Publications by authors named "Sae Hwan Lee"

89 Publications

Adverse outcomes after surgeries in patients with liver cirrhosis among Korean population: A population-based study.

PLoS One 2021 14;16(6):e0253165. Epub 2021 Jun 14.

Department of Gastroenterology and Hepatology, Soonchunhyang University School of Medicine, Seoul, Korea.

Background: Patients with liver cirrhosis have an increased risk of in-hospital mortality or postoperative complication after surgery. However, large-scale studies on the prognosis of these patients after surgery are lacking. The aim of the study was to investigate the adverse outcomes of patients with liver cirrhosis after surgery over five years.

Methods And Findings: We used the Health Insurance Review and Assessment Service-National Inpatient Samples (HIRA-NIS) between 2012 and 2016. In-hospital mortality and hospital stay were analyzed using the data. Mortality rates according to the surgical department were also analyzed. Of the 1,662,887 patients who underwent surgery, 16,174 (1.0%) patients had cirrhosis. The in-hospital mortality (8.0% vs. 1.0%) and postoperative complications such as respiratory (6.0% vs. 5.3%) or infections (2.8% vs. 2.4%) was significantly higher in patients with cirrhosis than in those without cirrhosis. In addition, the total hospitalization period and use of the intensive care unit were significantly higher in patients with liver cirrhosis. In propensity score matching analysis, liver cirrhosis increased the risk of adverse outcome significantly [adjusted OR (aOR) 1.67, 95% CI 1.56-1.79, P<0.001], especially in-hospital mortality. In liver cirrhosis group, presence of decompensation or varices showed significantly increased postoperative complication or mortality. Adverse outcomes in patients with cirrhosis was the highest in patients who underwent otorhinolaryngology surgery (aOR 1.86), followed by neurosurgery (aOR 1.72), thoracic and cardiovascular surgery (aOR 1.56), and plastic surgery (aOR 1.36).

Conclusion: The adverse outcomes of patients with cirrhosis is significantly high after surgery, despite advances in cirrhosis treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253165PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202950PMC
June 2021

Effect of antiviral therapy in patients with low HBV DNA level on transarterial chemoembolization for hepatocellular carcinoma.

J Viral Hepat 2021 Jul 5;28(7):1011-1018. Epub 2021 Apr 5.

Department of Internal Medicine, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan, South Korea.

Antiviral therapy improves survival in patients with hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC). However, the effect of antiviral therapy in patients with low-level viremia HBV-HCC receiving non-curative therapy remains unclear. We aimed to evaluate the role of antiviral therapy in patients with low-level viremia and treated with transarterial chemoembolization (TACE). This retrospective study evaluated 206 patients with HBV-HCC who underwent TACE as an initial treatment. Of those, 135 patients received antiviral therapy (antiviral group), and 71 did not (non-antiviral group). The definition of low-level viremia was an HBV DNA level <2000 IU/ml. Kaplan-Meier curves, log-rank tests and Cox regression analysis were used for statistical analyses. The median follow-up duration was 39 months (1-174 months). Overall survival (OS) did not differ between groups (P = .227). Barcelona Clinic Liver Cancer stage (BCLC), Child-Pugh (CP) class and α-fetoprotein level were independent prognostic factors for OS. Antiviral therapy (hazard ratio [HR], 0.503, P = .022) was a prognostic factor for 2-year survival. On subgroup analysis, antiviral therapy improved short-term survival in patients with BCLC stage 0 and A (P = .037) and CP class A (P = .04). In patients with low-level viremia, antiviral therapy yielded short-term survival benefits, particularly in patients with early-stage HCC.
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http://dx.doi.org/10.1111/jvh.13508DOI Listing
July 2021

Application of Hepatic Venous Pressure Gradient to Predict Prognosis in Cirrhotic Patients with a Low Model for End-Stage Liver Disease Score.

Diagnostics (Basel) 2020 Oct 10;10(10). Epub 2020 Oct 10.

Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Seoul 04401, Korea.

Background/aim: We aimed to derive a model representing the dynamic status of cirrhosis and to discriminate patients with poor prognosis even if the Model for End-Stage Liver Disease (MELD) score is low.

Methods: This study retrospectively enrolled 700 cirrhotic patients with a MELD score of less than 20 who underwent hepatic venous pressure gradient (HVPG) measurement. A model named H6C score (= HVPG + 6 × CTP score) to predict overall survival was derived and internal and external validations were conducted with the derivation and validation cohorts.

Results: The H6C score using the HVPG was developed based on a multivariate Cox regression analysis. The H6C score showed a great predictive power for overall survival with a time-dependent AUC of 0.733, which was superior to that of a MELD of 0.602. In patients with viral etiology, the performance of the H6C score was much improved with a time-dependent AUC of 0.850 and was consistently superior to that of the MELD (0.748). Patients with an H6C score below 45 demonstrated an excellent overall survival with a 5-year survival rate of 91.5%. Whereas, patients with an H6C score above 64 showed a dismal prognosis with a 5-year survival rate of 51.1%. The performance of the H6C score was further verified to be excellent in the validation cohort.

Conclusion: This new model using the HVPG provides an excellent predictive power in cirrhotic patients, especially with viral etiology. In patients with H6C above 64, it would be wise to consider early liver transplantation to positively impact long-term survival, even when the MELD score is low.
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http://dx.doi.org/10.3390/diagnostics10100805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599657PMC
October 2020

Comparison of clinical practice guidelines for the management of chronic hepatitis B: When to start, when to change, and when to stop.

Clin Mol Hepatol 2020 10 28;26(4):411-429. Epub 2020 Aug 28.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.

Clinical practice guidelines are important for guiding the management of specific diseases by medical practitioners, trainees, and nurses. In some cases, the guidelines are utilized as a reference for health policymakers in controlling diseases with a large public impact. With this in mind, practice guidelines for the management of chronic hepatitis B (CHB) have been developed in the United States, Europe, and Asian-Pacific regions to suggest the best-fit recommendations for each social and medical circumstance. Recently, the Korean Association for the Study of the Liver published a revised version of its clinical practice guidelines for the management of CHB. The guidelines included updated information based on newly available antiviral agents, the most recent opinion on the initiation and cessation of treatment, and updates for the management of drug resistance, partial virological response, and side effects. Additionally, CHB management in specific situations was comprehensively revised. This review compares the similarities and differences among the various practice guidelines to identify unmet needs and improve future recommendations.
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http://dx.doi.org/10.3350/cmh.2020.0049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641563PMC
October 2020

Tenofovir-based combination therapy or monotherapy for multidrug-resistant chronic hepatitis B: Long-term data from a multicenter cohort study.

J Viral Hepat 2020 12 20;27(12):1306-1318. Epub 2020 Aug 20.

Department of Internal Medicine, Yonsei University Medical College, Seoul, Korea.

The treatment of multidrug-resistant (MDR) chronic hepatitis B (CHB) is challenging. Herein, we report a multicenter prospective cohort study for the evaluation of tenofovir disoproxil fumarate (TDF)-based therapy for MDR CHB in a real-life setting. The inclusion criteria comprised patients with resistance to more than two nucleos(t)ide analogue (NA) classes and hepatitis B virus (HBV) DNA level of ≥200 IU/mL. The primary end-point was virologic response (VR), defined as undetectable HBV DNA (<20 IU/mL) after 60 months. A total of 236 patients met the inclusion criteria. The mean HBV DNA level was 4.16 ± 1.44 log IU/mL; 26.7% of patients had liver cirrhosis. Before the initiation of TDF, 33.5%, 44.9% and 21.6% of patients had mutations resistant to L-NA + adefovir, L-NA + entecavir (ETV) and L-NA + adefovir + ETV, respectively. A total of 184 patients received TDF-based combination therapy [TDF + ETV (n = 178) or TDF + L-NA (n = 6)], and 52 patients received TDF monotherapy. In the entire cohort, the VR rates were 77.2%, 89.9% and 92.2% at 12, 36 and 60 months, respectively. The VR rates were not significantly different between the combination therapy and the monotherapy group after 12 (76.2% vs 80.4%, P = .533), 36 (89.8% vs 90.3%, P = 1.000) or 60 (92.9% vs 87.5%, P = .499) months. Also, there was no significant difference in the cumulative VR rates for 5 years between the treatment groups (P = .910). Newly developed antiviral resistance was not observed. TDF-based therapy was effective for the treatment of MDR CHB. The efficacy of TDF monotherapy was not different from that of the TDF-based combination therapy.
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http://dx.doi.org/10.1111/jvh.13363DOI Listing
December 2020

Prevalence, incidence and risk factors of tamoxifen-related non-alcoholic fatty liver disease: A systematic review and meta-analysis.

Liver Int 2020 06 7;40(6):1344-1355. Epub 2020 Apr 7.

Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung-si, Korea.

Background & Aims: Tamoxifen is associated with an increased risk of developing fatty liver. The aim of this systematic review and meta-analysis was to evaluate the prevalence and incidence of fatty liver developed after tamoxifen treatment in breast cancer patients.

Methods: A systematic search of PubMed (Medline), EMBASE, OVID Medline, the Cochrane Library and other databases was performed for this review. The abstracts obtained from the search were reviewed by two investigators who chose manuscripts for full-text review. The event rates were calculated with a random-effects model and quality-effects model.

Results: The search yielded 165 references. Of these, 24 were included in the quantitative summary. We analysed the data of a total of 6,962 patients treated with tamoxifen and 975 patients not treated with tamoxifen. The prevalence of fatty liver among patients with breast cancer taking tamoxifen was 40.25 per 100 patients and the incidence rate was 12.37 per 100 person-years. The incidence of fatty liver was much higher in the tamoxifen group than in the control group [incidence rate ratio: 3.12, 95% CI (confidence interval): 2.05-4.75, I  = 61%], regardless of region. The main risk factors were body mass index (BMI) [hazard ratio (HR): 1.15, 95% CI: 1.09-1.22] and hypercholesterolaemia (HR: 1.01, 95% CI: 1.00-1.02).

Conclusion: The use of tamoxifen was associated with increased risks in the incidence and prevalence of fatty liver, especially in patients with high BMI and hypercholesterolaemia.
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http://dx.doi.org/10.1111/liv.14434DOI Listing
June 2020

Change in Portal Pressure and Clinical Outcome in Cirrhotic Patients with Gastric Varices after Plug-Assisted Retrograde Transvenous Obliteration.

Gut Liver 2020 11;14(6):783-791

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea.

Background/aims: Plug-assisted retrograde transvenous obliteration (PARTO) is widely used to manage gastric varices with a portosystemic shunt. It is not clear whether portal pressure and the incidence of complications increase after PARTO. The aim of this study was to determine the changes in portal pressure and the associated changes in liver function, ascites, hepatic encephalopathy, and especially esophageal varix (EV) after PARTO.

Methods: From March 2012 to February 2018, 54 patients who underwent PARTO were analyzed retrospectively. The parameters collected included liver function and episodes of cirrhotic complications before and at 1 and 6 months after PARTO.

Results: The analysis of 54 patients showed improvement in liver function during the 6-month follow-up period (Model for End-Stage Liver Disease score: change from 11.46±4.35 to 10.33±2.96, p=0.021). Among these 54 patients, 25 patients were evaluated for their hepatic venous pressure gradient (HVPG) before and after PARTO (change from 12.52±3.83 to 14.68±5.03 mm Hg; p<0.001). Twenty-five patients with portal pressure measured before and after PARTO were evaluated for risk factors affecting liver function improvement and EV deterioration. No factor associated with portal pressure was affected by liver function improvement. Post-PARTO portal pressure was a risk factor affecting EV deterioration (HVPG-post: odds ratio, 1.341; 95% confidence interval, 1.017 to 1.767; p=0.037).

Conclusions: The artificial blockade of the portosystemic shunt evidently leads to an increase in HVPG. Liver function was improved over the 6-month follow-up period. Portal pressure after PARTO was a significant risk factor for EV deterioration. Portal pressure measurement is helpful for predicting the patient's clinical outcome.
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http://dx.doi.org/10.5009/gnl19293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667928PMC
November 2020

Propranolol plus endoscopic ligation for variceal bleeding in patients with significant ascites: Propensity score matching analysis.

Medicine (Baltimore) 2020 Jan;99(5):e18913

Department of Internal Medicine, Gangneug Asan Hospital, Republic of Korea.

The use of beta-blockers in decompensated cirrhosis accompanying ascites is still under debate. The aim of this study was to compare overall survival (OS) and incidence of cirrhotic complications between endoscopic variceal ligation (EVL) only and EVL + non-selective beta-blocker (NSBB) combination therapy in cirrhotic patients with significant ascites (≥grade 2).This retrospective study included 271 consecutive cirrhotic patients with ascites who were treated with EVL only or EVL + NSBB combination therapy as a primary prophylaxis of esophageal varices. The primary outcome was all-cause mortality. Propensity score matching was performed between the 2 groups to minimize baseline difference.Median observation period was 42.1 months (interquartile range, 18.4-75.1 months). All patients had deteriorated liver function: 81.1% Child-Pugh class B and 18.9% Child-Pugh class C. All-cause mortality was significantly higher in the EVL + NSBB group than in the EVL only group not only in non-matched cohort, but also in matched cohort (48.9% vs 31.2%; P = .039). More people died from hepatic failure in the EVL + NSBB group than that in the EVL only group (40.5% vs 20.0%; P = .020). However, the incidence of variceal bleeding, hepatorenal syndrome (HRS), or spontaneous bacterial peritonitis (SBP) was not significantly different between the 2 groups.The use of NSBB might worsen the prognosis of cirrhotic patients with significant ascites. These results suggest that EVL alone is a more appropriate treatment option for prophylaxis of esophageal varices than propranolol combination therapy when patients have significant ascites.
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http://dx.doi.org/10.1097/MD.0000000000018913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004788PMC
January 2020

Relation of fibroblast growth factor receptor 2 expression to hepatocellular carcinoma recurrence after liver resection.

PLoS One 2020 15;15(1):e0227440. Epub 2020 Jan 15.

Department of Pathology, College of Medicine, Soonchunhyang University, Seoul, Korea.

Background: Hepatocellular carcinoma (HCC) recurrence after liver resection depends upon the stage and histological grade of the tumor and the expression of certain biomarkers. However, it remains unclear which of these factors has the highest predictive value regarding HCC recurrence after surgical resection.

Methods: This study investigated the associations among clinicopathological characteristics, expression of biomarkers, and HCC recurrence after liver resection. Fifty-four patients having undergone liver resection for HCC were enrolled prospectively, and their data were analyzed retrospectively. Evaluated variables were clinical data, laboratory findings, modified Union for International Cancer Control (UICC) stage, vascular invasion, histological differentiation, and immunohistochemical staining for fibroblast growth factor receptor 2 (FGFR2), vascular endothelial growth factor, and tumor-necrosis-factor-related apoptosis-inducing ligand receptors 1 and 2.

Results: Mean patient age was 58.6 years (range, 30-71), and the mean and SD for follow-up duration were 51.2 ± 34.8 months. Cumulative 1-, 3-, and 5-year recurrence rates were 32.9%, 53.6%, and 68.1%, respectively. In univariate analysis, FGFR2 (p = 0.026) and Edmonson-Steiner grade (E-S grade) (p = 0.030) were associated with recurrence after resection in HCC patients. In multivariate analyses, increased FGFR2 expression (p = 0.017) was the only significant predictor of HCC recurrence.

Conclusions: High FGFR2 expression had marginal association with poor E-S grade (p = 0.056). More intensive surveillance of HCC recurrence is warranted in HCC patients with increased FGFR2 expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227440PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961981PMC
April 2020

Usefulness of noninvasive methods including assessment of liver stiffness by 2-dimensional shear wave elastography for predicting esophageal varices.

Dig Liver Dis 2019 12 4;51(12):1706-1712. Epub 2019 Jul 4.

Division of Gastroenterology and Hepatology, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea.

Background: The aim of this study was to predict the presence of esophageal varices (EVs) by noninvasive tools combined with 2-dimensional shear wave elastography (2D-SWE), and to compare the diagnostic capabilities of 2D-SWE with those of transient elastography (TE).

Methods: Between January 2015 and December 2017, 289 patients with compensated advanced chronic liver disease (cACLD) who underwent consecutive 2D-SWE and EGD were enrolled. Capabilities for predicting the presence of EVs of 2D-SWE and models combining 2D-SWE with other noninvasive tools (modified LS-spleen-diameter-to-platelet-ratio score [mLSPS], platelet-spleen ratio score) were compared. A subgroup analysis was performed on 177 patients who also underwent simultaneous TE.

Results: The area under receiver operating characteristics (AUROCs) for detecting EVs for 2D-SWE alone vs. mLSPS, which included 2D-SWE, were 0.757 (95% confidence interval [CI], 0.701-0.810) and 0.813 (95% CI, 0.763-.857), respectively. The AUROCs for predicting varices needing treatment (VNT) for 2D-SWE and mLSPS were 0.712 (95% CI, 0.621-0.738) and 0.834 (95% CI, 0.785-0.875), respectively. For the 195 patients who underwent simultaneous TE and 2D-SWE, no differences in diagnostic performance were observed.

Conclusions: The diagnostic performance of 2D-SWE is similar to that of TE for predicting the presence of EVs. The mLSPS, which includes 2D-SWE, seemed to be useful for predicting EVs.
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http://dx.doi.org/10.1016/j.dld.2019.06.007DOI Listing
December 2019

miR551b Regulates Colorectal Cancer Progression by Targeting the ZEB1 Signaling Axis.

Cancers (Basel) 2019 May 27;11(5). Epub 2019 May 27.

Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan-si 31151, Korea.

Our current understanding of the role of microRNA 551b (miR551b) in the progression of colorectal cancer (CRC) remains limited. Here, studies using both ectopic expression of miR551b and miR551b mimics revealed that miR551b exerts a tumor suppressive effect in CRC cells. Specifically, miR551b was significantly downregulated in both patient-derived CRC tissues and CRC cell lines compared to normal tissues and non-cancer cell lines. Also, miR551b significantly inhibited the motility of CRC cells in vitro, including migration, invasion, and wound healing rates, but did not affect cell proliferation. Mechanistically, miR551b targets and inhibits the expression of ZEB1 (Zinc finger E-box-binding homeobox 1), resulting in the dysregulation of EMT (epithelial-mesenchymal transition) signatures. More importantly, miR551b overexpression was found to reduce the tumor size in a xenograft model of CRC cells in vivo. Furthermore, bioinformatic analyses showed that miR551b expression levels were markedly downregulated in the advanced-stage CRC tissues compared to normal tissues, and ZEB1 was associated with the disease progression in CRC patients. Our findings indicated that miR551b could serve as a potential diagnostic biomarker and could be utilized to improve the therapeutic outcomes of CRC patients.
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http://dx.doi.org/10.3390/cancers11050735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563032PMC
May 2019

Curative Loco-regional Therapies for Early Hepatocellular Carcinoma: Is Combination Effective?

Authors:
Sae Hwan Lee

Korean J Gastroenterol 2019 03;73(3):121-123

Division of Gastroenterology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.

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http://dx.doi.org/10.4166/kjg.2019.73.3.121DOI Listing
March 2019

Estimation of renal function in patients with liver cirrhosis: Impact of muscle mass and sex.

J Hepatol 2019 05 8;70(5):847-854. Epub 2019 Jan 8.

Department of Internal Medicine, Gangneung Asan Hospital, Gangneung, Republic of Korea.

Background & Aims: Accurate evaluation of renal function in patients with liver cirrhosis is critical for clinical management. However, there are still discrepancies between the measured glomerular filtration rate (mGFR) and creatinine-based estimated GFR (eGFR). In this study, we compared the performance of 2 common eGFR measurements with mGFR and evaluated the impact of low muscle mass on overestimation of renal function in patients with cirrhosis.

Methods: This study included 779 consecutive cirrhotic patients who underwent Cr-ethylenediamine tetra acetic acid (EDTA) (as a mGFR) and abdominal computed tomography (CT). The eGFR was calculated using creatinine or cystatin C. Muscle mass was assessed in terms of the total skeletal muscle at L3 level using CT.

Results: Modification of diet in renal disease (MDRD)-eGFR was overestimated in 47% of patients. A multivariate analysis showed that female sex (adjusted odds ratio [aOR] 4.91), Child B and C vs. A (aOR 1.69 and 1.84) and skeletal muscle mass (aOR 0.89) were independent risk factors associated with overestimation. Interestingly, the effect of skeletal muscle mass on overestimation varied based on sex. Decreased muscle mass significantly enhanced the risk of overestimation of MDRD-eGFR in male patients, but not in female patients. Cystatin C-based eGFR showed a better correlation with mGFR than MDRD-eGFR; it was also better at predicting overall survival and the incidence of acute kidney injury than MDRD-eGFR.

Conclusions: The risk factors associated with overestimation included female sex, impaired liver function, and decreased muscle mass in males. In particular, eGFR in male patients with sarcopenia should be carefully interpreted. Creatinine-based eGFR was overestimated more often than cystatin C-based eGFR, with overestimation of eGFR closely related to poor prognostic performance.

Lay Summary: Overestimation of renal function frequently occurs in patients with liver cirrhosis when using serum creatinine. Decreased muscle mass has a great impact on overestimation of kidney function especially in male patients with cirrhosis. Compared with creatinine, cystatin C was more closely correlated with measured glomerular filtration rate and had a higher predictive ability for renal complications and survival than creatinine.
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http://dx.doi.org/10.1016/j.jhep.2018.12.030DOI Listing
May 2019

Efficacy and Safety of Daclatasvir and Asunaprevir in Patients with Hepatitis C Virus Genotype 1b Infection on Hemodialysis.

Gut Liver 2019 03;13(2):191-196

Division of Hepatology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Background/aims: We evaluated the efficacy and safety of daclatasvir (DCV) and asunaprevir (ASV) in patients with chronic hepatitis C virus (HCV) infection on hemodialysis.

Methods;: We performed a single-arm, multicenter prospective study. Twenty-one chronic hemodialysis patients with HCV infection were prospectively enrolled from February 2016 to April 2017. We evaluated the virological responses at weeks 4, 12, and 24 (end of treatment [EOT]) and the sustained virological response at 12 weeks after the EOT (SVR12). The tolerability and safety of the drugs were also assessed.

Results: None of the 20 patients had the NS5A resistance-associated variant (NS5A RAV), and one patient was indeterminate for the NS5A RAV. Seventeen patients (80%) completed the 24 weeks of treatment with DCV and ASV. Four patients discontinued the study prior to week 12. In an intention-to-treat analysis, the SVR12 was 76.1%. In a per-protocol analysis, patients who completed DCV and ASV treatment achieved an SVR12 of 100%. DCV and ASV were well tolerated by the majority of patients. Three patients discontinued treatment due to adverse events (AEs) including dizziness, dyspnea, and neutropenia. The patient with indeterminate NS5A RAV showed viral breakthrough and discontinued treatment.

Conclusions: DCV and ASV combination therapy in chronic hemodialysis patients with HCV infection achieved a high SVR12 rate with few AEs. To maximize the SVR12 rate, it is important to identify candidates by baseline RAV testing. Close monitoring of the safety and tolerability of DCV and ASV may be necessary in HCV-infected patients on hemodialysis. (ClinicalTrials.gov ID NCT02580474).
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http://dx.doi.org/10.5009/gnl18240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430432PMC
March 2019

Combined therapy of transarterial chemoembolization and stereotactic body radiation therapy versus transarterial chemoembolization for ≤5cm hepatocellular carcinoma: Propensity score matching analysis.

PLoS One 2018 31;13(10):e0206381. Epub 2018 Oct 31.

Department of Internal Medicine, Soonchunhyang University College of Medicine Cheonan Hospital, Cheonan, South Korea.

Patients with liver cirrhosis and hepatocellular carcinoma (HCC) are often ineligible for resection or local ablation therapy due to poor liver function and/or difficult location. The aim of this study is to evaluate therapeutic outcomes of stereotactic body radiotherapy (SBRT) combined with transarterial chemoembolization (TACE) compared with TACE alone for HCC measuring less than 5 cm. From March 2011 to December 2016, 85 patients underwent SBRT with TACE (SBRT-TACE group) and 114 underwent TACE (TACE group) at 4 tertiary hospitals. Local control rate (LCR), progression-free survival (PFS) and overall survival (OS) were compared after propensity-score matching (1:1 ratio). The SBRT-TACE group showed significantly higher 1- and 3-year LCR than the TACE group (91.1% and 89.9%, respectively vs 69.9% and 44.8%, respectively; P < 0.001). The SBRT-TACE group showed better 1- and 3-year PFS than the TACE group (56.5% and 32.3%, respectively vs 42.2% and 21.6%, respectively; P = 0.022). However, 1-, 3- and 5-year OS was not different between the SBRT-TACE and TACE groups (98.8%, 89.1% and 80.7%, respectively vs 99.7%, 83.3% and 71.0%, respectively; P = 0.206). In multivariate analysis, the overall SBRT added to TACE did not contribute to extend PFS. However, in patients with less than 2 tumors, the combined therapy was effective (HR 0.590, 95% CI 0.392-0.889, P = 0.012). SBRT-TACE is superior to TACE in terms of LCR. Particularly, SBRT-TACE may be an effective alternative in patients with HCC number (≤2), which is not indicated for resection or local ablation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206381PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209230PMC
April 2019

Clinical outcomes of patients with a single hepatocellular carcinoma less than 5 cm treated with transarterial chemoembolization.

Korean J Intern Med 2019 Nov 26;34(6):1223-1232. Epub 2018 Oct 26.

Department of Biostatistics, Soonchunhyang University Seoul Hospital, Seoul, Korea.

Background/aims: Transarterial chemoembolization (TACE) is performed for single hepatocellular carcinoma (HCC) that are not eligible for surgery or ablation therapy. We investigated the clinical outcomes of patients with a single HCC ≤ 5 cm treated with TACE.

Methods: This study analyzed 175 consecutive patients who underwent TACE as an initial treatment for single HCC ≤ 5 cm. Predictive factors for complete response (CR), recurrence after CR, and overall survival (OS) were evaluated.

Results: Total 119 patients (68%) achieved CR after TACE. Tumor size < 3 cm and hepatitis B virus infection were significant predictors of CR (p < 0.05). Recurrent HCC was detected in 73 patients (61.3%) after CR. Age > 65 years and absence of liver cirrhosis were predictive factors for non-recurrence after CR (p < 0.05). The OS for all patients was 80.7 ± 5.6 months, and the 1-, 3-, and 5-year OS rates were 88.1%, 64.8%, and 49.9%, respectively. In multivariate analysis for OS, CR (hazard ratio [HR], 0.467; 95% confidence interval [CI], 0.292 to 0.747) and Child class A (HR, 0.390; 95% CI, 0.243 to 0.626) were significant factors. The OS for the CR and Child class A group were 92 and 93.6 months, respectively, and that of the non-CR and Child B, C group were 53.3 and 50.7 months, respectively (p < 0.001).

Conclusion: TACE can be a valid treatment in patients with a single HCC ≤ 5 cm not suitable for curative treatment, especially in patients with Child class A and CR after TACE.
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http://dx.doi.org/10.3904/kjim.2018.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823578PMC
November 2019

A Long Noncoding RNA Regulates Hepatitis C Virus Infection Through Interferon Alpha-Inducible Protein 6.

Hepatology 2019 03 13;69(3):1004-1019. Epub 2019 Feb 13.

Liver Center and Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Long noncoding RNAs (lncRNAs) play a critical role in the regulation of many important cellular processes. However, the mechanisms by which lncRNAs regulate viral infection and host immune responses are not well understood. We sought to explore lncRNA regulation of hepatitis C virus (HCV) infection and interferon response. We performed RNA sequencing (RNAseq) in Huh7.5.1 cells with or without interferon alpha (IFNα) treatment. Clustered regularly interspaced short palindromic repeats/Cas9 guide RNA (gRNA) was used to knock out selected genes. The promoter clones were constructed, and the activity of related interferon-stimulated genes (ISGs) were detected by the secrete-pair dual luminescence assay. We constructed the full-length and four deletion mutants of an interferon-induced lncRNA RP11-288L9.4 (lncRNA-IFI6) based on predicted secondary structure. Selected gene mRNAs and their proteins, together with HCV infection, in Huh7.5.1 cells and primary human hepatocytes (PHHs) were monitored by quantitative real-time PCR (qRT-PCR) and western blot. We obtained 7,901 lncRNAs from RNAseq. A total of 1,062 host-encoded lncRNAs were significantly differentially regulated by IFNα treatment. We found that lncRNA-IFI6 gRNA significantly inhibited HCV infection compared with negative gRNA control. The expression of the antiviral ISG IFI6 was significantly increased following lncRNA-IFI6 gRNA editing compared with negative gRNA control in Japanese fulminant hepatitis 1 (JFH1)-infected Huh7.5.1 cells and PHHs. We observed that lncRNA-IFI6 regulation of HCV was independent of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling. lncRNA-IFI6 negatively regulated IFI6 promoter function through histone modification. Overexpression of the truncated spatial domain or full-length lncRNA-IFI6 inhibited IFI6 expression and increased HCV replication. Conclusion: A lncRNA, lncRNA-IFI6, regulates antiviral innate immunity in the JFH1 HCV infection model. lncRNA-IFI6 regulates HCV infection independently of the JAK-STAT pathway. lncRNA-IFI6 exerts its regulatory function via promoter activation and histone modification of IFI6 through its spatial domain.
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http://dx.doi.org/10.1002/hep.30266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393205PMC
March 2019

Hepatitis B virus reactivation after radiotherapy for hepatocellular carcinoma and efficacy of antiviral treatment: A multicenter study.

PLoS One 2018 30;13(7):e0201316. Epub 2018 Jul 30.

Department of Internal Medicine, University of Ulsan College of Medicine, Gangneung Asan Hospital, Gangneung, South Korea.

Convincing data that support routine use of preventive therapy against hepatitis B virus (HBV) reactivation in radiotherapy (RT) for hepatocellular carcinoma (HCC) are lacking. The aim of this study was to investigate the incidence, clinical significance, and risk factors of HBV reactivation after RT. Medical records of 133 HBsAg (+) HCC patients who received radiotherapy from March 2009 to February 2016 were reviewed. Patients were divided into two groups: 1) non-antiviral group, those who did not receive antiviral therapy before RT (n = 27); and antiviral group (those who underwent antiviral therapy before RT) (n = 106). Factors related to HBV reactivation in HCC patients were evaluated. 17 (12.7%) of 133 patients developed HBV reactivation after RT. Patients in the antiviral group had significantly lower rates of HBV reactivation than those in the non-antiviral group (7.5% vs. 33.3%, p<0.001). HBV related hepatitis was also lower in the antiviral group (3.8% vs. 14.8%, p = 0.031). In multivariate analysis, absence of antiviral treatment (OR: 8.339, 95% CI: 2.532-27.470, p<0.001) and combined treatment of RT with transarterial chemoembolizatoin (TACE) (OR: 5.313, 95% CI: 1.548-18.232, p = 0.008) were risk factors for HBV reactivation. HBV reactivation can occur after radiotherapy. Combination treatment of RT with TACE and non-antiviral treatment are major risk factors for HBV reactivation during or after RT. Therefore, preventive antiviral therapy should be recommended for patients with HCC who are scheduled to receive RT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201316PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066246PMC
January 2019

Efficacy and safety of sofosbuvir plus ribavirin for Korean patients with hepatitis C virus genotype 2 infection: A retrospective multi-institutional study.

Clin Mol Hepatol 2018 09 4;24(3):311-318. Epub 2018 Jun 4.

Department of Internal Medicine, Konkuk University School of Medicine, Chungju, Korea.

Background/aims: Sofosbuvir plus ribavirin is a standard treatment for patients infected with chronic hepatitis C virus (HCV) genotype 2 in Korea. The purpose of this study was to examine the efficacy and safety of this treatment in Korean patients with chronic HCV genotype 2 infection.

Methods: We retrospectively analyzed clinical data of patients treated with sofosbuvir plus ribavirin for chronic HCV genotype 2 from May 2016 to December 2017 at eight hospitals located in the Daejeon-Chungcheong area.

Results: A total of 172 patients were treated with sofosbuvir plus ribavirin. Of them, 163 patients completed the treatment, and 162 patients were tested for sustained virologic response 12 weeks after treatment discontinuation (SVR12). Mean age was 59.6±12.3 years (27-96), and 105 (64.4%) patients were female. Of the total patients, 49 (30.1%) were diagnosed with cirrhosis, and 31 of them were treated for 16 weeks. Sofosbuvir plus ribavirin was the first-line treatment for 144 (88.3%) patients. Eleven (6.7%) patients were intolerant to previous interferon-based treatment. Eight (5.0%) patients relapsed after interferon-based treatment. HCV RNA non-detection rate at 4, 8, and 12 weeks was 97.5%, 99.1%, and 99.3%, respectively, and SVR12 was 98.8% (161/163). During treatment, 18 (11.0%) patients had to reduce their administrated dose of ribavirin because of anemia. One patient stopped the treatment because of severe anemia. Other adverse events, including dizziness, indigestion, and headache, were found in 26 (16.0%) patients.

Conclusion: A 12-16 week treatment with sofosbuvir plus ribavirin is remarkably effective and well tolerated in Korean patients with chronic HCV genotype 2 infection.
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http://dx.doi.org/10.3350/cmh.2017.0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166109PMC
September 2018

Follow-up Creatinine Level Is an Important Predictive Factor of In-hospital Mortality in Cirrhotic Patients with Spontaneous Bacterial Peritonitis.

J Korean Med Sci 2018 Mar 19;33(12):e99. Epub 2018 Mar 19.

Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea.

Background: Spontaneous bacterial peritonitis (SBP) is one of the severe complications of liver cirrhosis. Early detection of high-risk patients is essential for prognostic improvement. The aim of this study is to investigate the predictive factors related to in-hospital mortality in patients with SBP.

Methods: This was a retrospective study of 233 SBP patients (181 males, 52 females) who were admitted to four tertiary referral hospitals between August 2002 and February 2013. The patients' laboratory and radiologic data were obtained from medical records. The Child-Turcotte-Pugh (CTP) score and model for end-stage liver disease sodium model (MELD-Na) scores were calculated using the laboratory data recorded at the time of the SBP episode.

Results: The causes of liver cirrhosis were hepatitis B (44.6%), alcohol (43.8%), hepatitis C (6.0%), and cryptogenic cirrhosis (5.6%). The mean MELD-Na and CTP scores were 27.1 and 10.7, respectively. Thirty-one of the patients (13.3%) died from SBP in hospital. Multivariate analysis revealed that maximum creatinine level during treatment was a statistically significant factor for in-hospital mortality (P = 0.005). The prognostic accuracy of the maximum creatinine level during treatment was 78.0% (P < 0.001). The optimal cutoff point for the maximum serum creatinine was 2 mg/dL (P < 0.001).

Conclusion: The follow-up creatinine level during treatment is an important predictive factor of in-hospital mortality in cirrhotic patients with SBP. Patients with SBP and a serum creatinine level during treatment of ≥ 2.0 mg/dL might have a high risk of in-hospital mortality.
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http://dx.doi.org/10.3346/jkms.2018.33.e99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852424PMC
March 2018

Platelet count is associated with sustained virological response rates in treatments for chronic hepatitis C.

Korean J Intern Med 2019 Sep 14;34(5):989-997. Epub 2018 Mar 14.

Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea.

Background/aims: This study was conducted to clarify the sustained virological response (SVR) prediction ability of baseline and treatment-related factors in patients with chronic hepatitis C virus (HCV) infection.

Methods: This retrospective study collected data at four tertiary referral hospitals between June 2004 and July 2012. Out of 476 patients, 330 treatment-naïve patients with chronic HCV infection were recruited. Pegylated interferon α-2a/- 2b plus ribavirin was administered for either 24 or 48 weeks depending on the HCV genotype. The baseline and treatment-related predictive factors of SVR were evaluated by analyzing data measured before treatment (i.e., baseline) and during treatment.

Results: SVR rates for genotypes 1 and 2 were 63% (97/154) and 79.5% (140/176), respectively (p = 0.001). Multivariate analysis for baseline factors revealed that young age (p = 0.009), genotype 2 (p = 0.001), HCV RNA level of < 800,000 IU/mL (p < 0.001), and a baseline platelet count of > 150 × 103 /µL (p < 0.001) were significant SVR predictors, regardless of the genotype. In particular, predictive accuracy for achievement of SVR was 87.3% for a baseline platelet count of > 150 × 103 /µL. In multivariate analysis for treatment-related factors, SVR was associated with achievement of a rapid virological response (RVR; p < 0.001), treatment adherence of ≥ 80/80/80 (p < 0.001).

Conclusion: Young age, genotype 2, low HCV RNA level, RVR, and treatment adherence were significantly associated with SVR. In addition, platelet count was an independent predictive factor for SVR. Therefore, platelet count could be used to develop individualized treatment regimens and to optimize treatment outcomes in patients with chronic HCV infection.
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http://dx.doi.org/10.3904/kjim.2017.322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718746PMC
September 2019

Effect of tenofovir on renal function in patients with chronic hepatitis B.

Medicine (Baltimore) 2018 Feb;97(7):e9756

Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul Department of Internal Medicine, College of Medicine, Soonchunhyang University, Cheonan Department of Internal Medicine, College of Medicine, Soonchunhyang University, Bucheon Biostatistical Consulting Unit, Soonchunhyang University, Seoul, Korea UB Songdo Hospital, Ulaanbaatar, Mongolia.

Tenofovir disoproxil fumarate (TDF) is widely used to treat patients with hepatitis B virus (HBV) infection. We investigated the effect of TDF on renal insufficiency in patients with chronic hepatitis B (CHB).A consecutive cohort analysis was applied to CHB patients taking prescribed TDF from January 2012 to May 2016 at Soonchunhyang University Seoul Hospital. Alterations over time in corrected calcium, phosphate, creatinine, and estimated glomerular filtration rate (eGFR) were analyzed using the generalized estimating equation method. The percentage increase in creatinine from baseline to the maximum creatinine level (delta creatinine) was compared according to the underlying disease using the Mann-Whitney U test. Cox proportional hazard regression model was used to determine risk factors associated with renal insufficiency.The baseline creatinine, eGFR, corrected calcium, and phosphate levels were 0.72 ± 0.01 mg/dL (mean ± SD), 106.37 ± 1.06 mL/min/1.73 m, 8.82 ± 0.04 mg/dL, and 3.42 ± 0.05 mg/dL, respectively. The creatinine level had increased significantly at 12, 24, 48, 72, and 96 weeks, while the eGFR level had decreased significantly at these 5 time points. Multivariate analysis confirmed that age ≥60 years and the baseline bilirubin level were independently associated with the risk of renal insufficiency. Delta creatinine was significantly higher in patients with diabetes mellitus (DM) than in patients without DM.Renal function was decreased from baseline in CHB patients receiving TDF therapy, which indicates that the renal function of patients undergoing treatment with TDF should be monitored regularly. Old age, DM, and serum bilirubin were risk factors for the development of renal insufficiency in CHB patients receiving TDF therapy.
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http://dx.doi.org/10.1097/MD.0000000000009756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839852PMC
February 2018

Clinical significance of radiation-induced liver disease after stereotactic body radiation therapy for hepatocellular carcinoma.

Korean J Intern Med 2018 Nov 28;33(6):1093-1102. Epub 2017 Aug 28.

Department of Internal Medicine, Soon Chun Hyang University Cheonan Hospital, Cheonan, Korea.

Background/aims: The aim of this study was to investigate parameters that predict radiation-induced liver disease (RILD) following stereotactic body radiotherapy (SBRT) in patients with hepatocellular carcinoma (HCC) and to identify the clinical significance of RILD.

Methods: We retrospectively reviewed the medical records of 117 HCC patients who were treated by SBRT from March 2011 to February 2015. RILD was defined as elevated liver transaminases more than five times the upper normal limit or a worsening of Child-Pugh (CP) score by 2 within 3 months after SBRT. All patients were assessed at 1 month and every 3 months after SBRT.

Results: Median follow-up was 22.5 months (range, 3 to 56) after SBRT. RILD was developed in 29 of the 117 patients (24.7%). On univariate analysis, significant predictive factors of RILD were pretreatment CP score (p < 0.001) and normal liver volume (p = 0.002). Multivariate analysis showed that CP score was a significant predictor of RILD (p < 0.001). The incidence of RILD increased above a CP score of 6 remarkably. The rate of recovery from RILD decreased significantly above a CP score of 8. Survival analysis showed that CP score was an independent prognostic factor of overall survival (p = 0.001).

Conclusion: CP score is a significant factor to predict RILD in patients with chronic liver disease. RILD can be tolerated by patients with a CP score ≤ 7. However, careful monitoring of liver function is needed for patients with a CP score 7 after SBRT.
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http://dx.doi.org/10.3904/kjim.2016.412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234411PMC
November 2018

A prospective comparative assessment of the accuracy of the FibroScan in evaluating liver steatosis.

PLoS One 2017 15;12(8):e0182784. Epub 2017 Aug 15.

Department of Biostatistics, College of Medicine, Soonchunhyang University, Seoul, Korea.

Background/aims: Recent studies have demonstrated the utility of the FibroScan® device in diagnosing liver steatosis, but its usefulness has not been thoroughly appraised. We investigated the usefulness of the controlled attenuation parameter (CAP) in detecting and quantifying liver steatosis.

Methods: A prospective analysis was applied to 79 chronic liver disease patients who underwent a liver biopsy, a FibroScan investigation, ultrasonography, and hepatic steatosis index (HSI). The presence and degree of steatosis as measured by the FibroScan device, ultrasonography and HSI were compared with the results for the liver biopsy tissue.

Results: There was substantial concordance between the liver biopsy results and the CAP as evaluated by the kappa (κ) index test for detecting liver steatosis (κCAP = 0.77, P<0.001; κultrasonography = 0.60, P<0.001; κHSI = 0.47, P<0.001). The areas under the receiver operating characteristic curve (AUROCs) of the CAP, ultrasonography, and HSI were 0.899 [95% confidence interval (CI) = 0.826-0.972)], 0.859 (95% CI = 0.779-0.939), and 0.766 (95% CI = 0.655-0.877), respectively. The optimal CAP cutoff value for differentiating between normal and hepatic steatosis was 247 dB/m, which produced sensitivity and specificity values of 91.9% and 85.7%, respectively, as well as a positive predictive value of 85.0% and a negative predictive value of 92.3%.

Conclusion: The CAP produces results that are highly concordant with those of a liver biopsy in detecting steatosis. Therefore, the CAP is a noninvasive and reliable tool for evaluating liver steatosis, even in the early stages.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182784PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557594PMC
October 2017

Useful Endoscopic Ultrasonography Parameters and a Predictive Model for the Recurrence of Esophageal Varices and Bleeding after Variceal Ligation.

Gut Liver 2017 Nov;11(6):843-851

Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.

Background/aims: To identify the usefulness of endoscopic ultrasonography with a mini-probe (EUM) and to create a predictive model for esophageal variceal (EV) recurrence and bleeding following esophageal variceal ligation (EVL).

Methods: A total of 144 patients who received EUM prior to prophylactic EVL and met the inclusion criteria were enrolled. EUM findings, EV diameter, paraesophageal vein diameter, and the number of perforating veins were assessed.

Results: EV recurrence was observed in 42 patients (29.2%), 10 of whom experienced EV bleeding. Larger diameter of the paraesophageal vein (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.17 to 1.96; p=0.002) and perforating vein (OR, 3.27; 95% CI, 1.11 to 9.65; p=0.032) were significant predictive factors for EV recurrence. However, the diameter of the paraesophageal vein was the only significant risk factor for EV bleeding (adjusted OR, 1.51; 95% CI, 1.06 to 2.16; p=0.022). The areas under the curves of the predictive model for EV recurrence and bleeding were 0.872 (95% CI, 0.811 to 0.934) and 0.811 (95% CI, 0.630 to 0.992), respectively.

Conclusions: The diameter of the paraesophageal vein was a significant predictive factor for EV recurrence and bleeding. The predictive model constructed based on the significant EUM findings exhibited good performance.
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http://dx.doi.org/10.5009/gnl16458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669601PMC
November 2017

Tenofovir disoproxil fumarate monotherapy is superior to entecavir-adefovir combination therapy in patients with suboptimal response to lamivudine-adefovir therapy for nucleoside-resistant HBV: a 96-week prospective multicentre trial.

Antivir Ther 2018 ;23(3):219-227

Department of Internal Medicine, Chungnam National University Hospital, Daejeon, Korea.

Background: A complete virological response is closely related to the long-term outcome of patients with chronic hepatitis B and prevention of emerging HBV mutations. We aimed to evaluate the efficacy of tenofovir disoproxil fumarate (TDF) monotherapy compared to entecavir-adefovir dipivoxil (ETV-ADV) combination therapy in patients with suboptimal responses to long-term lamivudine-adefovir dipivoxil (LAM-ADV) therapy for nucleoside analogue-resistant chronic hepatitis B.

Methods: Patients (n=60) were randomized to TDF monotherapy or ETV-ADV combination therapy for 96 weeks. All patients had the rt204I/V mutation and serum HBV DNA was measured (>60 IU/ml) during LAM-ADV therapy. The primary end point was a complete virological response (HBV DNA <20 IU/ml) at week 96.

Results: The median duration of prior LAM-ADV rescue therapy was 43 (7-108) months. A complete virological response was achieved in 86.6% and 53.3% of patients in the TDF and ETV-ADV groups, respectively, at week 96 (P=0.005). Reduction in serum HBV DNA was significantly greater in the TDF group than in ETV-ADV group (-3.2 ±1.2 versus -2.6 ±1.2; P=0.01). Hepatitis B e antigen loss (22.2% versus 16.6%; P=0.731) and biochemical responses (76.7% versus 73.3%; P=0.766) were not different between the TDF and ETV-ADV groups. No newly emerged mutations were detected. Both therapies demonstrated favourable safety profiles.

Conclusions: TDF therapy achieved a better complete virological response than ETV-ADV therapy in chronic hepatitis B patients with suboptimal response to long-term LAM-ADV rescue therapy. (KCT0000627).
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http://dx.doi.org/10.3851/IMP3169DOI Listing
September 2019

Ginsenoside Rg3 restores hepatitis C virus-induced aberrant mitochondrial dynamics and inhibits virus propagation.

Hepatology 2017 09 1;66(3):758-771. Epub 2017 Aug 1.

Department of Medicine, University of California, San Diego, La Jolla, CA.

Hepatitis C virus (HCV) alters mitochondrial dynamics associated with persistent viral infection and suppression of innate immunity. Mitochondrial dysfunction is also a pathologic feature of direct-acting antiviral (DAA) treatment. Despite the high efficacy of DAAs, their use in treating patients with chronic hepatitis C in interferon-sparing regimens occasionally produces undesirable side effects such as fatigue, migraine, and other conditions, which may be linked to mitochondrial dysfunction. Here, we show that clinically prescribed DAAs, including sofosbuvir, affect mitochondrial dynamics. To counter these adverse effects, we examined HCV-induced and DAA-induced aberrant mitochondrial dynamics modulated by ginsenoside, which is known to support healthy mitochondrial physiology and the innate immune system. We screened several ginsenoside compounds showing antiviral activity using a robust HCV cell culture system. We investigated the role of ginsenosides in antiviral efficacy, alteration of mitochondrial transmembrane potential, abnormal mitochondrial fission, its upstream signaling, and mitophagic process caused by HCV infection or DAA treatment. Only one of the compounds, ginsenoside Rg3 (G-Rg3), exhibited notable and promising anti-HCV potential. Treatment of HCV-infected cells with G-Rg3 increased HCV core protein-mediated reduction in the expression level of cytosolic p21, required for increasing cyclin-dependent kinase 1 activity, which catalyzes Ser616 phosphorylation of dynamin-related protein 1. The HCV-induced mitophagy, which follows mitochondrial fission, was also rescued by G-Rg3 treatment.

Conclusion: G-Rg3 inhibits HCV propagation. Its antiviral mechanism involves restoring the HCV-induced dynamin-related protein 1-mediated aberrant mitochondrial fission process, thereby resulting in suppression of persistent HCV infection. (Hepatology 2017;66:758-771).
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http://dx.doi.org/10.1002/hep.29177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755973PMC
September 2017

Efficacy and safety of daclatasvir plus asunaprevir for Korean patients with HCV genotype Ib infection: a retrospective multi-institutional study.

Clin Mol Hepatol 2017 Mar 16;23(1):51-56. Epub 2017 Mar 16.

Department of Internal Medicine, Chungbuk University College of Medicine, Cheongju, Korea.

Background/aims: The combination of daclatasvir (DCV) and asunaprevir (ASV) has demonstrated a high sustained virologic response at 12 weeks (SVR12) and a low rate of adverse events in previous clinical studies. The purpose of this study was to clarify the results of treatment and side effects in Korean patients with chronic hepatitis C virus (HCV) genotype Ib infection.

Methods: We retrospectively analyzed clinical data from chronic HCV genotype Ib patients treated with DCV+ASV from August 2015 to September 2016 at five hospitals in the Daejeon-Chungcheong area.

Results: A total of 152 patients were examined for resistance associated variants (RAVs). Among them, 15 (9.9%) were positive for Y93 and one (0.7%) was positive for L31. Of 126 patients treated with DCV+ASV, 83 patients completed treatment and 76 patients were included in safety and efficacy analysis. Five (6.6%) were positive for Y93 and 12 (15.8%) exhibited cirrhotic change. DCV+ASV was the first-line treatment for 58 (76.3%) patients. Eleven (14.5%) patients relapsed after previous treatment that included interferon and seven (9.2%) of these patients were found to be intolerant of interferon. Adverse events occurred in 10 (13.2%) patients and two patients stopped the medication because of severe itching and skin rash. SVR12 was 89.5% (68/76) in all patients and 91.5% (65/71) in RAV-negative patients.

Conclusions: DCV+ASV showed good efficacy in patients with HCV Ib infection in Korea. Close monitoring is needed for severe adverse events and treatment failure, which were uncommon.
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http://dx.doi.org/10.3350/cmh.2016.0053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381834PMC
March 2017

Usefulness of AFP, AFP-L3, and PIVKA-II, and their combinations in diagnosing hepatocellular carcinoma.

Medicine (Baltimore) 2017 Mar;96(11):e5811

Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, College of Medicine, Soonchunhyang University, Seoul Department of Internal Medicine, College of Medicine, Soonchunhyang University, Cheonan Department of Internal Medicine, College of Medicine, Soonchunhyang University, Bucheon Biostatistical Consulting Unit Department of Laboratory Medicine, Soonchunhyang University, Seoul, Republic of Korea.

Alpha-fetoprotein (AFP), Lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II) are widely used as tumor markers for the diagnosis of hepatocellular carcinoma (HCC). This study compared the diagnostic values of AFP, AFP-L3, and PIVKA-II individually and in combination to find the best biomarker or biomarker panel.Seventy-nine patients with newly diagnosed HCC and 77 non-HCC control patients with liver cirrhosis were enrolled. AFP, AFP-L3, and PIVKA-II were measured in the same serum samples using microchip capillary electrophoresis and a liquid-phase binding assay on an automatic analyzer. Receiver-operating characteristic curve analyses were also applied to all combinations of the markers.When the 3 biomarkers were analyzed individually, AFP showed the largest area under the receiver-operating characteristic curve (AUC) (0.751). For combinations of the biomarkers, the AUC was highest (0.765) for "PIVKA-II > 40 mAU/mL and AFP > 10 ng/mL." The combination of "PIVKA-II > 40 mAU/mL and AFP > 10 ng/mL and AFP-L3 > 10%" had worse sensitivity and lower AUC (P = 0.001). The highest AUC of a single biomarker was highest for AFP and of a combination was "PIVKA-II > 40 mAU/mL and AFP > 10 ng/mL," with this also being the case when the cut-off value of AFP and AFP-L3 was changed.Alpha-fetoprotein showed the best diagnostic performance as a single biomarker for HCC. The diagnostic value of AFP was improved by combining it with PIVKA-II, but adding AFP-L3 did not contribute to the ability to distinguish between HCC and non-HCC liver cirrhosis. These findings were not altered when the cut-off value of AFP and AFP-L3 was changed.
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http://dx.doi.org/10.1097/MD.0000000000005811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369875PMC
March 2017

Predictive Factors for Complete Response and Recurrence after Transarterial Chemoembolization in Hepatocellular Carcinoma.

Gut Liver 2017 May;11(3):409-416

Department of Biostatistics, Soonchunhyang University Hospital, Seoul, Korea.

Background/aims: To investigate the predictive factors for complete response (CR) and recurrence after CR in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE).

Methods: Among 691 newly diagnosed HCC patients, 287 were treated with TACE as a first therapy. We analyzed the predictive factors for CR, recurrence after CR, and overall survival (OS).

Results: Eighty-one patients (28.2%) achieved CR after TACE, and recurrence after CR was detected in 35 patients (43.2%). In multivariate analyses, tumor size (≤5 cm) and single nodularity were predictive factors for CR, with hazard ratios (HRs) of 0.35 (p=0.002) and 0.41 (p<0.001), respectively. Elevated serum α-fetoprotein (AFP) (>20 ng/mL) level and multinodularity exhibited significant relationships with recurrence after CR, with HRs of 2.220 (p=0.026) and 3.887 (p<0.001), respectively. Tumor size (>5 cm), multinodularity, elevated serum AFP (>20 ng/mL) level, Child-Turcotte-Pugh score (B and C), and portal vein thrombosis were significant factors for OS.

Conclusions: In patients treated with TACE as a first therapy, tumor size (≤5 cm) and single nodularity were predictive factors for CR, and multinodularity and elevated serum AFP (>20 ng/mL) levels were predictive factors for recurrence after CR. These factors were also significant for OS.
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http://dx.doi.org/10.5009/gnl16001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417784PMC
May 2017