstract

    Current 2nd-generation drug-eluting stents (DES) have dramatically improved clinical outcomes after percutaneous coronary intervention for coronary artery disease. However, DES implantation has major long-term limitations related to the permanent presence of foreign material in the coronary artery. Bioresorbable vascular scaffolds (BVS) were designed to overcome this limitation of permanent metal-based DES. However, because of immature manufacturing technology, BVS have several drawbacks, such as the thicker strut, poor deliverability, poor radio-opacity, poor radial strength, and cumbersome procedure to meet the principle of PSP (Preparation, Sizing, and Post-dilatation). Initial studies indicated that BVS outcomes were non-inferior to those of current DES and recent follow-up data of trials have revealed an additional critical drawback, higher rate of scaffold thrombosis, on the top of the existing limitations of BVS. Thus attention must be paid to the appropriate BVS-specific implantation protocols (i.e., PSP), as well as adequate intensity and duration of dual antiplatelet therapy. In any case, current BVS need further technical evolution to replace current metallic DES in routine clinical use.

    PubMed IF 5.8 순환기내과
18. 1622017

    제1저자 강시혁 · 교신저자 최의근

    Kang SH, Choi EK, Han KD, Lee SR, Lim WH, Cha MJ, Cho Y, Oh IY, Oh S

    Risk of Ischemic Stroke in Patients With Non-Valvular Atrial Fibrillation Not Receiving Oral Anticoagulants - Korean Nationwide Population-Based Study.

    Circ J. 2017;81(8):1158-1164.

    Abstract

    BACKGROUND Atrial fibrillation, the most common cardiac arrhythmia, is associated with an elevated thromboembolic risk, including ischemic stroke. Guidelines recommend the stratification of individual stroke risk and tailored antithrombotic therapy. This study investigated the demographics, comorbidities, and prognosis of non-valvular AF (NVAF) in Korean patients.

    METHODS AND RESULTS We extracted data on 10,846 patients with newly diagnosed NVAF who were naïve to oral anticoagulants from the National Health Insurance Service-National Sample Cohort. CHADS₂and CHA₂DS₂-VASc scores were calculated for each subject using claims data. The study endpoints were ischemic stroke, thromboembolism, and mortality. Mean age was 63.7 years, and 46.8% of the patients were women. Women were older and had higher CHADS₂and CHA₂DS₂-VASc scores. During 30,138 person-years of follow-up, ischemic stroke occurred at a rate of 2.95/100 person-years. CHADS₂and CHA₂DS₂-VASc scores showed good performance in risk prediction. CHA₂DS₂-VASc score performed better at discriminating stroke risk in patients with low-risk profiles. The presence of female sex and vascular disease added little improvement in risk prediction.

    CONCLUSIONS Korean NVAF patients had high risk of stroke and mortality, and had multiple comorbidities. While both CHADS₂and CHA₂DS₂-VASc schema had good performance in risk prediction, CHA₂DS₂-VASc score was superior in identifying truly low-risk patients. Given that Asian ethnicity is associated with bleeding events, individualized accurate risk prediction is necessary to improve patient outcomes.

    PubMed IF 5.8 순환기내과
19. 1612017

    제1저자 강시혁 · 교신저자 채인호

    Kang SH, Han D, Kim S, Yoon CH, Park JJ, Suh JW, Cho YS, Youn TJ, Chae IH

    Hemostasis pad combined with compression device after transradial coronary procedures: A randomized controlled trial.

    PLoS One. 2017;12(7):e0181099.

    Abstract

    BACKGROUND Arterial access and hemostasis are important processes during percutaneous coronary procedures. In this study, we tested if the use of chitosan-based pads on top of compression devices could improve hemostasis efficacy compared with compression devices alone after transradial coronary angiography or interventions.

    METHODS This study was a single-center open-label randomized controlled trial. Patients who underwent coronary angiography or intervention with the transradial approach were randomly assigned to the study (compression device and a chitosan-based pad) or control (compression devices alone) group in a 2:1 fashion. The primary endpoint was time to hemostasis, categorized into ≤5, 6-10, 11-20, and >20 minutes.

    RESULTS Between April and July 2016, 95 patients were enrolled (59 were assigned to the study arm and 36 to the control arm). Time to hemostasis, the primary endpoint, was significantly lower in the study group than in the control group (p<0.001). Both groups showed low rates of vascular complications.

    CONCLUSIONS This study suggests that the use of a hemostasis pad in combination with rotatory compression devices is a safe and effective hemostasis strategy after radial artery access.

    TRIAL REGISTRATION ClinicalTrials.gov NCT02954029.

    PubMed IF 2.8 순환기내과
20. 1602017

    제1저자 임우현 · 교신저자 최의근

    Lim WH, Choi EK, Han KD, Rhee TM, Lee HJ, Lee SR, Kang SH, Cha MJ, Oh S

    Proteinuria Detected by Urine Dipstick Test as a Risk Factor for Atrial Fibrillation: A Nationwide Population-Based Study.

    Sci Rep. 2017;7(1):6324.

    Abstract

    Proteinuria is one of the well-known risk factors for cardiovascular disease. However the impact of proteinuria on the incidence of atrial fibrillation (AF) is unclear. In this study, we investigated the association between proteinuria detected using urine dipstick test and the risk of AF. A total of 18,201,275 individuals were analyzed, who had no prior AF and had received biennial health checkups provided by the National Health Insurance Service between 2005 and 2008 in Korea. Incidences of AF were ascertained through the end of 2015. During a mean follow-up of 9.6 years, a total of 324,764 (1.8%) developed AF (1.86 per 1,000 person-years). In Cox regression models, proteinuria was associated with an increased risk of AF: adjusted HR and 95% CI of AF occurrence were 1.13 (1.10-1.16), 1.34 (1.31-1.38), 1.53 (1.48-1.58), 1.82 (1.71-1.94), and 1.86 (1.61-2.16) in individuals with trace, 1+, 2+, 3+, and 4+ proteinuria, respectively, compared with those without proteinuria. The result was consistent even after additional adjustment for estimated glomerular filtration rate. In addition, the risk of AF further increased or decreased according to the follow-up dipstick test results. Thus, proteinuria measured with a dipstick test might be considered a potent risk factor for AF development.

    PubMed IF 4.9 순환기내과
21. 1592017

    제1저자 오태정 · 교신저자 최성희

    Oh TJ, Ahn CH, Kim BR, Kim KM, Moon JH, Lim S, Park KS, Lim C, Jang H, Choi SH

    Circulating sortilin level as a potential biomarker for coronary atherosclerosis and diabetes mellitus.

    Cardiovasc Diabetol. 2017;16(1):92.

    Abstract

    CONTEXT A previous genome-wide association study showed that a genetic variant of sortilin was associated with the risk of coronary artery disease (CAD). However, the role of circulating sortilin is still unknown. We investigated the potential role of plasma sortilin as a biomarker for CAD and diabetes mellitus.

    METHODS We enrolled statin-naïve subjects with CAD (n = 31) who underwent coronary artery bypass surgery and control subjects (n = 116) who were free from CAD as evaluated by coronary CT angiography. The presence of diabetes mellitus was evaluated and plasma sortilin levels were measured with a commercial ELISA kit.

    RESULTS Plasma sortilin levels were higher in subjects with CAD and subjects with diabetes mellitus than in those without CAD or diabetes mellitus. Subjects in the highest sortilin tertile group were older and had higher glucose and HbA1c levels, but lipid profiles in the three tertile groups were comparable. Multivariable logistic regression analysis revealed that sortilin levels were independently associated with CAD. In addition, the receiver operating characteristic curve analysis showed that plasma sortilin levels could identify the presence of CAD or diabetes mellitus.

    CONCLUSIONS Elevated circulating sortilin levels are associated with CAD and diabetes mellitus and can be used as a biomarker of both diseases in statin-naïve subjects.

    PubMed IF 15.6 내분비대사내과
22. 1582017

    제1저자 김정희 · 교신저자 조남한, 신찬수

    Kim JH, Hong AR, Choi HJ, Ku EJ, Cho NH, Shin CS

    Sex-based Differences in the Association between Body Composition and Incident Fracture Risk in Koreans.

    Sci Rep. 2017;7(1):5975.

    Abstract

    The relative contribution of lean mass and fat mass on bone health is inconclusive. We investigated the relative contributions of lean and fat masses on fragility fracture risk in Korean men and women. This was an ongoing prospective community-dwelling cohort study at Ansung beginning in 2001, which included 2,189 men and 2,625 women over 40 years old. Study subjects were classified into the following four groups according to lean mass (LM)/height² and percentage fat mass (PF). Clinical fragility fracture events were assessed at baseline and biennially using self-reported questionnaires. During a median follow-up of 9.4 years, 77 (3.5%) men and 203 (7.7%) women experienced at least one incident fracture. In Cox proportional hazard models, men with low LM under normal and high PF had a 2.16 and 2.59- fold higher risk for fragility fractures than normal ones even after adjusting for covariates. However, in women, low LM or high FM was not associated with fracture risk. We demonstrated sex-based differences in the association of body composition and incident fracture risk in Koreans aged over 40 years during a 10-year follow-up duration. Maintaining muscle mass in men is vital to maintaining bone health and preventing fragility fractures in Koreans.

    PubMed IF 4.9 내분비대사내과
23. 1572017

    제1저자 조유리 · 교신저자 이정훈

    Cho Y, Lee JH, Lee DH, Cho EJ, Yu SJ, Yi NJ, Lee KW, Kim YJ, Yoon JH, Suh KS

    Comparison of treatment outcome between living donor liver transplantation and sorafenib for patients with hepatocellular carcinoma beyond the Milan criteria.

    Oncotarget. 2017;8(29):47555-47564.

    Abstract

    For patients with advanced hepatocellular carcinoma (HCC), sorafenib is the only systemic treatment recommended by international guidelines. We recently reported that HCC patients with a low MoRAL (model to predict tumor recurrence after LDLT) score (≤ 314.8) have excellent treatment outcomes after living-donor liver transplantation (LDLT), even though they are beyond the Milan criteria. In the present study, we investigated whether LDLT offers a better treatment outcome than sorafenib for patients with HCC beyond the Milan criteria according to the MoRAL score. A retrospective cohort study of 325 consecutive patients who were treated with either LDLT (n = 122) or sorafenib (n = 203) for HCC beyond the Milan criteria from 2005 to 2014 at a tertiary hospital was performed. The primary and secondary endpoints were overall survival (OS) and time-to-progression. When baseline characteristics were balanced using inverse probability weighting, OS was significantly longer in the LDLT group than in the sorafenib group (5-year OS rate, 71.9% vs. 4.9%; HR=0.1; P < 0.001). The LDLT group exhibited a significantly lower risk of tumor progression (5-year recurrence rate, 34.7% vs. 96%; HR=0.14; P < 0.001) than the sorafenib group. The increase in OS with LDLT was predominantly among patients with a low MoRAL score (5-year OS rate, 81.1% vs. 5.8%; HR=0.06; P < 0.001) compared with those with a high MoRAL score (5-year OS rate, 28.3% vs. 4.3%; HR = 0.42; P = 0.047). Patients with a low MoRAL score and without extrahepatic metastasis or hepatic vein invasion might be good candidates for LDLT instead of sorafenib treatment if there is a willing living related donor.

    PubMed IF 5.168 소화기내과
24. 1562017

    제1저자 이해영 · 교신저자 이해영

    Lee HY

    The J Curve Phenomenon is Still Valid in the Era of Primary Revascularization.

    Korean Circ J. 2017;47(4):440-441.

    PubMed IF 3.4 순환기내과
25. 1552017

    제1저자 신동현, 이정훈 · 교신저자 백승운

    Sinn DH, Lee JH, Kim K, Ahn JH, Lee JH, Kim JH, Lee DH, Yoon JH, Kang W, Gwak GY, Paik YH, Choi MS, Lee JH, Koh KC, Paik SW

    A Novel Model for Predicting Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis B and Normal Alanine Aminotransferase Levels.

    Gut Liver. 2017;11(4):528-534.

    Abstract

    BACKGROUND/AIMS Hepatocellular carcinoma (HCC) can develop in chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels. Therefore, methods that can stratify an individual's HCC risk are needed.

    METHODS A simple HCC risk score was developed from 971 patients with CHB who had elevated hepatitis B virus DNA levels (>2,000 IU/mL) with normal or mildly elevated ALT levels (<80 U/L). The score was validated from an independent cohort of 507 patients.

    RESULTS A 4-point risk scale was developed, with HCC risk ranging from 0% to 17.8% at 5 years for the lowest and highest risk scores. The D²AS score had high area under the receiver operating curves (AUROCs) for predicting development of HCC at 3/5 years (0.895/0.884). The calculated AUROCs to predict the development of HCC at 3/5 years were 0.889/0.876 in the validation cohort, with 5-year HCC incidence rates ranging from 0% to 13.8% at 5 years for the lowest and highest risk scores.

    CONCLUSIONS The D²AS risk score can play a valuable role in risk stratification and may be useful for guiding clinical decisions for enhanced surveillance or treatment to reduce the HCC risk in CHB patients with normal or mildly elevated ALT levels.

    PubMed IF 4.1 소화기내과
26. 1542017

    제1저자 이경희 · 교신저자 유철규

    Lee KH, Jeong J, Koo YJ, Jang AH, Lee CH, Yoo CG

    Exogenous neutrophil elastase enters bronchial epithelial cells and suppresses cigarette smoke extract-induced heme oxygenase-1 by cleaving sirtuin 1.

    J Biol Chem. 2017;292(28):11970-11979.

    Abstract

    An imbalance between oxidative stress and antioxidant activity plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke, a major risk factor of COPD, induces cellular oxidative stress, but levels of antioxidants such as heme oxygenase-1 (HO-1) are reduced in individuals with severe COPD. In this study, we evaluated the molecular mechanism of reduced HO-1 expression in human bronchial epithelial cells. We found that cigarette smoke extract (CSE) increases HO-1 levels via activation of NFE2-related factor 2 (Nrf2). However, pretreating cells with the protease neutrophil elastase (NE) suppressed the CSE-induced expression of HO-1 mRNA and protein. NE also decreased the sirtuin 1 (SIRT1) level, but did not inhibit CSE-induced nuclear translocation and DNA-binding activity of Nrf2. Transfection of cells with a Myc/His-tagged SIRT1 expression vector completely blocked the NE-mediated suppression of HO-1 expression. We further noted that the NE-induced down-regulation of SIRT1 was not due to decreased transcription or proteasomal/lysosomal degradation or loss of solubility. Immunofluorescence staining revealed that NE enters the cell cytoplasm, and we observed that NE directly cleaved SIRT1 in vitro, indicating that SIRT1 levels are decreased via direct degradation by internalized NE. Of note, we observed decreased SIRT1 levels in NE-treated primary human bronchial epithelial cells and in lung homogenates from both smokers and patients with COPD. In conclusion, NE suppresses CSE-induced HO-1 expression by cleaving SIRT1. This finding indicates the importance of cross-talk between oxidative stress and protease responses in the pathogenesis of COPD.

    PubMed IF 4.1 호흡기내과
27. 1532017

    제1저자 곽수헌, 채지수 · 교신저자 박경수, 김종일

    Kwak SH, Chae J, Choi S, Kim MJ, Choi M, Chae JH, Cho EH, Hwang TJ, Jang SS, Kim JI, Park KS, Bang YJ

    Findings of a 1303 Korean whole-exome sequencing study.

    Exp Mol Med. 2017;49(7):e356.

    Abstract

    Ethnically specific data on genetic variation are crucial for understanding human biology and for clinical interpretation of variant pathogenicity. We analyzed data obtained by deep sequencing 1303 Korean whole exomes; the data were generated by three independent whole exome sequencing projects (named the KOEX study). The primary focus of this study was to comprehensively analyze the variant statistics, investigate secondary findings that may have clinical actionability, and identify loci that should be cautiously interpreted for pathogenicity. A total of 495 729 unique variants were identified at exonic regions, including 169 380 nonsynonymous variants and 4356 frameshift insertion/deletions. Among these, 76 607 were novel coding variants. On average, each individual had 7136 nonsynonymous single-nucleotide variants and 74 frameshift insertion/deletions. We classified 13 pathogenic and 13 likely pathogenic variants in 56 genes that may have clinical actionability according to the guidelines of the American College of Medical Genetics and Genomics, and the Association for Molecular Pathology. The carrier frequency of these 26 variants was 2.46% (95% confidence interval 1.73-3.46). To identify loci that require cautious interpretation in clinical sequencing, we identified 18 genes that are prone to sequencing errors, and 671 genes that are highly polymorphic and carry excess nonsynonymous variants. The catalog of identified variants, its annotation and frequency information are publicly available (http://koex.snu.ac.kr). These findings should be useful resources for investigating ethnically specific characteristics in human health and disease.

    PubMed IF 17.5 내분비대사내과
28. 1522017

    제1저자 손호영, 황보율 · 교신저자 박영주, 이은경, 김종일

    Son HY, Hwangbo Y, Yoo SK, Im SW, Yang SD, Kwak SJ, Park MS, Kwak SH, Cho SW, Ryu JS, Kim J, Jung YS, Kim TH, Kim SJ, Lee KE, Park DJ, Cho NH, Sung J, Seo JS, Lee EK, Park YJ, Kim JI

    Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.

    Nat Commun. 2017;8:15966.

    Abstract

    Thyroid cancer is the most common cancer in Korea. Several susceptibility loci of differentiated thyroid cancer (DTC) were identified by previous genome-wide association studies (GWASs) in Europeans only. Here we conducted a GWAS and a replication study in Koreans using a total of 1,085 DTC cases and 8,884 controls, and validated these results using expression quantitative trait loci (eQTL) analysis and clinical phenotypes. The most robust associations were observed in the NRG1 gene (rs6996585, P=1.08 × 10^-10) and this SNP was also associated with NRG1 expression in thyroid tissues. In addition, we confirmed three previously reported loci (FOXE1, NKX2-1 and DIRC3) and identified seven novel susceptibility loci (VAV3, PCNXL2, INSR, MRSB3, FHIT, SEPT11 and SLC24A6) associated with DTC. Furthermore, we identified specific variants of DTC that have different effects according to cancer type or ethnicity. Our findings provide deeper insight into the genetic contribution to thyroid cancer in different populations.

    PubMed IF 18.1 내분비대사내과
29. 1512017

    제1저자 박세훈 · 교신저자 이하정

    Park S, Lee SM, Park JS, Hong JS, Chin HJ, Na KY, Kim DK, Oh KH, Joo KW, Kim YS, Lee H

    Midterm eGFR and Adverse Pregnancy Outcomes: The Clinical Significance of Gestational Hyperfiltration.

    Clin J Am Soc Nephrol. 2017;12(7):1048-1056.

    Abstract

    BACKGROUND AND OBJECTIVES Although hemodynamic adaptation plays a crucial role in maintaining gestation, the clinical significance of midterm renal hyperfiltration (MRH) on pregnancy outcomes is unknown.

    DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was an observational cohort study. Women with a singleton pregnancy and a serum creatinine measurement during their second trimester were followed at two university hospitals in Korea between 2001 and 2015. Those with substantial renal function impairment or who delivered during the second trimester were not considered. MRH was represented by the highest eGFR, which was calculated using the Chronic Kidney Disease Epidemiology Collaboration method. An adverse pregnancy event was defined by the composition of preterm birth (gestational age <37 weeks), low birth weight (<2.5 kg), and preeclampsia.

    RESULTS Data from 1931 pregnancies were included. The relationship between midterm eGFR and adverse pregnancy outcomes, which occurred in 538 mothers, was defined by a nonlinear U-shaped curve. The adjusted odds ratio and associated 95% confidence interval (95% CI) of an adverse pregnancy outcome for eGFR levels below and above the reference level of 120-150 ml/min per 1.73 m² were 1.97 (95% CI, 1.34 to 2.89; P<0.001) for ≥150 ml/min per 1.73 m²; 1.57 (95% CI, 1.23 to 2.00; P<0.001) for 90-120 ml/min per 1.73 m²; and 4.93 (95% CI, 1.97 to 12.31; P<0.001) for 60-90 ml/min per 1.73 m². Moreover, among mothers without baseline CKD, women with adverse pregnancy outcomes had less prominent MRH than those without (P<0.001).

    CONCLUSIONS We identified a unique U-shaped relationship between midterm eGFR and adverse pregnancy outcomes, and the optimal range of midterm eGFR levels was 120-150 ml/min per 1.73 m². In those without evident functional renal impairment, the absence of prominent MRH might be a significant risk factor for poor pregnancy outcomes.

    PubMed IF 7 신장내과
30. 1502017

    제1저자 강신의 · 교신저자 송영욱

    Kang SE, Lee SJ, Lee JY, Yoo HJ, Park JK, Lee EY, Lee EB, Song YW

    Serum levels of IgG antibodies against alpha-enolase are increased in patients with Behçet's disease and are associated with the severity of oral ulcer, erythrocyte sedimentation rates, and C-reactive protein.

    Clin Exp Rheumatol. 2017;35 Suppl 108(6):67-74.

    Abstract

    OBJECTIVES Behçet's disease (BD) is a chronic inflammatory disease of unknown etiology, characterised by recurrent oral and genital ulcers, skin lesions, uveitis, and arthritis. It is regarded as vasculitis and anti-endothelial cell antibodies (AECA) are found in patients with BD. One of the endothelial cell antibodies was reported to recognise alpha-enolase. This study aimed to investigate expression of alpha-enolase in the surface of peripheral blood cells and serum anti-alpha-enolase antibody (AEA), and their association with clinical manifestations or disease activity of BD.

    METHODS Cell surface alpha-enolase expression was examined from several cell types of peripheral blood, including lymphocytes, monocytes, and neutrophils using flow cytometry in patients with BD and healthy controls (HCs). IgG AEA levels were measured by enzyme-linked immunosorbent assay (ELISA) in sera from 110 patients with BD, and age/sex matched 110 HCs. Association of alpha-enolase or AEA with clinical manifestation was analysed.

    RESULTS The frequency of surface alpha-enolase-expressing cells was increased in BD in lymphocytes and monocytes. Serum AEA levels were in- creased in BD patients (median [IQR], 0.360 [0.268-0.482], p < 0.0001), particularly with mucocutaneous involvement (0.367 [0.273-0.490], p < 0.0001) compared to HCs (0.274 [0.231-0.357]). The levels of AEA were correlated with the number of oral ulcer, ESR, and CRP. There was no association between serum levels of AEA and other clinical manifestations.

    CONCLUSIONS Serum AEA was increased in BD patients and correlated with oral ulcer, ESR and CRP.

    PubMed IF 3.2 류마티스내과

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