Publications by authors named "Ju Hyun Shim"

150 Publications

Sorafenib Combined with Chemoembolization for Locally Advanced Hepatocellular Carcinoma with Macroscopic Vascular Invasion: A Propensity Score Analysis.

Life (Basel) 2021 Oct 10;11(10). Epub 2021 Oct 10.

Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea.

The purpose of this study was to compare the efficacy and safety of transarterial chemoembolization (TACE) plus sorafenib with those of TACE alone in patients with locally advanced hepatocellular carcinoma (HCC). Treatment-naïve patients with preserved hepatic reserve (Child-Pugh score ≤ 7) who received TACE plus sorafenib ( = 91) or TACE alone ( = 109) for locally advanced HCC with macrovascular invasion were retrospectively evaluated. Propensity score matching (PSM) was used to correct selection bias, and 63 pairs were created. In the entire study population, the median progression-free survival (PFS) and overall survival (OS) with TACE plus sorafenib were better than those with TACE alone. After PSM, the median PFS (7.0 vs. 4.3 months; = 0.017) and OS (17.5 vs. 12.8 months; = 0.049) were again significantly longer with TACE plus sorafenib than with TACE alone. Stratified Cox regression analysis and doubly robust estimation revealed that treatment type was significantly associated with both PFS and OS. In the subgroup analysis, TACE plus sorafenib did not show a significant survival benefit for patients with main portal vein or inferior vena cava invasion. Major complications were similar in both groups ( = 0.330). In conclusion, TACE plus sorafenib showed better survival outcomes than TACE alone in patients with locally advanced HCC.
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http://dx.doi.org/10.3390/life11101066DOI Listing
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, and the relevant risk factors including coronary parameters.

Methods: The study population consisted of 993 stroke-free subjects with LC who were screened by magnetic resonance angiography (MRA) of the head and neck as a pre-liver transplant workup, and 6,099 health checkup participants who underwent MRA examination. The two cohorts were matched for cerebrovascular risk factors, and the prevalence rates of atherosclerosis in the major intracranial and extracranial arteries were compared in 755 matched pairs. Also, traditional, hepatic and coronary variables related to the cerebral atherosclerosis were assessed in cirrhotics.

Results: Overall, intracranial atherosclerosis was significantly less prevalent in the LC samples than the matched controls (2.3% vs. 5.4%; P=0.002), whereas the prevalence of extracranial atherosclerosis were similar (4.4% vs. 5.8%; P=0.242). These results were maintained in multivariate analyses in the pooled samples, with the corresponding adjusted odds ratios (ORs) for LC of 0.56 and 0.77 (95% CIs, 0.36-0.88 and 0.55-1.09), respectively. In the cirrhotic series, 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 factor predicting both intra- and extra-cranial atherosclerosis (adjusted ORs, 4.06 and 5.43; 95% CIs, 1.45-11.41 and 2.68-11.00, respectively).

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

Magnetic Resonance Imaging for Surveillance of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Diagnostics (Basel) 2021 Sep 12;11(9). Epub 2021 Sep 12.

Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.

Our meta-analysis aimed to evaluate the diagnostic performance of surveillance magnetic resonance imaging (sMRI) for detecting hepatocellular carcinoma (HCC), and to compare the diagnostic performance of sMRI between different protocols. Original articles about the diagnostic accuracy of sMRI for detecting HCC were found in major databases. The meta-analytic pooled sensitivity and specificity of sMRI for detecting HCC were determined using a bivariate random effects model. The pooled sensitivity and specificity of full MRI and abbreviated MRI protocols were compared using bivariate meta-regression. In the total seven included studies (1830 patients), the pooled sensitivity of sMRI for any-stage HCC and very early-stage HCC were 85% (95% confidence interval, 79-90%; = 0%) and 77% (66-85%; = 32%), respectively. The pooled specificity for any-stage HCC and very early-stage HCC were 94% (90-97%; = 94%) and 94% (88-97%; = 96%), respectively. The pooled sensitivity and specificity of abbreviated MRI protocols were 87% (80-94%) and 94% (90-98%), values that were comparable with those of full MRI protocols (84% [76-91%] and 94% [89-99%]; = 0.83). In conclusion, sMRI had good sensitivity for detecting HCC, particularly very early-stage HCC. Abbreviated MRI protocols for HCC surveillance had comparable diagnostic performance to full MRI protocols.
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http://dx.doi.org/10.3390/diagnostics11091665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469328PMC
September 2021

Integrated prognostic and histogenomic justification of stage-directed therapy for single large hepatocellular carcinoma: a Korean nationwide registry study.

Gut 2021 Sep 7. Epub 2021 Sep 7.

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, The Republic of Korea

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http://dx.doi.org/10.1136/gutjnl-2021-325844DOI Listing
September 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 hepatitis B virus (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 tumors.

Approach And Results: We profiled a cohort of 108 HBV-infected iCCAs using whole-genome sequencing, deep sequencing, and RNA sequencing, together with pre-constructed datasets of HBV-infected hepatocellular carcinoma (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 9 different sites. The most common insertional hotspot (7 tumors) was in the TERT 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, and were associated with enrichment of epithelial-mesenchymal transition-related genes. A distinctive intergenic insertion, between DMRTA1 and LINC01239 (chr9p21.3), had oncogenic effects through activation of the 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

Role of the alpha-fetoprotein response in immune checkpoint inhibitor-based treatment of patients with hepatocellular carcinoma.

J Cancer Res Clin Oncol 2021 Aug 30. Epub 2021 Aug 30.

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

Purpose: The dynamics of serum alpha-fetoprotein (AFP) level have been found to be a useful predictor of therapeutic responsiveness in patients with hepatocellular carcinoma (HCC). We evaluated whether AFP changes were able to accurately reflect imaging-based responses and predict prognosis in patients receiving therapies including immune-checkpoint inhibitors (ICIs).

Methods: A total of 108 HCC patients with baseline serum AFP ≥ 20 ng/mL who received ICI-based treatment were included. We evaluated AFP-based responses, coupled with radiographic responses by RECIST, at 6-10 (time-point 1, TP1) and 14-18 weeks (time-point 2, TP2) of therapy in terms of the change of AFP from baseline, with a > 20% decrease or increase in level corresponding to the AFP response and progression, respectively. We examined the correlations between AFP and imaging-based responses, and the prognostic implications of the AFP-based measure.

Results: Based on AFP change, there were 24 and 20 responders and 74 and 24 progressors at TP1 and TP2, respectively. The AFP responders yielded radiological objective responses in 90.9% (10/11) and 93.8% (15/16) of the cases at TP1 and TP2, respectively, compared with only 1.4% and none, respectively, of the AFP progressors at the corresponding times. The agreement between progression by RECIST and increased AFP level at the two time-points was 93.8% and 95.0%, respectively. The accuracy of the AFP-based criterion for predicting radiologic response/progression was comparable at TP1 and TP2. Both "AFP responder" and "AFP progressor" at TP1 or TP2 independently predicted the overall survival of patients (adjusted hazard ratios [95% confidence intervals], 0.360 [0.174-0.743] and 0.315 [0.117-0.850]; and 2.525 [1.362-4.679] and 3.908 [1.563-9.769], respectively).

Conclusion: Our study suggests that on-treatment AFP changes can complement imaging findings and provide prognostic information for evaluating patients with AFP-producing HCC treated with ICI-based regimens.
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http://dx.doi.org/10.1007/s00432-021-03727-yDOI Listing
August 2021

Chemoembolization for Single Large Hepatocellular Carcinoma with Preserved Liver Function: Analysis of Factors Predicting Clinical Outcomes in a 302 Patient Cohort.

Life (Basel) 2021 Aug 17;11(8). Epub 2021 Aug 17.

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

The purpose of this study was to define the role of transcatheter arterial chemoembolization (TACE) in patients with a single large hepatocellular carcinoma (HCC) and define the patient groups benefiting from TACE. Treatment-naïve patients with preserved liver function who received TACE as the first-line treatment for single large (>5 cm) HCC without macrovascular invasion and extrahepatic metastasis between 2007 and 2019 were retrospectively analyzed. Overall survival, progression-free survival, radiologic tumor response, complications, and predictors of survival were analyzed using multivariate analysis, and then a pretreatment risk-prediction model was created using the four predictive factors of tumor size, tumor type, ALBI grade, and ECOG performance status. Patients with scores of 0 (n = 54), 1-2 (n = 170), and 3-6 (n = 78) according to the model were classified as low-, intermediate-, and high-risk, respectively. The corresponding median OS values were 141, 55, and 28 months, respectively. The percentage of major complications increased as tumor size increased (4-21%). Asymptomatic, nodular HCC patients with a tumor size of 5-7 cm and ALBI grade 1 benefited the most from TACE. By contrast, the value of TACE in the treatment of single huge HCC (>10 cm) with high complication rates remains unclear.
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http://dx.doi.org/10.3390/life11080840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400325PMC
August 2021

Salvage living donor liver transplantation versus repeat liver resection for patients with recurrent hepatocellular carcinoma and Child-Pugh class A liver cirrhosis: A propensity score-matched comparison.

Am J Transplant 2021 Aug 12. Epub 2021 Aug 12.

Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.

Following curative liver resection (LR), resectable tumor recurrence in patients with preserved liver function leads to deciding between a repeat LR and a salvage liver transplantation (LT), if a donor's liver is available. This retrospective study compared survival outcomes and recurrence pattern following salvage living donor LT (LDLT) and repeat LR in patients with recurrent hepatocellular carcinoma (HCC). We reviewed the medical records of patients who underwent repeat LR (n = 163) or LDLT (n = 84) for recurrent HCC following curative resections, between January 2005 and December 2017 at a single institution. A 1:1 propensity score matching led to 42 patients per group. Disease-specific and recurrence-free survival were significantly better in the salvage LDLT group than in the repeat LR group (p = .042; HR = 2.40; 95% CI, 0.69-6.00 and p < .001; HR = 4.23; 95% CI, 2.05-8.71, respectively). Despite significant differences in recurrence patterns between the two groups (p = .019), the patient death rates, after recurrence, were similar for both groups (p = .760). This study indicates that salvage LDLT is superior to repeat LR for treating patients with transplantable, intrahepatic HCC recurrence, even in patients with Child-Pugh class A liver cirrhosis.
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http://dx.doi.org/10.1111/ajt.16790DOI Listing
August 2021

Neutrophil-to-Lymphocyte Ratio as a Biomarker Predicting Overall Survival after Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma.

Cancers (Basel) 2021 Jun 6;13(11). Epub 2021 Jun 6.

Asan Medical Center, Department of Clinical Epidemiology and Biostatistics, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul 05505, Korea.

The clinical impact of neutrophil-to-lymphocyte ratio (NLR) in predicting outcomes in hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) remain unclear, and additional large-scale studies are required. This retrospective study evaluated outcomes in treatment-naïve patients who received TACE as first-line treatment for intermediate-stage HCC between 2008 and 2017. Patients who underwent TACE before and after 2013 were assigned to the development ( = 495) and validation ( = 436) cohorts, respectively. Multivariable Cox analysis identified six factors predictive of outcome, including NLR, which were used to create models predictive of overall survival (OS) in the development cohort. Risk scores of 0-3, 4-7, and 8-12 were defined as low, intermediate, and high risk, respectively. Median OS times in the low-, medium-, and high-risk groups in the validation cohort were 48.1, 24.3, and 9.7 months, respectively ( < 0.001). Application to the validation cohort of time-dependent ROC curves for models predictive of OS showed AUC values of 0.72 and 0.70 at 3 and 5 years, respectively. Multivariable logistic regression analysis found that NLR ≥ 3 was a significant predictor (odds ratio, 3.4; < 0.001) of disease progression 6 months after TACE. Higher baseline NLR was predictive of poor prognosis in patients who underwent TACE for intermediate-stage HCC.
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http://dx.doi.org/10.3390/cancers13112830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201147PMC
June 2021

Meta-Analysis of the Accuracy of Abbreviated Magnetic Resonance Imaging for Hepatocellular Carcinoma Surveillance: Non-Contrast versus Hepatobiliary Phase-Abbreviated Magnetic Resonance Imaging.

Cancers (Basel) 2021 Jun 14;13(12). Epub 2021 Jun 14.

Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.

We aimed to determine the performance of surveillance abbreviated magnetic resonance imaging (AMRI) for detecting hepatocellular carcinoma (HCC), and to compare the performance of surveillance AMRI according to different protocols. Original research studies reporting the performance of surveillance AMRI for the detection of HCC were identified in MEDLINE, EMBASE, and Cochrane databases. The pooled sensitivity and specificity of surveillance AMRI were calculated using a hierarchical model. The pooled sensitivity and specificity of contrast-enhanced hepatobiliary phase (HBP)-AMRI and non-contrast (NC)-AMRI were calculated and compared using bivariate meta-regression. Ten studies, including 1547 patients, reported the accuracy of surveillance AMRI. The pooled sensitivity and specificity of surveillance AMRI for detecting any-stage HCC were 86% (95% confidence interval (CI), 80-90%; = 0%) and 96% (95% CI, 93-98%; = 80.5%), respectively. HBP-AMRI showed a significantly higher sensitivity for detecting HCC than NC-AMRI (87% vs. 82%), but significantly lower specificity (93% vs. 98%) ( = 0.03). Study quality and MRI magnet field strength were factors significantly associated with study heterogeneity ( ≤ 0.01). In conclusion, surveillance AMRI showed good overall diagnostic performance for detecting HCC. HBP-AMRI had significantly higher sensitivity for detecting HCC than NC-AMRI, but lower specificity.
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http://dx.doi.org/10.3390/cancers13122975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231787PMC
June 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

Clinicopathological and molecular characterization of chromophobe hepatocellular carcinoma.

Liver Int 2021 Oct 15;41(10):2499-2510. Epub 2021 Jun 15.

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

Background And Aims: Chromophobe hepatocellular carcinoma (HCC) is a newly included subtype of HCC in the 5th edition of the WHO classification with distinctive histological features (chromophobic cytoplasm with anaplastic nuclei and pseudocyst formation) and is strongly associated with the alternative lengthening of telomeres (ALT) phenotype. However, the clinicopathologic characterization and molecular features of chromophobe HCC are unknown.

Methods: To comprehensively characterize chromophobe HCC, whole exome sequencing, copy number variation, and transcriptomic analyses were performed in 224 surgically resected HCC cases. Additionally, telomere-specific fluorescence in situ hybridization was used to assess ALT. These genomic profiles and ALT status were compared with clinicopathological features among subtypes of HCC, particularly chromophobe HCC and conventional HCC.

Results: Chromophobe HCC was observed in 10.3% (23/224) cases and, compared to conventional HCC, was more frequent in females (P = .023). The overall and recurrence-free survival outcomes were similar between patients with chromophobe HCC and conventional HCC. However, chromophobe HCC displayed significantly more upregulated genes involving cell cycle progression and DNA repair. Additionally, ALT was significantly enriched in chromophobe HCC (87%; 20/23) compared to conventional HCC (2.2%, 4/178; P < .001). Somatic mutations in ALT-associated genes, including ATRX, SMARCAL1, FANCG, FANCM, SP100, TSPYL5, and RAD52 were more frequent in chromophobe HCC (30.4%, 7/23 cases) compared to conventional HCC (11.8%, 21/178 cases; P = .024).

Conclusions: Chromophobe HCC is a unique subtype of HCC with a prevalence of ~10%. Compared to conventional HCC, chromophobe HCC is associated with female predominance and ALT, although overall and recurrence-free outcomes are similar to conventional HCC.
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http://dx.doi.org/10.1111/liv.14975DOI Listing
October 2021

MRI Features for Predicting Microvascular Invasion of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Liver Cancer 2021 Apr 11;10(2):94-106. Epub 2021 Mar 11.

Department of Radiology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Republic of Korea.

Purpose: Microvascular invasion (MVI) is an important prognostic factor in patients with hepatocellular carcinoma (HCC). However, the reported results of magnetic resonance imaging (MRI) features for predicting MVI of HCC are variable and conflicting. Therefore, this meta-analysis aimed to identify the significant MRI features for MVI of HCC and to determine their diagnostic value.

Methods: Original studies reporting the diagnostic performance of MRI for predicting MVI of HCC were identified in MEDLINE and EMBASE up until January 15, 2020. Study quality was assessed using QUADAS-2. A bivariate random-effects model was used to calculate the meta-analytic pooled diagnostic odds ratio (DOR) and 95% confidence interval (CI) for each MRI feature for diagnosing MVI in HCC. The meta-analytic pooled sensitivity and specificity were calculated for the significant MRI features.

Results: Among 235 screened articles, we found 36 studies including 4,274 HCCs. Of the 15 available MRI features, 7 were significantly associated with MVI: larger tumor size (>5 cm) (DOR = 5.2, 95% CI [3.0-9.0]), rim arterial enhancement (4.2, 95% CI [1.7-10.6]), arterial peritumoral enhancement (4.4, 95% CI [2.8-6.9]), peritumoral hypointensity on hepatobiliary phase imaging (HBP) (8.2, 95% CI [4.4-15.2]), nonsmooth tumor margin (3.2, 95% CI [2.2-4.4]), multifocality (7.1, 95% CI [2.6-19.5]), and hypointensity on T1-weighted imaging (T1WI) (4.9, 95% CI [2.5-9.6]). Both peritumoral hypointensity on HBP and multifocality showed very high meta-analytic pooled specificities for diagnosing MVI (91.1% [85.4-94.8%] and 93.3% [74.5-98.5%], respectively).

Conclusions: Seven MRI features including larger tumor size, rim arterial enhancement, arterial peritumoral enhancement, peritumoral hypointensity on HBP, nonsmooth margin, multifocality, and hypointensity on T1WI were significant predictors for MVI of HCC. These MRI features predictive of MVI can be useful in the management of HCC.
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http://dx.doi.org/10.1159/000513704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077694PMC
April 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

Prognostic Molecular Indices of Resectable Hepatocellular Carcinoma: Implications of S100P for Early Recurrence.

Ann Surg Oncol 2021 Oct 30;28(11):6466-6478. Epub 2021 Mar 30.

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

Background: Although hepatocellular carcinomas (HCCs) often recur in patients undergoing hepatectomy, there are no reliable biomarkers of this undesirable event. Recent RNA-based efforts have developed valuable genetic indices prognostic of cancer outcomes. We aimed to identify molecular predictors of early recurrence after resection of HCC, and reveal the genomolecular structure of the resected tumors.

Method: Based on the transcriptomic and genomic datasets of 206 HCC samples surgically resected in the Asan Medical Center (AMC), we performed a differential gene expression analysis to identify quantitative markers associated with early recurrence and used the unsupervised clustering method to classify genomolecular subtypes.

Results: Differential gene expression profiling revealed that S100P was the highest-ranked overexpressed gene in HCCs that recurred within 2 years of surgery. This trend was reproduced in immunohistochemical studies of the original cohort and an independent AMC cohort. S100P expression also independently predicted HCC-specific mortality post-resection (adjusted hazard ratio 1.09, 95% confidence interval 1.01-1.19; p = 0.042). Validation in a Chinese cohort and in in vitro experiments confirmed the prognostic value of S100P in HCC. We further identified five discrete molecular subtypes of HCC; a subtype with stem cell features ('AMC-C4') was associated with the worst prognosis, both in our series and another two Asian datasets, and S100P was most strongly upregulated in that subtype.

Conclusion: We identified a promising prognostic biomolecule, S100P, associated with early recurrence after HCC resection, and established the genomolecular architecture of tumors affecting clinical outcomes, particularly in Asian patients. These new insights into molecular mediators should contribute to effective care for affected patients.
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http://dx.doi.org/10.1245/s10434-021-09825-yDOI Listing
October 2021

Combined Chemoembolization and Radiotherapy Versus Chemoembolization Alone for Hepatocellular Carcinoma Invading the Hepatic Vein or Inferior Vena Cava.

Cardiovasc Intervent Radiol 2021 Jul 21;44(7):1060-1069. Epub 2021 Mar 21.

Department of Radiology and Research Institute of Radiology, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine , 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Korea.

Purpose: To evaluate the efficacy and safety of transarterial chemoembolization (TACE) plus radiotherapy compared with TACE alone for patients with hepatocellular carcinoma (HCC) invading the hepatic vein (HV) or inferior vena cava (IVC).

Materials And Methods: Data from 79 patients who underwent TACE plus radiotherapy as a first-line treatment for non-metastatic HCC invading the HV or IVC between 2006 and 2018 were retrospectively evaluated. These findings were compared with data from a historical control group, consisting of 80 patients who received TACE alone between 2000 and 2006.

Results: Baseline characteristics were similar in both groups. Median progression-free survival (PFS) (8.1 vs. 4.4 months, P = 0.003) and overall survival (OS) (18.3 vs. 9.5 months, P = 0.002) were longer in the TACE plus radiotherapy than in the TACE alone group. Multivariate analysis showed that PFS and OS were significantly associated with treatment type. Subgroup analyses found that TACE plus radiotherapy showed better OS than TACE alone in patients with Child-Pugh class A, maximal tumor size < 9 cm, tumor number < 4, serum alpha-fetoprotein level ≥ 400 ng/mL, infiltrative tumor, IVC tumor thrombus, and combined portal vein invasion. The major complication rates were similar between the TACE plus radiotherapy (16.5%) and the TACE alone (13.8%) group (P = 0.664) CONCLUSION: Both TACE plus radiotherapy and TACE alone showed similar safety in treating non-metastatic HCC invading the HV or IVC. TACE plus radiotherapy seems effective to prolong OS and PFS compared to TACE alone in this specific patient group.
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http://dx.doi.org/10.1007/s00270-021-02815-3DOI Listing
July 2021

Safe use of right lobe living donor livers with moderate steatosis in adult-to-adult living donor liver transplantation: a retrospective study.

Transpl Int 2021 05 30;34(5):872-881. Epub 2021 Mar 30.

Division of Transplantation, Department of Surgery, and Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN, USA.

Hepatic steatosis (HS) beyond a certain degree can jeopardize living donor (LD) safety, particularly in right lobe (RL) donors, making it a major obstacle for donor pool expansion in adult-to-adult living donor liver transplantation (ALDLT). From July 2004 to June 2016, 58 LDs donated their RLs despite having moderate HS (30%-50% steatosis) determined by intraoperative biopsy at a single center. We performed greedy matching to compare the outcomes of the donors and recipients of this group with those of LDs with no HS. The mean left lobe (LL) HS value in the 58 cases was 20.9 ± 12.4%, which was significantly lower than the mean RL HS value (38.8 ± 6.7%, P < 0.001). The mean ratio of the remnant LL to the total liver volume was 37.8 ± 2.2. No differences were observed in the postoperative liver function and donor and recipient morbidity and mortality rates. The liver regeneration rates in recipients and donors at 1 month, 6 months, and 1 year postoperatively did not differ significantly. The patient and graft survival rates of the recipients showed no differences. The use of well-selected RL grafts with moderate steatosis does not impair graft function, recipient outcomes, or donor safety.
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http://dx.doi.org/10.1111/tri.13859DOI Listing
May 2021

Surveillance failure in ultrasound for hepatocellular carcinoma: a systematic review and meta-analysis.

Gut 2021 Mar 1. Epub 2021 Mar 1.

Department of Radiology, Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Republic of Korea.

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http://dx.doi.org/10.1136/gutjnl-2020-323615DOI Listing
March 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

Diagnostic performance of ultrasonography-guided core-needle biopsy according to MRI LI-RADS diagnostic categories.

Ultrasonography 2021 Jul 3;40(3):387-397. Epub 2020 Nov 3.

Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: According to the American Association for the Study of Liver Diseases (AASLD) guidelines, biopsy is a diagnostic option for focal hepatic lesions depending on the Liver Imaging Reporting and Data System (LI-RADS) category. We evaluated the diagnostic performance of ultrasonography-guided core-needle biopsy (CNB) according to LI-RADS categories.

Methods: A total of 145 High-risk patients for hepatocellular carcinoma (HCC) who underwent magnetic resonance imaging (MRI) followed by CNB for a focal hepatic lesion preoperatively were retrospectively enrolled. Focal hepatic lesions on MRI were evaluated according to LI-RADS version 2018. Pathologic results were categorized into HCC, non-HCC malignancies, and benignity. The categorization was defined as correct when the CNB pathology and surgical pathology reports were identical. Nondiagnostic results were defined as inadequate CNB pathology findings for a specific diagnosis. The proportion of correct categorizations was calculated for each LI-RADS category, excluding nondiagnostic results.

Results: After excluding 16 nondiagnostic results, 131 lesions were analyzed (45 LR-5, 24 LR-4, 4 LR-3, and 58 LR-M). All LR-5 lesions were HCC, and CNB correctly categorized 97.8% (44/45) of LR-5 lesions. CNB correctly categorized all 24 LR-4 lesions, 16.7% (4/24) of which were non-HCC malignancies. All LR-M lesions were malignant, and 62.1% (36/58) were non-HCC malignancies. CNB correctly categorized 93.1% (54/58) of LR-M lesions, and 12.5% (3/24) of lesions with CNB results of HCC were confirmed as non-HCC malignancies.

Conclusion: In agreement with AASLD guidelines, CNB could be helpful for LR-4 lesions, but is unnecessary for LR-5 lesions. In LR-M lesions, CNB results of HCC did not exclude non-HCC malignancy.
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http://dx.doi.org/10.14366/usg.20110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217794PMC
July 2021

Chronic Viral Hepatitis Is Associated with Colorectal Neoplasia: A Systematic Review and Meta-Analysis.

Dig Dis Sci 2021 Nov 12;66(11):3715-3724. Epub 2021 Jan 12.

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

Background: Chronic viral hepatitis is associated with a wide range of extrahepatic diseases; however, evidence on a link between chronic viral hepatitis and colorectal neoplasia is still lacking.

Aims: To analyze the association between chronic viral hepatitis and prevalence of colorectal neoplasia.

Methods: A systematic review of articles published in the MEDLINE, EMBASE, and Cochrane Library between 2000 and 2020 was performed. Subgroup analyses based on the types of colorectal neoplasia and the etiology of chronic viral hepatitis were conducted.

Results: Twelve eligible studies with 48,428 hepatitis B virus (HBV) patients and 46,561 hepatitis C virus (HCV) patients were included. Chronic viral hepatitis was significantly associated with an increased risk of both colorectal adenoma (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.16-2.02; I = 83%) and colorectal cancer (CRC) (OR, 1.32; 95% CI, 1.08-1.61; I = 94%). The etiology of chronic viral hepatitis was an independent factor related to heterogeneity for CRC subgroup analysis revealed an increased risk of CRC in both HBV (OR, 1.18; 95% CI, 1.09-1.27; I = 37%) and HCV (OR, 1.88; 95% CI, 1.78-1.97; I = 0%). HCV was associated with an increased risk of colorectal adenoma (OR, 1.48; 95% CI, 1.22-1.79; I = 0%); however, HBV was not associated with an increased risk of colorectal adenoma and had considerable heterogeneity (OR, 1.65; 95% CI, 0.88-3.09; I = 90%).

Conclusion: Our meta-analysis showed that chronic viral hepatitis is associated with an increased risk of colorectal neoplasia. The strategy of stricter screening colonoscopy may benefit from patients with chronic viral hepatitis.
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http://dx.doi.org/10.1007/s10620-020-06745-xDOI Listing
November 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

Prediction of transarterial chemoembolization refractoriness in patients with hepatocellular carcinoma using imaging features of gadoxetic acid-enhanced magnetic resonance imaging.

Acta Radiol 2020 Nov 16:284185120971844. Epub 2020 Nov 16.

Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background: Repeated transarterial chemoembolization (TACE) can be associated with loss of its efficacy and subsequent tumor progression.

Purpose: To identify features of gadoxetic acid-enhanced magnetic resonance imaging (MRI) associated with TACE refractoriness and to develop a prediction model for estimating the risk of TACE refractoriness.

Material And Methods: Among 1025 patients with intermediate-stage hepatocellular carcinoma (HCC) who underwent TACE as a first-line treatment during 2010-2017, 427 patients who underwent preoperative gadoxetic acid-enhanced MRI were analyzed. According to the date of initial TACE, patients were divided into the development cohort (n = 211) and the test cohort (n = 216). TACE refractoriness was determined according to the Japan Society of Hepatology guidelines. Univariable and multivariable analyses were performed to investigate the association between clinical/MRI features and TACE refractoriness. The performance of the prediction model was internally and externally assessed using the C-index of discrimination and a Hosmer-Lemeshow goodness-of-fit test for calibration.

Results: By analyzing 427 patients, we constructed a prediction model with the following independent features associated with TACE refractoriness: maximum tumor size; tumor number; peritumoral hypointensity on hepatobiliary phase (HBP); and the presence of non-hypervascular hypointense nodule on HBP. This system enabled the prediction of TACE refractoriness in the development cohort (C-index, 0.796) and the test cohort (C-index, 0.738) with good discrimination and calibration abilities.

Conclusion: The prediction model based on gadoxetic acid-enhanced MRI features in addition to the known predictors including tumor size and number can be used to estimate the risk of TACE refractoriness in patients with intermediate-stage HCC.
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http://dx.doi.org/10.1177/0284185120971844DOI Listing
November 2020

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

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

Continued value of the serum alpha-fetoprotein test in surveilling at-risk populations for hepatocellular carcinoma.

PLoS One 2020 26;15(8):e0238078. Epub 2020 Aug 26.

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

Backgrounds And Aims: Because of the known limitations of ultrasonography (US) alone, we re-evaluated whether complimentary testing for serum alpha-fetoprotein (AFP) is helpful in surveilling for hepatocellular carcinoma (HCC) in high-risk populations.

Methods: We included, from a hospital-based cancer registry, 1,776 asymptomatic adults who were surveilled biannually with the AFP test and US and eventually diagnosed with HCC between 2007 and 2015. Based on the screening results, these patients were divided into three groups: AFP (positive for AFP only; n = 298 [16.8%]), US (positive for US only; n = 978 [55.0%]), and AFP+US (positive for both; n = 500 [28.2%]). We compared the outcomes of the three groups, calculating the survival of the AFP group both as observed survival and as survival corrected for lead-time.

Results: In terms of tumor-related factors, the separate AFP and US groups were more likely to have early stage HCC and to receive curative treatments than the combined AFP+US group (Ps<0.05). The AFP group had significantly better overall and cancer-specific survival than the AFP+US group after adjusting for covariates (adjusted hazard ratios [HRs] 0.68 and 0.62, respectively). In analyses correcting for lead-time in the AFP group (doubling time 120 days), the respective adjusted HRs for the AFP group were unchanged (0.74 and 0.67), but they were no longer significant after additional adjustment for tumor stage and curative treatment (0.87 and 0.81).

Conclusions: HCC cases detected by the AFP test without abnormal ultrasonic findings appear to have better survival, possibly as a result of stage migration and the resulting cures. Complementary AFP surveillance, together with US, could be helpful for at-risk patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449471PMC
October 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
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