SCI 발표논문

1. 28482019

   제1저자 김슬기, 김태민 · 교신저자 김동완

   Kim S, Kim TM, Kim DW, Kim S, Kim M, Ahn YO, Keam B, Heo DS

   Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib.

   Cancer Res Treat. 2019;51(3):951-962.

   Abstract

   PURPOSE Amplified mesenchymal-epithelial transition factor, MET, is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). Although multiple MET tyrosine kinase inhibitors (TKIs) are being actively developed for MET-driven NSCLC, the mechanisms of acquired resistance to MET-TKIs have not been well elucidated. To understand the mechanisms of resistance and establish therapeutic strategies, we developed an in vitro model using the MET-amplified NSCLC cell line EBC-1.

   MATERIALS AND METHODS We established capmatinib-resistant NSCLC cell lines and identified alternative signaling pathways using 3' mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative polymerase chain reaction and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the resistant cell lines.

   RESULTS We found that EBC-CR1 showed an epidermal growth factor receptor (EGFR)‒dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells that had overexpression of EGFR-MET heterodimer dramatically responded to combined capmatinib with afatinib. In addition, EBC-CR3 cells derived from EBC-CR1 cells that activated EGFR with amplified phosphoinositide-3 kinase catalytic subunit α (PIK3CA) were sensitive to combined afatinib with BYL719, a phosphoinositide 3-kinase α (PI3Kα) inhibitor.

   CONCLUSION Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3Kα inhibitors may be effective therapeutic strategies in capmatinib-resistant NSCLC patients.

   PubMed IF 4.2 혈액종양내과
2. 28472019

   제1저자 남아롱, 김지원 · 교신저자 오도연

   Nam AR, Kim JW, Park JE, Bang JH, Jin MH, Oh DY, Bang YJ

   Jab1 Silencing Inhibits Proliferation and Sensitizes to Cisplatin in Biliary Tract Cancer.

   Cancer Res Treat. 2019;51(3):886-900.

   Abstract

   PURPOSE Jab1 is a coactivator of c-Jun that enhances the transcriptional function of c-Jun. Jab1 is frequently overexpressed in various cancers and is associatedwith poor prognosis of cancer patients. Thus, Jab1 could be a potential therapeutic target in cancer. However, the role of Jab1 in biliary tract cancer (BTC) has not been studied.

   MATERIALS AND METHODS We performed in vitro and in vivo experiments to evaluate the therapeutic potential ofJab1 inhibition in BTC.

   RESULTS Among 8 BTC cell lines, many showed higher Jab1 expression levels. In addition, Jab1 silencing by siRNA increased p27 expression levels. SNU478 and HuCCT-1 cells exhibited profound Jab1 knockdown and increased p27 expression by Jab1-specific siRNA transfection. Jab1 silencing induced anti-proliferative and anti-migratory effects and resulted in G1 cell cycle arrest in SNU478 and HuCCT-1 cells. In addition, Jab1 silencing potentiated the anti-proliferative and anti-migratory effects of cisplatin by increasing DNA damage. Interestingly,Jab1 knockdown increased PTEN protein half-life, resulting in increased PTEN expression. In the HuCCT-1 mouse xenograft model, stable knockdown of Jab1 by shRNA also showed anti-proliferative effects in vivo, with decreased Ki-67 expression and AKT phosphorylation and increased Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and p27 expression.

   CONCLUSION Jab1 knockdown demonstrated anti-proliferative and anti-migratory effects in BTC cells by increasing DNA damage and stabilizing PTEN, resulting in G1 cell cycle arrest. In addition, Jab1 silencing potentiated the anti-proliferative effects of cisplatin. Our data suggest that Jab1 may be a potential therapeutic target in BTC that is worthy of further investigations.

   PubMed IF 4.2 혈액종양내과
3. 28462019

   제1저자 김수정, 김소연 · 교신저자 김동완

   Kim SJ, Kim S, Kim DW, Kim M, Keam B, Kim TM, Lee Y, Koh J, Jeon YK, Heo DS

   Alterations in PD-L1 Expression Associated with Acquisition of Resistance to ALK Inhibitors in ALK-Rearranged Lung Cancer.

   Cancer Res Treat. 2019;51(3):1231-1240.

   Abstract

   PURPOSE The purpose of this study was to evaluate the relationships between the resistance of anaplastic lymphoma kinase (ALK)‒positive non-small cell lung cancer (NSCLC) to ALK inhibitors and the programmed cell death-1/programmed cell death-ligand 1 (PD-L1) pathway, we evaluated alterations in PD-L1 following acquisition of resistance to ALK inhibitors in ALK-positive lung cancer.

   MATERIALS AND METHODS We established ALK inhibitor-resistant cell lines (H3122CR1, LR1, and CH1) by exposing the parental H3122 ALK-translocated NSCLC cell line to ALK inhibitors. Then, the double-resistant cell lines H3122CR1LR1 and CR1CH1 were developed by exposing the H3122CR1 to other ALK inhibitors. We compared the alterations in PD-L1 expression levels using western blotting, flow cytometry, and quantitative polymerase chain reaction. We also investigated gene expression using RNA sequencing. The expression of PD-L1 in the tumors from 26 ALK-positive metastatic NSCLC patients (11 ALK inhibitor-naïve and 15 ALK inhibitor-resistant patients) was assessed by immunohistochemistry and analyzed.

   RESULTS PD-L1 was expressed at higher levels in ALK inhibitor-resistant cell lines than in the ALK inhibitor-naïve parental cell line at the total protein, surface protein, and mRNA levels. Furthermore, PD-L1 expression in the double-resistant cell lines was much higher than that in the single resistant cell lines. RNA sequencing demonstrated that expression of immune-related genes were largely involved in ALK inhibitor resistance. The mean value of the PD-L1 H-score was 6.5 pre-treatment and 35.0 post-treatment, and the fold difference was 5.42 (p=0.163).

   CONCLUSION PD-L1 expression increased following acquisition of ALK inhibitor resistance in ALK-positive NSCLC cell lines and tumors.

   PubMed IF 4.2 혈액종양내과
4. 28452019

   제1저자 곽민선 · 교신저자 임정윤

   Kwak MS, Yim JY, Yi A, Chung GE, Yang JI, Kim D, Kim JS, Noh DY

   Nonalcoholic fatty liver disease is associated with breast cancer in nonobese women.

   Dig Liver Dis. 2019;51(7):1030-1035.

   Abstract

   BACKGROUND Growing evidence supports that nonalcoholic fatty liver disease (NAFLD) is associated with extrahepatic cancers. Nonalcoholic fatty liver disease (NAFLD) and breast cancer share similar risk factors, including obesity.

   AIM The aim of this case-control study was to investigate the association between NAFLD and breast cancer.

   METHODS Subjects who received health screening, including mammography and breast and hepatic ultrasonography simultaneously, were included. Subjects diagnosed with breast cancer were matched with controls. Conditional logistic regression analyses were performed.

   RESULTS Among 270 breast cancer patients and 270 controls, 81 cancer patients (30.0%) and 54 controls (20.0%) had NAFLD (P = 0.008). NAFLD was significantly associated with breast cancer in multivariate analysis (P = 0.046). When the interaction between obesity (BMI < 25 kg/m² vs. ≥25 kg/m²) and NAFLD in breast cancer patients was examined, a significant effect modification between obesity and NAFLD in breast cancer was noted (P = 0.021). The subgroup analysis showed that NAFLD was significantly associated with breast cancer in the nonobese subgroup (odds ratio 3.04, 95% confidence interval 1.37-4.32, P = 0.002) but not in the obese group (P = 0.163).

   CONCLUSIONS NAFLD was significantly associated with breast cancer independent of traditional risk factors, and this association existed in the nonobese subgroup but not in the obese subgroup.

   PubMed IF 4.9 소화기내과
5. 28442019

   제1저자 남아롱, 김미화 · 교신저자 오도연

   Nam AR, Jin MH, Park JE, Bang JH, Oh DY, Bang YJ

   Therapeutic Targeting of the DNA Damage Response Using an ATR Inhibitor in Biliary Tract Cancer.

   Cancer Res Treat. 2019;51(3):1167-1179.

   Abstract

   PURPOSE The DNA damage response (DDR) is a multi-complex network of signaling pathways involved in DNA damage repair, cell cycle checkpoints, and apoptosis. In the case of biliary tract cancer (BTC), the strategy of DDR targeting has not been evaluated, even though many patients have DNA repair pathway alterations. The purpose of this study was to test the DDR-targeting strategy in BTC using an ataxia-telangiectasia and Rad3-related (ATR) inhibitor.

   MATERIALS AND METHODS A total of nine human BTC cell lines were used for evaluating anti-tumor effect of AZD6738 (ATR inhibitor) alone or combination with cytotoxic chemotherapeutic agents through MTT assay, colony-forming assays, cell cycle analyses, and comet assays. We established SNU478-mouse model for in vivo experiments to confirm our findings.

   RESULTS Among nine human BTC cell lines, SNU478 and SNU869 were the most sensitive to AZD6738, and showed low expression of both ataxia-telangiectasia mutated (ATM) and p53. AZD6738 blocked p-Chk1 and p-glycoprotein and increased γH2AX, a marker of DNA damage, in sensitive cells. AZD6738 significantly increased apoptosis, G2/M arrest and p21, and decreased CDC2. Combinations of AZD6738 and cytotoxic chemotherapeutic agents exerted synergistic effects in colony-forming assays, cell cycle analyses, and comet assays. In our mouse models, AZD6738 monotherapy decreased tumor growth and the combination with cisplatin showed more potent effects on growth inhibition, decreased Ki-67, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling than monotherapy with each drug.

   CONCLUSION In BTC, DDR targeting strategy using ATR inhibitor demonstrated promising antitumor activity alone or in combination with cytotoxic chemotherapeutic agents. This supports further clinical development of DDR targeting strategy in BTC.

   PubMed IF 4.2 혈액종양내과
6. 28432019

   제1저자 김지혜 · 교신저자 박경우

   Kim CH, Park KW, Kang J, Park BE, Cha KS, Rhew JY, Jeon HK, Shin ES, Oh JH, Jeong MH, Kim S, Hwang KK, Yoon JH, Lee SY, Park TH, Moon KW, Kwon HM, Hur SH, Ryu JK, Lee BR, Park YW, Chae IH, Kim HS, HOST–ASSURE Investigators

   Long-Term Comparison of Platinum Chromium Everolimus-Eluting Stent vs. Cobalt Chromium Zotarolimus-Eluting Stent - 3-Year Outcomes From the HOST-ASSURE Randomized Clinical Trial.

   Circ J. 2019;83(7):1489-1497.

   Abstract

   BACKGROUND There are limited data on the long-term outcome of platinum chromium-based everolimus-eluting stents (PtCr-EES) vs. cobalt chromium-based zotarolimus-eluting stents (CoCr-ZES).

   METHODS AND RESULTS A total of 3,755 patients undergoing percutaneous coronary intervention (PCI) were randomized 2:1 to PtCr-EES or CoCr-ZES, and 96.0% of patients completed the 3-year clinical follow-up. The primary outcome was target lesion failure (TLF), defined as a composite of cardiac death, target vessel-related myocardial infarction (MI), and clinically-driven target lesion revascularization (TLR). At 3 years, TLF occurred in 5.3% and in 5.4% of the PtCr-EES and CoCr-ZES groups, respectively (hazard ratio 0.978; 95% confidence interval 0.730-1.310, P=0.919). There were no significant differences in the individual components of TLF. Routine angiographic follow-up was performed in 38.9% of the total patients. In a landmark analysis of the subgroup that had follow-up angiography, the clinically-driven TLR rate of CoCr-ZES was significantly higher than PtCr-EES group during the angiography follow-up period (P=0.009). Overall definite and probable stent thrombosis rates were very low in both groups (0.5% vs. 0.6%, P=0.677).

   CONCLUSIONS PtCr-EES and CoCr-ZES had similar and excellent long-term outcomes in both efficacy and safety after PCI in an all-comer population.

   PubMed IF 5.8 순환기내과
7. 28422019

   제1저자 최원석, 장형우 · 교신저자 임청, 서정원

   Choi W, Chang HW, Kang SH, Yoon CH, Cho YS, Youn TJ, Chae IH, Kim DJ, Kim JS, Park KH, Kim HS, Lim C, Suh JW

   Comparison of Minimally Invasive Direct Coronary Artery Bypass and Percutaneous Coronary Intervention Using Second-Generation Drug-Eluting Stents for Coronary Artery Disease - Propensity Score-Matched Analysis.

   Circ J. 2019;83(7):1572-1580.

   Abstract

   BACKGROUND Some studies comparing minimally invasive direct coronary artery bypass (MIDCAB) and percutaneous coronary intervention (PCI) have reported MIDCAB's superiority, but they did not investigate contemporary PCI with newer generation drug-eluting stents (DES). We compared clinical outcomes after MIDCAB with previously reported outcomes after PCI with second-generation DES.

   METHODS AND RESULTS We retrospectively reviewed the records of patients treated with MIDCAB. Baseline characteristics and clinical outcomes after MIDCAB were compared with those for left anterior descending artery disease treated via PCI. The primary outcomes were major adverse cardiovascular and cerebrovascular events (MACCE), a composite of cardiovascular death, non-fatal myocardial infarction, ischemic stroke, and target vessel revascularization (TVR). A propensity score-matching (PSM) analysis was conducted to adjust for between-group differences in baseline characteristics. We analyzed 77 patients treated with MIDCAB and 2,206 treated with PCI. The MIDCAB group was older and had more severe coronary disease and a higher incidence of left ventricular dysfunction. Over a 3-year follow-up, the PCI group had favorable MACCE outcomes. After PSM, there were no between-group differences in MACCE (MIDCAB, 15.6% vs. PCI, 23.4%; hazard ratio [HR], 0.80; 95% CI: 0.38-1.68, P=0.548) or TVR (MIDCAB, 2.6% vs. PCI, 5.2%; HR, 0.51; 95% CI: 0.10-3.09, P=0.509).

   CONCLUSIONS Clinical outcomes were similar between MIDCAB and PCI using second-generation DES over 3 years of follow-up.

   PubMed IF 5.8 순환기내과
8. 28412019

   제1저자 유승근, 송영신 · 교신저자 박영주, 서정선

   Yoo SK, Song YS, Lee EK, Hwang J, Kim HH, Jung G, Kim YA, Kim SJ, Cho SW, Won JK, Chung EJ, Shin JY, Lee KE, Kim JI, Park YJ, Seo JS

   Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer.

   Nat Commun. 2019;10(1):2764.

   Abstract

   Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAF^V600E and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.

   PubMed IF 18.1 내분비대사내과
9. 28402019

   제1저자 이춘수, 조현재 · 교신저자 김효수

   Lee CS, Cho HJ, Lee JW, Lee J, Kwon YW, Son T, Park H, Kim J, Kim HS

   Identification of Latrophilin-2 as a Novel Cell-Surface Marker for the Cardiomyogenic Lineage and Its Functional Significance in Heart Development.

   Circulation. 2019;139(25):2910-2912.

   PubMed IF 41.3 순환기내과
10. 28392019

    제1저자 박지석 · 교신저자 최의근

    Park J, Choi EK, Han KD, Choi YJ, Lee SR, Cha MJ, Kang J, Park KW, Oh S, Lip GYH

    Antithrombotic Therapy in Patients With Atrial Fibrillation After Percutaneous Coronary Intervention During 2-Year Follow-Up, from a Nationwide Population Study.

    Am J Cardiol. 2019;123(12):1921-1926.

    Abstract

    Patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI) are recommended to receive oral anticoagulants (OAC) and concomitant antiplatelet agents followed by OAC monotherapy continued beyond a year after PCI. However, long-term prescription patterns of antithrombotic therapy in real-world clinical practice were not fully investigated. From the National Health Insurance Service database of Korea, we obtained records of patients with AF who underwent PCI between 2009 and 2013. Patients without repeated PCI or death within 2 years following the procedure were included. Prescription records of antithrombotic therapy including anticoagulants and antiplatelet agents were reviewed at 3-month intervals after discharge. We investigated 8,891 patients. At discharge, 76.1% of the patients received dual antiplatelet therapy (DAPT) and only 17.1% received OAC. Although the proportion of patients receiving DAPT gradually decreased, >70% of patients received only antiplatelet agents (DAPT or single antiplatelet therapy) a year after PCI. During the 2-year follow-up, the proportion of patients receiving OAC remained <20%, and only 1.5% of the patients received OAC monotherapy a year after PCI. Female gender, previous myocardial infarction, peripheral vascular disease, and prescription of DAPT at discharge were associated with underprescription of OAC a year after PCI. In conclusion, a significant proportion (76%) of patients with AF who underwent PCI were not prescribed OAC at discharge despite the high risk of stroke contrary to the current guidelines. Most patients continued to receive antiplatelet agents without OAC beyond the 1-year time point after PCI.

    PubMed IF 2.5 순환기내과
11. 28382019

    제1저자 이은주 · 교신저자 김효수

    Lee EJ, Hwang I, Kim GH, Moon D, Kang SY, Hwang IC, Lee SY, Marie PJ, Kim HS

    Endothelin-1 Augments Therapeutic Potency of Human Mesenchymal Stem Cells via CDH2 and VEGF Signaling.

    Mol Ther Methods Clin Dev. 2019;13:503-511.

    Abstract

    In our previous study, we identified differences in the levels of CDH2 and vascular endothelial growth factor (VEGF) between effective and ineffective clones of human umbilical cord blood (hUCB) mesenchymal stem cells (MSCs), with regard to the infarcted rat myocardium. In this study, we compared gene expression profiles between the effective and ineffective clones and identified that endothelin-1 (EDN1) is enriched in the effective clone. In the mechanistic analyses, EDN1 significantly increased expression of CDH2 and VEGF through endothelin receptor A (EDNRA), which was prevented by EDNRA blocker, BQ123. To decipher how EDN1 induced gene expression of CDH2, we performed a promoter activity assay and identified GATA2 and MZF1 as inducers of CDH2. EDN1 significantly enhanced the promoter activity of the CDH2 gene, which was obliterated by the deletion or point mutation at GATA2 or MZF1 binding sequence. Next, therapeutic efficacy of EDN1-priming of hUCB-MSCs was tested in a rat myocardial infarction (MI) model. EDN1-primed MSCs were superior to naive MSCs at 8 weeks after MI in improving myocardial contractility (p < 0.05), reducing fibrosis area (p < 0.05), increasing engraftment efficiency (p < 0.05), and improving capillary density (p < 0.05). In conclusion, EDN1 induces CDH2 and VEGF expression in hUCB-MSCs, leading to the improved therapeutic efficacy in rat MI, suggesting that EDN1 is a potential priming agent for MSCs in regenerative medicine.

    PubMed IF 4.875 순환기내과
12. 28372019

    제1저자 최유정 · 교신저자 최의근

    Choi YJ, Choi EK, Han KD, Park J, Moon I, Lee E, Choe WS, Lee SR, Cha MJ, Lim WH, Oh S

    Increased risk of atrial fibrillation in patients with inflammatory bowel disease: A nationwide population-based study.

    World J Gastroenterol. 2019;25(22):2788-2798.

    Abstract

    BACKGROUND Inflammatory bowel disease (IBD), a chronic inflammatory disease of the gastrointestinal tract, could play a role in the pathophysiology of atrial fibrillation (AF).

    AIM To investigate the association between IBD and AF development.

    METHODS We performed a population-based cohort study using records in the Korean National Health Insurance Services database between 2010 and 2014. A total of 37696 patients with IBD (12349 with Crohn's disease and 25397 with ulcerative colitis) were identified. The incidence rate of newly diagnosed AF in patients with IBD was compared with that in a 3 times larger cohort of 113088 age- and sex-matched controls without IBD.

    RESULTS During 4.9 ± 1.3 years of follow-up, 1120 patients newly diagnosed with AF (348 in the IBD group and 772 in controls) were identified. After adjustments using multivariable Cox proportional hazards, patients with IBD were at a 36% [95% confidence interval (CI) 20%-54%] higher risk of AF than controls. The association between IBD and the development of AF was stronger in younger than in older patients. Patients without cardiovascular risk factors showed a higher risk of AF primarily. Additionally, patients receiving immun-omodulators [Hazard ration (HR) 1.46, 95%CI 1.31-1.89], systemic corticosteroids (HR 1.37, 95%CI 1.10-1.71), or biologics agents (HR 2.38, 95%CI 1.51-3.75) were at higher risk of AF than patients without them.

    CONCLUSION IBD significantly increased the risk of AF, and the impact of IBD on developing AF was in patients with moderate to severe disease.

    PubMed IF 7.7 순환기내과
13. 28362019

    제1저자 최홍미 · 교신저자 김형관, 박성지

    Choi HM, Kim HK, Park SJ, Lee HJ, Yoon YE, Park JB, Kim YJ, Cho GY, Hwang IC, Sohn DW, Oh JK

    Predictors of paravalvular aortic regurgitation after surgery for Behcet's disease-related severe aortic regurgitation.

    Orphanet J Rare Dis. 2019;14(1):132.

    Abstract

    BACKGROUND Behcet's disease (BD)-related aortic regurgitation (AR) is known to be associated with paravalvular leakage (PVL) after successful aortic valve (AV) surgery. This study aimed to determine predictors of PVL after successful AV surgery in BD patients. We retrospectively collected data of 35 patients (42.1 ± 9.1 years, 27 men) who underwent surgery for severe BD-related AR at two tertiary centers. The diagnosis was established based on echocardiographic, surgical, and/or pathological findings in conjunction with the International Study Group criteria for BD. A total of 76 cases of AV surgery in 35 patients were analyzed.

    RESULTS A median follow-up duration was 8.0 years (interquartile range, 5.4-14.3 years). PVL developed in 18 patients (51.4%) within 2 years after the first surgery. Six patients who met the diagnostic criteria for BD did not develop PVL, in whom 5 patients took immunosuppressive therapy (IST). However, 4 of 9 patients (44.4%) who did not meet the diagnostic criteria developed PVL, in whom four (44.4%) patients took IST. On multivariable analysis, postoperative IST and concomitant aortic root replacement (ARR) were two independent predictors for less PVL development (HR 0.38, 95% CI 0.17-0.89, p = 0.025 for postoperative IST; HR 0.17, 95% CI 0.08-0.36, p < 0.001 for concomitant ARR). Preoperative IST use did not determine PVL development (p = 0.75).

    CONCLUSIONS Postoperative, but not preoperative, IST and concomitant ARR were independent predictors of less development of PVL. Special attention is required for early diagnosis BD-related AR, especially in patients not satisfying the current diagnostic criteria.

    PubMed IF 3.6 순환기내과
14. 28352019

    제1저자 박지석, 신종환 · 교신저자 김학령

    Park J^*, Shin J^*, Kim HL, Song KJ, Jung JH, Lee HJ, You KM, Lim WH, Seo JB, Kim SH, Zo JH, Kim MA, Korean Cardiac Arrest Research Consortium (KoCARC) Investigators

    Clinical Factors Associated with Obstructive Coronary Artery Disease in Patients with Out-of-Hospital Cardiac Arrest: Data from the Korean Cardiac Arrest Research Consortium (KoCARC) Registry.

    J Korean Med Sci. 2019;34(22):e159.

    Abstract

    BACKGROUND Although coronary artery disease (CAD) is a major cause of out-of-hospital cardiac arrest (OHCA), there has been no convinced data on the necessity of routine invasive coronary angiography (ICA) in OHCA. We investigated clinical factors associated with obstructive CAD in OHCA.

    METHODS Data from 516 OHCA patients (mean age 58 years, 83% men) who underwent ICA after resuscitation was obtained from a nation-wide OHCA registry. Obstructive CAD was defined as the lesions with diameter stenosis ≥ 50% on ICA. Independent clinical predictors for obstructive CAD were evaluated using multiple logistic regression analysis, and their prediction performance was compared using area under the receiver operating characteristic curve with 10,000 repeated random permutations.

    RESULTS Among study patients, 254 (49%) had obstructive CAD. Those with obstructive CAD were older (61 vs. 55 years, P < 0.001) and had higher prevalence of hypertension (54% vs. 36%, P < 0.001), diabetes mellitus (29% vs. 21%, P = 0.032), positive cardiac enzyme (84% vs. 74%, P = 0.010) and initial shockable rhythm (70% vs. 61%, P = 0.033). In multiple logistic regression analysis, old age (≥ 60 years) (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.36-3.00; P = 0.001), hypertension (OR, 1.74; 95% CI, 1.18-2.57; P = 0.005), positive cardiac enzyme (OR, 1.72; 95% CI, 1.09-2.70; P = 0.019), and initial shockable rhythm (OR, 1.71; 95% CI, 1.16-2.54; P = 0.007) were associated with obstructive CAD. Prediction ability for obstructive CAD increased proportionally when these 4 factors were sequentially combined (P < 0.001).

    CONCLUSION In patients with OHCA, those with old age, hypertension, positive cardiac enzyme and initial shockable rhythm were associated with obstructive CAD. Early ICA should be considered in these patients.

    PubMed IF 3.2 순환기내과
15. 28342019

    제1저자 권순일, 홍준기 · 교신저자 최의근

    Kwon S^*, Hong J^*, Choi EK, Lee E, Hostallero DE, Kang WJ, Lee B, Jeong ER, Koo BK, Oh S, Yi Y

    Deep Learning Approaches to Detect Atrial Fibrillation Using Photoplethysmographic Signals: Algorithms Development Study.

    JMIR Mhealth Uhealth. 2019;7(6):e12770.

    Abstract

    BACKGROUND Wearable devices have evolved as screening tools for atrial fibrillation (AF). A photoplethysmographic (PPG) AF detection algorithm was developed and applied to a convenient smartphone-based device with good accuracy. However, patients with paroxysmal AF frequently exhibit premature atrial complexes (PACs), which result in poor unmanned AF detection, mainly because of rule-based or handcrafted machine learning techniques that are limited in terms of diagnostic accuracy and reliability.

    OBJECTIVE This study aimed to develop deep learning (DL) classifiers using PPG data to detect AF from the sinus rhythm (SR) in the presence of PACs after successful cardioversion.

    METHODS We examined 75 patients with AF who underwent successful elective direct-current cardioversion (DCC). Electrocardiogram and pulse oximetry data over a 15-min period were obtained before and after DCC and labeled as AF or SR. A 1-dimensional convolutional neural network (1D-CNN) and recurrent neural network (RNN) were chosen as the 2 DL architectures. The PAC indicator estimated the burden of PACs on the PPG dataset. We defined a metric called the confidence level (CL) of AF or SR diagnosis and compared the CLs of true and false diagnoses. We also compared the diagnostic performance of 1D-CNN and RNN with previously developed AF detectors (support vector machine with root-mean-square of successive difference of RR intervals and Shannon entropy, autocorrelation, and ensemble by combining 2 previous methods) using 10 5-fold cross-validation processes.

    RESULTS Among the 14,298 training samples containing PPG data, 7157 samples were obtained during the post-DCC period. The PAC indicator estimated 29.79% (2132/7157) of post-DCC samples had PACs. The diagnostic accuracy of AF versus SR was 99.32% (70,925/71,410) versus 95.85% (68,602/71,570) in 1D-CNN and 98.27% (70,176/71,410) versus 96.04% (68,736/71,570) in RNN methods. The area under receiver operating characteristic curves of the 2 DL classifiers was 0.998 (95% CI 0.995-1.000) for 1D-CNN and 0.996 (95% CI 0.993-0.998) for RNN, which were significantly higher than other AF detectors (P<.001). If we assumed that the dataset could emulate a sufficient number of patients in training, both DL classifiers improved their diagnostic performances even further especially for the samples with a high burden of PACs. The average CLs for true versus false classification were 98.56% versus 78.75% for 1D-CNN and 98.37% versus 82.57% for RNN (P<.001 for all cases).

    CONCLUSIONS New DL classifiers could detect AF using PPG monitoring signals with high diagnostic accuracy even with frequent PACs and could outperform previously developed AF detectors. Although diagnostic performance decreased as the burden of PACs increased, performance improved when samples from more patients were trained. Moreover, the reliability of the diagnosis could be indicated by the CL. Wearable devices sensing PPG signals with DL classifiers should be validated as tools to screen for AF.

    PubMed IF 6.3 순환기내과
16. 28332019

    제1저자 이주명, 최길우 · 교신저자 구본권

    Lee JM, Choi G, Koo BK, Hwang D, Park J, Zhang J, Kim KJ, Tong Y, Kim HJ, Grady L, Doh JH, Nam CW, Shin ES, Cho YS, Choi SY, Chun EJ, Choi JH, Nørgaard BL, Christiansen EH, Niemen K, Otake H, Penicka M, de Bruyne B, Kubo T, Akasaka T, Narula J, Douglas PS, Taylor CA, Kim HS

    Identification of High-Risk Plaques Destined to Cause Acute Coronary Syndrome Using Coronary Computed Tomographic Angiography and Computational Fluid Dynamics.

    JACC Cardiovasc Imaging. 2019;12(6):1032-1043.

    Abstract

    OBJECTIVES The authors investigated the utility of noninvasive hemodynamic assessment in the identification of high-risk plaques that caused subsequent acute coronary syndrome (ACS).

    BACKGROUND ACS is a critical event that impacts the prognosis of patients with coronary artery disease. However, the role of hemodynamic factors in the development of ACS is not well-known.

    METHODS Seventy-two patients with clearly documented ACS and available coronary computed tomographic angiography (CTA) acquired between 1 month and 2 years before the development of ACS were included. In 66 culprit and 150 nonculprit lesions as a case-control design, the presence of adverse plaque characteristics (APC) was assessed and hemodynamic parameters (fractional flow reserve derived by coronary computed tomographic angiography [FFR_CT], change in FFR_CT across the lesion [△FFR_CT], wall shear stress [WSS], and axial plaque stress) were analyzed using computational fluid dynamics. The best cut-off values for FFR_CT, △FFR_CT, WSS, and axial plaque stress were used to define the presence of adverse hemodynamic characteristics (AHC). The incremental discriminant and reclassification abilities for ACS prediction were compared among 3 models (model 1: percent diameter stenosis [%DS] and lesion length, model 2: model 1 + APC, and model 3: model 2 + AHC).

    RESULTS The culprit lesions showed higher %DS (55.5 ± 15.4% vs. 43.1 ± 15.0%; p < 0.001) and higher prevalence of APC (80.3% vs. 42.0%; p < 0.001) than nonculprit lesions. Regarding hemodynamic parameters, culprit lesions showed lower FFR_CT and higher △FFR_CT, WSS, and axial plaque stress than nonculprit lesions (all p values <0.01). Among the 3 models, model 3, which included hemodynamic parameters, showed the highest c-index, and better discrimination (concordance statistic [c-index] 0.789 vs. 0.747; p = 0.014) and reclassification abilities (category-free net reclassification index 0.287; p = 0.047; relative integrated discrimination improvement 0.368; p < 0.001) than model 2. Lesions with both APC and AHC showed significantly higher risk of the culprit for subsequent ACS than those with no APC/AHC (hazard ratio: 11.75; 95% confidence interval: 2.85 to 48.51; p = 0.001) and with either APC or AHC (hazard ratio: 3.22; 95% confidence interval: 1.86 to 5.55; p < 0.001).

    CONCLUSIONS Noninvasive hemodynamic assessment enhanced the identification of high-risk plaques that subsequently caused ACS. The integration of noninvasive hemodynamic assessments may improve the identification of culprit lesions for future ACS. (Exploring the Mechanism of Plaque Rupture in Acute Coronary Syndrome Using Coronary CT Angiography and Computational Fluid Dynamic [EMERALD]; NCT02374775).

    PubMed IF 19 순환기내과
17. 28322019

    제1저자 김우진 · 교신저자 김태민, 박철기

    Kim WJ, Dho YS, Ock CY, Kim JW, Choi SH, Lee ST, Kim IH, Kim TM, Park CK

    Clinical observation of lymphopenia in patients with newly diagnosed glioblastoma.

    J Neurooncol. 2019;143(2):321-328.

    Abstract

    PURPOSE Lymphopenia in patients with glioblastoma (GBM) is related to treatment as well as disease progression. This retrospective study investigated the prevalence, influencing factors, recoverability, and clinical significance of lymphopenia in GBM patients treated with concomitant chemoradiotherapy (CCRT).

    PATIENTS AND METHODS A total of 219 patients with newly diagnosed GBM who had received at least 3 cycles of adjuvant temozolomide (TMZ) followed by CCRT with TMZ were enrolled. Serial data on complete blood cell counts, including differential cell counts, were collected just before a new phase and before every treatment cycle of the regimen. Relationships between white blood cell (WBC) variable changes and treatment modalities as well as survival were analyzed. Lymphopenia was classified using the definition of the Common Terminology Criteria for Adverse Events version 5.0.

    RESULTS A total of 92 patients (42.0%) showed decreased levels of lymphocytes (< 1500/µL) at baseline. The WBC count, absolute neutrophil count, lymphocyte count, and neutrophil-to-lymphocyte ratio were all significantly decreased after RT/TMZ treatment and did not recover during the adjuvant TMZ period. However, these metrics all began to recover 3 months after the last TMZ cycle, except for the lymphocyte count. The proportion of lymphopenia patients (< 1500 lymphocytes/µL) increased to 74.8% after RT/TMZ and remained steady at approximately 71.5% (range 63.7-75.3%) throughout the management period. Moreover, the number of patients with grade 3 lymphopenia (< 500 lymphocytes/µL) also increased significantly after treatment to reach 2.9% (from 0.9% at baseline). Statistically, 75.7% of lymphopenia patients were predicted to recover in a median time of 240.3 days (95% confidence interval ± 104.7 days) after TMZ withdrawal. There were no dose-dependent relationships between RT or TMZ and lymphopenia. Grade 3 (< 500 lymphocytes/µL) lymphopenia measured at 1 month after RT/TMZ predicted significantly reduced survival (13.0 months vs. 19.5 months, p = 0.011).

    CONCLUSION Lymphopenia is a frequent event during GBM disease progression and treatment. Treatment-related lymphopenia is profound and prolonged and can be used as a prognostic factor for GBM patients.

    PubMed IF 3.4 혈액종양내과
18. 28312019

    제1저자 송진희 · 교신저자 김나영

    Song CH, Kim N, Lee SM, Nam RH, Choi SI, Kang SR, Shin E, Lee DH, Lee HN, Surh YJ

    Effects of 17β-estradiol on colorectal cancer development after azoxymethane/dextran sulfate sodium treatment of ovariectomized mice.

    Biochem Pharmacol. 2019;164:139-151.

    Abstract

    Estrogen is known to have a protective effect in colorectal cancer (CRC) development. Previously, we reported the anti-inflammatory and antitumorigenic effects of 17β-estradiol (E2) in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated male mice. The aim of this study was to investigate whether ovariectomy in a female AOM/DSS mouse model increases colorectal tumorigenesis and whether tumorigenesis is reduced by estrogen supplementation after ovariectomy. Clinical symptoms and histological severity of colitis and the levels of inflammatory mediators were evaluated in the colon of AOM/DSS-treated ovariectomized (OVX) mice. The levels of E2, myeloperoxidase (MPO), and NF-κB-dependent cytokines (interleukin (IL)-1β and IL-6) were measured by ELISA. Furthermore, quantitative real-time (qRT) PCR and Western blot analysis were performed. Ovariectomy did not aggravate AOM/DSS-induced colitis at 2 weeks. At weeks 10 and 16, ovariectomy significantly increased tumor number and incidence rate in only the proximal colon after AOM/DSS treatment (F_AOM/DSS vs OVX_AOM/DSS), and these increases were significantly reduced by E2 supplementation (OVX_AOM/DSS vs OVX_AOM/DSS/E2). However, ovariectomy did not affect CRC development in the distal colon (F_AOM/DSS vs OVX_AOM/DSS). At week 2, E2 administration to AOM/DSS-treated OVX mice attenuated the histological severity of colitis by decreasing the protein and/or mRNA levels of estrogen receptor alpha (ERα) and NF-κB-related mediators (i.e., COX-2, TNF-α, and IL-6) and by enhancing estrogen receptor beta (ERβ) and nuclear Nrf2 protein expression and the mRNA expression of related antioxidant enzyme genes (i.e., HO-1, GCLC, GCLM, and NQO1). Endogenous estrogen in females protects against the development of proximal colon cancer, and exogenous E2 replacement in OVX female mice showed protective effects against AOM/DSS-induced colitis and carcinogenesis. The mechanism could involve modulating ERs-, NF-κB- and Nrf2-mediated pathways.

    PubMed IF 6.5 소화기내과
19. 28302019

    제1저자 박은숙, 이아람, 김두현, 이정훈 · 교신저자 이정훈, 김균환

    Park ES, Lee AR, Kim DH, Lee JH, Yoo JJ, Ahn SH, Sim H, Park S, Kang HS, Won J, Ha YN, Shin GC, Kwon SY, Park YK, Choi BS, Lee YB, Jeong N, An Y, Ju YS, Yu SJ, Chae HB, Yu KS, Kim YJ, Yoon JH, Zoulim F, Kim KH

    Identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients.

    J Hepatol. 2019;70(6):1093-1102.

    Abstract

    BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) is one the most potent nucleot(s)ide analogues for treating chronic hepatitis B virus (HBV) infection. Phenotypic resistance caused by genotypic resistance to TDF has not been reported. This study aimed to characterize HBV mutations that confer tenofovir resistance.

    METHODS Two patients with viral breakthrough during treatment with TDF-containing regimens were prospectively enrolled. The gene encoding HBV reverse transcriptase was sequenced. Eleven HBV clones harboring a series of mutations in the reverse transcriptase gene were constructed by site-directed mutagenesis. Drug susceptibility of each clone was determined by Southern blot analysis and real-time PCR. The relative frequency of mutants was evaluated by ultra-deep sequencing and clonal analysis.

    RESULTS Five mutations (rtS106C [C], rtH126Y [Y], rtD134E [E], rtM204I/V, and rtL269I [I]) were commonly found in viral isolates from 2 patients. The novel mutations C, Y, and E were associated with drug resistance. In assays for drug susceptibility, the IC₅₀ value for wild-type HBV was 3.8 ± 0.6 µM, whereas the IC₅₀ values for CYE and CYEI mutants were 14.1 ± 1.8 and 58.1 ± 0.9 µM, respectively. The IC₉₀ value for wild-type HBV was 30 ± 0.5 µM, whereas the IC₉₀ values for CYE and CYEI mutants were 185 ± 0.5 and 790 ± 0.2 µM, respectively. Both tenofovir-resistant mutants and wild-type HBV had similar susceptibility to the capsid assembly modulator NVR 3-778 (IC₅₀ <0.4 µM vs. IC₅₀ = 0.4 µM, respectively).

    CONCLUSIONS Our study reveals that the quadruple (CYEI) mutation increases the amount of tenofovir required to inhibit HBV by 15.3-fold in IC₅₀ and 26.3-fold in IC₉₀. These results demonstrate that tenofovir-resistant HBV mutants can emerge, although the genetic barrier is high.

    LAY SUMMARY Tenofovir is the most potent nucleotide analogue for the treatment of chronic hepatitis B virus infection and there has been no hepatitis B virus mutation that confers >10-fold resistance to tenofovir up to 8 years. Herein, we identified, for the first time, a quadruple mutation that conferred 15.3-fold (IC₅₀) and 26.3-fold (IC₉₀) resistance to tenofovir in 2 patients who experienced viral breakthrough during tenofovir treatment.

    PubMed IF 40.1 소화기내과
20. 28292019

    제1저자 이동화 · 교신저자 임수

    Lee DH, Chun EJ, Oh TJ, Kim KM, Moon JH, Choi SH, Park KS, Jang HC, Lim S

    Effect of cilostazol, a phosphodiesterase-3 inhibitor, on coronary artery stenosis and plaque characteristics in patients with type 2 diabetes: ESCAPE study.

    Diabetes Obes Metab. 2019;21(6):1409-1418.

    Abstract

    AIM To perform a prospective study to evaluate the effect of cilostazol (CTZ) compared with aspirin (acetylsalicylic acid; ASA) in Korean people with diabetes and subclinical coronary atherosclerosis.

    MATERIALS AND METHODS A total of 100 people with diabetes who had mild to moderate coronary atherosclerosis, assessed by coronary computed tomographic angiography (CCTA), were randomly assigned to either 200 mg/d CTZ or 100 mg/d ASA (n = 50 each group). The primary outcome was change in coronary artery stenosis assessed by CCTA after 12 months of treatment. Secondary outcomes included changes in plaque composition, coronary artery calcium score and cardiac markers.

    RESULTS The mean age, body mass index and glycated haemoglobin concentration were 61.5 years, 25.0 kg/m² and 56.8 mmol/mol, respectively, and were well matched between the two groups. Coronary artery stenosis decreased in the CTZ group (from 44.0 ± 2.1% to 40.4 ± 2.5%) but remained unchanged in the ASA group (from 38.9 ± 2.1% to 40.6 ± 2.1%). In the CTZ group, the non-calcified portion of plaques decreased significantly (from 20.6 ± 3.0 to 17.3 ± 3.0 mm³ ), whereas it did not change significantly in the ASA group (15.2 ± 2.8 vs 16.6 ± 2.9 mm³ ). Increases in HDL cholesterol, decreases in triglycerides, liver enzyme and high-sensitivity C-reactive protein levels, and reductions in abdominal visceral fat area and insulin resistance were observed only in the CTZ group.

    CONCLUSION CTZ treatment for 12 months decreased coronary artery stenosis and the non-calcified plaque component. These results suggest that CTZ treatment may be an option for preventing the progression of coronary atherosclerosis in people with diabetes.

    PubMed IF 6.1 내분비대사내과
21. 28282019

    제1저자 박하람 · 교신저자 안용운, 김태민

    Park HR, Ahn YO, Kim TM, Kim S, Kim S, Lee YS, Kim M, Keam B, Kim DW, Heo DS

    NK92-CD16 cells are cytotoxic to non-small cell lung cancer cell lines that have acquired resistance to tyrosine kinase inhibitors.

    Cytotherapy. 2019;21(6):603-611.

    Abstract

    BACKGROUND Treatment with tyrosine kinase inhibitors (TKIs) has improved the outcomes for patients with non-small cell lung cancer (NSCLC) harboring targetable driver mutations. However, acquired resistance to TKIs invariably develops within approximately 1 year of treatment by various mechanisms, including gatekeeper mutations, alternative pathway activation and histological transformations. Because immunotherapy is an option for patients with drug-resistant cancers, we generated several TKI-resistant NSCLC cell lines in vitro, and then evaluated the cytotoxicity of NK92-CD16 cells to these resistant cells.

    MATERIALS AND METHODS TKI-resistant NSCLC cells (H3122CR1, H3122LR1, H3122CR1LR1, PC-9GR, PC-9ER, EBC-CR1 and EBC-CR2) were established from NCI-H3122 (EML4-ALK fusion), PC-9 (EGFR exon19 deletion) and EBC-1 (MET amplification) after continuous exposure to crizotinib, ceritinib, gefitinib, erlotinib and capmatinib. Expression of ligands for natural killer (NK) cell receptors and total EGFR were analyzed using flow cytometry. NK cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) using anti-EGFR monoclonal antibody (mAb) cetuximab were measured using NK92-CD16 as effectors and detected using the ⁵¹Chromium-release assay.

    RESULTS We found that NK92-CD16 cells preferentially killed TKI-resistant NSCLC cells when compared with their parental NSCLC cells. Mechanistically, intracellular adhesion molecule 1 (ICAM-1) was up-regulated in the TKI-resistant NSCLC cells and patients' tumors, and the ICAM-1 up-regulated cancer cells lines were less susceptible to NK cytotoxicity by blocking ICAM-1. Moreover, NK92-CD16 cell-induced cytotoxicity toward TKI-resistant NSCLC cells was enhanced in the presence of cetuximab, an EGFR-targeting mAb.

    CONCLUSION These data suggest that combinational treatment with NK cell-based immunotherapy and cetuximab may be promising for patients with TKI-resistant NSCLC.

    PubMed IF 4.5 혈액종양내과
22. 28272019

    제1저자 권영재 · 교신저자 김나영

    Kwon YJ, Kim N, Baek SM, Lee HS, Lee J, Hwang YJ, Yoon H, Shin CM, Park YS, Kim JW, Lee DH

    The prevalence of histologic atrophy and intestinal metaplasia in the corpus has decreased over 15 years in females in the Korean population.

    Helicobacter. 2019;24(3):e12579.

    Abstract

    BACKGROUND The aim of this study was to investigate the trends of atrophy and intestinal metaplasia (IM) in 2002 subjects without significant gastroduodenal diseases.

    MATERIALS AND METHODS A total of 2002 subjects were prospectively enrolled and divided into three periods (2003-2007, 2008-2012, and 2013-2018). Trends of H pylori and atrophy/IM scored by Updated Sydney System were analyzed according to sex, and multivariate logistic analysis was performed for the risk factors for atrophy/IM.

    RESULTS H pylori-negative and H pylori-positive subjects were 1220 (61.0%) and 782 (38.0%), respectively. H pylori positivity decreased from 149/303 (49.2%), 207/515 (40.2%) and 426/1184 (36.0%), in the three periods, respectively (P < 0.001). The prevalence of atrophy (P < 0.001) and IM in the corpus (P < 0.001) significantly decreased over 15 years in females, but not in males. The mean grade of atrophy and IM was higher in males (0.36 and 0.51) than in females (0.28 and 0.41) in the corpus (P = 0.027) and in the antrum (P = 0.006), respectively. Similarly, the mean grade of IM in males (0.34) was higher in females (0.19; P < 0.001) in the corpus. Multivariate analysis showed that old age, study period, and H pylori were statistically significant in atrophy of antrum and corpus, and IM in the corpus. In cases of IM of antrum, old age, H pylori, and smoking were statistically significant.

    CONCLUSION A significant decrease in atrophy and IM in the corpus in females over 15 years suggests sex- or gender-specific characteristics.

    PubMed IF 4.6 소화기내과
23. 28262019

    제1저자 김범석 · 교신저자 이근욱, 이세훈

    Keam B, Lee KW, Lee SH, Kim JS, Kim JH, Wu HG, Eom KY, Kim S, Ahn SH, Chung EJ, Kwon SK, Jeong WJ, Jung YH, Kim JW, Heo DS

    A Phase II Study of Genexol-PM and Cisplatin as Induction Chemotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma.

    Oncologist. 2019;24(6):751-e231.

    Abstract

    LESSONS LEARNED Induction chemotherapy with Genexol-PM and cisplatin demonstrated modest tumor response in locally advanced head and neck squamous cell carcinoma.Considering favorable toxicity profiles and promising survival data, further studies on this regimen are warranted in patients with head and neck squamous cell carcinoma.

    BACKGROUND Genexol-PM is a polymeric micellar formulation of paclitaxel without Cremophor EL. We investigated the efficacy and safety of Genexol-PM plus cisplatin as induction chemotherapy (IC) in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC).

    METHODS Patients received Genexol-PM (230 mg/m²) and cisplatin (60 mg/m²) every 3 weeks as IC. After three cycles of IC, definitive treatment of either concurrent chemoradiotherapy (CCRT) with weekly cisplatin (30 mg/m²) or surgery was performed. The primary endpoint was overall response rate (ORR) after IC.

    RESULTS Of 52 patients enrolled, 47 completed three cycles of IC, and the ORR was 55.8% (95% confidence interval, 42.3-69.3). Although there was one treatment-related death, toxicity profiles to Genexol-PM and cisplatin were generally favorable, and the most common grade 3 or 4 toxicities were neutropenia (15.4%), anorexia (7.7%), and general weakness (7.7%). Fifty-one patients received definitive treatment (CCRT [n = 44] or radical surgery [n = 7]). The rate of complete response following CCRT was 81.8% (36/44). After a median follow-up of 39 months, estimates of progression-free survival (PFS) and overall survival (OS) at 3 years were 54.3% and 71.3%, respectively.

    CONCLUSION IC with Genexol-PM and cisplatin demonstrated modest tumor response with well-tolerated toxicity profiles for patients with LA-HNSCC.

    PubMed IF 4.7 혈액종양내과
24. 28252019

    제1저자 김충종, 송경호 · 교신저자 김의석, 박경화

    Kim CJ, Song KH, Park KH, Kim M, Choe PG, Oh MD, Lee SH, Jang HC, Kang SJ, Kim HY, Cheon S, Kwak YG, Choi HJ, Kwon KT, Jeon JH, Kim ES, Kim HB, Korea INfectious Diseases (KIND) Study Group

    Impact of antimicrobial treatment duration on outcome of Staphylococcus aureus bacteraemia: a cohort study.

    Clin Microbiol Infect. 2019;25(6):723-732.

    Abstract

    OBJECTIVES To assess the outcome of Staphylococcus aureus bacteraemia (SAB) according to factors associated with necessity for longer treatment in conjunction with the duration of treatment.

    METHODS We prospectively collected the data of patients with SAB consecutively during 12 to 39 months from 11 hospitals. If multiple episodes of SAB occurred in one patient, only the first episode was enrolled. Factors associated with necessity for longer treatment were defined as follows: persistent bacteraemia, metastatic infection, prosthesis and endocarditis. If any of the factors were present, then the case was defined as longer antibiotic treatment warranted (LW) group; those without any factors were defined as shorter antibiotic treatment sufficient (SS) group. Poor outcome was defined as a composite of 90-day mortality or 30-day recurrence. Duration of antibiotic administration was classified as <14 or ≥14 days in the SS group and <28 or ≥28 days in the LW group.

    RESULTS Among 2098 cases, the outcome was analysed in 1866 cases, of which 591 showed poor outcome. The SS group accounted for 964 cases and the LW group for 852. On multivariate analysis, age over 65 years, pneumonia, higher Sequential Organ Failure Assessment (SOFA) score and chronic liver diseases were risk factors for poor outcome. Administration of antibiotics less than the recommendation was associated with poor outcome, but this significance was observed only in the LW group (adjusted odds ratio = 1.68; 95% confidence interval, 1.00-2.83; p 0.05).

    CONCLUSIONS Inappropriately short antibiotic treatment was associated with poor outcome in the LW group. Vigilant evaluation for risk factors to determine the duration of treatment may improve the outcome among patients with SAB.

    PubMed IF 8.7 감염내과
25. 28242019

    제1저자 송영신 · 교신저자 박영주

    Song YS, Yoo SK, Kim HH, Jung G, Oh AR, Cha JY, Kim SJ, Cho SW, Lee KE, Seo JS, Park YJ

    Interaction of BRAF-induced ETS factors with mutant TERT promoter in papillary thyroid cancer.

    Endocr Relat Cancer. 2019;26(6):629-641.

    Abstract

    Synergistic effects of BRAFV600E and TERT promoter mutations on the poor clinical outcomes in papillary thyroid cancer (PTC) have been demonstrated. The potential mechanism of this phenomenon has been proposed: MAPK pathway activation by the BRAFV600E mutation may upregulate E-twenty six (ETS) transcription factors, increasing TERT expression by binding to the ETS-binding site generated by the TERT promoter mutation; however, it has not yet been fully proven. This article provides transcriptomic insights into the interaction between BRAFV600E and TERT promoter mutations mediated by ETS factors in PTC. RNA sequencing data on 266 PTCs from The Cancer Genome Atlas and 65 PTCs from our institute were analyzed for gene expression changes and related molecular pathways, and the results of transcriptomic analyses were validated by in vitro experiments. TERT mRNA expression was increased by the coexistence of BRAFV600E and TERT promoter mutations (fold change, 16.17; q-value = 7.35 × 10-12 vs no mutation). In the ETS family of transcription factors, ETV1, ETV4 and ETV5 were upregulated by the BRAFV600E/MAPK pathway activation. These BRAFV600E-induced ETS factors selectively bound to the mutant TERT promoter. The molecular pathways activated by BRAFV600E were further augmented by adding the TERT promoter mutation, and the pathways related to immune responses or adhesion molecules were upregulated by TERT expression. The mechanism of the synergistic effect between BRAFV600E and TERT promoter mutations on cancer invasiveness and progression in PTC may be explained by increased TERT expression, which may result from the BRAF-induced upregulation of several ETS transcription factors.

    PubMed IF 4.4 내분비대사내과
26. 28232019

    제1저자 최영훈 · 교신저자 이상협

    Choi YH, Lee JW, Lee SH, Choi JH, Kang J, Lee BS, Paik WH, Ryu JK, Kim YT

    A High Monocyte-to-Lymphocyte Ratio Predicts Poor Prognosis in Patients with Advanced Gallbladder Cancer Receiving Chemotherapy.

    Cancer Epidemiol Biomarkers Prev. 2019;28(6):1045-1051.

    Abstract

    BACKGROUND Monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) have been reported to be prognostic markers in various cancers. However, the prognostic value of these inflammatory biomarkers, particularly MLR, in gallbladder cancer remains to be determined.

    METHODS From 2005 to 2016, 178 patients with histologically confirmed gallbladder adenocarcinoma who underwent palliative chemotherapy were queried in this study. The association between survival and various clinical and laboratory variables, including MLR, NLR, and PLR, was investigated. The optimal cutoff values for MLR, NLR, and PLR were determined using the maxstat package of R.

    RESULTS Patients with high MLR (>0.24) were expected to have shorter progression-free survival [PFS; hazard ratio (HR), 2.100; 95% confidence interval (CI), 1.397-3.157; P < 0.001] and overall survival (OS; HR, 2.533; 95% CI, 1.664-3.856; P < 0.001) compared with patients with low MLR (≤0.24). In multivariate Cox model, CA 19-9, stage, and MLR were independent factors for PFS. MLR was also an independent predictor of OS along with PLR, age, and CA 19-9, whereas NLR was not significantly associated with OS. Time-dependent receiver operating characteristic (ROC) analysis showed that the area under the curve of MLR for predicting OS was greater than that of NLR and PLR at most time points.

    CONCLUSIONS MLR independently predicts survival in gallbladder cancer patients undergoing chemotherapy. Future prospective studies are needed to validate its value as a prognostic biomarker.

    IMPACT MLR is an inexpensive and easily available biomarker for predicting prognosis in patients with gallbladder cancer undergoing chemotherapy.

    PubMed IF 3.7 소화기내과
27. 28222019

    제1저자 이소령 · 교신저자 최의근

    Lee SR, Choi EK, Han KD, Jung JH, Cha MJ, Oh S, Lip GYH

    Non-Vitamin K Antagonist Oral Anticoagulants in Asian Patients With Supranormal Renal Function.

    Stroke. 2019;50(6):1480-1489.

    Abstract

    Background and Purpose- In clinical trials, the reduced efficacy of non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention was reported for patients with nonvalvular atrial fibrillation with a creatinine clearance (CrCl) >95 mL/min compared with that of warfarin. We examined the effectiveness, safety, and net clinical benefit of NOACs compared with warfarin in Asian patients with atrial fibrillation and supranormal renal function. Methods- Using data from the Korean National Health Insurance Service database from January 2014 to December 2016, we included patients with nonvalvular atrial fibrillation with CrCl >80 mL/min. Among these incident oral anticoagulant users with rivaroxaban (n=6297), dabigatran (n=4241), apixaban (n=3395), edoxaban (n=1187), and warfarin (n=9884) were analyzed. Propensity score weighting was used to balance covariates across study groups. Hazard ratios for ischemic stroke, intracranial hemorrhage, gastrointestinal bleeding, major bleeding, all-cause death, and the composite outcome defined as ischemic stroke+intracranial hemorrhage+gastrointestinal bleeding+all-cause death were analyzed using Cox regression analysis with warfarin as the reference. Results- Baseline characteristics were well balanced among all groups (mean age, 66±11 years; 63% were men; mean CHA₂DS₂-VASc score, 3.0±1.8). Forty-five percent of the patients had CrCl >95 mL/min. Pooled NOACs yielded lower risks of ischemic stroke (hazard ratio, 0.51; 95% CI, 0.43-0.60) and the composite outcome (hazard ratio, 0.64; 95% CI, 0.58-0.70) than warfarin in patients with CrCl >80 mL/min. These benefits were consistent in those with CrCl >95 mL/min. All 4 NOACs reduced the risks of ischemic stroke and the composite outcome in both patients with CrCl >80 mL/min and >95 mL/min. Conclusions- The NOACs showed better effectiveness and safety than warfarin in the patients with atrial fibrillation and supranormal renal function; this was consistently observed for all 4 NOACs and in patients with CrCl >95 mL/min.

    PubMed IF 11.1 6.239
28. 28212019

    제1저자 고성준 · 교신저자 이국래

    Koh SJ, Choi YI, Kim Y, Kim YS, Choi SW, Kim JW, Kim BG, Lee KL

    Walnut phenolic extract inhibits nuclear factor kappaB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice.

    Eur J Nutr. 2019;58(4):1603-1613.

    Abstract

    PURPOSE Walnuts (Juglans regia) are known to have anti-cancer and immunomodulatory effects. However, little information is available on the effects of walnut phenolic extract (WPE) on intestinal inflammation and colitis-associated colon cancer.

    METHODS COLO205 cells were pretreated with WPE and then stimulated with tumor necrosis factor (TNF)-α. In the acute colitis model, wild type mice (C57BL/6) were administered 4% dextran sulfate sodium (DSS) for 5 days. In the chronic colitis model, interleukin (IL)-10^-/- mice were administered with either the vehicle or WPE (20 mg/kg) by oral gavage daily for 2 weeks. In an inflammation-associated tumor model, wild type mice were administered a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption.

    RESULTS WPE significantly inhibited IL-8 and IL-1α expression in COLO205 cells. WPE attenuated both the TNF-α-induced IκB phosphorylation/degradation and NF-κB DNA binding activity. The administration of oral WPE significantly reduced the severity of colitis in both acute and chronic colitis models, including the IL-10^-/- mice. In immunohistochemical staining, WPE attenuated NF-κB signaling in the colons of both colitis models. Finally, WPE also significantly reduced tumor development in a murine model of colitis-associated colon cancer (CAC).

    CONCLUSIONS WPE ameliorates acute and chronic colitis and CAC in mice, suggesting that WPE may have potentials for the treatment of inflammatory bowel disease.

    PubMed IF 4.5 소화기내과
29. 28202019

    제1저자 정고은 · 교신저자 김영선

    Chung GE, Youn J, Kim YS, Lee JE, Yang SY, Lim JH, Song JH, Doo EY, Kim JS

    Dietary patterns are associated with the prevalence of nonalcoholic fatty liver disease in Korean adults.

    Nutrition. 2019;62:32-38.

    Abstract

    OBJECTIVES There is minimal research on the effect of overall dietary patterns on the development of nonalcoholic fatty liver disease (NAFLD) in the Korean population. The present study investigated the association between dietary patterns and NAFLD.

    METHODS A prospective cross-sectional study was performed on participants who visited a health care center for a health checkup. A semiquantitative food frequency questionnaire was administered to the participants to assess their food intake, and factor analysis was used to identify dietary patterns. Relationships between the dietary patterns and the risk of NAFLD were evaluated.

    RESULTS A total of 331 of the 1190 participants (27.8%) analyzed were diagnosed with NAFLD. Three factors were generated and defined as the traditional pattern, Western and high-carbohydrate pattern, and simple meal pattern using a factor analysis procedure. The traditional pattern revealed a positive correlation with NAFLD, and the simple meal pattern exhibited an inverse correlation with NAFLD. We adjusted for confounding factors, such as age, sex, waist circumference, smoking status, total energy intake, diabetes, and hypertension, and participants in the highest quartile of the traditional dietary pattern exhibited a higher prevalence of NAFLD (P for trend = 0.0373; odds ratio, 1.85; 95% confidence interval, 1.11-3.08) than participants in the lowest quartile. Participants in highest quintile of the simple meal pattern exhibited a decreased risk of NAFLD compared with the lowest quintile (P for trend = 0.0233; odds ratio 0.59; 95% confidence interval 0.34-1.00).

    CONCLUSIONS The traditional dietary pattern was associated with an increased risk of NAFLD, and the simple meal pattern was associated with a decreased risk of NAFLD in the Korean population. This finding supports the use of dietary patterns to predict the risk of NAFLD and potentially serve as a dietary prevention strategy in individuals who are at high risk of developing NAFLD.

    PubMed IF 3.6 소화기내과
30. 28192019

    제1저자 강은정 · 교신저자 윤형진, 이하정

    Kang E, Park M, Park PG, Park N, Jung Y, Kang U, Kang HG, Kim DK, Oh KH, Joo KW, Kim YS, Yoon HJ, Lee H

    Acute kidney injury predicts all-cause mortality in patients with cancer.

    Cancer Med. 2019;8(6):2740-2750.

    Abstract

    BACKGROUND Acute kidney injury (AKI) is a critical issue in cancer patients because it is not only a morbid complication but also able to interrupt timely diagnostic evaluation or planned optimal treatment. However, the impact of AKI on overall mortality in cancer patients remains unclear.

    METHODS We conducted a retrospective cohort study of 67 986 cancer patients, from 2004 to 2013 to evaluate the relationship between AKI and all-cause mortality. We used KDIGO AKI definition and grading system.

    RESULTS During 3.9 ± 3.1 years of follow-up, 33.8% of the patients experienced AKI at least once. Among AKI events, stage 1, 2, and 3 was 71.0%, 13.8%, and 15.1%, respectively. AKI incidence was highest in hematologic malignancies, followed by urinary tract cancer, and hepatocellular carcinoma. Male sex, older age, underlying diabetes and hypertension, lower serum albumin and plasma hemoglobin, more frequent radio-contrast exposure, entrance of clinical trials, and receiving chemotherapy were associated with AKI occurrence. AKI development was an independent risk factor for elevated mortality in cancer patients with dose-responsive manner (Stage 1, hazard ratio [HR] 1.183, 95% confidence interval [CI] 1.145-1.221, P < 0.001; Stage 2, HR 1.710, 95% CI 1.629-1.796; Stage 3, HR 2.000, 95% CI 1.910-2.095; No AKI, reference group) even after adjustment. This tendency was reproduced in various cancer types except thyroid cancer and in various treatment modalities, however, not shown in patients with baseline renal dysfunction.

    CONCLUSION AKI was an independent risk factor for all-cause mortality in overall cancer patients with dose-responsive manner.

    PubMed IF 3.5 신장내과

서울대학교병원 내과 교실이 발표한 SCI 논문입니다. 제목을 누르면 Abstract · 그림 등을, 저자 이름을 누르면 소속 · PubMed · ORCID 를 볼 수 있습니다. 굵은 이름은 동문과 연결된 저자입니다.