SCI 발표논문

1. 2982021

   제1저자 나지은 · 교신저자 신동현, 이정훈

   Na JE, Sinn DH, Lee JH, Jang HJ, Baek SY, Kim KA, Kang WS, Gwak GY, Paik YH, Kim YJ, Choi MS, Yoon JH, Lee JH, Koh KC, Paik SW

   Efficacy of entecavir versus tenofovir in preventing hepatocellular carcinoma in patients with chronic hepatitis B with maintained virologic response.

   J Viral Hepat. 2021;28(10):1392-1399.

   Abstract

   BACKGROUND & AIMS Several studies suggested that efficacy of tenofovir in reducing the risk of the development of hepatocellular carcinoma (HCC) might be better than that of entecavir. It remains unknown whether a change in therapy can further reduce the risk of HCC in patients receiving entecavir therapy and achieved goal of antiviral therapy, a maintained undetectable hepatitis B virus (HBV) DNA level in the serum.

   METHODS A total of 1336 treatment-naïve chronic HBV mono-infected adult patients, who started entecavir or tenofovir treatment and achieved a maintained virologic response during follow-up were analysed.

   RESULTS During a median 4.4 years of follow-up (range, 1.0-7.4 years) after achieving virologic response, 99 patients developed HCC. The 5-year cumulative HCC incidence rate was 7.3% and 6.3% for the entecavir and tenofovir groups, respectively, with similar risk of HCC between the two groups (adjusted HR, 0.82; 95% CI, 0.52-1.29; p = 0.3). The risk of HCC was similar in the propensity score-matched cohort (HR, 1.02; 95% CI, 0.68-1.52; p = 0.94) and inverse probability treatment weighting analysis (HR, 1.11; 95% CI, 0.74-1.66; p = 0.62). In the subgroup analysis, HCC risk was similar between the two drugs in both patients with and without cirrhosis.

   DISCUSSION In patients showing maintained virologic response, no difference in the risk of HCC between entecavir and tenofovir was observed. This indicates entecavir might be as effective as tenofovir in the prevention of HCC among those patients and suggest that a change in therapy in anticipation of further reducing the risk of HCC might not be necessary for patients receiving entecavir and showing virologic response.

   PubMed IF 2.3 소화기내과
2. 2972021

   제1저자 박세훈 · 교신저자 한경도, 김동기

   Park S, Cho S, Lee S, Kim Y, Park S, Kim YC, Han SS, Lee H, Lee JP, Joo KW, Lim CS, Kim YS, Han K, Kim DK

   The Prognostic Significance of Body Mass Index and Metabolic Parameter Variabilities in Predialysis CKD: A Nationwide Observational Cohort Study.

   J Am Soc Nephrol. 2021;32(10):2595-2612.

   Abstract

   BACKGROUND The association between variabilities in body mass index (BMI) or metabolic parameters and prognosis of patients with CKD has rarely been studied.

   METHODS In this retrospective observational study on the basis of South Korea's national health screening database, we identified individuals who received ≥3 health screenings, including those with persistent predialysis CKD (eGFR <60 ml/min per 1.73 m² or dipstick albuminuria ≥1). The study exposure was variability in BMI or metabolic parameters until baseline assessment, calculated as the variation independent of the mean and stratified into quartiles (with Q4 the highest quartile and Q1 the lowest). We used Cox regression adjusted for various clinical characteristics to analyze risks of all-cause mortality and incident myocardial infarction, stroke, and KRT.

   RESULTS The study included 84,636 patients with predialysis CKD. Comparing Q4 versus Q1, higher BMI variability was significantly associated with higher risks of all-cause mortality (hazard ratio [HR], 1.66; 95% confidence interval [95% CI], 1.53 to 1.81), P [for trend] <0.001), KRT (HR, 1.20; 95% CI, 1.09 to 1.33; P<0.001), myocardial infarction (HR, 1.19; 95% CI, 1.05 to 1.36, P=0.003), and stroke (HR, 1.19; 95% CI, 1.07 to 1.33, P=0.01). The results were similar in the subgroups divided according to positive or negative trends in BMI during the exposure assessment period. Variabilities in certain metabolic syndrome components (e.g., fasting blood glucose) also were significantly associated with prognosis of patients with predialysis CKD. Those with a higher number of metabolic syndrome components with high variability had a worse prognosis.

   CONCLUSIONS Higher variabilities in BMI and certain metabolic syndrome components are significantly associated with a worse prognosis in patients with predialysis CKD.

   PubMed IF 9.7 신장내과
3. 2962021

   제1저자 박세훈, 강성진 · 교신저자 임예지, 이하정

   Park S^*, Kang SJ^*, Lee JW, Kim JE, Kim Y, Kim K, Park M, Kim YC, Kim YS, Lim Y, Lee H

   Association between early post-transplant hypertension or related antihypertensive use and prognosis of kidney transplant recipients: a nationwide observational study.

   J Nephrol. 2021;34(5):1457-1465.

   Abstract

   BACKGROUND Additional research is warranted for the clinical significance of post-transplant hypertension and related antihypertensive medication use in kidney transplant (KT) recipients.

   METHODS This observational study included nationwide KT recipients who maintained a functioning graft for at least 1 year after KT in South Korea, observed between 2008 and 2017. The use of antihypertensive medications lasting between 6 months and 1 year was the main exposure, and those who had inconsistent/transient use of antihypertensive drugs were excluded. The prognostic outcome included death-censored graft failure (DCGF), death-with functioning graft (DWFG), and major adverse cerebrocardiovascular events (MACCEs).

   RESULTS We included 8,014 patients without post-transplant hypertension and 6,114 recipients who received treatment for hypertension in the post-transplant period. Those with post-transplant hypertension had a significantly higher risk of DCGF than those without [adjusted hazard ratio (HR) 1.27 (1.09-1.48)]. Post-transplant hypertension patients who required multiple drugs showed a significantly higher risk of DWFG [HR 1.57 (1.17-2.10)] and MACCE [HR 1.35 (1.01-1.81)] than the controls. Among the single-agent users, those who received beta-blockers showed a significantly higher risk of DCGF, although the risks of DWFG or MACCE were similar between the types of antihypertensive agents. Among the multiple agent users, the prognosis was similar, regardless of the prescribed types of antihypertensive agents.

   CONCLUSION Post-transplant hypertension was associated with poor post-transplant prognosis, particularly when multiple types of medications were required for treatment. During initial prescription of antihypertensive medication, clinicians may consider that beta-blockers were associated with a higher risk of DCGF in the single-agent users.

   PubMed IF 2.6 신장내과
4. 2952021

   제1저자 이창훈 · 교신저자 곽민선

   Lee CH, Han KD, Yoo J, Kwak MS

   Synergistic harmful interaction between sustained physical inactivity and hypertension/diabetes mellitus on the risk of all-cause mortality: a retrospective observational cohort study.

   J Hypertens. 2021;39(10):2058-2066.

   Abstract

   OBJECTIVE Hypertension, diabetes mellitus and physical inactivity can cause cardiovascular complications or premature death. However, it has not been clarified whether those major comorbidities and physical activity interact in affecting health outcomes. The aim of this study is to evaluate the potential interaction between temporal physical activity profiles and hypertension or diabetes mellitus on the risk for all-cause mortality.

   METHODS This study used Korea National Health Insurance Service (KNHIS) database and included about 6.5 million participants who underwent health screening in 2009 and 2011. Physical activity was evaluated as 2-year change based on self-reported survey using 7-day recall method, and grouped as remained active, inactive-to-active, active-to-inactive, or remained inactive. Participants were categorized into groups according to the presence of hypertension/diabetes mellitus. Outcome included all-cause mortality.

   RESULTS In total, 6 554 082 participants (48.4 ± 13.3 years; 56.7% men) were included. During a median 6.4-year follow-up, 83 241 deaths occurred. Compared with the 'remained active' group, other groups had a higher mortality risk after adjustment for covariates [adjusted hazard ratio (aHR) 1.17, 95% CI 1.13-1.21 in the 'inactive-to-active' group, aHR 1.28, 95% CI 1.24-1.32 in the 'active-to-inactive' group, aHR 1.52, 95% CI 1.48-1.57 in the 'remained inactive' group). Hypertension and diabetes mellitus were significant effect modifiers in the association between physical activity and the risk of all-cause mortality (P for interaction <0.001). The harmful effects of persistent physical inactivity on all-cause mortality were the most obvious in those with both hypertension and diabetes mellitus among groups.

   CONCLUSION Sustained physical inactivity was associated with increased risk of all-cause mortality in those with hypertension or diabetes mellitus more strongly than in those without. Physicians should emphasize sustained physical activity even more in patients with hypertension or diabetes mellitus.

   PubMed IF 5.6 소화기내과
5. 2942021

   제1저자 이해영 · 교신저자 김철호

   Lee HY, Kim KI, Ihm SH, Rhee MY, Sohn IS, Park S, Jeon ES, Song JM, Pyun WB, Sung KC, Kim MH, Kim SH, Kim SY, Kim SJ, Kim EJ, Shin J, Lee SY, Chun KJ, Jeong JO, Chae SC, Yoo KD, Choi YJ, Park YH, Kim CH

   A Randomized, Double-blind, Active-controlled, Two Parallel-Group, Optional Titration, Multicenter, Phase IIIb Study to Evaluate the Efficacy and Safety of Fimasartan Versus Perindopril Monotherapy With and Without a Diuretic Combination in Elderly Patients With Essential Hypertension.

   Clin Ther. 2021;43(10):1746-1756.

   Abstract

   PURPOSE The efficacy and tolerability of fimasartan in elderly patients have not been fully evaluated. This study was therefore conducted to determine the efficacy and tolerability of fimasartan compared with perindopril in elderly Korean patients aged >70 years with essential hypertension (defined by a mean sitting systolic blood pressure [SBP] ≥140 mm Hg).

   METHODS This randomized, double-blind, active-controlled, 2 parallel-group, optional titration, multicenter, Phase IIIb trial (FITNESS [Fimasartan in the Senior Subjects]) enrolled 241 patients from 23 cardiac centers in the Republic of Korea between August 2017 and December 2019. After the placebo run-in period, treatment started with fimasartan 30 mg or perindopril arginine 2.5 mg once daily at a 1:1 ratio; if BP was not controlled at week 4, the dose was doubled. If BP was not controlled at week 8, a diuretic combination (fimasartan 60 mg/hydrochlorothiazide 12.5 mg or perindopril arginine 5 mg/indapamide 1.25 mg) was administered. After 16 weeks of the double-blind treatment, the patients with controlled BP participated in an 8-week open-label extension study, with the 2 groups unified by fimasartan 60 mg with or without hydrochlorothiazide 12.5 mg for 8 weeks. The primary outcome was a change in SBP for 8 weeks. The secondary outcomes included a change in sitting diastolic BP (DBP) for 8 weeks and changes in SBP and DBP for 4, 16, and 24 weeks.

   FINDINGS At week 8, mean SBP significantly decreased from baseline in both groups: -14.2 (14.4) mm Hg in the fimasartan group and -9.0 (16.1) mm Hg in the perindopril group. The difference between the 2 groups was 5.4 (2.1) mm Hg, indicating the noninferiority of fimasartan to perindopril. Moreover, fimasartan exhibited a higher BP-lowering effect than perindopril (P = 0.0108). In addition, reductions in SBP and DBP from baseline to weeks 4, 8, and 16 were significantly greater in the fimasartan group than in the perindopril group, although the SBP reduction was comparable at week 16. Both groups reported an excellent mean compliance rate of 97.4% (4.7%) through week 16. During the study period, 82 adverse events were reported in 52 patients, 40 in the fimasartan group and 42 in the perindopril group (P = 0.4647). Dizziness was the most commonly reported adverse event (7 cases). Remarkably, only 1 case of orthostatic hypotension was reported during the study period.

   IMPLICATIONS In elderly patients with essential hypertension, fimasartan 30 to 60 mg with a possible hydrochlorothiazide 12.5-mg combination was noninferior to perindopril 2.5 to 5 mg with a possible indapamide 1.25-mg combination. Furthermore, fimasartan exhibited higher BP-lowering efficacy than perindopril. There was no difference in tolerability between the 2 groups. Clinicaltrials.gov Identifier: NCT03246555.

   PubMed IF 3.7 순환기내과
6. 2932021

   제1저자 김화정, 김유정 · 교신저자 권정혜

   Kim HJ, Kim YJ, Kwon JH, Won YW, Lee HY, Baek SK, Ryu H, Kim DY

   Current Status and Cardinal Features of Patient Autonomy after Enactment of the Life-Sustaining Treatment Decisions Act in Korea.

   Cancer Res Treat. 2021;53(4):917-925.

   Abstract

   PURPOSE The main purpose of the Life-Sustaining Treatment Decisions Act recently enacted in Korea is to respect the patient's self-determination. We aimed to investigate the current status and features of patient self-determination after implementation of the law.

   MATERIALS AND METHODS Between February 2018 and January 2019, 54,635 cancer deaths were identified from the National Health Insurance Service (NHIS) database. We analyzed the characteristics of decedents who complied with the law process by self-determination compared with decedents with family determination and with decedents who did not comply with the law process.

   RESULTS In multivariable analysis, patients with self-determination were younger, were less likely to live in rural areas, were less likely to belong to the highest income quintile, were less likely to be treated in general hospitals, and were more likely to show a longer time from cancer diagnosis compared with patients with family determination. Compared with patients who did not comply with the law process, patients with self-determination were younger, lived in Seoul or capital area, were less likely to belong to the highest income quintile, were treated in general hospitals, were less likely to have genitourinary or hematologic malignancies, scored higher on the Charlson comorbidity index, and showed a longer time from cancer diagnosis. Patients with self-determination were more likely to use hospice and less likely to use intensive care units (ICUs) at the end-of-life (EOL).

   CONCLUSION Decedents with self-determination were more likely to be younger, reside in the Seoul or capital area, show a longer time from cancer diagnosis, and were less likely to belong to the highest income quintile. They utilized hospice more frequently, and received less ICU care at the EOL.

   PubMed IF 4.2 혈액종양내과
7. 2922021

   제1저자 정석송, 조유리 · 교신저자 박상민, 김원

   Jeong S, Cho Y, Park SM, Kim W

   Differential Effectiveness of Tenofovir and Entecavir for Prophylaxis of Hepatocellular Carcinoma in Chronic Hepatitis B Patients Depending on Coexisting Cirrhosis and Prior Exposure to Antiviral Therapy: A Systematic Review and Meta-analysis.

   J Clin Gastroenterol. 2021;55(9):e77-e86.

   Abstract

   GOALS This meta-analysis evaluated the comparative effectiveness of tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) in reducing the risk of hepatocellular carcinoma (HCC).

   BACKGROUND It is unclear whether TDF or ETV is more effective in reducing the risk of HCC in chronic hepatitis B (CHB) patients with or without underlying cirrhosis.

   METHODS We searched the MEDLINE database through April 13, 2020, for studies involving CHB treated with TDF and/or ETV. Primary and secondary outcomes were the incidence of HCC and overall survival, respectively, calculated as risk ratios (RRs). Adjusted results were further evaluated by pooling propensity score matched cohorts.

   RESULTS Of the 229 records identified, 17 studies were included in the quantitative analysis. TDF treatment was associated with a significantly lower risk of HCC development [RR, 0.63; 95% confidence interval (CI), 0.43-0.93; P=0.024] and mortality (RR, 0.69; 95% CI, 0.57-0.84; P=0.003) than ETV treatment. Moreover, TDF significantly lowered HCC risk in patients with cirrhosis (RR, 0.69; 95% CI, 0.56-0.84) and antiviral treatment-naive patients (RR, 0.59; 95% CI, 0.35-0.98) compared with ETV. Among treatment-naive patients, TDF significantly prolonged survival compared with ETV (RR, 0.69; 95% CI, 0.52-0.91).

   CONCLUSIONS TDF likely confers a lower risk of HCC development and longer survival in patients with CHB, especially among treatment-naive patients and those with underlying cirrhosis, than ETV.

   PubMed IF 2.7 소화기내과
8. 2912021

   제1저자 김연욱 · 교신저자 이춘택

   Kim YW, Kwon BS, Lim SY, Lee YJ, Park JS, Cho YJ, Yoon HI, Lee KW, Lee JH, Chung JH, Ji E, Lee CT

   Lung cancer probability and clinical outcomes of baseline and new subsolid nodules detected on low-dose CT screening.

   Thorax. 2021;76(10):980-988.

   Abstract

   BACKGROUND Limited data are available regarding the management of subsolid nodules detected on lung cancer screening with low-dose CT (LDCT). We aimed to determine the characteristics of screen-detected subsolid nodules, and to evaluate the probability of lung cancer and the clinical course of subsolid nodules detected at baseline and during follow-up screening.

   METHODS We evaluated 50 132 asymptomatic adults (22 631 never-smokers and 27 501 ever-smokers) who underwent LDCT screening for lung cancer between May 2003 and June 2019 at a tertiary centre in South Korea. The incidence, characteristics and clinical outcomes of the baseline and new screen-detected subsolid nodules were determined.

   RESULTS A total of 6725 subsolid nodules (5116 pure ground glass opacity nodules and 1609 part-solid nodules) were detected in 4545 participants (1484 new subsolid nodules detected in 937 (1.9%) participants; the overall incidence of subsolid nodules: 10.7% in never-smokers and 7.7% in ever-smokers, p<0.001). Among 4918 subsolid nodules that underwent follow-up with CT scans (the mean number of CT scans, including the baseline LDCT scan: 4.6), 2116 nodules (30.0% of baseline subsolid nodules and 78.9% of new subsolid nodules) resolved spontaneously. Among 293 biopsied subsolid nodules, 227 (77.5%) nodules were diagnosed as lung cancer, of which 226 (99.6%) were adenocarcinomas. No significant difference was observed in pathological invasiveness or the initial stage between the baseline and new cancerous subsolid nodules. Multivariable analyses revealed that new detection at follow-up screening was significantly associated with a lower probability of lung cancer (OR 0.26, 95% CI 0.14 to 0.49) and overall growth (OR 0.39, 95% CI 0.26 to 0.59), but with a higher probability of resolution (OR 6.30, 95% CI 5.09 to 7.81).

   CONCLUSIONS LDCT screening led to a considerably high rate of subsolid nodule detection, particularly in never-smokers. Compared with the baseline subsolid nodules, the new subsolid nodules were associated with a lower probability of lung cancer and higher probability of spontaneous resolution, indicating their more inflammatory nature. Less aggressive follow-up may be allowed for new subsolid nodules, particularly in screening programmes for Asian populations.

   PubMed IF 9.1 호흡기내과
9. 2902021

   제1저자 김세훈 · 교신저자 김태범

   Kim SH, Lee T, Jang AS, Park CS, Jung JW, Kim MH, Kwon JW, Moon JY, Yang MS, Lee J, Choi JH, Shin YS, Kim HK, Kim S, Kim JH, Lee SY, Nam YH, Kim SH, Kim TB, Cohort for Reality and Evolution of Adult Asthma (COREA) Study Group

   Pragmatic Randomized Controlled Trial for Stepping Down Asthma Controller Treatment in Patients Controlled with Low-Dose Inhaled Corticosteroid and Long-Acting β2-Agonist: Step-Down of Intervention and Grade in Moderate Asthma Study.

   J Allergy Clin Immunol Pract. 2021;9(10):3638-3646.e3.

   Abstract

   BACKGROUND Current asthma guidelines recommend stepping down controller treatment when the condition is well-controlled for a certain time. However, the optimal step-down strategy for well-controlled patients receiving a low-dose inhaled corticosteroid (ICS) with a long-acting β₂-agonist (LABA) remains unclear.

   OBJECTIVE This study was a randomized, open-label, three-arm, parallel pragmatic trial comparing two kinds of step-down approaches for maintaining treatment.

   METHODS Adults with asthma who were aged 18 years or older, and who had been stable with low-dose ICS/LABA for at least 3 months, were enrolled. Subjects (n = 225) were randomly allocated into one of three groups (maintaining low-dose ICS/LABA [G1], discontinuing LABA [G2], and reducing ICS/LABA to once daily [G3]), and were observed for 6 months. The primary end point was a change in Asthma Control Test (ACT) scores between randomization and the final 6-month follow-up.

   RESULTS The change in ACT was analyzed in the per-protocol population; noninferiority was not demonstrated in either step-down group compared with the maintenance group (95% confidence interval of the difference, G2 vs G1 = -1.40-0.55; G3 vs G1 = -1.19-0.77). Although over 90% of patients were fine, higher rates of treatment failure were observed in step-down groups (G1: 0%; G2: 9.46%; and G3: 9.09%; P = .027). There were no significant differences between step-down approaches in terms of ACT change or treatment failure.

   CONCLUSIONS Both step-down methods were not noninferior to maintenance of treatment. Step-down therapy can be attempted when patients are stable, but appropriate monitoring and supervision are necessary with precautions regarding loss of disease control.

   PubMed IF 6.6 알레르기내과
10. 2892021

    제1저자 차명진 · 교신저자 김효수

    Cha MJ, Oh GC, Ki YJ, Chang M, Kang J, Han JK, Yang HM, Park KW, Kang HJ, Koo BK, Oh S, Kim HS

    Time Course and Risk Factors of New-Onset Complete Atrioventricular Block After Transcatheter Aortic Valve Implantation.

    Int Heart J. 2021;62(5):988-996.

    Abstract

    In this study, we aimed to investigate the time course of new-onset complete atrioventricular block (CAVB) and its reversibility after transcatheter aortic valve implantation (TAVI). We analyzed 206 consecutive patients without baseline CAVB who underwent successful TAVI. The incidence of new-onset CAVB was determined to be 12.6% (26/206). Among these patients, 14 recovered from CAVB within 2 weeks (6.8%, 14/206), while the remaining 12 (5.8%, 12/206) underwent permanent pacemaker (PPM) insertion. Among the 12 patients who received the PPM, 4 were able to recover from CAVB within 4 months. Thus, only 8 among 206 patients (3.8%) showed persistent CAVB. Early-onset CAVB on the day of the procedure was the strongest predictor of PPM implantation (OR = 127). The electrocardiographic changes that occurred after TAVI were mostly recovered after 1 month. The most critical procedural factor that predicts CAVB and PPM insertion is the deep implantation (>4 mm) of a big valve (oversizing index >5.9%). In conclusion, the incidence of CAVB after TAVI was estimated to be at 12.6%. Two-thirds of these patients recovered from CAVB within 3 days, resulting in a final rate of persistent CAVB of 4%. To prevent CAVB, we have to implant an appropriate valve type with an optimal size and depth.

    PubMed IF 1.4 순환기내과
11. 2882021

    제1저자 Enerelt Natsagdorj · 교신저자 김상균

    Natsagdorj E, Kim SG, Choi J, Kang S, Kim B, Lee E, Chung H, Cho SJ

    Clinical Outcomes of Endoscopic Submucosal Dissection for Early Gastric Cancer in Patients with Comorbidities.

    J Gastric Cancer. 2021;21(3):258-267.

    Abstract

    PURPOSE As the rate of endoscopic resection for early gastric cancer (EGC) has increased in patients with comorbid diseases, it is necessary to elucidate the efficacy of endoscopic submucosal dissection (ESD) for EGC in patients with comorbidities. This study aimed to analyze the clinical outcomes of ESD for EGC in patients with comorbidities.

    MATERIALS AND METHODS A total of 969 patients with 1,015 lesions who underwent ESD for EGC at Seoul National University Hospital between 2010 and 2014 were analyzed. The short- and long-term clinical outcomes were evaluated according to the comorbidity status.

    RESULTS Comorbidities were observed in 558 patients (57.6%). The comorbidity group had a higher proportion of patients using antithrombotic agents (29.5% vs. 0.9%; P<0.0001). Although procedure-related complications (bleeding and perforation) were not significantly different between the two groups, the length of hospital stay was significantly longer (1.8 vs. 1.4 days, P=0.023), while survival was significantly shorter in the comorbidity group (5-year overall survival rate: 90.5% vs. 97.2%, P<0.0001; 5-year disease-specific survival rate: 97.9% vs. 100%, P=0.018; 5-year disease-free survival rate: 83.4% vs. 89.2%, P=0.007).

    CONCLUSIONS Gastric ESD can be performed in patients with comorbidities without increasing the risk of complications.

    PubMed IF 5.1 소화기내과
12. 2872021

    제1저자 남아롱, 윤지선 · 교신저자 오도연

    Nam AR, Yoon J, Jin MH, Bang JH, Oh KS, Seo HR, Kim JM, Kim TY, Oh DY

    ATR inhibition amplifies antitumor effects of olaparib in biliary tract cancer.

    Cancer Lett. 2021;516:38-47.

    Abstract

    Olaparib, a potent PARP inhibitor, has been shown to have great anti-tumor effects in some tumor types. Although biliary tract cancer (BTC) is a good candidate for DNA damage response (DDR)-targeted agents, targeted DDR inhibitors, including olaparib, are currently rarely evaluated in BTC. In our project, a total of ten BTC cell lines were used to assess the efficacy of olaparib. Olaparib alone showed moderate anti-proliferative effects in BTC cells and increased p-ATR and PD-L1 expression levels. In combination with an ATR inhibitor (AZD6738, ceralasertib) showed synergistic anti-proliferative effects and increased DNA strand breaks in vitro. PD-L1 induced by olaparib was also downregulated by ceralasertib through p-STAT-3 and YAP reduction with or without human primary peripheral blood mononuclear cells. In SNU478-xenograft models, the combination treatment significantly suppressed tumor growth. PD-L1 and YAP were strongly downregulated, similar to in vitro conditions, and expression of CXCR2 and CXCR4 was further reduced. In the current ongoing clinical trial (NCT04298021), BTC patients treated with olaparib and ceralasertib combination have shown tumor response. In conclusion, co-targeting of PARP and ATR might be a potential therapeutic approach for patients with BTC.

    PubMed IF 11.8 혈액종양내과
13. 2862021

    제1저자 최진우, 이송이, 조은주 · 교신저자 김효철, 조현종

    Choi JW, Lee SY, Cho EJ, Jeong DI, Kim DD, Kim HC, Cho HJ

    Gas generating microspheres for immediate release of Hsp90 inhibitor aiming at postembolization hypoxia in transarterial chemoembolization therapy of hepatocellular carcinoma.

    Int J Pharm. 2021;607:120988.

    Abstract

    CO₂ gas generating poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) was designed for rapid release of tanespimycin (17-AAG) in transarterial chemoembolization (TACE) treatment of hepatocellular carcinoma (HCC). As poorly water-soluble drug is generally released from PLGA MS in a sustained manner, the drug release profile should be controlled according to its clinical indications. In current study, responding to immediate increase in hypoxia inducible factor-1α (HIF-1α) level under hypoxia state followed by embolization of tumor feeding arteries, sodium bicarbonate (NaHCO₃) was added to PLGA/17-AAG MS for fast drug release by CO₂ gas generation in slightly acidic tumor microenvironment. With the aid of NaHCO₃, initial burst release of 17-AAG was available without losing the micron-size and spherical shape of designed MS for embolization of artery. Acid-responsive CO₂ gas generation and subsequent immediate release of 17-AAG from MS were successfully verified. PLGA/17-AAG/NaHCO₃ MS-treated group exhibited higher antiproliferation and apoptosis induction efficacies in McA-RH7777 and SNU-761 cells. McA-RH7777 tumor-implanted rats treated by TACE using PLGA/17-AAG/NaHCO₃ MS presented a complete therapeutic response. All these findings suggest that developed tumor microenvironment-responsive gas-generating MS can be efficiently applied to TACE therapy of HCC.

    PubMed IF 6 소화기내과
14. 2852021

    제1저자 김학령 · 교신저자 조상호

    Kim HL, Jo SH

    Current Evidence on Long-Term Prognostic Factors in Vasospastic Angina.

    J Clin Med. 2021;10(18):jcm10184270.

    Abstract

    Vasospastic angina (VSA) is characterized by a reversible spasm of the coronary arteries and is more prevalent in Asians. Vasodilators, such as calcium channel blockers, are effective in relieving coronary spasms and preventing clinical events. Therefore, the prognosis of VSA is generally known to be better than for significant organic stenosis caused by atherosclerosis. However, coronary vasospasm is sometimes associated with fatal complications such as sudden death, ventricular arrhythmia, and myocardial infarction. Thus, it is very important to identify and actively treat high-risk patients to prevent VSA complications. Here, we will review clinical factors associated with long-term prognosis in patients with VSA.

    PubMed IF 3.3 순환기내과
15. 2842021

    제1저자 이소령 · 교신저자 최의근

    Lee SR, Choi EK, Park SH, Jung JH, Han KD, Oh S, Lip GYH

    Off-label underdosed apixaban use in Asian patients with non-valvular atrial fibrillation.

    Eur Heart J Cardiovasc Pharmacother. 2021;7(5):415-423.

    Abstract

    AIMS To compare the effectiveness and safety of off-label underdosed apixaban with on-label standard dose apixaban in Asian patients with atrial fibrillation (AF).

    METHODS AND RESULTS Using the Korean nationwide claims database, we identified patients who were prescribed apixaban and did not fulfil the dose reduction criteria for apixaban between January 2015 and December 2017. A multivariable Cox hazard regression model was performed, and hazard ratios (HRs) for ischaemic stroke, major bleeding (MB), all-cause death, and composite outcome were analysed. Compared to patients prescribed on-label standard dose apixaban (n = 4194), patients prescribed off-label underdosed apixaban (n = 2890) showed a higher risk of ischaemic stroke [adjusted HR (aHR) 1.38, 95% confidence interval (CI) 1.06-1.81], all-cause death (aHR 1.19, 95% CI 1.01-1.39), and the composite outcome (aHR 1.17, 95% CI 1.03-1.34), but with no significant differences in MB between the two groups. Among the patients who did not meet any dose reduction criteria, off-label underdosed apixaban use was associated with a significantly higher risk of ischaemic stroke than on-label standard dose apixaban use (aHR 1.85, 95% CI 1.25-2.73). Among the patients who met a single dose reduction criterion, off-label underdosed apixaban use was associated with a higher risk of all-cause death than on-label standard dose apixaban (aHR 1.32, 95% CI 1.07-1.64).

    CONCLUSION The off-label underdosed apixaban group showed higher risks of ischaemic stroke, all-cause death, and composite clinical outcomes than the on-label standard dose apixaban group, but both showed comparable risks of MB. Label adherence to apixaban dosing should be emphasized to achieve the best clinical outcomes for Asian patients with AF.

    PubMed IF 8.2 순환기내과
16. 2832021

    제1저자 김정희, 이형철 · 교신저자 김수진

    Kim JH^*, Lee HC^*, Kim SJ, Yoon SB, Kong SH, Yu HW, Chai YJ, Choi JY, Lee KE, Lee KW, Min SK, Shin CS, Park KJ

    Perioperative hemodynamic instability in pheochromocytoma and sympathetic paraganglioma patients.

    Sci Rep. 2021;11(1):18574.

    Abstract

    For pheochromocytoma and sympathetic paraganglioma (PPGL), surgery can be used as a curative treatment; however, the life-threatening risk of perioperative hemodynamic instability (HI) presents challenges. This study aimed to analyze the incidence and predictive factors of perioperative HI. The electronic medical records of 114 consecutive patients who underwent surgery for PPGLs at our institution were retrospectively reviewed. HI was defined as one or more episodes of systolic blood pressure > 200 mmHg or mean blood pressure < 60 mmHg during surgery. The factors predictive of perioperative HI were determined using both univariate and multivariate analyses. Intraoperative HI occurred in 79 (69.3%) patients. In multivariate analysis, α-adrenergic receptor blocker duration (days) (odds ratio, 1.015; 95% confidence interval, 1.001-1.029) was a predictor for intraoperative HI. Postoperative hypotension occurred in 36 (31.6%) patients. Higher urine epinephrine levels, and greater preoperative highest heart rate (HR) were predictive factors for postoperative hypotension in PPGL patients. Caution should be taken in perioperative management for PPGL, especially with long duration of α-adrenergic receptor blocker use, higher urine epinephrine levels, and greater preoperative highest HR.

    PubMed IF 4.9 내분비대사내과
17. 2822021

    제1저자 이진우, 허진, 권유욱, 채정환 · 교신저자 김효수

    Lee JW^*, Hur J^*, Kwon YW^*, Chae CW^*, Choi JI, Hwang I, Yun JY, Kang JA, Choi YE, Kim YH, Lee SE, Lee C, Jo DH, Seok H, Cho BS, Baek SH, Kim HS

    KAI1(CD82) is a key molecule to control angiogenesis and switch angiogenic milieu to quiescent state.

    J Hematol Oncol. 2021;14(1):148.

    Abstract

    BACKGROUND Little is known about endogenous inhibitors of angiogenic growth factors. In this study, we identified a novel endogenous anti-angiogenic factor expressed in pericytes and clarified its underlying mechanism and clinical significance.

    METHODS Herein, we found Kai1 knockout mice showed significantly enhanced angiogenesis. Then, we investigated the anti-angiogenic roll of Kai1 in vitro and in vivo.

    RESULTS KAI1 was mainly expressed in pericytes rather than in endothelial cells. It localized at the membrane surface after palmitoylation by zDHHC4 enzyme and induced LIF through the Src/p53 pathway. LIF released from pericytes in turn suppressed angiogenic factors in endothelial cells as well as in pericytes themselves, leading to inhibition of angiogenesis. Interestingly, KAI1 had another mechanism to inhibit angiogenesis: It directly bound to VEGF and PDGF and inhibited activation of their receptors. In the two different in vivo cancer models, KAI1 supplementation significantly inhibited tumor angiogenesis and growth. A peptide derived from the large extracellular loop of KAI1 has been shown to have anti-angiogenic effects to block the progression of breast cancer and retinal neovascularization in vivo.

    CONCLUSIONS KAI1 from PC is a novel molecular regulator that counterbalances the effect of angiogenic factors.

    PubMed IF 47.8 순환기내과
18. 2812021

    제1저자 이영아, 이현정 · 교신저자 박영주, 김종일

    Lee YA, Lee H, Im SW, Song YS, Oh DY, Kang HJ, Won JK, Jung KC, Kwon D, Chung EJ, Hah JH, Paeng JC, Kim JH, Choi J, Kim OH, Oh JM, Ahn BC, Wirth LJ, Shin CH, Kim JI, Park YJ

    NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake.

    J Clin Invest. 2021;131(18):e144847.

    Abstract

    BACKGROUNDMolecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (131I-refractory) PTC.METHODSPTC samples from 106 pediatric patients (age range: 4.3-19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983-March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison.RESULTSWe identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAFV600E in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAFV600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAFV600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored 125I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received 131I therapy combined with selpercatinib, resulting in a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity.CONCLUSIONSIn pediatric patients with fusion oncogene PTC who have 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.FUNDINGThe Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830).TRIAL REGISTRATIONTwo patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).

    PubMed IF 14.3 내분비대사내과
19. 2802021

    제1저자 신희경, 박정환 · 교신저자 유정환, 김원

    Shin HK^*, Park JH^*, Yu JH, Jin YJ, Suh YJ, Lee JW, Kim W, Korean Nonalcoholic Fatty Liver Study Group (KNSG)

    Association between telomere length and hepatic fibrosis in non-alcoholic fatty liver disease.

    Sci Rep. 2021;11(1):18004.

    Abstract

    Telomere length has been linked to the prevalence and progression of metabolic disease. However, clinical implications of telomere length in biopsy-proven non-alcoholic fatty liver disease (NAFLD) patients remain unclear. Therefore, this study aimed to investigate the association of telomere length with the histological severity of NAFLD. The cross-sectional data derived from the prospectively enrolled Boramae NAFLD registry (n = 91) were analyzed. The liver tissues and clinical information were obtained from both NAFLD patients and non-NAFLD subjects. Binary logistic regression was performed to identify the independent association between telomere length and the histological severity of NAFLD. A total of 83 subjects with or without biopsy-proven NAFLD were included for analysis: non-NAFLD in 23 (27.7%), non-alcoholic fatty liver in 15 (18.1%), and non-alcoholic steatohepatitis (NASH) in 45 (54.2%). Telomere length measured from liver tissues showed a strong negative correlation (p < 0.001) with age, regardless of NAFLD status. Therefore, telomere length was corrected for age. Age-adjusted telomere length than decreased gradually with an increasing severity of fibrosis in patients with NAFLD (p < 0.028). In multivariate analysis, age-adjusted telomere length (odds ratio [OR] 0.59; 95% CI 0.37-0.92; p = 0.019) and high-density lipoprotein cholesterol (OR 0.94; 95% CI 0.80-0.99; p = 0.039) were independently associated with significant fibrosis. The age-adjusted telomere length tends to decrease along with the fibrosis stage of NAFLD. In particular, among the histological components of NAFLD, fibrosis severity seems to be related to telomere length in the liver.

    PubMed IF 4.9 소화기내과
20. 2792021

    제1저자 김진영 · 교신저자 변자민

    Kim J, Byun JM, Hong J, Koh Y, Shin DY, Kim I, Yoon SS, Park H, Bang SM

    Incidence, characteristics and risk factors of thromboembolic events in East Asian patients with BCR-ABL1 negative myeloproliferative neoplasms.

    Sci Rep. 2021;11(1):17819.

    Abstract

    The vascular complications have been a major cause of morbidity and mortality among all subtypes of BCR-ABL1 negative myeloproliferative neoplasms (MPN), but the ethnicity-specific data was limited. We therefore conducted a multi-center retrospective, longitudinal cohort study to evaluate the incidence, characteristics and risk factors of thromboembolic events of MPN patients. Of 256 patients, 27.3% experienced thromboembolic events, majority of which occurred before or within 12 months of MPN diagnosis. The multivariable Cox proportional analyses identified leukocytosis (HR 2.67, 95% CI 1.36-5.24, q = 0.004) and history of thrombosis (HR 9.68, 95% CI 2.00-46.88, q = 0.005) as the risk factors for thromboembolism. In subgroup analysis of polycythemia vera and hemoglobin concentration (HR 1.97, 95% CI 1.28-3.04, q = 0.002) appeared to be a significant risk factor of thrombosis, along with age and thrombosis history. In essential thrombocythemia, severity of the established IPSET score was closely correlated with the frequency of thromboembolic events. In primary myelofibrosis, history of thrombosis was associated with thrombosis events (HR 13.85, 95% CI 1.2-159.5, q = 0.035). Overall survival was worse in patients who experienced thromboembolic events. Our study highlighted the importance of recognizing high risk patients and implementing personalized intervention.

    PubMed IF 4.9 혈액종양내과
21. 2782021

    제1저자 박찬선 · 교신저자 박혜경, 강혜련

    Park CS, Yang MS, Kang DY, Park HJ, Park SY, Nam YH, Kim S, Jung JW, Park HK, Kang HR, Drug Allergy Work Group of KAAACI

    Risk factors of beta-lactam anaphylaxis in Korea: A 6-year multicenter retrospective adult case-control study.

    World Allergy Organ J. 2021;14(9):100580.

    Abstract

    BACKGROUND Beta-lactams (BLs) are commonly used antibiotics and leading causative agents of drug-induced anaphylaxis. Few studies on the culprit drugs and risk factors of BL-induced anaphylaxis are available. Our goal was to evaluate the culprit drugs and compare the risk factors in patients with BL-induced anaphylaxis to matched tolerant controls in a hospital setting.

    METHODS We retrospectively enrolled all patients who developed anaphylaxis from intravenous BL during hospitalization from 9 Korean hospitals. We compared clinical parameters between patients with BL-induced anaphylaxis and 4-fold BL-tolerant controls matched by age, sex, BL use, and the purpose of BL administration.

    RESULTS Seventy-four cases of BL-induced anaphylaxis and 296 BL-tolerant controls were enrolled. Cephalosporin accounted for 77% of total BL-induced anaphylaxis, and the top derivatives were ceftriaxone (23.0%), cefazedone (10.8%), and cefbuperazone (9.5%). Among penicillin derivatives, piperacillin (16.2%) was the most common, followed by ampicillin (2.7%). History of drug allergy (odds ratio [OR], 19.91; 95% confidence interval [CI] 5.33-74.44), previous exposure to the causative BL (OR, 7.71; 95% CI, 1.62-36.76), and concurrent administration of angiotensin-converting enzyme inhibitors (ACEIs) (OR, 5.97; 95% CI, 1.28-27.91) were independent risk factors associated with BL-induced anaphylaxis. Food allergy (OR, 13.93; 95% CI 1.31-148.9) and previous exposure to BL (OR, 6.59; 95% CI, 1.30-33.31) were identified as risk factors for cephalosporin-induced anaphylaxis.

    CONCLUSIONS To prevent BL-induced anaphylaxis, attention should be paid to histories of drug or food allergy, previous exposure to BLs, and ACEI use. The risk factors and clinical outcomes might vary according to the BL classes.

    PubMed IF 4 알레르기내과
22. 2772021

    제1저자 장세용, 장지은 · 교신저자 이해영

    Jang SY^*, Jang J^*, Yang DH, Cho HJ, Lim S, Jeon ES, Lee SE, Kim JJ, Kang SM, Baek SH, Cho MC, Choi DJ, Yoo BS, Kim KH, Park SK, Lee HY

    Impact of insulin therapy on the mortality of acute heart failure patients with diabetes mellitus.

    Cardiovasc Diabetol. 2021;20(1):180.

    Abstract

    BACKGROUND Patients with diabetes mellitus (DM) have a higher prevalence of heart failure (HF) than those without it. Approximately 40 % of HF patients have DM and they tend to have poorer outcomes than those without DM. This study evaluated the impact of insulin therapy on mortality among acute HF patients.

    METHODS A total of 1740 patients from the Korean Acute Heart Failure registry with DM were included in this study. The risk of all-cause mortality according to insulin therapy was assessed using the Cox proportional hazard models with inverse probability of treatment weighting to balance the clinical characteristics (pretreatment covariates) between the groups.

    RESULTS DM patients had been treated with either oral hypoglycemic agents (OHAs) alone (n = 620), insulin alone (n = 682), or insulin combined with OHAs (n = 438). The insulin alone group was associated with an increased mortality risk compared with the OHA alone group (HR = 1.41, 95 % CI 1.21-1.66]). Insulin therapy combined with OHAs also showed an increased mortality risk (HR = 1.29, 95 % CI 1.14-1.46) compared with the OHA alone group. Insulin therapy was consistently associated with increased mortality risk, regardless of the left ventricular ejection fraction (LVEF) or HF etiology. A significant increase in mortality was observed in patients with good glycemic control (HbA1c < 7.0 %) receiving insulin, whereas there was no significant association in patients with poor glycemic control (HbA1c ≥ 7.0%).

    CONCLUSIONS Insulin therapy was found to be associated with increased mortality compared to OHAs. The insulin therapy was harmful especially in patients with low HbA1c levels which may suggest the necessity of specific management strategies and blood sugar targets when using insulin in patients with HF.

    PubMed IF 15.6 순환기내과
23. 2762021

    제1저자 정재우, 오정석, 배보람 · 교신저자 강혜련, 이창현

    Jung JW^*, Oh JS^*, Bae B^*, Ahn YH, Kim LW, Choi J, Kim HY, Kang HR, Lee CH

    Ultra-high-resolution computed tomography shows changes in the lungs related with airway hyperresponsiveness in a murine asthma model.

    Sci Rep. 2021;11(1):17584.

    Abstract

    In vivo presentation of airway hyper-responsiveness (AHR) at the different time points of the allergic reaction is not clearly understood. The purpose of this study was to investigate how AHR manifests in the airway and the lung parenchyma in vivo following exposure to different stimuli and in the early and late phases of asthma after allergen exposure. Ovalbumin (OVA)-induced allergic asthma model was established using 6-week female BALB/c mice. Enhanced pause was measured with a non-invasive method to assess AHR. The dynamic changes of the airway and lung parenchyma were evaluated with ultra-high-resolution computed tomography (128 multi-detector, 1024 × 1024 matrix) for 10 h. While the methacholine challenge showed no grossly visible changes in the proximal airway and lung parenchyma despite provoking AHR, the OVA challenge induced significant immediate changes manifesting as peribronchial ground glass opacities, consolidations, air-trapping, and paradoxical proximal airway dilatations. After resolution of immediate response, multiple episodes of AHRs occurred with paradoxical proximal airway dilatation and peripheral air-trapping in late phase over a prolonged time period in vivo. Understanding of airflow limitation based on the structural changes of asthmatic airway would be helpful to make an appropriate drug delivery strategy for the treatment of asthma.

    PubMed IF 4.9 알레르기내과
24. 2752021

    제1저자 박세훈, 한경도 · 교신저자 김동기

    Park S^*, Han K^*, Lee S, Kim Y, Lee Y, Kang MW, Park S, Kim YC, Han SS, Lee H, Lee JP, Joo KW, Lim CS, Kim YS, Kim DK

    Cardiovascular or mortality risk of controlled hypertension and importance of physical activity.

    Heart. 2021;107(18):1472-1479.

    Abstract

    OBJECTIVE To investigate the risk of major adverse cardiac and cerebrovascular events (MACCEs) and all-cause death of patients with controlled hypertension and suggest the benefits of physical activity in their prognosis.

    METHODS People aged 40-69 years from the prospective UK Biobank cohort (UKB, n=220 026) and the retrospective Korean National Health Insurance Service cohort (KNHIS, n=3 593 202) were included in this observational cohort study, excluding those with previous cerebrocardiovascular diseases or hypertension without treatment. The study groups were stratified into normotension, controlled hypertension (patients with hypertension with systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg) and uncontrolled hypertension groups. The outcomes were MACCEs and all-cause mortality, analysed by Cox regression analysis.

    RESULTS We included 161 405/18 844/39 777 and 3 122 890/383 828/86 484 individuals with normotension/controlled hypertension/uncontrolled hypertension state from the UKB and KNHIS cohorts, respectively. The controlled hypertension group showed significantly higher risk of MACCEs (UKB: adjusted HR 1.73 (95% CI 1.55 to 1.92); KNHIS: 1.46 (95% CI 1.43 to 1.49)) and all-cause mortality (UKB: adjusted HR 1.28 (95% CI 1.18 to 1.39); KNHIS: 1.29 (95% CI 1.26 to 1.32)) than individuals with normotension. The controlled hypertension group not involved in any moderate or moderate-to-vigorous physical activity showed high risk of adverse outcomes, which was comparable with or even higher than the risk of patients with uncontrolled hypertension who were engaged in physical activity.

    CONCLUSIONS Controlled hypertension is associated with residual risks of adverse outcomes. Clinicians may encourage physical activity for patients with controlled hypertension, not being reassured by their achieved target blood pressure values.

    PubMed IF 4.4 신장내과
25. 2742021

    제1저자 박찬순, 박진주 · 교신저자 최동주

    Park CS^*, Park JJ^*, Mebazaa A, Lee HY, Kim KH, Yoo BS, Kang SM, Baek SH, Jeon ES, Kim JJ, Cho MC, Chae SC, Oh BH, Choi DJ

    Response to beta-blockers and natriuretic peptide level in acute heart failure: analysis of data from the Korean acute heart failure registry.

    Clin Res Cardiol. 2021;110(9):1392-1403.

    Abstract

    BACKGROUND To investigate the effect of beta-blockers according to NP levels and HF phenotypes because natriuretic peptide (NP) level can be used to risk-stratify HF patients regardless of left ventricular ejection fraction (LVEF).

    METHODS Of 5,625 patients in the Korean acute heart failure registry, we included patients with LVEF and NP levels. HF phenotypes were defined as HF with reduced ejection fraction (HFrEF) (EF ≤ 40%), HF with midrange ejection fraction (HFmrEF) (40% < EF < 50%), and HF with preserved EF (HFpEF) (EF ≥ 50%). Patients were further stratified by NP tertiles. Primary outcome was 5-year all-cause mortality according to beta-blocker use at discharge.

    RESULTS Both B-type NP (BNP) (r = -0.279, P < 0.001) and N-terminal pro-BNP (r = -0.186, P < 0.001) levels correlated inversely with LVEF. During a median follow-up duration of 961 days, 1560 (35.3%) patients died. In HFrEF, patients taking beta-blockers showed better survival regardless of NP levels. Regarding HFmrEF, there was no mortality difference between those taking and not taking beta-blockers. In HFpEF, beta-blocker use demonstrated lower mortality in those in the 3rd NP tertile (log-rank P = 0.041) but not in those in the 1st and 2nd NP tertiles (log-rank P > 0.05). After adjusting covariates, the use of beta-blockers was associated with a 38%-reduced mortality (hazard ratio: 0.62; 95% confidence interval: 0.39-0.98; P = 0.040) in HFpEF patients in the 3rd NP tertile but not in those in 1st and 2nd tertiles.

    CONCLUSIONS We confirm that the use of beta-blockers is beneficial in patients with HFrEF. Furthermore, we extend the benefits of beta-blockers to patients with HFpEF and high NP levels.

    CLINICAL TRIAL REGISTRATION ClinicalTrial.gov identifier: NCT01389843 URL: https://clinicaltrials.gov/ct2/show/NCT01389843.

    PubMed IF 3.4 순환기내과
26. 2732021

    제1저자 최인실, 김기환 · 교신저자 김진원

    Choi IS, Kim KH, Lee JH, Suh KJ, Kim JW, Park JH, Kim YJ, Kim JS, Kim JH, Kim JW

    A randomised phase II study of oxaliplatin/5-FU (mFOLFOX) versus irinotecan/5-FU (mFOLFIRI) chemotherapy in locally advanced or metastatic biliary tract cancer refractory to first-line gemcitabine/cisplatin chemotherapy.

    Eur J Cancer. 2021;154:288-295.

    Abstract

    BACKGROUND In locally advanced or metastatic biliary tract cancer (BTC), second-line chemotherapy is challenging after progression from first-line gemcitabine/cisplatin. This study evaluated whether irinotecan/5-fluorouracil (5-FU; mFOLFIRI) was superior to oxaliplatin/5-FU (mFOLFOX) as a second-line treatment in BTC.

    PATIENTS AND METHODS Patients diagnosed with BTC with disease progression after prior gemcitabine/cisplatin were randomised (1:1) to either mFOLFOX (control arm) or mFOLFIRI (experimental arm). Randomisation was stratified by tumour location (intrahepatic versus extrahepatic versus gallbladder versus ampulla of Vater) and ECOG performance status (0, 1 versus 2). The primary endpoint was the overall survival (OS) rate at 6 months.

    RESULTS In total, 120 patients were enrolled and 118 patients were randomised (mFOLFOX n = 59, mFOLFIRI n = 59). The baseline characteristics were well balanced between the two arms. The tumour location was intrahepatic bile duct in 48 patients (40.7%), extrahepatic bile duct in 29 patients (24.6%), gallbladder in 35 patients (29.7%) and ampulla of Vater in 6 patients (5.1%). At a median follow-up duration of 25.8 months, the 6-month OS rate was 54.1% in mFOLFOX and 44.1% in mFOLFIRI (p = 0.677). The median OS was 6.3 months (95% CI, 4.4-8.2) in mFOLFOX and 5.7 months (95% CI, 4.7-6.7) in mFOLFIRI (p = 0.677). The median progression-free survival was 2.8 months (95% CI, 2.3-3.3) in mFOLFOX and 2.1 months (95% CI, 1.1-3.1) in mFOLFIRI (p = 0.974). Of the 101 evaluable patients, the objective response rate and disease control rate were 5.9% and 66.7% in mFOLFOX and 4.0% and 64.0% in mFOLFIRI (p = 0.663 and p = 0.778, respectively). Peripheral neuropathy (37.5% versus 5.2%) and thrombocytopenia (35.7% versus 15.5%) in mFOLFOX and vomiting (19.0% versus 1.8%) and cholangitis (10.3% versus 0.0%) in mFOLFIRI occurred more frequently. No chemotherapy-related death was reported.

    CONCLUSION In the second-line treatment of BTC, mFOLFIRI was not superior to mFOLFOX. However, mFOLFIRI was tolerable and showed comparable efficacy to mFOLFOX. Adverse events were different between the two arms. CLINICALTRIALS.

    GOV IDENTIFIER NCT03464968.

    PubMed IF 7.9 혈액종양내과
27. 2722021

    제1저자 최정민 · 교신저자 이해영

    Choi J, Sung KC, Ihm SH, Yoon CH, Park SW, Park SH, Kim JY, Kwon SU, Lee HY

    Central blood pressure lowering effect of telmisartan-rosuvastatin single-pill combination in hypertensive patients combined with dyslipidemia: A pilot study.

    J Clin Hypertens (Greenwich). 2021;23(9):1664-1674.

    Abstract

    This multicenter, phase 4, Prospective Randomized Open, Blinded End-point (PROBE) study aimed to evaluate safety and efficacy of telmisartan/rosuvastatin single-pill combination (SPC) therapy on lowering central blood pressure (BP) compared with telmisartan monotherapy in hypertensive patients with dyslipidemia in Korea. Study was terminated earlier than planned due to COVID-19 pandemic, thus should be considered as a pilot study. Among 125 patients who met the inclusion criteria of hypertension and dyslipidemia (defined as 10-year Atherosclerotic Cardiovascular Disease risk score over 5%), 80 patients went through 4-week single-group run-in period with telmisartan 40-80 mg, then randomized to telmisartan 80 mg + rosuvastatin (10 or 20 mg) SPC group or telmisartan 80 mg monotherapy group. The central/brachial BP, brachial-ankle pulse wave velocity (baPWV), and augmentation index (AIx) were assessed at baseline and 16 weeks later. Mean brachial SBP changed from 135.80 ± 14.22 mmHg to 130.69 ± 13.23 mmHg in telmisartan/rosuvastatin group and from 134.37 ± 12.50 mmHg to 133.75 ± 12.30 mmHg in telmisartan monotherapy group without significant difference (between-group difference p = .149). Mean central SBP were reduced significantly in the telmisartan/rosuvastatin group with change from 126.72 ± 14.44 mmHg to 121.56 ± 14.56 mmHg while telmisartan monotherapy group showed no significant change (between-group difference p = .028). BaPWV changed from 1672.57 ± 371.72 m/s to 1591.75 ± 272.16 m/s in telmisartan/rosuvastatin group and from 1542.85 ± 263.70 m/s to 1586.12 ± 297.45 m/s in telmisartan group with no significance (between-group difference p = .078). Change of AIx had no significant difference (between-group difference p = .314). Both groups showed excellent compliance rate of 96.9 ± 4.5% with no significant difference in adverse rate. Telmisartan/rosuvastatin SPC therapy was more effective in lowering central BP compared with the telmisartan monotherapy. The results of this study showed benefit of additive statin therapy in hypertensive patients combined with dyslipidemia.

    PubMed IF 2.9 순환기내과
28. 2712021

    제1저자 김미화 · 교신저자 오도연

    Jin MH, Nam AR, Bang JH, Oh KS, Seo HR, Kim JM, Yoon J, Kim TY, Oh DY

    WEE1 inhibition reverses trastuzumab resistance in HER2-positive cancers.

    Gastric Cancer. 2021;24(5):1003-1020.

    Abstract

    BACKGROUND To date, many efforts have been made to understand the resistance mechanism of trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer. However, there is still a huge unmet medical need for patients with trastuzumab resistance.

    METHODS In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from ERBB2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773).

    RESULTS Here, we found higher PD-L1 expression in trastuzumab-resistant (HR) HER2-positive cancer cells than in parental cells, and blocking PD-L1 reversed the resistance to trastuzumab in HR cells. Trastuzumab upregulated PD-L1 expression via NF-κB activation in both parental and HR cells, however, led to DNA damage only in parental cells. The WEE1 inhibitor adavosertib, which downregulates PD-L1 expression, enhanced trastuzumab efficacy by blocking BRCA1-CMTM6-PD-L1 signals and the HER2-CDCP-1-SRC axis. Additionally, the levels of galectin-9, CD163, FoxP3, and CTLA-4 were diminished by blocking WEE1 in the presence of human PBMCs in vitro.

    CONCLUSION Taken together, the strategy of co-targeting HER2 and WEE1 could overcome resistance to trastuzumab in HER2-positive cancers, supporting further clinical development in HER2-positive cancer patients.

    PubMed IF 6.1 혈액종양내과
29. 2702021

    제1저자 정재훈, 민경환 · 교신저자 김동훈, 김학령

    Chung J, Min KW, Son BK, Kim DH, Kim HL

    Association between histological severity of Helicobacter pylori infection and cardiovascular risk scores in the Korean population.

    Atherosclerosis. 2021;333:124-130.

    Abstract

    BACKGROUND AND AIMS Although there have been several reports on the association between Helicobacter pylori (HP) infection and cardiovascular disease (CVD), most studies have been done through noninvasive testing such as serologic test or urea breath test. This study investigated the relationship between histological features of HP gastritis and cardiovascular risk scores.

    METHODS A total of 21,251 subjects (mean age, 43.8 ± 9.6 years; males, 72.1%) who underwent routine health checkup and gastric biopsy were retrospectively analyzed. The severity of gastritis was assessed using the updated Sydney system (USS). With four different risk predicting algorithms, we calculated Framingham coronary heart disease (CHD) risk score, ATP III revised Framingham CHD risk score, generalized Framingham risk against total CVD, and ACC/AHA 10-year risk of a first hard atherosclerotic-CVD event in each subject.

    RESULTS About half of the study subjects (51.2%, n = 10,890) were confirmed to have HP infection. Subjects with HP infection were younger (42.9 ± 9.0 vs. 44.7 ± 10.2 years, p < 0.001) than those without. After adjustment for age, most of the estimated 10-year cardiovascular risk increased as the grade of USS elements increased. As the sum of the USS scores increased, all the 4 estimated 10-year cardiovascular risk scores increased proportionally (p < 0.05 for each).

    CONCLUSIONS The histological features of gastritis assessed using USS were associated with various cardiovascular risk scores. This study provides strong evidence on an association between chronic inflammation and increased cardiovascular risk.

    PubMed IF 7.1 순환기내과
30. 2692021

    제1저자 이동석, 정지봉 · 교신저자 김지원

    Lee DS^*, Jeong JB^*, Kim JW, Lee KL, Kim BG, Kim SH, Kang HW

    Investigation of droplets released during digestive endoscopy using a high-speed camera (with video): a pilot study.

    Surg Endosc. 2021;35(9):5392-5396.

    Abstract

    BACKGROUND A large release of droplets is often expected around the periphery of the digestive endoscope insertion site. Therefore, a sense of alarm over infection because of droplets that may be released during digestive endoscopy examination is increasing. This study aimed to investigate the droplets released during digestive endoscopy using a high-speed camera.

    METHODS We utilized a high-speed camera (FASTCAM SA-3, Photron Limited) capable of recording small, transparent droplets with a black background and high-brightness lighting. The obtained video files were analyzed using post-processing software. We divided the 20 models into the control (a spray bottle model and a cough model) and experimental groups (digestive endoscopy models). The sedative, proficiency of digestive endoscopy and the amount of gas injected were modulated to change the level of released droplets.

    RESULTS For the control groups, droplets were clearly observed using a high-speed camera. However, no droplet larger than 10 µm in size was observed in the experimental groups. Furthermore, the changes in the sedative, proficiency of digestive endoscopy, and amount of gas injected did not affect droplet formation.

    CONCLUSIONS Based on high-speed camera photography, the risk of droplet generation during digestive endoscopy was not higher than that during violent expiratory events, such as coughing and sneezing.

    PubMed IF 3.3 소화기내과

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.