Publications by authors named "Sang Hoon Ahn"

569 Publications

Increased risk of hepatocellular carcinoma and mortality in chronic viral hepatitis with concurrent fatty liver.

Aliment Pharmacol Ther 2021 Nov 24. Epub 2021 Nov 24.

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

Background: Population-based data are lacking regarding whether fatty liver is a risk factor for hepatocellular carcinoma (HCC) and mortality in patients with chronic viral hepatitis.

Aim: To investigate the association of fatty liver with HCC incidence and mortality in patients with chronic viral hepatitis using a nationwide cohort METHODS: We included 57,385 patients with chronic hepatitis B (CHB) or chronic hepatitis C (CHC) who underwent health examinations. The patients were divided into three groups: no fatty liver, fatty liver index (FLI) <30, grade 1 (G1) fatty liver: 30≤ FLI <60, and grade 2 (G2) fatty liver: FLI >60.

Results: During a median 8.4-year follow-up, we documented 3496 HCC cases and 4146 deaths. Compared to patients with no fatty liver (n = 35,018), the risk of HCC was significantly higher in patients with G1 fatty liver (n = 14,544) (adjusted hazard ratio [aHR] = 1.50, 95% confidence interval [CI] = 1.38-1.64) and G2 fatty liver (n = 7,823) (aHR = 1.88, 95% CI = 1.67-2.12). The risk of mortality was significantly higher in patients with G1 fatty liver (aHR = 1.53, 95% CI = 1.41-1.66) and G2 fatty liver (aHR = 2.16, 95% CI = 1.94-2.42) compared to patients with no fatty liver.

Conclusions: Concurrent fatty liver was associated with a higher risk of HCC and mortality in patients with chronic viral hepatitis. Our results suggest the importance of management of fatty liver to reduce the risks of HCC and mortality in patients with chronic viral hepatitis.
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http://dx.doi.org/10.1111/apt.16706DOI Listing
November 2021

Contextual and individual factors associated with knowledge, awareness and attitude on liver diseases: A large-scale Asian study.

J Viral Hepat 2021 Nov 24. Epub 2021 Nov 24.

Kantar Health, Singapore, Singapore.

There are limited data to provide better understanding of the knowledge/awareness of general population towards liver health in Asia. We sought to identify the knowledge gaps and attitudes towards liver health and liver diseases as well as evaluate associated individual-level and macro-level factors based on contextual analysis. An online survey assessing knowledge, awareness and attitudes towards liver health and disease was conducted among 7500 respondents across 11 countries/territories in Asia. A liver index was created to measure the respondents' knowledge level and the degree of awareness and attitudes. Multilevel logistic regression was performed to identify individual factors and contextual effects that were associated with liver index. The overall liver index (0-100-point scale) was 62.4 with 6 countries/territories' liver indices greater than this. In the multilevel model, the inclusion of geographical information could explain for 9.6% of the variation. Residing in a country/territory with higher HBV prevalence (80% IOR: 1.20-2.79) or higher HCV death rate (80% IOR: 1.35-3.13) increased the individual probability of obtaining a high overall liver index. Individual factors like age, gender, education, household income, disease history and health screening behaviour were also associated with liver index (all p-values<0.001). The overall liver index was positively associated with the two macro-level factors viz. HBV prevalence and HCV death rate. There is a need to formulate policies especially in regions of lower HBV prevalence and HCV death rate to further improve the knowledge, awareness and attitudes of the general public towards liver diseases.
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http://dx.doi.org/10.1111/jvh.13636DOI Listing
November 2021

Non-back-reflecting polygon scanner with applications in surface cleaning.

Opt Express 2021 Oct;29(21):32939-32950

Polygon mirror scanners are attracting considerable interest owing to their rapid speed and large scanning area. Here, we focused on the back-reflection effect of the polygon scanner. A new polygon scanner system was designed based on a geometric analysis. The final equations for the design express the position of the laser beam source having the largest scanning length without the reflected beam traveling back to the fiber. The proposed system performed a raster scan on an area. Additionally, a paint stripping experiment was conducted to demonstrate the potential use of our scanner in commercial laser cleaning applications.
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http://dx.doi.org/10.1364/OE.438850DOI Listing
October 2021

Efficacy of entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide in treatment-naive hepatitis B patients.

Hepatol Int 2021 Nov 20. Epub 2021 Nov 20.

Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Background And Aims: Antiviral agents for chronic hepatitis B (CHB) reduced the risk of hepatocellular carcinoma (HCC) development. The outcomes of entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) were compared in patients with CHB.

Methods: Between 2017 and 2019, treatment-naïve patients with CHB treated with ETV, TDF, and TAF were recruited from three Korean tertiary institutes. The cumulative incidences of HCC and orthotopic liver transplantation (OLT) or mortality were calculated and compared using Kaplan-Meier analysis before and after trimatch.

Results: Among recruited 2082 patients, 43 patients developed HCC, whereas 66 developed OLT or mortality. Before trimatch, the cumulative incidence of HCC was statistically similar among patients treated with three antiviral agents (p = 0.340). However, the cumulative probability of OLT or mortality development in patients treated with ETV or TDF was significantly higher than that of patients with TAF before trimatch (all p < 0.05). On multivariate analysis, male sex [hazard ratio (HR) 2.990] and older age (HR 1.044) were independently associated with an increased risk of HCC development, whereas higher platelet count (HR 0.993) was independently associated with a decreased risk (all p < 0.05). The type of antiviral agents did not significantly influence the risk of HCC and OLT or mortality development (all p > 0.05). After trimatch, no significant difference in the cumulative probability for HCC and OLT or mortality according to antiviral agents was found (all p > 0.05).

Conclusions: The outcomes of ETV, TDF, and TAF on the risk of HCC and OLT or mortality were statistically similar in treatment-naïve patients with CHB.
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http://dx.doi.org/10.1007/s12072-021-10262-yDOI Listing
November 2021

Development and Pilot Testing of a Smartphone-Based Self-Care Program for Patients with Chronic Hepatitis B.

Int J Environ Res Public Health 2021 10 23;18(21). Epub 2021 Oct 23.

College of Nursing, Ansan University, Ansan 15328, Korea.

The purpose of this study is to develop a smartphone-based self-care program (Hep B Care) for patients with the chronic hepatitis B virus (HBV). To pilot test the feasibility of Hep B Care, 63 participants with chronic HBV were recruited from an outpatient clinic at S hospital, Seoul, South Korea (experimental group [EG]: = 30, control group [CG]: = 33) between February and July 2016. Hep B Care was developed based on the theory of self-care whilst having a chronic illness. During the 12-week intervention period, the application: (1) provided information about the disease, medication, nutrition, and exercise; (2) encouraged taking medication and exercise using alarms; and (3) enabled the exchange of messages between healthcare providers and patients. Salivary cortisol, fatigue, depression, anxiety, knowledge of the HBV, quality of life, and medication adherence were all measured as outcomes. Cortisol levels were significantly increased, knowledge of the HBV was improved, and the mean anxiety score was significantly decreased in the EG. Thus, Hep B Care partially improved health outcomes in the EG. We recommend that large trials be conducted among patients with the HBV. The smartphone-based self-care program for providing education and coaching is effective for improving knowledge and reducing anxiety among patients with the HBV.
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http://dx.doi.org/10.3390/ijerph182111139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582966PMC
October 2021

Dickkopf-1 promotes angiogenesis by upregulating VEGF receptor 2-mediated mTOR/p70S6K signaling in hepatocellular carcinoma.

Am J Cancer Res 2021 15;11(10):4788-4806. Epub 2021 Oct 15.

Yonsei Liver Center, Severance Hospital Seoul, Korea.

The expression of Dickkopf-1 (DKK1), a negative regulator of the Wnt/β-catenin signaling pathway, is upregulated in hepatocellular carcinoma (HCC). Here, we investigated the tumorigenic and angiogenic potential of DKK1 in HCC. Stable cell lines were established using the clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease 9 (CRISPR/Cas9)-based DKK1 knock-out system in Hep3B cells and the tetracycline-based DKK1 inducible system in Huh7 cells. Multicellular tumor spheroids (MCTSs) were cultured using Hep3B stable cells. We also employed xenografts generated using Hep3B stable cells and transgenic mouse models established using hydrodynamic tail vein injection. The angiogenic potential increased in HUVECs treated with CM from Huh7 stable cells with high DKK1 expression and Hep3B wild-type cells. DKK1 accelerated the downstream molecules of vascular endothelial growth factor receptor 2 (VEGFR2)-mediated mTOR/p70 S6 kinase (p70S6K) signaling. MCTSs generated using Hep3B wild-type cells promoted compact spheroid formation and increased the expression of CD31 and epithelial-mesenchymal transition (EMT) markers, and increased the VEGFR2-mediated mTOR/p70S6K signaling, compared to the controls (all <0.01). Xenograft tumors generated using Hep3B cells with DKK1 knock-out (n=10) exhibited slower growth than, the controls (n=10) and the expression of Ki-67, VEGFR2, CD31 and EMT markers decreased (all <0.05). In addition, forced DKK1 expression with HRAS in transgenic mouse livers (n=5) resulted in the formation of more tumors and increased expression of downstream molecules of VEGFR2-mediated mTOR/p70S6K signaling pathway as well as Ki67, CD31 and EMT markers (<0.05), compared to that of the controls (n=5). Our findings indicate that DKK1 facilitates angiogenesis and tumorigenesis by upregulating VEGFR2-mediated mTOR/p70S6K signaling in HCC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8569356PMC
October 2021

Besifovir therapy improves hepatic histology and reduces covalently closed circular DNA in chronic hepatitis B patients.

J Gastroenterol Hepatol 2021 Oct 15. Epub 2021 Oct 15.

Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea.

Background And Aim: Besifovir dipivoxil maleate (BSV) was reported to have comparable antiviral efficacy and superior renal and bone safety to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. The present study aims to evaluate changes of liver histology and intrahepatic covalently closed circular DNA (cccDNA) levels by BSV treatment in comparison with TDF therapy.

Methods: This is a subset study of the phase 3 trial comparing BSV with TDF. Among them, only CHB patients willing to participate in a histologic evaluation study were enrolled. Liver histologic examination and intrahepatic cccDNA quantification were performed.

Results: A total of 46 CHB patients received liver biopsies (BSV, n = 29; TDF, n = 17). After 48 weeks of treatment, virological response rate was comparable between the groups (P = 0.707). Follow-up liver biopsies showed that necroinflammation was significantly improved in the both groups. However, the histological response rate defined as the proportion of subjects whose modified histologic activity index score decreased by ≥ 2 without deterioration in fibrosis was higher in the BSV group than in the TDF group (77.8% vs 36.4%, P = 0.048). The proportion of subjects with Ishak fibrosis score 3 or more decreased from 77.7% to 55.5% in the BSV and that decreased from 72.7% to 45.4% in the TDF group. The intrahepatic cccDNA significantly decreased from baseline after 48 weeks of BSV or TDF treatment (P < 0.001) without intergroup differences (P = 0.349).

Conclusions: The BSV therapy improves hepatic histology and decreases intrahepatic cccDNA in CHB patients.
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http://dx.doi.org/10.1111/jgh.15710DOI Listing
October 2021

Liver Stiffness-Based Risk Prediction Model for Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease.

Cancers (Basel) 2021 Sep 11;13(18). Epub 2021 Sep 11.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.

Non-alcoholic fatty liver disease (NAFLD) is associated with an increased hepatocellular carcinoma (HCC) risk. We established and validated a liver stiffness (LS)-based risk prediction model for HCC development in patients with NAFLD. A total of 2666 and 467 patients with NAFLD were recruited in the training and validation cohorts, respectively. NAFLD was defined as controlled attenuated parameter ≥238 dB/m by transient elastography. Over a median of 64.6 months, HCC developed in 22 (0.8%) subjects in the training cohort. Subjects who developed HCC were older and had higher prevalence of diabetes and cirrhosis, lower platelet count, and higher AST levels compared to those who did not develop HCC (all < 0.05). In multivariate analysis, age ≥60 years (hazard ratio (HR) = 9.1), platelet count <150 × 10/μL (HR = 3.7), and LS ≥9.3 kPa (HR = 13.8) were independent predictors (all < 0.05) that were used to develop a risk prediction model for HCC development, together with AST ≥34 IU/L. AUCs for predicting HCC development at 2, 3, and 5 years were 0.948, 0.947, and 0.939, respectively. This model was validated in the validation cohort (AUC 0.777, 0.781, and 0.784 at 2, 3, and 5 years, respectively). The new risk prediction model for NAFLD-related HCC development showed acceptable performance in the training and validation cohorts.
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http://dx.doi.org/10.3390/cancers13184567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472221PMC
September 2021

Prognostic significance of surgery-induced sarcopenia in the survival of gastric cancer patients: a sex-specific analysis.

J Cachexia Sarcopenia Muscle 2021 Sep 17. Epub 2021 Sep 17.

Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea.

Background: Preoperative sarcopenia is associated with a poor long-term prognosis in patients with gastric cancer (GC). Most GC patients rapidly lose muscle mass after gastrectomy. This retrospective cohort study analysed the effect of postoperative muscle loss and surgery-induced sarcopenia on the long-term outcomes of patients with GC.

Methods: Preoperative and postoperative 1 year abdominal computed tomography scans were available for 1801 GC patients who underwent curative gastrectomy between January 2009 and December 2013 at Seoul National University Bundang Hospital. The patients were categorized into normal, presarcopenia, and sarcopenia groups according to the skeletal muscle index (SMI) measured on computed tomography scans. Patients who were not sarcopenic prior to gastrectomy but became sarcopenic after surgery were defined as the surgery-induced sarcopenia group.

Results: There were 1227 men and 574 women included in the study. The mean age of the patients was 59.5 ± 12.3 years. Multivariable Cox-regression analyses showed that preoperative SMI was not associated with overall survival (OS). However, postoperative sarcopenia was associated with significantly worse OS only in men [hazard ratio (HR), 1.75; 95% confidence interval (CI), 1.08-2.85]. SMI loss was an independent risk factor for OS in the entire cohort and in men (HR, 1.01; 95% CI, 1.00-1.02, for the entire cohort; HR, 1.02; 95% CI, 1.01-1.04, for men). The surgery-induced sarcopenia group was associated with significantly higher mortality (HR, 1.84; 95% CI, 1.16-2.90, for the cohort; HR, 2.73; 95% CI, 1.54-4.82, for men), although SMI loss and surgery-induced sarcopenia were not risk factors in women. Similar results were obtained for relapse-free survival.

Conclusions: Postoperative muscle mass loss and surgery-induced sarcopenia are prognostic factors for survival in patients with GC. Impact of postoperative muscle mass loss and surgery-induced sarcopenia on survival outcomes is dependent on the sex.
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http://dx.doi.org/10.1002/jcsm.12793DOI Listing
September 2021

Episodic Detectable Viremia Does Not Affect Prognosis in Untreated Compensated Cirrhosis With Serum Hepatitis B Virus DNA <2,000 IU/mL.

Am J Gastroenterol 2021 Sep 10. Epub 2021 Sep 10.

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

Introduction: The necessity of antiviral therapy (AVT) for hepatitis B virus (HBV)-infected compensated cirrhosis with low-level viremia (LLV) is controversial. Herein, we evaluated its natural history.

Methods: From 3 tertiary hospitals, we enrolled untreated patients with compensated cirrhosis with persistent serum HBV-DNA levels <2,000 IU/mL; LLV was defined as having at least 1 detectable serum HBV-DNA (20-2,000 IU/mL) episode, whereas maintained virological response (MVR) was defined as having persistently undetectable serum HBV-DNA (<20 IU/mL). When serum HBV-DNA was ≥2,000 IU/mL during follow-up, AVT was administered according to guidelines. Study end points were development of cirrhotic complication event (CCE) or hepatocellular carcinoma (HCC).

Results: Among 567 patients analyzed, cumulative HCC risk at 3, 5, and 7 years was comparable between LLV (n = 391) vs MVR (n = 176) groups (5.7%, 10.7%, and 17.3% vs 7.2%, 15.5%, and 19.4%, respectively [P = 0.390]). CCE risk was also comparable between 2 groups (7.5%, 12.8%, and 13.7% vs 7.8%, 12.3%, and 14.6%, respectively [P = 0.880]). By multivariate analysis, LLV (vs MVR) was not associated with HCC or CCE risks, with adjusted hazard ratios of 1.422 (95% confidence interval [CI] 0.694-2.913; P = 0.336) and 1.816 (95% CI: 0.843-3.911; P = 0.128), respectively. Inverse probability of treatment weighting analysis yielded comparable outcomes between 2 groups, regarding HCC and CCE risks with hazard ratios of 0.903 (95% CI: 0.528-1.546; P = 0.711) and 1.192 (95% CI: 0.675-2.105; P = 0.545), respectively.

Discussion: Episodic LLV among untreated patients with compensated cirrhosis does not increase the risk of disease progression compared with MVR status. Thus, the benefits of AVT for episodic LLV should be re-evaluated.
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http://dx.doi.org/10.14309/ajg.0000000000001497DOI Listing
September 2021

Long-term effects of entecavir and tenofovir treatment on the fibrotic burden in patients with chronic hepatitis B.

J Gastroenterol Hepatol 2021 Sep 3. Epub 2021 Sep 3.

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

Background And Aim: Antiviral therapy (AVT) induces fibrosis regression in patients with chronic hepatitis B. We investigated long-term effects of entecavir (ETV) versus tenofovir (TDF) on fibrotic burden.

Methods: Treatment-naïve chronic hepatitis B patients who had begun ETV or TDF were recruited from four tertiary hospitals. The aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4) were used to determine fibrotic burden.

Results: In the entire population (n = 3277), although patients treated with ETV had higher baseline APRI (1.71 vs 1.07, P < 0.001) and FIB-4 (3.60 vs 2.80, P < 0.001) than those treated with TDF, significant fibrosis regression was identified during 6 years of AVT in both ETV (APRI, mean 1.71 → 0.48, P < 0.001; FIB-4, mean 3.60 → 2.21, P < 0.001) and TDF groups (APRI, mean 1.07 → 0.43, P < 0.001; FIB-4, mean 2.80 → 2.19, P < 0.001). In patients without cirrhosis (n = 2366), baseline APRI was significantly higher in ETV group than in TDF group (1.72 vs 0.97, P < 0.001); however, they became similar after 6 months. Similarly, baseline FIB-4 was significantly higher in ETV group than in TDF group (3.25 vs 2.35, P < 0.001), but became similar from 4 to 6 years. In patients with cirrhosis (n = 911), baseline APRI (1.70 vs 1.34, P < 0.001) and FIB-4 (4.62 vs 3.91, P = 0.005) were higher in ETV group than in TDF, however, both parameters became statistically similar from 6 months to 6 years.

Conclusion: Significant regression of APRI and FIB-4 was observed during long-term ETV and TDF treatment. Despite higher baseline fibrotic burden in ETV group, fibrotic burden between the groups eventually converged through significant fibrosis regression after 1 to 4 years of AVT.
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http://dx.doi.org/10.1111/jgh.15678DOI Listing
September 2021

Prevalence and Risk Factors of Cardiovascular Disease in Patients with Chronic Hepatitis B.

Dig Dis Sci 2021 Sep 2. Epub 2021 Sep 2.

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

Background: The association between chronic hepatitis B (CHB) and cardiovascular disease (CVD) remains unclear. We investigated the prevalence and risk factors of CVD in patients with CHB.

Methods: Data from the Korean National Health and Nutrition Examination Surveys 2008-2011 were analyzed. Significant liver fibrosis was defined as the highest nonalcoholic fatty liver disease fibrosis score quartile, highest Forns index quintile, or fibrosis-4 ≥ 2.67. The CVD risk was calculated using the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score from the 2013 ACC/AHA Guidelines.

Results: Among the 506 subjects with CHB, 15 (3.0%) and 150 (29.6%) patients had a CVD history and significant liver fibrosis, respectively. Patients with CVD history were significantly older; showed a significantly higher prevalence of hypertension, metabolic syndrome, and significant liver fibrosis; and had a significantly higher platelet count, lower aspartate and alanine aminotransferase levels, higher triglyceride level, lower high-density lipoprotein level, and higher ASCVD risk than those without (all p < 0.05). In multivariate analysis, higher ASCVD risk (odds ratio [OR] = 1.090) and significant liver fibrosis (OR = 4.341) independently predicted the risk of CVD history (p < 0.05). The prevalence of CVD risk (6.7% vs. 1.4%; OR = 5.014) and high ASCVD risk (> 15%) (34.0% vs. 7.3%; OR = 6.538) was significantly higher in patients with significant liver fibrosis than in those without (all p < 0.05).

Conclusions: Significant liver fibrosis was independently associated with the risk of CVD history in patients with CHB. Prospective studies are needed to validate the longitudinal association between fibrotic burden and CVD development in patients with CHB.
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http://dx.doi.org/10.1007/s10620-021-07157-1DOI Listing
September 2021

The Incidence and Risk Factors for Metachronous Gastric Cancer in the Remnant Stomach after Gastric Cancer Surgery.

Gut Liver 2021 Sep 1. Epub 2021 Sep 1.

Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea.

Background/aims: Less invasive surgical treatment is performed in East Asia to preserve postoperative digestive function and reduce complications such as postgastrectomy syndromes, but there is an issue of metachronous gastric cancer (GC) in the remaining stomach. This study aimed to analyze the incidence of metachronous GC and its risk factors in patients who had undergone partial gastrectomy.

Methods: A total of 3,045 GC patients who had undergone curative gastric partial resection at Seoul National University Bundang Hospital were enrolled and analyzed retrospectively for risk factors, including age, sex, smoking, alcohol, status, family history of GC, histological type, and surgical method.

Results: Metachronous GC in the remaining stomach occurred in 35 of the 3,045 patients (1.1%): 23 in the distal gastrectomy group (18 with Billroth-I anastomosis, five with Billroth-II anastomosis), seven in the proximal gastrectomy (PG) group, and five in the pylorus-preserving gastrectomy (PPG) group. Univariate and multivariate Cox regression analyses showed that age ≥60 years (p=0.005) and surgical method used (PG or PPG, p<0.001) were related risk factors for metachronous GC, while male sex and intestinal type histology were potential risk factors.

Conclusions: Metachronous GC was shown to be related to older age and the surgical method used (PG or PPG). Regular and careful follow-up with endoscopy should be performed in the case of gastric partial resection, especially in patients with male sex and intestinal type histology as well as those aged ≥60 years undergoing the PG or PPG surgical method.
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http://dx.doi.org/10.5009/gnl210202DOI Listing
September 2021

Effect of tenofovir alafenamide vs. tenofovir disoproxil fumarate on hepatocellular carcinoma risk in chronic hepatitis B.

J Viral Hepat 2021 Nov 4;28(11):1570-1578. Epub 2021 Sep 4.

Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea.

It is unclear whether tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) is more effective for preventing hepatocellular carcinoma (HCC) development in patients with chronic hepatitis B (CHB). In this study, we compared the effectiveness of these two antiviral agents for preventing HCC. We included treatment-naïve CHB patients undergoing antiviral therapy with TDF only (TDF group) or a TAF-based regimen (TAF group) at three academic teaching hospitals from 2012 to 2019. The TAF group included patients receiving TAF as first-line treatment and patients switching from TDF to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded. Cumulative probabilities of HCC were assessed using Kaplan-Meier methodology. In total, 2,117 patients were included: 1,832 in the TDF group and 285 in the TAF group. The annual HCC incidence was not significantly different between TDF and TAF groups: 1.66 vs. 1.19 per 100 person-years [PY], respectively (multivariate analysis: adjusted hazard ratio [HR] 0.774 [reference: TDF group]; p = .438). Male, liver cirrhosis, hepatitis B e antigen negativity, Fibrosis-4 index>3.25 and low albumin were independently associated with a higher risk of HCC. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results: 1.56 vs. 1.19 per 100 PY, respectively (HR 1.175; p = .708) and 1.66 vs. 1.29 per 100 PY, respectively (HR 0.888; p = .446). The risk of HCC development was not significantly different between TDF and TAF groups of CHB patients. Further studies with a larger sample size and longer follow-up are required to validate our results.
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http://dx.doi.org/10.1111/jvh.13601DOI Listing
November 2021

Impact of tenofovir alafenamide vs. entecavir on hepatocellular carcinoma risk in patients with chronic hepatitis B.

Hepatol Int 2021 Oct 16;15(5):1083-1092. Epub 2021 Aug 16.

Department of Internal Medicine, Kyungpook National University School of Medicine, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, Republic of Korea.

Background And Aims: Whether entecavir (ETV) or tenofovir alafenamide (TAF) is better at preventing hepatocellular carcinoma (HCC) development among patients with chronic hepatitis B (CHB) remains unclear. The present study was conducted to explore the ability of these two antivirals to prevent HCC.

Methods: From 2012 to 2019, treatment-naïve CHB patients undergoing ETV or TAF therapy were recruited at three academic teaching hospitals. The TAF group comprised patients starting TAF as first-line antiviral and those switching antivirals from tenofovir disoproxil fumarate to TAF. Patients with decompensated cirrhosis or HCC at enrollment were excluded from the analysis. Cumulative probabilities of HCC were assessed using the Kaplan-Meier method.

Results: In total, 1810 patients (1525 and 285 in ETV and TAF groups, respectively) were recruited. The annual HCC incidence was statistically not different between the ETV and TAF groups (1.67 vs. 1.19 per 100 person-years, respectively) with an adjusted hazard ratio (HR) of 0.681 (p = 0.255), as determined by multivariate analysis. Male, hypertension, liver cirrhosis, FIB-4 index, and albumin were independent prognostic factors for HCC development. Propensity score-matched and inverse probability of treatment weighting analyses yielded similar results, with non-statistically different HCC incidence between the ETV and TAF groups (1.07 vs. 1.19 per 100 person-years (HR = 0.973; p = 0.953) and 1.67 vs. 1.89 per 100 person-years, respectively (HR = 0.949; p = 0.743).

Conclusions: These findings suggest that ETV- and TAF-treated CHB patients have similar risk of developing HCC. Further studies with the larger sample size and longer follow-up are needed to validate these results.
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http://dx.doi.org/10.1007/s12072-021-10234-2DOI Listing
October 2021

No influence of hepatic steatosis on the 3-year outcomes of patients with quiescent chronic hepatitis B.

J Viral Hepat 2021 Nov 16;28(11):1545-1553. Epub 2021 Aug 16.

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

The influence of hepatic steatosis on the natural history of chronic hepatitis B (CHB) virus is unclear. Therefore, we investigated whether concurrent steatosis in patients with CHB influences the probability of hepatitis B surface antigen (HBsAg) loss, fibrosis progression and hepatocellular carcinoma (HCC) development. This study enrolled treatment-naïve patients with virologically (HBV DNA <2,000 IU/ml) and biochemically (alanine aminotransferase level <40 IU/L) quiescent CHB who underwent transient elastography between January 2004 and December 2015 and completed 3 years of follow-up. RESULTS: The mean age of the study population (n = 720) was 52.0 years, and there were more men than women (n = 419, 58.2%). The mean HBV DNA level was 321.6 IU/ml. During the 3-year period, 74 (10.3%) patients achieved HBsAg seroclearance. Lower HBV DNA levels (hazard ratio = 0.995, p < .05) were independently associated with HBsAg seroclearance, while hepatic steatosis was not (p > .05). Fibrosis progressed in 89 (12.4%) patients. Male gender (odds ratio [OR] = 1.720) and higher body mass index (OR = 1.083) were independently associated with an increased probability of fibrosis progression (all p < .05), while higher total cholesterol levels (OR = 0.991) and higher liver stiffness values (OR = 0.862) were independently associated with a decreased probability of fibrosis progression (all p < .05). HCC developed in 46 (6.4%) patients. Male gender (OR = 3.917) and higher AST levels (OR = 1.036) were independently associated with an increased probability of HCC development (p < .05). Hepatic steatosis was not associated with the probability of HBsAg seroclearance, fibrosis progression or HCC development in patients quiescent CHB in our study. Further studies with longer follow-up periods are required to validate our findings.
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http://dx.doi.org/10.1111/jvh.13594DOI Listing
November 2021

Expression of the immune checkpoint receptors PD-1, LAG3, and TIM3 in the immune context of stage II and III gastric cancer by using single and chromogenic multiplex immunohistochemistry.

Oncoimmunology 2021 25;10(1):1954761. Epub 2021 Jul 25.

Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.

We sought to determine the clinicopathological significance of PD-1, LAG3, and TIM3 in gastric cancer (GC) by examining their expression and immune context. Immunohistochemistry (IHC) for PD-1, TIM3, LAG3, and tumor-infiltrating immune cell (TIIC) markers was performed in 385 stage II/III GCs. Epstein-Barr virus (EBV) and microsatellite stability (MSI) testing were performed for molecular classification. Chromogenic multiplex IHC (mIHC) for PD1, TIM3, LAG3, CD3, CD8, FOXP3, CD68, and cytokeratin was performed in 58 of the total samples. PD-1, LAG3, and TIM3 expression in TIICs was observed in 91 (23.6%), 193 (50.1%), and 257 (66.8%) GCs by single IHC, respectively. The expression was associated with EBV and MSI-H molecular subtypes (p ≤ 0.001). A positive expression of LAG3 in the invasive margin of the tumor was associated with better prognosis in univariate ( = .020) and multivariate ( = .026) survival analyses. The expression of different immune checkpoint receptors (ICRs) was significantly positively correlated. Dual or triple ICR expression was more frequent in high PD-1 and TIM3 density groups than in low-density groups by mIHC (all p ≤ 0.05). ICRs were mainly expressed in CD3CD8 and CD3CD8 T cells. Fifty-eight GCs were classified into three groups by clustering analysis based on mIHC, and the group with the highest ICR expression in TIICs showed significantly better outcomes in progression-free survival ( = .020). In GC, PD-1, LAG3, and TIM3 expression is positively correlated and associated with better prognosis. Our study provides information for the application of effective immune checkpoint inhibitors against GC.
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http://dx.doi.org/10.1080/2162402X.2021.1954761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312618PMC
October 2021

Risk stratification using sarcopenia status among subjects with metabolic dysfunction-associated fatty liver disease.

J Cachexia Sarcopenia Muscle 2021 10 1;12(5):1168-1178. Epub 2021 Aug 1.

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

Background: Sarcopenia is a significant indicator of the severity of non-alcoholic fatty liver disease. We investigated whether sarcopenia could identify subgroups with different risk of liver fibrosis and atherosclerotic cardiovascular disease (ASCVD) among subjects with metabolic dysfunction-associated fatty liver disease (MAFLD).

Methods: Subjects from the Korea National Health and Nutrition Examination Survey 2008-2011 were selected (n = 8361). Sarcopenia was defined using the sarcopenia index. Hepatic steatosis was defined as a fatty liver index ≥30. Significant liver fibrosis was defined as a fibrosis-4 index (FIB-4) ≥2.67 or the highest quartile of non-alcoholic fatty liver disease fibrosis score (NFS). High probability of ASCVD was defined as ASCVD risk score >10%.

Results: The mean age was 48.5 ± 15.6 years, and 42.6% of subjects were male. The prevalence of MAFLD was 37.3% (n = 3116 of 8361), and the proportion of sarcopenic subjects was 9.9% among those with MAFLD. After adjusting for confounders, the risk of significant liver fibrosis significantly increased from non-sarcopenic subjects with MAFLD [odds ratio (OR) = 1.57 by FIB-4 and 2.13 by NFS] to sarcopenic subjects with MAFLD (OR = 4.51 by FIB-4 and 5.72 by NFS), compared with subjects without MAFLD (all P < 0.001). The risk for high probability of ASCVD significantly increased from non-sarcopenic subjects with MAFLD (OR = 1.47) to sarcopenic subjects with MAFLD (OR = 4.08), compared with subjects without MAFLD (all P < 0.001).

Conclusions: The risks of significant liver fibrosis and ASCVD differed significantly according to sarcopenic status among subjects with MAFLD. An assessment of sarcopenia might be helpful in risk stratification among subjects with MAFLD.
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http://dx.doi.org/10.1002/jcsm.12754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517359PMC
October 2021

Controlled attenuation parameter value and the risk of hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy.

Hepatol Int 2021 Aug 14;15(4):892-900. Epub 2021 Jul 14.

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.

Background: Controlled attenuation parameter (CAP) can evaluate hepatic steatosis in patients with chronic hepatitis B (CHB). However, prognostic implications of CAP value remain unclear. We evaluated the association between CAP and the risk of hepatocellular carcinoma (HCC) in patients with CHB under antiviral therapy and maintained virologic response.

Methods: A total of 1823 CHB patients who were taking nucleos(t)ide analogue and showing suppressed hepatitis B virus replication were analyzed. The primary outcome was incident HCC during follow-up. Patients were grouped into those with and without advanced chronic liver disease (ACLD) (liver stiffness measurement cutoff: 10 kPa), and those with and without hepatic steatosis (CAP cutoff: 222 dB/m).

Results: During 6.4 years of follow-up, 127 patients (7.0%) newly developed HCC. Among patients with ACLD (n = 382), the cumulative HCC incidence rate was lower for those with CAP ≥ 222 (11.0% at 5 years) than those with CAP < 222 (24.0% at 5 years, p = 0.002), and was an independent factor associated with HCC. When CAP value was further stratified, the cumulative HCC incidence rate decreased in dose-dependent manner according to an increase in CAP value (24.0%, 13.9%, 12.8% and 6.0% at 5 years for those with CAP < 222, 222-246, 247-273 and ≥ 274, respectively). Among patients without ACLD (n = 1441), there was no significance difference in HCC risk according to CAP value (HCC incidence rate: 3.3% and 4.0% at 5 years for those with CAP < 222 and CAP ≥ 222, p = 0.20).

Conclusions: Among CHB patients under antiviral therapy showing suppressed HBV replication, low CAP value predicted higher risk for HCC among ACLD patients, indicating that CAP value has a prognostic implication in this population.
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http://dx.doi.org/10.1007/s12072-021-10205-7DOI Listing
August 2021

Cardiovascular Risk Is Elevated in Lean Subjects with Nonalcoholic Fatty Liver Disease.

Gut Liver 2021 Jul 12. Epub 2021 Jul 12.

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

Background/aims: Nonalcoholic fatty liver disease (NAFLD) and obesity are independently associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality in patients with NAFLD. Many NAFLD patients are lean, but their ASCVD risk compared to obese subjects with NAFLD is unclear.

Methods: Data from the 2008 to 2011 Korea National Health and Nutrition Examination Surveys database were analyzed (n=4,786). NAFLD was defined as a comprehensive NAFLD score ≥40 or a liver fat score ≥-0.640. ASCVD risk was evaluated using the American College of Cardiology/ American Heart Association guidelines.

Results: The frequency of subjects without NAFLD, with obese NAFLD, and with lean NAFLD was 62.4% (n=2,987), 26.6% (n=1,274), and 11.0% (n=525), respectively. Subjects with lean NAFLD had a significantly higher ASCVD score and prevalence of a high ASCVD risk (mean 15.6±14.0, 51.6%) than those with obese NAFLD and without NAFLD (mean 11.2±11.4, 39.8%; mean 7.9±10.9, 25.5%; all p<0.001). Subjects with lean NAFLD and significant liver fibrosis showed a significantly higher odds ratio for a high risk for ASCVD than those with obese NAFLD with or without significant liver fibrosis (odds ratio, 2.60 vs 1.93; p=0.023).

Conclusions: Subjects with lean NAFLD had a significantly higher ASCVD score and prevalence of high risk for ASCVD than those with obese NAFLD. Similarly, lean subjects with significant liver fibrosis had a higher probability of ASCVD than obese subjects in the subpopulation with NAFLD.
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http://dx.doi.org/10.5009/gnl210084DOI Listing
July 2021

Risk assessment of hepatocellular carcinoma and liver-related events using ultrasonography and transient elastography in patients with chronic hepatitis B.

J Viral Hepat 2021 10 23;28(10):1362-1372. Epub 2021 Aug 23.

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

Cirrhosis has prognostic value. We investigated whether the combined use of ultrasonography (US) and transient elastography (TE) to diagnose cirrhosis is beneficial for the risk assessment of hepatocellular carcinoma (HCC) and liver-related events in patients with chronic hepatitis B (CHB). A total of 9300 patients with CHB who underwent US and TE in two institutions between 2006 and 2018 were enrolled. TE value ≥13 kPa was set to indicate cirrhosis. Patients were divided into four groups: US(+)TE(+) (cirrhosis by US and TE), US(+)TE(-) (cirrhosis by US, but not by TE), US(-)TE(+) (cirrhosis by TE, but not by US) and US(-)TE(-) (non-cirrhosis by US and TE).The patients were predominantly male (n = 5474, 58.9%) with a mean age of 47.5 years. The proportions of patients with cirrhosis diagnosed by US and TE were 17.2% (n = 1595) and 13.2% (n = 1225), respectively. The proportion of patients with discordant results in diagnosing cirrhosis by US and TE was 18.7% (n = 1740). During follow-up (median: 60.0 months), HCC and liver-related events developed in 481 (5.2%) and 759 (8.2%) patients, respectively. The cumulative incidence rates of HCC and liver-related events were highest in the US(+)TE(+) group, intermediate-high in the US(-)TE(+) group, intermediate-low in the US(+)TE(-) group and lowest in the US(-)TE(-) group (overall p < .001). Cirrhosis assessed using US and TE was a major predictor of HCC and liver-related event development in patients with CHB. Cirrhosis assessed using TE seemed better in predicting HCC or liver-related events than using US, when cirrhosis diagnosis was discordant by US and TE.
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http://dx.doi.org/10.1111/jvh.13560DOI Listing
October 2021

Development and initial validation of the nonalcoholic fatty liver disease self-management questionnaire.

Res Nurs Health 2021 10 13;44(5):844-853. Epub 2021 Jun 13.

College of Medicine, Department of Internal Medicine and Institute of Gastroenterology, Yonsei University, Seoul, Republic of Korea.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing, and self-management is essential to improve health outcomes in this population. Despite the importance of self-management, there is no instrument to assess it in patients with NAFLD. The purpose of this study was to develop and validate an initial version of a self-management questionnaire for patients with NAFLD. This was a methodological and psychometric study conducted between April and November 2019. The NAFLD self-management questionnaire was developed after a theoretical and literature review and focus group interviews in three phases: (1) item generation, (2) item evaluation, and (3) psychometric evaluation. Participants (N = 155) were recruited from a hospital in Seoul, South Korea. Items were generated based on clinical NAFLD guidelines and the individual and family self-management theory. Construct validity was assessed using exploratory factor analysis. Six-factors were extracted from 22 items: lifestyle management, medical treatment compliance, management of medication and dietary supplements, alcohol consumption management, sleep management, and family support. These factors accounted for 67.4% of the total variance; each factor had an eigenvalue greater than 1, and Cronbach's alpha for the scale was 0.87. The NAFLD self-management questionnaire showed acceptable initial validity and reliability. The instrument can prove useful in the formulation of tailored interventions based on individual patients' care needs. Furthermore, it may be used as an indicator of health outcomes in this population.
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http://dx.doi.org/10.1002/nur.22164DOI Listing
October 2021

YAP/TAZ Suppress Drug Penetration Into Hepatocellular Carcinoma Through Stromal Activation.

Hepatology 2021 Nov 25;74(5):2605-2621. Epub 2021 Aug 25.

Yonsei Liver Center, Yonsei University College of Medicine, Seoul, Korea.

Background And Aims: HCC is the most predominant type of liver cancer affecting 800,000 people globally each year. Various small-molecule compounds targeting diverse oncogenic signaling pathways have been tested for patients with HCC, and clinical outcomes were not satisfactory. In this study, we investigated molecular signaling that determines the efficiency of drug delivery into HCC.

Approach And Results: Hydrodynamics-based transfection (HT) was performed to develop mouse models for HCC induced by various oncogenes. Mice bearing liver cancer were treated with verteporfin at 5 weeks after HT. Multicellular HCC organoid (MCHO) models were established that contained various types of stromal cells, such as hepatic stellate cells, fibroblasts, and endothelial cells together with HCC cells. Tumor organoids were treated with verteporfin, and distributions of the drug in the organoids were assessed using fluorescence microscopy. Murine HCC models developed by HT methods showed that a high Yes-associated protein/Transcriptional co-activator with PDZ-binding motif (YAP/TAZ) activity in HCC cells impaired verteporfin penetration into the cancer. Activation of tumor stroma was observed in HCC with a high YAP/TAZ activity. Consistent with the findings in the in vivo models of HCC, MCHOs with activated YAP/TAZ signaling showed stromal activation and impaired penetration of verteporfin into the tumor organoids. Inhibition of YAP/TAZ transcriptional activity in HCC cells significantly increased drug penetration into the MCHO.

Conclusions: Drug delivery into liver cancer is impaired by YAP/TAZ signaling in tumor cells and subsequent activation of stroma by the signaling. Disrupting or targeting activated tumor stroma might improve drug delivery into HCC with an elevated YAP/TAZ activity.
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http://dx.doi.org/10.1002/hep.32000DOI Listing
November 2021

Predictive Performance of CAGE-B and SAGE-B Models in Asian Treatment-Naive Patients Who Started Entecavir for Chronic Hepatitis B.

Clin Gastroenterol Hepatol 2021 Jun 6. Epub 2021 Jun 6.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul; Institute of Gastroenterology, Yonsei University College of Medicine, Seoul; Yonsei Liver Center, Severance Hospital, Seoul. Electronic address:

Background & Aims: Cirrhosis and age (CAGE-B) and stiffness and age (SAGE-B) models assess the risk of hepatocellular carcinoma (HCC) development in white patients with chronic hepatitis B (CHB) undergoing sustained antiviral therapy (AVT). Herein, we checked the predictive performance of these models in Asian patients with CHB.

Methods: We reviewed 734 treatment-naive patients with CHB who started entecavir between 2006 and 2011 and were followed up for more than 5 years without HCC development during AVT. The predictive performance of CAGE-B and SAGE-B models was calculated using area under the receiver operating characteristic curves (AUROCs).

Results: Median liver stiffness assessed using transient elastography after 5 years of AVT was 6.8 kPa. Median CAGE-B and SAGE-B models after 5 years of AVT were 7.0 and 6.0, respectively. More than 5 years after AVT initiation, 66 patients (9.0%) developed HCC. The AUROCs of the CAGE-B and SAGE-B models were 0.764 and 0.785 after 7 years and 0.799 and 0.802 after 10 years of AVT, respectively. The cumulative incidence of HCC was significantly higher in the high-risk groups according to CAGE-B and SAGE-B risk stratification than in the medium- and low-risk groups (P < .05 in all cases). The SAGE-B model showed a higher likelihood ratio (χ) (76.2 vs 71.4) and linear trend (χ) (74.1 vs 58.6) than the CAGE-B model, whereas the CAGE-B model showed higher Akaike information criteria (64.3 vs 50.3).

Conclusions: Both SAGE-B and CAGE-B showed acceptable performance in predicting HCC after 5 years of AVT in Asian patients with CHB.
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http://dx.doi.org/10.1016/j.cgh.2021.06.001DOI Listing
June 2021

Correlation between tumor infiltrating immune cells and peripheral regulatory T cell determined using methylation analyses and its prognostic significance in resected gastric cancer.

PLoS One 2021 4;16(6):e0252480. Epub 2021 Jun 4.

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea.

Peripheral regulatory T cells (pTregs) are a highly immunosuppressive fraction of CD4+ T cells. We aimed to evaluate the clinical significance of pTregs in patients with gastric cancer and to determine the correlation between pTregs and immune cell infiltration in tumor microenvironment. pTregs status was determined by assessing the pTreg/total T-cell ratio (ratio of Foxp3 Treg-specific demethylated region (TSDR) to CD3G/CD3D demethylation, so-called Cellular Ratio of Immune Tolerance "ImmunoCRIT") using methylation analyses in 433 patients with gastric cancer who received curative surgery. Among 422 evaluable patients, 230 (54.5%) had high ImmunoCRIT (> 21.0). Patients with high ImmunoCRIT had significantly shorter disease-free survival (DFS) and overall survival (OS) than those with high ImmunoCRIT (p = 0.030, p = 0.008, respectively). In multivariate analysis, high ImmunoCRIT kept a prognostic role for shorter OS (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.4-2.9; p = 0.005). CD3+ cell density and CD4+ cell density was significantly higher within the tumor in high ImmunoCRIT group than those in low ImmunoCRIT group (CD3+ cell, 202.12/mm2 vs. 172.2/mm2, p = 0.029; CD4+ cell, 56.5/mm2 vs. 43.5/mm2, p = 0.007). In conclusion, the peripheral ImmunoCRIT determined by epigenetic methylation analysis provides prognostic information in resected gastric tumors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252480PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177409PMC
November 2021

The Prognostic Role of On-Treatment Liver Stiffness for Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis B.

J Hepatocell Carcinoma 2021 25;8:467-476. Epub 2021 May 25.

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

Background: Dynamic changes in fibrosis markers occur under long-term antiviral treatment (AVT) for chronic hepatitis B. We evaluated prognostic values of on-treatment liver stiffness (LS) compared to ultrasonography findings and determined its optimal cutoff.

Methods: The cumulative probability of hepatocellular carcinoma (HCC) was assessed among 880 patients receiving entecavir or tenofovir for ≥2 years. LS was measured using transient elastography.

Results: After ≥2 years' AVT, the proportion of patients with cirrhosis on ultrasonography decreased from 54.7% to 44.9% and the mean LS decreased from 13.6 to 8.2 kPa (both p<0.001). However, unlike cirrhosis on ultrasonography before AVT (p<0.001), that after ≥2 years' AVT did not discriminate HCC risk (p=0.792). Using the Contal and O'Quigley's method, pre-AVT and on-treatment LS of 12.0 and 6.4 kPa, respectively, were chosen as optimal cutoffs to successfully discriminate HCC risk (both p<0.001). However, through stratification using both pre-AVT and on-treatment LS, the prognosis was finally determined according to on-treatment LS of 6.4 kPa, regardless of pre-AVT LS of 12.0 kPa. Using on-treatment LS of 12 kPa suggested by Caucasians with CHB receiving long-term AVT, patients with higher LS were more likely to develop HCC than those with lower LS (p=0.017); however, there was no significant difference between those with on-treatment LS of 6.4-11.9 and ≥ 12.0 kPa (p=0.920).

Conclusion: For HCC risk stratification in patients receiving long-term AVT, on-treatment LS cutoff should be lowered to 6.4 kPa, which is more predictive than 12 kPa or cirrhosis on ultrasonography. Further studies are required for validation.
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http://dx.doi.org/10.2147/JHC.S300382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164698PMC
May 2021

Tenofovir is Associated With Higher Risk of Kidney Function Decline Than Entecavir in Patients With Chronic Hepatitis B.

Clin Gastroenterol Hepatol 2021 May 21. Epub 2021 May 21.

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address:

Of the antiviral agents currently available to patients with chronic hepatitis B (CHB), entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are 2 of 3 first-line agents. Given the well-known renal and bone toxicity associated with TDF, major international hepatitis B virus treatment guidelines recommend ETV over TDF in patients with predisposing factors to kidney function decline. However, as evidenced by recent studies, nephrotoxicity of antiviral agents is still an issue under debate. Therefore, we investigated the differences in the risk of kidney function decline in patients with treatment-naive CHB who were treated with ETV or TDF.
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http://dx.doi.org/10.1016/j.cgh.2021.05.032DOI Listing
May 2021

Hepatitis B Core-Related Antigen: From Virology to Clinical Application.

Semin Liver Dis 2021 05 6;41(2):182-190. Epub 2021 May 6.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.

Hepatitis B core-related antigen (HBcrAg) is a composite measure of the serum levels of hepatitis B e antigen, hepatitis B core antigen, and a 22-kDa precore protein. It has been shown to reflect the level and transcriptional activity of covalently closed circular DNA in the liver. Longitudinal cohort studies have improved our understanding of the role of this novel viral marker in the natural history of chronic hepatitis B. HBcrAg kinetics reflect the response to peginterferon, and its role in defining guidelines for stopping peginterferon therapy has been evaluated. HBcrAg is a marker of intrahepatic viral activity, which may influence the risk of hepatocellular carcinoma. In this article, we review the virology and role of HBcrAg in defining phases of chronic hepatitis B. Furthermore, the function of HBcrAg in predicting treatment outcomes and its role in monitoring response to novel antiviral agents will be discussed.
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http://dx.doi.org/10.1055/s-0041-1723088DOI Listing
May 2021

Revised Korean Antiviral Guideline Reduces the Hepatitis B-related Hepatocellular Carcinoma Risk in Cirrhotic Patients.

J Korean Med Sci 2021 Apr 26;36(16):e105. Epub 2021 Apr 26.

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

Background: Since September 2015, the initiation of antiviral therapy (AVT) for patients with chronic hepatitis B (CHB)-related cirrhosis has been reimbursed according to the revised Korean Association for the Study of Liver (KASL) guideline, if the patient had hepatitis B virus DNA level ≥ 2,000 IU/L, regardless of aminotransferase or alanine aminotransferase levels. This study investigated whether the KASL guideline implementation reduced the risk of CHB-related hepatocellular carcinoma (HCC) in patients with cirrhosis in South Korea.

Methods: A total of 429 patients with CHB-related cirrhosis who initiated AVT between 2014 and 2016 were recruited. The risk of HCC development was compared between patients who initiated AVT before and after September 2015 (pre-guideline [n = 196, 45.7%] vs. post-guideline implementation [n = 233, 54.3%]).

Results: Univariate analysis showed that AVT initiation before guideline implementation, older age, male gender, and diabetes significantly predicted increased risk of HCC development (all < 0.05). Subsequent multivariate analysis showed that AVT initiation before guideline implementation (HR = 1.941), older age (HR = 5.762), male gender (HR = 2.555), and diabetes (HR = 1.568) independently predicted increased risk of HCC development (all < 0.05). Additionally, multivariate analysis showed that AVT initiation before guideline implementation (HR = 2.309), male gender (HR = 3.058), and lower platelet count (HR = 0.989) independently predicted mortality ( < 0.05). The cumulative incidences of HCC and mortality were significantly higher in patients who initiated AVT before guideline implementation than in those who initiated AVT after guideline implementation (all < 0.05, log-rank test).

Conclusion: The prognosis of patients with CHB-related cirrhosis who initiated AVT improved after guideline implementation according to the revised KASL guideline.
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http://dx.doi.org/10.3346/jkms.2021.36.e105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076846PMC
April 2021

Treatment efficacy by hepatic arterial infusion chemotherapy vs. sorafenib after liver-directed concurrent chemoradiotherapy for advanced hepatocellular carcinoma.

J Cancer Res Clin Oncol 2021 Oct 23;147(10):3123-3133. Epub 2021 Apr 23.

Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.

Background: We compared the clinical efficacies of hepatic arterial infusion chemotherapy (HAIC) vs. sorafenib as sequential maintenance therapy following liver-directed concurrent chemoradiotherapy (LD-CCRT) for locally advanced-stage hepatocellular carcinoma (HCC).

Methods: Patients undergoing HAIC with 5-fluorouracil and cisplatin (HAIC-maintain group, n = 151) or sorafenib (Sorafenib-maintain group, n = 37) after LD-CCRT were consecutively enrolled. The study endpoints were overall survival (OS), progression-free survival (PFS), and treatment response rates.

Results: The median OS among HAIC-maintain and Sorafenib-maintain groups were 15.9 and 24.3 months (p = 0.287), whereas the median PFS were 8.1 and 9.1 months (p = 0.651), respectively. During the planned treatments, the radiological objective response rate (54.3% vs. 64.9%; p = 0.246), and conversion rate to surgical resection or liver transplantation after successful down-staging (15.9% vs. 18.9%; p = 0.657) were comparable between the HAIC-maintain and Sorafenib-maintain groups. Similar results were found after the inverse probability of treatment weighting and propensity score-matching analyses. Regarding treatment-related adverse events, the HAIC-maintain group showed worse profiles in terms of leukopenia (all grades [p = 0.001] and grades 3 or 4 [p = 0.041]) and hypoalbuminemia (p = 0.001) than the Sorafenib-maintain group.

Conclusions: The overall clinical efficacies between the sequential treatment of HAIC vs. sorafenib after LD-CCRT were comparable for locally advanced HCC.
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http://dx.doi.org/10.1007/s00432-021-03632-4DOI Listing
October 2021
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