Publications by authors named "Han Chu Lee"

211 Publications

Cirrhosis, Age, and Liver Stiffness-Based Models Predict Hepatocellular Carcinoma in Asian Patients with Chronic Hepatitis B.

Cancers (Basel) 2021 Nov 9;13(22). Epub 2021 Nov 9.

Department of Gastroenterology, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam-si 13496, Gyeonggi-do, Korea.

Objectives: Predicting hepatocellular carcinoma (HCC) in patients with chronic hepatitis B who received long-term therapy with potent nucleos(t)ide analogs is of utmost importance to refine the strategy for HCC surveillance.

Methods: We conducted a multicenter retrospective cohort study to validate the CAGE-B and SAGE-B scores, HCC prediction models developed for Caucasian patients receiving entecavir (ETV) or tenofovir (TFV) for >5 years. Consecutive patients who started ETV or TFV at two hospitals in Korea from January 2009 to December 2015 were identified. The prediction scores were calculated, and model performance was assessed using receiver operating characteristics (ROC) curves.

Results: Among 1557 patients included, 57 (3.7%) patients had HCC during a median follow-up of 93 (95% confidence interval, 73-119) months. In the entire cohort, CAGE-B predicted HCC with an area under the ROC curve of 0.78 (95% CI, 0.72-0.84). Models that have "liver cirrhosis" in the calculation, such as AASL (0.79 (0.72-0.85)), CU-HCC (0.77 (0.72-0.82)), and GAG-HCC (0.79 (0.74-0.85)), showed accuracy similar to that of CAGE-B ( > 0.05); however, models without "liver cirrhosis", including SAGE-B (0.71 (0.65-0.78)), showed a lower predictive ability than CAGE-B. CAGE-B performed well in subgroups of patients treated without treatment modification (0.81 (0.73-0.88)) and of male sex (0.79 (0.71-0.86)).

Conclusions: This study validated the clinical usefulness of the CAGE-B score in a large number of Asian patients treated with long-term ETV or TFV. The results could provide the basis for the reappraisal of HCC surveillance strategies and encourage future prospective validation studies with liver stiffness measurements.
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http://dx.doi.org/10.3390/cancers13225609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615754PMC
November 2021

The role of muscle depletion and visceral adiposity in HCC patients aged 65 and over undergoing TACE.

BMC Cancer 2021 Oct 30;21(1):1164. Epub 2021 Oct 30.

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 44-gil, Songpa-gu, Seoul, 05505, Republic of Korea.

Background: The incidence of hepatocellular carcinoma (HCC) has been increasing among the elderly populations. Trans-arterial chemoembolization (TACE), a widely used first-line non-curative therapy for HCCs is an issue in geriatrics. We investigated the prognosis of elderly HCC patients treated with TACE and determined the factors that affect the overall survival.

Methods: We included 266 patients who were older than 65 years and had received TACE as initial treatment for HCC. We analyzed the skeletal muscle index (SMI) and visceral-to-subcutaneous fat ratio (VSR) around the third lumbar vertebrae using computed tomography scans. Muscle depletion with visceral adiposity (MDVA) was defined by falling below the median SMI and above the median VSR value sex-specifically. We evaluated the overall survival in association with MDVA and other clinical factors.

Results: The mean age was 69.9 ± 4.5 years, and 70.3% of the patients were men. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, 29, 136, and 101 patients were classified as BCLC 0, A, and B stages, respectively, and 79 (29.7%) had MDVA. During the median follow-up of 4.1 years, patients with MDVA had a shorter life expectancy than those without MDVA (P = 0.007) even though MDVA group had a higher objective response rate after the first TACE (82.3% vs. 75.9%, P = 0.035). Multivariate analysis revealed that MDVA (Hazard ratio [HR] 1.515) age (HR 1.057), liver function (HR 1.078), tumor size (HR 1.083), serum albumin level (HR 0.523), platelet count (HR 0.996), tumor stage (stage A, HR 1.711; stage B, HR 2.003), and treatment response after the first TACE treatment (HR 0.680) were associated with overall survival.

Conclusions: MDVA is a critical prognostic factor for predicting survival in the elderly patients with HCC who have undergone TACE.
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http://dx.doi.org/10.1186/s12885-021-08905-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557070PMC
October 2021

Cervicocerebral atherosclerosis and its hepatic and coronary risk factors in patients with liver cirrhosis.

Clin Mol Hepatol 2021 Oct 12. Epub 2021 Oct 12.

Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background/aims: This study aimed to investigate the silent atherosclerotic burden of cervicocephalic vessels in cirrhotic patients compared with the general population, as well as the relevant risk factors including coronary parameters.

Methods: This study included 993 stroke-free patients with liver cirrhosis (LC) who underwent magnetic resonance angiography (MRA) of the head and neck as a pre-liver transplant assessment and 6099 health checkup participants who underwent MRA examination. The two cohorts were matched for cerebrovascular risk factors, and the prevalence of atherosclerosis in major intracranial and extracranial arteries was compared in 755 matched pairs. Moreover, traditional, hepatic, and coronary variables related to cerebral atherosclerosis were assessed in cirrhotic patients.

Results: Overall, intracranial atherosclerosis was significantly less prevalent in the LC group than in the matched control group (2.3% vs. 5.4%, P=0.002), whereas the prevalence of extracranial atherosclerosis was similar between groups (4.4% vs. 5.8%, P=0.242). These results were maintained in multivariate analyses of the pooled samples, with corresponding adjusted ORs of LC of 0.56 and 0.77 (95% CIs, 0.36-0.88 and 0.55-1.09). In the LC group, lower platelet count was inversely correlated with intracranial atherosclerosis (adjusted OR, 0.31; 95% CI, 0.13-0.76). Coronary artery calcium (CAC) score ≥100 was the only predictive factor for both intracranial and extracranial atherosclerosis (adjusted ORs, 4.06 and 5.43; 95% CIs, 1.45-11.41 and 2.68-11.00, respectively).

Conclusions: LC confers protection against intracranial atherosclerosis, and thrombocytopenia may be involved in this protective effect. High CAC score could serve as a potential surrogate for cervicocerebral vascular screening in asymptomatic cirrhotic patients.
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http://dx.doi.org/10.3350/cmh.2021.0202DOI Listing
October 2021

Comprehensive characterization of viral integrations and genomic aberrations in HBV-infected intrahepatic cholangiocarcinomas.

Hepatology 2021 Sep 3. Epub 2021 Sep 3.

Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background And Aims: Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought to identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV-infected iCCA (HBV-iCCA) tumors.

Approach And Results: We profiled a cohort of 108 HBV-iCCAs using whole-genome sequencing, deep sequencing, and RNA sequencing, together with preconstructed data sets of HBV-infected HCC (HBV-HCC; n = 167) and combined hepatocellular cholangiocarcinoma (HBV-cHCC/CCA; n = 59), and conventional (n = 154) and fluke-related iCCAs (n = 16). Platforms based on primary iCCA cell lines to evaluate the functional effects of chimeric transcripts were also used. We found that HBV had inserted at multiple sites in the iCCA genomes in 45 (41.7%) of the tumors. Recurrent viral integration breakpoints were found at nine different sites. The most common insertional hotspot (7 tumors) was in the TERT (telomerase reverse transcriptase) promoter, where insertions and mutations (11 tumors) were mutually exclusive, and were accompanied by promoter hyperactivity. Recurrent HBV integration events (5 tumors) were also detected in FAT2 (FAT atypical cadherin 2), and were associated with enrichment of epithelial-mesenchymal transition-related genes. A distinctive intergenic insertion (chr9p21.3), between DMRTA1 (DMRT like family A1) and LINC01239 (long intergenic non-protein coding RNA 1239), had oncogenic effects through activation of the mammalian target of rapamycin (mTOR)/4EBP/S6K pathway. Regarding the mutational profiles of primary liver cancers, the overall landscape of HBV-iCCA was closer to that of nonviral conventional iCCA, than to HBV-HCC and HBV-cHCC/CCA.

Conclusions: Our findings provide insight into the behavior of iCCAs driven by various pathogenic mechanisms involving HBV integration events and associated genomic aberrations. This knowledge should be of use in managing HBV carriers.
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http://dx.doi.org/10.1002/hep.32135DOI Listing
September 2021

Risk of Hepatitis B Virus Reactivation in Patients Treated With Immunotherapy for Anti-cancer Treatment.

Clin Gastroenterol Hepatol 2021 Jun 26. Epub 2021 Jun 26.

Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Background & Aims: Hepatitis B virus (HBV) reactivation is a well-known complication in patients with chronic hepatitis B treated with cytotoxic chemotherapy. However, the risk of HBV reactivation through use of immune checkpoint inhibitors (ICIs) is not well understood. Therefore, we aimed to evaluate the risk of HBV reactivation and hepatic adverse events in patients with cancer receiving ICIs according to cancer type and virologic serology.

Methods: This historical cohort study included 3465 patients with cancer treated with ICIs between January 2015 and September 2020. The primary outcome was the occurrence of HBV reactivation, and the secondary outcome was presence of hepatic adverse events during ICI treatment.

Results: The mean patient age was 62.2 years, and 68.8% of patients were men. Of the 3465 eligible patients, 511 (14.7%) showed hepatitis B surface antigen (HBsAg) positivity. The incidence rates of HBV reactivation of the total patients, HBsAg-positive patients, and HBsAg-negative patients were 0.14% (5/3465), 1.0% (5/511), and 0.0% (0/2954), respectively. Among HBsAg-positive patients, HBV reactivation occurred at a rate of 0.5% (2/409) and 2.9% (3/102) in patients with and without hepatocellular carcinoma, respectively. The HBV reactivation rates were 0.4% (2/464) and 6.4% (3/47) in patients with and without antiviral prophylaxis, respectively. Grade 3-4 hepatitis occurred in 23 (4.5%) HBsAg-positive, and 218 (7.4%) HBsAg-negative patients. No HBV-related fatality occurred. Only 2 patients (0.4%) experienced HBsAg seroclearance after ICI treatment among HBsAg-positive patients.

Conclusions: In general, HBV reactivation was rarely observed in patients with antiviral prophylaxis while undergoing ICI treatment. However, HBV reactivation may occur in HBsAg-positive patients without antiviral prophylaxis or noncompliant with antiviral prophylaxis.
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http://dx.doi.org/10.1016/j.cgh.2021.06.019DOI Listing
June 2021

Prospective Multi-Center Korean Registry of Transcatheter Arterial Chemoembolization with Drug-Eluting Embolics for Nodular Hepatocellular Carcinoma: A Two-Year Outcome Analysis.

Korean J Radiol 2021 10 1;22(10):1658-1670. Epub 2021 Jun 1.

Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Objective: To assess the two-year treatment outcomes of chemoembolization with drug-eluting embolics (DEE) for nodular hepatocellular carcinoma (HCC).

Materials And Methods: This study was a prospective, multicenter, registry-based, single-arm trial conducted at five university hospitals in Korea. Patients were recruited between May 2011 and April 2013, with a target population of 200. A DC Bead loaded with doxorubicin was used as the DEE agent. Patients were followed up for two years. Per-patient and per-lesion tumor response analysis, per-patient overall survival (OS) and progression-free survival (PFS) analysis, and per-lesion tumor control analysis were performed.

Results: The final study population included 152 patients, with 207 target lesions for the per-lesion analysis. At one-month, six-month, one-year, and two-year per-patient assessments, complete response (CR) rates were 40.1%, 43.0%, 33.3%, and 19.6%, respectively. The objective response (OR) rates were 91.4%, 55.4%, 35.1%, and 19.6%, respectively. The cumulative two-year OS rate was 79.7%. The cumulative two-year PFS rate was 22.4% and the median survival was 9.3 months. In multivariable analysis, the Child-Pugh score ( = 0.019) was an independent predictor of OS, and tumor multiplicity ( < 0.001), tumor size ( = 0.020), and Child-Pugh score ( = 0.006) were independent predictors of PFS. In per-lesion analysis, one-month, six-month, one-year and two-year CR rates were 57.5%, 58.5%, 45.2%, and 33.3%, respectively, and the OR rates were 84.1%, 65.2%, 46.6%, and 33.3%, respectively. The cumulative two-year per-lesion tumor control rate was 36.2%, and the median time was 14.1 months. The Child-Pugh score ( < 0.001) was the only independent predictor of tumor control. Serious adverse events were reported in 11 patients (7.2%).

Conclusion: DEE chemoembolization for nodular HCCs in the Korean population showed acceptable survival, tumor response, and safety profiles after a two-year follow-up. Good liver function (Child-Pugh score A5) was a key predictor of per-patient OS, PFS, and per-lesion tumor control.
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http://dx.doi.org/10.3348/kjr.2020.1117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484153PMC
October 2021

Clinical Outcomes with Multikinase Inhibitors after Progression on First-Line Atezolizumab plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma: A Multinational Multicenter Retrospective Study.

Liver Cancer 2021 Apr 3;10(2):107-114. Epub 2021 Mar 3.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Introduction: Atezolizumab-bevacizumab is the new standard of care for first-line treatment of advanced hepatocellular carcinoma (HCC). However, the optimal sequence of therapy after disease progression on atezolizumab-bevacizumab is unclear.

Methods: This multinational, multicenter, and retrospective study assessed clinical outcomes of patients with advanced HCC who received subsequent systemic therapy after progression on atezolizumab-bevacizumab between July 2016 and April 2019.

Results: Among 71 patients treated with atezolizumab-bevacizumab, a total of 49 patients who received subsequent systemic therapy were included in this analysis; the median age was 60 years (range, 37-80) and 73.5% were male. All patients were classified as Child-Pugh A and Barcelona-Clinic Liver Cancer stage C. Multikinase inhibitors (MKIs), including sorafenib ( = 29), lenvatinib ( = 19), and cabozantinib ( = 1), were used as second-line therapy for all patients. The objective response rate and disease control rate were 6.1 and 63.3%, respectively, in all patients. With a median follow-up duration of 11.0 months, median progression-free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI] 1.8-4.9) and 14.7 months (95% CI 8.1-21.2) in all patients. Median PFS with lenvatinib was significantly longer than that with sorafenib (6.1 vs. 2.5 months; = 0.004), although there was no significant difference in median OS (16.6 vs. 11.2 months; = 0.347). Treatment-related adverse events (TRAEs) of any grade and grade 3 occurred in 42 (85.7) and 8 (16.3%) of patients. Common TRAEs included hand-foot syndrome ( = 26, 53.1%), fatigue ( = 14, 28.6%), hypertension ( = 14, 28.6%), and diarrhea ( = 12, 24.5%).

Conclusion: Second-line treatment with MKIs, mostly sorafenib and lenvatinib, showed comparable efficacy and manageable toxicities in patients with advanced HCC after disease progression on atezolizumab-bevacizumab.
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http://dx.doi.org/10.1159/000512781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077483PMC
April 2021

Kinetics of the neutrophil-lymphocyte ratio during PD-1 inhibition as a prognostic factor in advanced hepatocellular carcinoma.

Liver Int 2021 09 24;41(9):2189-2199. Epub 2021 May 24.

Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background And Aims: Programmed death 1 (PD-1) inhibitors have improved survival outcomes and produced durable responses in advanced hepatocellular carcinoma (HCC) for some patients. Here, we evaluated the relationship between the baseline and kinetics of the neutrophil-lymphocyte ratio (NLR) and clinical outcomes in nivolumab-treated HCC patients.

Methods: All consecutive HCC patients treated with nivolumab between July 2017 and June 2020 were screened for the eligibility. The NLRs were calculated before and at 2, 4 and 6 weeks after treatment. Survival outcomes were compared based on the baseline and kinetics of NLR. We additionally analysed the association of the baseline and dynamic changes in the NLR with hyperprogression (HPD).

Results: Among the 194 included cases, most patients were male (82.0%) and had a Child-Pugh Class A disease (70.6%). Patients with a baseline NLR ≥ 3 (hazard ratio [HR] 2.46; 95% CI 1.63-3.71) had a poorer overall survival than patients with baseline NLR < 3. During the treatment, the NLR increased rapidly in patients developing HPD, and only a ΔNLR at 4 weeks was predictive of HPD. The risk of HPD increased by 20% for every 20% increase in the ΔNLR at 4 weeks. Accordingly, an NLR increase at 4 weeks (HR 1.79; 95% CI 1.19-2.68) was associated with an increased risk of death, especially among patients with a baseline NLR ≥ 3.

Conclusions: The baseline and on-treatment kinetics for the NLR are effective prognostic indicators in nivolumab-treated patients with HCC. This may help to guide patient selection and on-treatment strategies for immunotherapies in advanced HCC.
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http://dx.doi.org/10.1111/liv.14932DOI Listing
September 2021

Tenofovir Alafenamide for Drug-Resistant Hepatitis B: A Randomized Trial for Switching From Tenofovir Disoproxil Fumarate.

Clin Gastroenterol Hepatol 2021 May 4. Epub 2021 May 4.

Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Background & Aims: It remains unknown whether tenofovir alafenamide (TAF) could replace tenofovir disoproxil fumarate (TDF) in patients with drug-resistant hepatitis B virus (HBV).

Methods: In this multicenter randomized non-inferiority trial, 174 patients with HBV resistant to multiple drugs (lamivudine, entecavir, and/or adefovir) under TDF monotherapy for ≥96 weeks were randomized 1:1 to switch to TAF (n = 87) or continue TDF (n = 87) for 48 weeks. The primary endpoint was proportion of patients with HBV DNA <60 IU/mL at week 48.

Results: At baseline, 84 and 80 patients had HBV DNA <60 IU/mL in the TAF and TDF groups, respectively. At week 48, the proportion of patients with HBV DNA <60 IU/mL was 98.9% (86/87) in TAF group, showing non-inferiority to TDF group (97.7%, 85/87; difference, 1.1%; 95% confidence interval, -2.7% to 5.0%). Changes in median alanine aminotransferase at week 48 from baseline were statistically different between TAF and TDF groups (-3 IU/L vs +2 IU/L; P = .02). TAF group showed a statistically greater increase in bone mineral density at spine (+1.84% vs +0.08%; P = .01) and numerically higher increase in mean estimated glomerular filtration rate (+8.2% vs +4.5%; P = .06) compared with TDF group. Compared with TDF group, TAF group showed significantly greater increases in mean body weight (0.71 vs -0.37 kg; P = .01) and total, low-density lipoprotein, and high-density lipoprotein cholesterol levels (P < .001 for all) at week 48 from baseline.

Conclusions: TAF could be substituted for TDF in patients with multidrug-resistant HBV for improved bone and renal safety without a loss of efficacy. However, increases in body weight and cholesterol levels with TAF treatment would be a concern. ClinicalTrials.gov no.: NCT03241641.
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http://dx.doi.org/10.1016/j.cgh.2021.04.045DOI Listing
May 2021

Radiofrequency ablation versus stereotactic body radiation therapy for small (≤ 3 cm) hepatocellular carcinoma: A retrospective comparison analysis.

J Gastroenterol Hepatol 2021 Jul 5;36(7):1962-1970. Epub 2021 Mar 5.

Department of Radiation Oncology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Background And Aim: We compared the clinical outcomes of radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) in small (≤ 3 cm) hepatocellular carcinoma.

Methods: A total of 266 patients treated with RFA (n = 179) or SBRT (n = 87) were reviewed. Local control rates (LCRs), intrahepatic recurrence-free survival (IHRFS) rates, and overall survival (OS) rates were compared. Inverse probability of treatment weighting (IPTW) was used to adjust for imbalances in baseline characteristics between the two groups.

Results: The median follow-up period was 50.3 months, and treatment method (RFA vs SBRT) was not a significant prognostic factor for LCR, OS, and IHRFS in both multivariate and IPTW-adjusted analyses. The 4-year LCRs after RFA and SBRT were 92.7% and 95.0%, respectively. Perivascular location was a significant prognostic factor for LCR in the entire patients and in the RFA group, but not in the SBRT group. The 4-year OS rates in the RFA and SBRT groups were 78.1% and 64.1%, respectively (P = 0.012). After IPTW adjustment, the 4-year LCRs (90.6% vs 96.3%) and OS rates (71.8% vs 70.2%) were not significantly different between the two groups. The rate of grade ≥ 3 adverse events was 0.6% (n = 1) in the RFA group and 1.1% (n = 1) in the SBRT group.

Conclusions: The two treatment methods showed comparable outcomes in terms of LCR, OS rate, and IHRFS rate after IPTW adjustment. SBRT seems to be a viable alternative method for small hepatocellular carcinomas that are not suitable for RFA due to tumor location.
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http://dx.doi.org/10.1111/jgh.15442DOI Listing
July 2021

Clinical outcomes of systemic therapy in patients with unresectable or metastatic combined hepatocellular-cholangiocarcinoma.

Liver Int 2021 06 11;41(6):1398-1408. Epub 2021 Mar 11.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background & Aims: The optimal systemic chemotherapy for combined hepatocellular-cholangiocarcinoma (cHCC-CCA) has not yet been defined. The definition and classification of cHCC-CCA has changed recently in the 5th edition of WHO classification. We reviewed the pathological findings with the new classification and analysed the efficacy of systemic chemotherapy in patients with unresectable/metastatic cHCC-CCA.

Methods: Among 254 patients with histologically confirmed cHCC-CCA from 1999 to 2015 in Asan Medical Center, Seoul, Korea, 99 patients who received systemic chemotherapy for unresectable/metastatic disease were included. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were retrospectively evaluated.

Results: Sorafenib (n = 62) and cytotoxic chemotherapy (n = 37) were administered as first-line chemotherapies; the ORR was 14.1%, and the median PFS and OS were 3.8 and 10.6 months, respectively, with a median follow-up duration of 39.6 months. The efficacy outcomes were not significantly different between patients who received sorafenib and those who received cytotoxic chemotherapy (ORR, 9.7% vs 21.6%, P = .14; median PFS, 4.2 vs 2.9 months, P = .52; median OS, 10.7 vs 10.6 months, P = .34). In multivariate analysis, large intrahepatic tumour burden (≥30% of liver volume), elevated serum bilirubin and non-platinum containing first-line chemotherapy remained as significant prognostic factors for poorer OS.

Conclusions: The efficacy outcomes according to first-line treatment were not significantly different between sorafenib and cytotoxic chemotherapy, and pathological findings were not found to help for determining appropriate therapeutic agent or assessing the prognosis. To overcome the poor treatment outcomes, further studies are needed to find proper treatment targets, biomarkers and the best treatment strategies.
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http://dx.doi.org/10.1111/liv.14813DOI Listing
June 2021

Variceal bleeding is aggravated by portal venous invasion of hepatocellular carcinoma: a matched nested case-control study.

BMC Cancer 2021 Jan 5;21(1):11. Epub 2021 Jan 5.

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.

Background: We hypothesized that portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) increases portal pressure and causes esophageal varices and variceal bleedings. We examined the incidence of high-risk varices and variceal bleeding and determined the indications for variceal screening and prophylaxis.

Methods: This study included 1709 asymptomatic patients without any prior history of variceal hemorrhage or endoscopic prophylaxis who underwent upper endoscopy within 30 days before or after initial anti-HCC treatment. Of these patients, 206 had PVTT, and after 1:2 individual matching, 161 of them were matched with 309 patients without PVTT. High-risk varices were defined as large/medium varices or small varices with red-color signs and variceal bleeding. Bleeding rates from the varices were compared between matched pairs. Risk factors for variceal bleeding in the entire set of patients with PVTT were also explored.

Results: In the matched-pair analysis, the proportion of high-risk varices at screening (23.0% vs. 13.3%; P = 0.003) and the cumulative rate of variceal bleeding (4.5% vs. 0.4% at 1 year; P = 0.009) were significantly greater in the PVTT group. Prolonged prothrombin time, lower platelet count, presence of extrahepatic metastasis, and Vp4 PVTT were independent risk factors related to high-risk varices in the total set of 206 patients with PVTT (Adjusted odds ratios [95% CIs], 1.662 [1.151-2.401]; 0.985 [0.978-0.993]; 4.240 [1.783-10.084]; and 3.345 [1.457-7.680], respectively; Ps < 0.05). During a median follow-up of 43.2 months, 10 patients with PVTT experienced variceal bleeding episodes, 9 of whom (90%) had high-risk varices. Presence of high-risk varices and sorafenib use for HCC treatment were significant predictors of variceal bleeding in the complete set of patients with PVTT (Adjusted hazard ratios [95% CIs], 26.432 [3.230-216.289]; and 5.676 [1.273-25.300], respectively; Ps < 0.05).

Conclusions: PVTT in HCC appears to increase the likelihood of high-risk varices and variceal bleeding. In HCC patients with PVTT, endoscopic prevention could be considered, at least in high-risk variceal carriers taking sorafenib.
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http://dx.doi.org/10.1186/s12885-020-07708-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786454PMC
January 2021

A simple and clinically applicable model to predict liver-related morbidity after hepatic resection for hepatocellular carcinoma.

PLoS One 2020 5;15(11):e0241808. Epub 2020 Nov 5.

Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background & Aim: Hepatic resection is a treatment option for patients with hepatocellular carcinoma (HCC). However, factors associated with candidacy for resection and predictive of liver-related morbidity after resection for HCC remain unclear. This study aimed to assess candidacy for liver resection in patients with HCC and to design a model predictive of liver-related morbidity after resection.

Methods: A retrospective analysis of 1,565 patients who underwent liver resection for HCC between January 2016 and December 2017 was performed. The primary outcome was liver-related morbidity, including post-hepatectomy biochemical dysfunction (PHBD), ascites, hepatic encephalopathy, rescue liver transplantation, and death from any cause within 90 days. PHBD was defined as international normalized ratio (INR) > 1.5 or hyperbilirubinemia (> 2.9 mg/dL) on postoperative day ≥ 5.

Results: The 1,565 patients included 1,258 (80.4%) males and 307 (19.6%) females with a mean age of 58.3 years. Of these patients, 646 (41.3%) and 919 (58.7%) patients underwent major and minor liver resection, respectively. Liver-related morbidity was observed in 133 (8.5%) patients, including 77 and 56 patients who underwent major and minor resection, respectively. A total of 83 (5.3%) patients developed PHBD. Multivariate analysis identified cut-off values of the platelet count, serum albumin concentration, and ICG R15 value for predicting liver-related morbidity after resection. A model predicting postoperative liver-related morbidity was developed, which included seven factors: male sex, age ≥ 55 years, ICG R15 value ≥ 15%, major resection, platelet count < 150,000/mm3, serum albumin concentration < 3.5 g/dL, and INR > 1.1.

Conclusion: Hepatic resection for HCC was safe with 90-day liver-related morbidity and mortality rates of 8.5% and 0.8%, respectively. The developed point-based scoring system with seven factors could allow the prediction of the risk of liver-related morbidity after resection for HCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241808PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643950PMC
January 2021

Real-World Efficacy and Safety of Lenvatinib in Korean Patients with Advanced Hepatocellular Carcinoma: A Multicenter Retrospective Analysis.

Liver Cancer 2020 Sep 29;9(5):613-624. Epub 2020 Jul 29.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Introduction/objective: Lenvatinib demonstrated efficacy and safety in patients with advanced hepatocellular carcinoma (HCC) in the randomized phase III REFLECT trial. Considering the discrepancies in patients between clinical trial data and daily practice, an account of practical experience is needed.

Methods: We conducted a multicenter retrospective analysis in which 3 tertiary referral centers participated. A total of 92 patients with advanced HCC treated with lenvatinib between September 2018 and January 2020 were analyzed.

Results: Lenvatinib was used as the first-line therapy for 67 (72.8%) patients, and for 25 (27.2%) patients previously treated with other systemic therapy including immune checkpoint inhibitors. At the time of initiation of lenvatinib, 74 (80.4%) and 18 (19.6%) patients were classified as Child-Pugh A and B, respectively. Thirty-five patients (38.0%) had extensive disease that would have excluded them from the REFLECT trial. In the Child-Pugh A group, the response rate graded according to the Response Evaluation Criteria in Solid Tumors v1.1 was 21.1%, median progression-free survival (PFS) was 4.6 (95% confidence interval [CI] 3.1-6.1) months, and overall survival (OS) was 10.7 (95% CI 4.8-16.5) months for patients treated with first-line lenvatinib ( = 57). With second- or later-line lenvatinib ( = 17), median PFS and OS were 4.1 (95% CI 3.1-5.1) and 6.4 (95% CI 5.1-7.7) months, respectively. In the Child-Pugh B group ( = 18), median PFS and OS were 2.6 (95% CI 0.6-4.6) and 5.3 (95% CI 2.0-8.5) months, respectively. The most common grade 3-4 toxicities were hyperbilirubinemia ( = 8; 8.7%), AST elevation ( = 6; 6.5%), and diarrhea ( = 5; 5.4%) across all study patients.

Conclusions: In this real-world study, lenvatinib was found to be well tolerated and effective in more heterogeneous HCC patient populations.
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http://dx.doi.org/10.1159/000508901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548882PMC
September 2020

Development of machine learning-based clinical decision support system for hepatocellular carcinoma.

Sci Rep 2020 09 9;10(1):14855. Epub 2020 Sep 9.

Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.

There is a significant discrepancy between the actual choice for initial treatment option for hepatocellular carcinoma (HCC) and recommendations from the currently used BCLC staging system. We develop a machine learning-based clinical decision support system (CDSS) for recommending initial treatment option in HCC and predicting overall survival (OS). From hospital records of 1,021 consecutive patients with HCC treated at a single centre in Korea between January 2010 and October 2010, we collected information on 61 pretreatment variables, initial treatment, and survival status. Twenty pretreatment key variables were finally selected. We developed the CDSS from the derivation set (N = 813) using random forest method and validated it in the validation set (N = 208). Among the 1,021 patients (mean age: 56.9 years), 81.8% were male and 77.0% had positive hepatitis B BCLC stages 0, A, B, C, and D were observed in 13.4%, 26.0%, 18.0%, 36.6%, and 6.3% of patients, respectively. The six multi-step classifier model was developed for treatment decision in a hierarchical manner, and showed good performance with 81.0% of accuracy for radiofrequency ablation (RFA) or resection versus not, 88.4% for RFA versus resection, and 76.8% for TACE or not. We also developed seven survival prediction models for each treatment option. Our newly developed HCC-CDSS model showed good performance in terms of treatment recommendation and OS prediction and may be used as a guidance in deciding the initial treatment option for HCC.
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http://dx.doi.org/10.1038/s41598-020-71796-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481788PMC
September 2020

Lymphocyte to monocyte ratio-based nomogram for predicting outcomes of hepatocellular carcinoma treated with sorafenib.

Hepatol Int 2020 Sep 1;14(5):776-787. Epub 2020 Aug 1.

Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.

Background: The ability of the pretreatment lymphocyte to monocyte ratio (LMR) to predict outcomes of patients with hepatocellular carcinoma (HCC) receiving sorafenib is not conclusively determined.

Methods: We retrospectively studied patients treated with sorafenib for HCC in two tertiary referral centres in Asia and North America. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Predictive factors for the outcomes were determined by Cox proportional hazards models. A risk assessment tool was developed.

Results: Compared to the North America cohort, the Asia cohort was more heavily pretreated (72.1% vs. 35.2%; p < 0.001), had higher hepatitis B virus infection (87.6% vs. 5.6%; p < 0.001), and more distant metastases (83.2% vs. 25.4%; p < 0.001). Lower monocyte count in the Asia cohort (median 462.7 vs. 600.0/μL; p = 0.023) resulted in a higher LMR (median 2.6 vs. 1.8; p < 0.001). High LMR was associated with a significantly higher OS [hazard ratio (HR) 0.88; 95% confidence interval (CI) 0.81‒0.97; p = 0.007]. This was confirmed in a sensitivity analysis including patients treated in Asia only (HR 0.89; 95% CI 0.81‒0.97; p = 0.010). An OS nomogram was constructed with the following variables selected in the multivariate Cox model: LMR, treatment location, previous treatment, performance status, alpha-fetoprotein, lymph node metastasis, and Child‒Pugh score. The concordance score was 0.71 (95% CI, 0.67‒0.75). LMR did not predict PFS.

Conclusion: LMR measured before sorafenib administration predicts OS in advanced HCC patients. Our OS nomogram, incorporating LMR, can be offered to clinicians to improve their ability to assess prognosis, strengthen the prognosis-based decision-making, and inform patients in the clinic.
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http://dx.doi.org/10.1007/s12072-020-10076-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080900PMC
September 2020

Effectiveness and Safety of Nivolumab in Child-Pugh B Patients with Hepatocellular Carcinoma: A Real-World Cohort Study.

Cancers (Basel) 2020 Jul 20;12(7). Epub 2020 Jul 20.

Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

Nivolumab has shown durable response and safety in patients with hepatocellular carcinoma (HCC) in previous trials. However, real-world data of nivolumab in HCC patients, especially those with Child-Pugh class B, are limited. To investigate the effectiveness and safety of nivolumab in a real-world cohort of patients with advanced HCC, we retrospectively evaluated 203 patients with HCC who were treated with nivolumab between July 2017 and February 2019. Of 203 patients, 132 patients were classified as Child-Pugh class A and 71 patients were Child-Pugh class B. Objective response rate was lower in patients with Child-Pugh class B than A (2.8% vs. 15.9%; = 0.010). Child-Pugh class B was an independent negative predictor for objective response. Median overall survival was shorter in Child-Pugh B patients (11.3 vs. 42.9 weeks; adjusted hazard ratio [AHR], 2.10; < 0.001). In Child-Pugh B patients, overall survival of patients with Child-Pugh score of 8 or 9 was worse than patients with Child-Pugh score of 7 (7.4 vs. 15.3 weeks; AHR, 1.93; < 0.020). In conclusion, considering the unsatisfactory response in Child-Pugh B patients, nivolumab may not be used in unselected Child-Pugh B patients. Further studies are needed in this patient population.
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http://dx.doi.org/10.3390/cancers12071968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409289PMC
July 2020

Stereotactic body radiation therapy for small (≤5 cm) hepatocellular carcinoma not amenable to curative treatment: Results of a single-arm, phase II clinical trial.

Clin Mol Hepatol 2020 10 10;26(4):506-515. Epub 2020 Jul 10.

Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background/aims: Stereotactic body radiation therapy (SBRT) is used as an alternative ablative treatment in patients with hepatocellular carcinoma (HCC) not suitable for curative treatments. The purpose of this prospective study was to evaluate the long-term efficacy of SBRT for small (≤5 cm) HCCs.

Methods: A phase II, single-arm clinical trial on SBRT for small HCCs was conducted at an academic tertiary care center. The planned SBRT dose was 45 Gy with a fraction size of 15-Gy over 3 consecutive days. The primary endpoint was 2-year local control rate. Radiologic responses were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) and the modified RECIST criteria.

Results: Between 2013 and 2016, 50 patients (53 lesions) were enrolled, with a median follow-up period of 47.8 months (range, 2.9-70.6). Patients' age ranged from 41 to 74 years, and 80% were male. Median tumor size was 1.3 cm (range, 0.7-3.1). The 2- and 5-year local control rates were 100% and 97.1%, respectively. The 5-year overall survival rate was 77.6%. Six months after SBRT, radiologic responses were evident in 44 lesions (83%) according to the RECIST criteria and 49 (92.4%) according to the modified RECIST criteria. None of the patients showed grade ≥3 adverse events.

Conclusion: SBRT showed excellent results as an ablative treatment for patients with small HCCs while showing minimal toxicities. SBRT can be a good alternative for both curative and salvage intents in patients with HCCs that are unsuitable for curative treatments.
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http://dx.doi.org/10.3350/cmh.2020.0038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641557PMC
October 2020

Regorafenib Versus Nivolumab After Sorafenib Failure: Real-World Data in Patients With Hepatocellular Carcinoma.

Hepatol Commun 2020 Jul 16;4(7):1073-1086. Epub 2020 Jun 16.

Department of Gastroenterology Liver Center University of Ulsan College of Medicine Seoul Republic of Korea.

Regorafenib and nivolumab are drugs approved for second-line treatment of patients with hepatocellular carcinoma (HCC) after sorafenib failure. However, the effectiveness of regorafenib and nivolumab following sorafenib has not been directly compared. This study retrospectively evaluated 373 patients with HCC who were treated with regorafenib (n = 223) or nivolumab (n = 150) after sorafenib failure between July 2017 and February 2019. Progression-free survival (PFS; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.06;  = 0.150), time to progression (TTP; HR, 0.95; 95% CI, 0.77-1.19; = 0.680), and overall survival (OS; HR, 0.83; 95% CI, 0.64-1.07; = 0.154) did not differ significantly between groups of patients treated with regorafenib and nivolumab, findings consistently observed by multivariable-adjusted, propensity score-matched, and inverse probability treatment weighting (IPTW) analyses. However, the objective response rate was significantly higher in the nivolumab than in the regorafenib group (13.3% vs. 4.0%; = 0.002). When the effectiveness of regorafenib and nivolumab was compared in nonprogressors to treatment, defined as patients who achieved complete response, partial response, or stable disease after first response evaluation, PFS (HR, 0.50; 95% CI, 0.33-0.75; = 0.001), TTP (HR, 0.48; 95% CI, 0.31-0.73; < 0.001), and OS (HR, 0.51; 95% CI, 0.31-0.87; = 0.013) were significantly longer in the 59 nonprogressors to nivolumab than in the 104 nonprogressors to regorafenib, findings also observed by multivariable-adjusted and IPTW analyses. Survival outcomes in patients treated with regorafenib and nivolumab after sorafenib failure did not differ significantly. However, nivolumab may be more effective than regorafenib in nonprogressors.
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http://dx.doi.org/10.1002/hep4.1523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327222PMC
July 2020

IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation.

Future Oncol 2020 May 30;16(15):975-989. Epub 2020 Apr 30.

PLA Cancer Center, People's Liberation Army (PLA) 81 Hospital, Nanjing 210016, PR China.

Hepatocellular carcinoma recurs in 70-80% of cases following potentially curative resection or ablation and the immune component of the liver microenvironment plays a key role in recurrence. Many immunosuppressive mechanisms implicated in HCC recurrence are modulated by VEGF and/or immune checkpoints such as PD-L1. Atezolizumab (PD-L1 inhibitor) plus bevacizumab (VEGF inhibitor) has been shown to significantly improve overall survival, progression-free survival and overall response rate in unresectable HCC. Dual PD-L1/VEGF blockade may be effective in reducing HCC recurrence by creating a more immune-favorable microenvironment. We describe the rationale and design of IMbrave 050 (NCT04102098), a randomized, open-label, Phase III study comparing atezolizumab plus bevacizumab versus active surveillance in HCC patients at high-risk of recurrence following curative resection or ablation. The primary end point is recurrence-free survival. NCT04102098.
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http://dx.doi.org/10.2217/fon-2020-0162DOI Listing
May 2020

Entecavir-resistant hepatitis B virus decreases surface antigenicity: A full genome and functional characterization.

Liver Int 2020 07 12;40(7):1564-1577. Epub 2020 Apr 12.

Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, Konkuk University School of Medicine, Seoul, Korea.

Background And Aim: Since polymerase and surface genes overlap in hepatitis B virus (HBV), an antiviral-induced mutation in the polymerase gene may alter the surface antigenicity in patients with chronic hepatitis B (CHB), but this possibility has not been clearly confirmed. This study aimed to determine the drug susceptibility and surface antigenicity of the patient-derived mutants.

Patients And Methods: Full-length HBV genomes isolated from four entecavir-resistant CHB patients were cloned and sequenced. Around 10 clones of full-length HBV obtained from each patient were analysed and registered in the NCBI GenBank. Representative clones were further characterized by in vitro drug susceptibility and surface antigenicity assays.

Results: The rtL180M + rtM204V mutations were common among all the clones analysed. Additionally, the ETV resistance mutations rtT184A/L, rtS202G and rtM250V were found among three patients. Most of the ETV-resistant mutants had amino acid alterations within the known epitopes recognized by T- and B-cells in the HBV surface and core antigens. The in vitro drug susceptibility assay showed that all tested clones were resistant to ETV treatment. However, they were all susceptible to ADV and TDF. More importantly, the rtI169T mutation in the RT domain, led to the sF161L mutation in the overlapping S gene, which decreased in surface antigenicity.

Conclusions: The ETV resistance mutations can affect the antigenicity of the HBsAg proteins due to changes in the overlapping sequence of this surface antigen. Thus, the apparent decline or disappearance of HBsAg needs to be interpreted cautiously in patients with previous or current antiviral resistance mutations.
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http://dx.doi.org/10.1111/liv.14446DOI Listing
July 2020

Evaluation of transarterial chemoembolization refractoriness in patients with hepatocellular carcinoma.

PLoS One 2020 4;15(3):e0229696. Epub 2020 Mar 4.

Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background & Aim: In clinical practice, transarterial chemoembolization (TACE) has been widely used for the treatment of hepatocellular carcinoma (HCC) beyond as well as within guideline recommendations. Here we aimed to verify whether two consecutive non-responses could be an optimal criterion for creating a rule to stop TACE being performed on these patients.

Methods: This study evaluated 200 patients with HCC beyond the Milan criteria, initially treated with TACE. TACE response was determined using the mRECIST criteria via dynamic CT or MRI. Median follow-up duration was 23.9 months.

Results: Within the 200 patients analyzed, 183 (91.5%) were male, with a total median age of 59.8 years. The mean size of the largest tumor was 6.8 cm, with 80 (40.0%) patients with ≥4 tumors. After the first TACE procedure, complete response, partial response, stable disease, or progressive disease were observed in 48 (24.0%), 87 (43.5%), 59 (29.5%) and 6 (3.0%) of patients, respectively. 45 (22.5%) patients showed no objective response (OR) following two consecutive TACE sessions. Of these, 28 received a subsequent TACE, with a 10.7% OR rate. Patients without OR showed poorer survival when compared to patients who achieved OR after repeated TACE. Multivariable analysis showed that size of the largest tumor >5cm and high alpha-fetoprotein of >200 ng/mL were significant factors associated with failure of OR to two consecutive TACE sessions.

Conclusion: Patients showing no OR to two consecutive TACE sessions will present a poor OR to subsequent TACE procedures. Early transition to systemic therapy may be advocated in such cases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229696PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055892PMC
June 2020

Clinical outcomes of stereotactic body radiation therapy for small hepatocellular carcinoma.

J Gastroenterol Hepatol 2020 Nov 20;35(11):1953-1959. Epub 2020 Feb 20.

Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background And Aim: The purpose of this study was to investigate the long-term oncologic outcomes after stereotactic body radiation therapy (SBRT) for small hepatocellular carcinoma (HCC).

Methods: A total of 290 patients with HCC were registered between March 2007 and July 2013. A dose of 10-15 Gy per fraction was given over three to four consecutive days, resulting in a total dose of 30-60 Gy. Overall and recurrence-free survivals were estimated from the date of the start of SBRT to the date of death, the last follow-up examination, or to the date of tumor recurrence.

Results: The median follow-up period of all patients was 38.2 months, and the median tumor size was 1.7 cm. Overall survival (OS) rate at 5 years was 44.9%. Multivariate analyses revealed that age, Child-Pugh class, tumor size, and albumin levels were significant factors for OS. The 5-year local control rate was 91.3%. In multivariate analysis, tumor size and albumin were significantly associated with local tumor control. However, there was a negative correlation between total dose and tumor size in Pearson's correlation analysis (r = -0.111, P = 0.046).

Conclusions: Stereotactic body radiation therapy was an excellent ablative treatment option for patients with small HCC. Tumor size was a significant factor for local tumor control after SBRT, although the total dose was negatively correlated with tumor size. Considering the low OS rates and the high local tumor control rates, the combined SBRT and systemic therapies may be beneficial for improving survival outcomes.
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http://dx.doi.org/10.1111/jgh.15011DOI Listing
November 2020

Circulating tumor cells are associated with poor outcomes in early-stage hepatocellular carcinoma: a prospective study.

Hepatol Int 2019 Nov 5;13(6):726-735. Epub 2019 Nov 5.

Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.

Background: Previous studies evaluating association between circulating tumor cells (CTCs) and clinical outcomes in hepatocellular carcinoma (HCC) have shown inconsistent results due to suboptimal detection methods and patient heterogeneity.

Methods: Patients undergoing surgery for early-stage HCC were prospectively enrolled. The CTC numbers were determined using a tapered slit platform, which detects CTCs based on the cell size and morphology. Survival and recurrence were evaluated, and Cox proportional hazards models were used to demonstrate the prognostic significance of CTC.

Results: Of 105 patients, 25 had increased CTC numbers after surgery (ΔCTC > 0, defined as positive) and a significantly higher level of recurrence (p = 0.042). A positive ΔCTC was seen to be an independent predictor of recurrence (hazard ratio 2.28), along with hepatitis B virus infection, alanine aminotransferase level, and the presence of satellite nodules (all p < 0.05). Subgroup analyses showed that a positive ΔCTC was associated with lower survival and higher recurrence among patients with low alpha-fetoprotein levels and cirrhosis (all p < 0.05).

Conclusion: Calculation of ΔCTC based on the physical properties of the cells is predictive of recurrence in patients with early HCC undergoing surgery.
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http://dx.doi.org/10.1007/s12072-019-09994-9DOI Listing
November 2019

Combined transarterial chemoembolization and radiotherapy as a first-line treatment for hepatocellular carcinoma with macroscopic vascular invasion: Necessity to subclassify Barcelona Clinic Liver Cancer stage C.

Radiother Oncol 2019 12 7;141:95-100. Epub 2019 Sep 7.

Department of Radiation Oncology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Background And Purpose: Systemic therapy such as sorafenib is the standard for Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC); however, the survival benefits are modest especially for HCC with macroscopic vascular invasion (MVI). Transarterial chemoembolization (TACE) plus external beam radiotherapy (RT) is an alternative treatment to sorafenib, with favorable clinical results. We evaluated the outcomes of respiratory-gated RT and TACE in treatment-naïve BCLC stage C HCC patients with MVI and proposed a subclassification model.

Methods: In this study, 639 patients received TACE plus RT for HCC with MVI as a first-line treatment between January 2010 and December 2015.

Results: Main/bilateral portal vein and/or inferior vena cava tumor thrombus was observed in 353 (55.2%) patients. The median radiation dose was 39 Gy (range 24-50) with a 2.5-Gy (2-5) median fraction size. The median overall survival was 10.7 months, with 1- and 2-year survival rates of 46.5% and 23.9%, respectively. In the multivariate analysis, Child-Pugh classification B, tumor size >10 cm, infiltrative/diffuse type, presence of extrahepatic metastasis, alpha-fetoprotein >150,000 ng/mL, and radiation dose ≤40 Gy were significant predictors for poor overall survival. Subclassification of patients into very low, low, intermediate, and high-risk groups showed median survivals of 84.8, 14.7, 10.3, and 5.7 months, respectively (p < 0.001).

Conclusion: TACE plus RT is an effective and safe treatment for HCC with MVI and could be considered a first-line treatment option. The subclassification scheme accurately predicted the prognosis of these patients and may be useful for tailored treatment.
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http://dx.doi.org/10.1016/j.radonc.2019.08.009DOI Listing
December 2019

Epidemiological and Clinical Characteristics of Hepatitis C Virus Infection in South Korea from 2007 to 2017: A Prospective Multicenter Cohort Study.

Gut Liver 2020 03;14(2):207-217

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

Background/aims: This study aimed to elucidate the epidemiological and clinical characteristics of chronic hepatitis C (CHC) patients in South Korea from 2007 to 2017 and to compare the treatment patterns between two periods before and after the first approval of direct-acting antivirals (DAA) in South Korea in 2015.

Methods: This prospective, multicenter cohort enrolled 2,758 patients with hepatitis C virus (HCV) viremia at seven tertiary centers, and clinical data were prospectively collected with questionnaire surveys focused on lifetime risk factors related to HCV infection.

Results: The HCV patients had a mean age of 57.3 years (50.8% male). Among them, 14.3% showed a positive history of transfusion before HCV screening and 5.6% reported intravenous drug use (IVDU), with significant differences in these risk factors between men and women. The proportions of patients with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC) were 69.5%, 18.9%, and 11.5%, respectively. The mean alanine aminotransaminase level was within the upper normal limit at 49.9%, and the major genotypes were 1b (48.2%) and 2 (46.4%). The overall treatment rate was 53.8%, showing a rapid transition from interferon-based therapy to DAA therapy. In the post-DAA-approval era, the untreated group was older, had a higher prevalence of HCC, and had less education than the treated group.

Conclusions: More than 90% of CHC patients were over 40 years old, the major genotypes were 1b and 2, and IVDU was observed in less than 6% of CHC patients. Approximately half of the patients underwent antiviral therapy even in the DAA era, showing an unmet need with regard to HCV elimination.
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http://dx.doi.org/10.5009/gnl19005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096238PMC
March 2020

A Prospective Evaluation of the Reliability and Utility of Quality of Life Measures in Patients With Hepatocellular Carcinoma.

Am J Clin Oncol 2019 07;42(7):555-563

Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul.

Objectives: Little is known about how quality of life (QOL) can assist clinical decision-making for patients with hepatocellular carcinoma (HCC). This study aimed to investigate the reliability and validity of QOL as well as its prognostic value and utility.

Materials And Methods: A prospective cohort of 300 HCC patients at various stages was recruited from 2015 to 2017 in Korea. The subjects answered the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30) and QLQ-HCC18 and the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. Prognostic nomograms including the QOL scales were developed. The prediction performance of the Barcelona Clinic Liver Cancer (BCLC) and the American Joint Committee on Cancer (AJCC) staging systems when they were incorporated with QOL was investigated.

Results: The EORTC QLQ-C30 and QLQ-HCC18 subscales showed higher reliability than FACT-Hep subscales. With regard to the validity, both questionnaires discriminated the patients by stages, treatment modalities, and performance status effectively. Multivariable analysis revealed that EORTC role functioning and EORTC appetite loss subscales were statistically associated with overall survival and disease progression. The developed nomograms accurately estimated the 1-year overall survival and disease progression-free rates. Incorporating the EORTC role functioning subscale or Hepatobiliary Cancer Subscale of FACT-Hep with the BCLC and AJCC systems improved the prognostic classification. Incorporating QOL into the AJCC system showed better predictive accuracy than incorporating performance status into it did.

Conclusions: The findings suggest that QOL data can serve as a reliable predictive factor and assist prognostic calculation for HCC patients.
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http://dx.doi.org/10.1097/COC.0000000000000555DOI Listing
July 2019

Monotherapy with tenofovir disoproxil fumarate for adefovir-resistant vs. entecavir-resistant chronic hepatitis B: A 5-year clinical trial.

J Hepatol 2019 07 13;71(1):35-44. Epub 2019 Mar 13.

Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Background & Aims: Tenofovir disoproxil fumarate (TDF) monotherapy has displayed non-inferior efficacy to TDF plus entecavir (ETV) combination therapy in patients with hepatitis B virus (HBV) resistant to ETV and/or adefovir (ADV). Nonetheless, the virologic response rate was suboptimal in patients receiving up to 144 weeks of TDF monotherapy. We aimed to assess the efficacy and safety of TDF monotherapy given for up to 240 weeks.

Methods: One trial enrolled patients with ETV resistance without ADV resistance (n = 90), and another trial included patients with ADV resistance (n = 102). Most patients (91.2%) also had lamivudine resistance. Patients were randomized 1:1 to receive TDF monotherapy or TDF + ETV combination therapy for 48 weeks, and then TDF monotherapy until week 240. We compared efficacy between the studies and safety in the pooled population at 240 weeks.

Results: At week 240, the proportion of patients with serum HBV DNA <15 IU/ml was not significantly different between the ETV and ADV resistance groups in the full analysis set (84.4% vs. 73.5%; p = 0.07), which was significantly different by on-treatment analysis (92.7% vs. 79.8%; p = 0.02). Virologic blips associated with poor medication adherence occurred in 7 patients throughout the 240 weeks. None developed additional HBV resistance mutations. Among the 170 HBV e antigen (HBeAg)-positive patients at baseline, 12 (7.1%) achieved HBeAg seroconversion at week 240. None achieved HBV surface antigen seroclearance. Significant decreases from baseline were observed at week 240 in the estimated glomerular filtration rate (-3.21 ml/min/1.73 m by the CKD-EPI equation, p <0.001) and bone mineral density (g/cm) at the femur (-2.48%, p <0.001).

Conclusions: Up to 240 weeks of TDF monotherapy provided an increasing virologic response rate in heavily pretreated patients with HBV resistant to ETV and/or ADV. However, it was associated with poor serological responses and decreasing renal function and bone mineral density. (ClinicalTrials.gov No, NCT01639066 and NCT01639092).

Lay Summary: In patients chronically infected with hepatitis B virus resistant to multiple drugs including lamivudine, entecavir, and/or adefovir, tenofovir disoproxil fumarate (TDF) monotherapy showed non-inferior efficacy compared with the combination therapy of TDF plus entecavir. Nonetheless, short-term TDF monotherapy was associated with suboptimal virologic response, and its long-term safety was uncertain. This study displayed that 240 weeks of TDF monotherapy provided a virologic response in most of those patients, but it was associated with poor serological responses and decreasing renal function and bone mineral density.
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http://dx.doi.org/10.1016/j.jhep.2019.02.021DOI Listing
July 2019

Long-term clinical outcomes in patients with autoimmune hepatitis according to treatment response in Asian country.

Liver Int 2019 05 25;39(5):985-994. Epub 2019 Mar 25.

Department of Gastroenterology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background & Aims: As surrogate markers for autoimmune hepatitis (AIH), serum alanine aminotransferase (ALT) and immunoglobulin G (IgG) are convenient to measure under immunosuppression. However, the long-term prognosis of patients who achieve complete biochemical remission (CBR) in comparison with patients who achieve only biochemical remission (BR) is uncertain.

Methods: A total of 291 patients (89.7% female) diagnosed with AIH were retrospectively reviewed. CBR was defined as normal ALT and IgG levels with immunosuppression, while BR was defined as normal ALT levels. CBR was further divided into early CBR (<1year) and late CBR (≥1year) by the timing of remission. Liver-related adverse outcomes including liver-related death, liver transplantation and hepatocellular carcinoma were evaluated.

Results: With immunosuppressive treatment, 222 (76.3%) patients achieved CBR (early CBR: 168 and late CBR: 54). BR was achieved in 55 (18.9%) patients and 14 (4.8%) patients remained non-remission. With a median follow-up duration of 6.6 years, the risk of liver-related mortality was the lowest in patients with CBR, followed by patients with late CBR, BR and non-response. The cumulative risk of liver-related adverse outcomes was the highest in patients with non-response (8.51/100 person-years [PYs]), followed by BR (1.95/100 PYs), late CBR (1.89/100 PYs) and early CBR (0.75/100 PYs). By multivariable analysis, age, cirrhosis and treatment responses were independently associated with liver-related adverse outcomes.

Conclusions: Patients with CBR within 1 year after treatment initiation had the lowest risk of liver-related adverse outcomes. Patients with late CBR and those with only BR had a comparable risk of long-term outcomes.
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http://dx.doi.org/10.1111/liv.14082DOI Listing
May 2019

Characterization of Hepatocellular Carcinoma Patients with Amplification Assessed by Fluorescence in situ Hybridization: A Large Cohort Study.

Liver Cancer 2019 Feb 22;8(1):12-23. Epub 2018 May 22.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background: amplification is a relatively novel type of genetic aberration that has been proposed to be a driver of hepatocarcinogenesis. Selective inhibitors of , a receptor of , have been developed as targeted therapies for hepatocellular carcinoma (HCC). Despite the role of in mediating HCC progression, the clinicopathological characterization of patients exhibiting amplification remains unclear. Immunohistochemical staining is the simplest and most widely used method of identifying aberrations in the gene, although its specificity is very low.

Methods: This study investigated the prognostic significance of amplification in a large cohort of 989 HCC patients using fluorescence in situ hybridization (FISH), which has a high degree of specificity. In addition, FISH data from formalin-fixed, paraffin-embedded sections were compared with copy number variation (CNV) data obtained from fresh frozen sections to validate the use of FISH as a diagnostic tool.

Results: amplifications were detected by FISH in 51 (5.15%) of the 989 patients, and were independently associated with poor survival and a higher risk of tumor recurrence, as well as with poor prognostic factors such as a high α-fetoprotein level, hepatitis B or C virus infection, a large tumor size, microvascular invasion, and necrosis. In addition, amplification was associated with mutation, and was mutually exclusive with mutation. The results of the FISH and CNV analyses exhibited a significant concordance rate of 96% (κ = 0.618, < 0.001).

Conclusions: These data indicate that amplification represents a unique molecular subtype associated with poor prognostic characteristics, which supports the hypothesis that the signaling pathway plays an important role in hepatocarcinogenesis. We have also demonstrated that FISH is a viable alternative to CNV analysis, offering a number of advantages in the clinical setting.
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http://dx.doi.org/10.1159/000488541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388559PMC
February 2019
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