Journal of Liver Cancer

Original Articles

PNPLA3 I148M is unrelated to HCC occurrence but associates with poorer tumor differentiation in Korean MASLD: a prospective cohort of 562 patients: Jaejun Lee, Dong Yeop Lee, Jung Hoon Cha, Hee Sun Cho, Keungmo Yang, Hyun Yang, Mi Young Byun, Seok Keun Cho, Seong Wook Yang, Si Hyun Bae, Pil Soo Sung; Received October 17, 2025 Accepted November 16, 2025 Published online December 4, 2025; DOI: https://doi.org/10.17998/jlc.2025.11.16 [Accepted]

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Abstract PDF: Background
The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), but its role in hepatocellular carcinoma (HCC) development is unclear. This study examines the association between the PNPLA3 I148M variant and HCC occurrence.
Methods
A total of 562 MASLD patients, with and without HCC, were prospectively and consecutively enrolled at two university-affiliated hospital between June 2024 and June 2025. Genomic DNA was extracted from buccal swabs or liver biopsy samples, and single nucleotide polymorphism (SNP) genotyping was performed to determine the rs738409 genotype at codon 148 of PNPLA3. The histological grade of HCC was assessed using the Edmondson-Steiner (ES) grading system in patients who underwent core-needle liver biopsy.
Results
Among 474 non-HCC patients, the GG genotype was found in 39.9%, GC in 37.1%, and CC in 23.0%. In 88 HCC patients, these frequencies were 45.5%, 36.4%, and 18.2%, respectively. No significant differences in GG genotype distribution were observed between HCC and non-HCC groups (P = 0.509), nor in subgroups by sex, age, obesity status, cirrhosis status, Fibrosis-4 Index, or Liver Stiffness Measurement. However, among HCC patients with histological grading, the GG genotype was significantly associated with higher ES grades (P = 0.0076).
Conclusions
The PNPLA3 I148M GG genotype was not significantly associated with increased HCC occurrence in Korean MASLD patients within the present cohort. Although the GG genotype is known to play a role in development and progression of MASLD, further studies are warranted to clarify its contribution to tumor initiation and dedifferentiation.

Heavy smoking increases early mortality risk in patients with hepatocellular carcinoma after curative treatment: Jaejun Lee, Jong Young Choi, Soon Kyu Lee; J Liver Cancer. 2024;24(2):253-262. Published online June 7, 2024; DOI: https://doi.org/10.17998/jlc.2024.06.02

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6 Citations

Backgrounds/Aims
Although cigarette smoking has been associated with an increased risk of hepatocellular carcinoma (HCC), its association with HCC mortality remains underexplored. We aimed to evaluate the effect of smoking on early mortality in HCC patients following curative treatment.
Methods
Data from the Korean Primary Liver Cancer Registry were examined for HCC patients who underwent liver resection or radiofrequency ablation between 2015 and 2018. Smoking cumulative dose was assessed in pack-years. The primary outcome was the 3-year overall survival (OS).
Results
Among 1,924 patients, 161 were classified as heavy smokers (≥40 pack-years). Heavy smokers exhibited a lower 3-year survival rate (77.1%) than nonsmokers (83.3%), with a significant difference observed in the 3-year OS (P=0.016). The assessment of smoking pack-years in relation to 3-year OS revealed a dose-dependent pattern, with the hazard ratio exceeding 1.0 at 20 pack-years and continuing to rise until 40 pack-years, reaching peak at 1.21 (95% confidence interval, 1.01-1.45). Multivariate Cox-regression analysis revealed heavy smoking, age ≥60 years, underlying cirrhosis, tumor size >3 cm, vascular invasion, and Child-Pugh class B/C as risk factors for 3-year OS. Subgroup analyses of patients with a tumor size <3 cm, absence of vascular invasion, and meeting the Milan criteria also showed inferior outcomes for heavy smokers in all three subgroups.
Conclusions
Heavy smoking, defined as a history of >40 pack-years, was linked to poorer 3-year survival outcomes in HCC patients undergoing curative treatments, underscoring the importance of smoking cessation in this population.

Citations

Citations to this article as recorded by

Differential Exercise Requirements for Nonalcoholic Fatty Liver Disease Resolution Across Age Groups: A Longitudinal Study of Korean Military Officers
Jaejun Lee, Dong Yeup Lee, Jae Hyeop Jung, Eunkyoung Bae, Jeong A. Yu, Hyun Yang
Journal of Physical Activity and Health.2025; 22(3): 323. CrossRef
Current Trends and Impact of Liver Biopsy on Survival in Hepatocellular Carcinoma: A Korean Multicenter Analysis
Seong Joon Chun, Jeong-Ju Yoo, Sang Gyune Kim, Young-Seok Kim
Diagnostics.2025; 15(7): 818. CrossRef
A comprehensive analysis of the impact of smoking on adverse clinical outcomes of steatotic liver diseases
Keungmo Yang, Jaejun Lee, Ji Won Han, Hyun Yang, Seung Yun Chae, Beom Sun Chung, Tom Ryu
Therapeutic Advances in Gastroenterology.2025;[Epub] CrossRef
Aged Garlic Extract and Its Bioactive Molecules S-Allyl-Cysteine and S1-Propenyl-Cysteine: A Review Focusing on Evidences Supporting Their Use for Mitigating the Effects of Cigarette Smoking
Roberto Gambari, Alessia Finotti
Molecules.2025; 30(17): 3496. CrossRef
Smoking and liver diseases: an updated review of pathogenesis, progression, and therapeutic implications
Gasser El-Azab, Ehab Elkhouly, Rania Abouyoussef, Hanaa Nagdy
Clinical and Experimental Medicine.2025;[Epub] CrossRef
Impacts of smoking on alcoholic liver disease: a nationwide cohort study
Jeong-Ju Yoo, Dong Hyeon Lee, Sang Gyune Kim, Jae Young Jang, Young Seok Kim, Log Young Kim
Frontiers in Public Health.2024;[Epub] CrossRef

Case Report

Multidisciplinary treatment with immune checkpoint inhibitors for advanced stage hepatocellular carcinoma: Ahlim Lee, Jaejun Lee, Hyun Yang, Soo-Yoon Sung, Chang Ho Jeon, Su Ho Kim, Moon Hyung Choi, Young Joon Lee, Ho Jong Chun, Si Hyun Bae; J Liver Cancer. 2022;22(1):75-83. Published online March 18, 2022; DOI: https://doi.org/10.17998/jlc.2022.03.04

7,184 Views
112 Downloads
6 Citations

Abstract PDF

Hepatocellular carcinoma (HCC) is a cytotoxic chemotherapy-resistant tumor and most HCCs arise in a background of liver cirrhosis of various causes. Although the IMBrave150 trial showed remarkable advancements in the treatment of unresectable HCC with atezolizumab plus bevacizumab (AteBeva), therapeutic outcomes were unsatisfactory in more than half of the patients. Accordingly, many ongoing trials combine conventional modalities with new drugs such as immune checkpoint inhibitors for better treatment outcomes, and they are expected to benefit patients with limited responses to conventional treatment. Here, two patients with advanced stage HCC with preserved liver function and good performance status showed partial response after treatment with combination or sequential therapy of AteBeva, hepatic arterial infusion chemotherapy, radiation therapy, and transarterial chemoembolization. These findings indicate the efficacy of multidisciplinary treatment against advanced HCC. Additional studies are required to establish optimal treatment strategies.

Citations

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Multidisciplinary treatment strategies for the assessment of immune, coagulation, and biomarker responses after transarterial chemoembolization for hepatocellular carcinoma
Tian Song, Kan-Hua Wu, Hao Yang, Wen-Li Xie, Lan Shen
World Journal of Gastrointestinal Surgery.2025;[Epub] CrossRef
Navigating the Therapeutic Pathway and Optimal First-Line Systemic Therapy for Hepatocellular Carcinoma in the Era of Immune Checkpoint Inhibitors
Hyun Phil Shin, Moonhyung Lee
Medicina.2025; 61(12): 2164. CrossRef
Complications of immunotherapy in advanced hepatocellular carcinoma
Young-Gi Song, Jeong-Ju Yoo, Sang Gyune Kim, Young Seok Kim
Journal of Liver Cancer.2024; 24(1): 9. CrossRef
Higher objective responses by hepatic arterial infusion chemotherapy following atezolizumab and bevacizumab failure than when used as initial therapy in hepatocellular carcinoma: a retrospective study
Jae-Sung Yoo, Ji Hoon Kim, Hee Sun Cho, Ji Won Han, Jeong Won Jang, Jong Young Choi, Seung Kew Yoon, Suho Kim, Jung Suk Oh, Ho Jong Chun, Pil Soo Sung
Abdominal Radiology.2024; 49(9): 3127. CrossRef
Feasibility of additional radiotherapy in patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab
Tae Hyun Kim, Bo Hyun Kim, Yu Ri Cho, Young-Hwan Koh, Joong-Won Park
Journal of Liver Cancer.2023; 23(2): 330. CrossRef
Is multidisciplinary treatment effective for hepatocellular carcinoma with portal vein tumor thrombus?
Won Hyeok Choe
Journal of Liver Cancer.2022; 22(1): 1. CrossRef

Original Article

Infiltration of T Cells and Programmed Cell Death Ligand 1-expressing Macrophages as a Potential Predictor of Lenvatinib Response in Hepatocellular Carcinoma: Pil Soo Sung, Sung Woo Cho, Jaejun Lee, Hyun Yang, Jeong Won Jang, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon; J Liver Cancer. 2020;20(2):128-134. Published online September 30, 2020; DOI: https://doi.org/10.17998/jlc.20.2.128

6,231 Views
112 Downloads
8 Citations

Abstract PDF

Background/Aims
Lenvatinib was recently proven to be non-inferior to sorafenib in treating unresectable hepatocellular carcinoma (HCC) in a phase-3 randomized controlled trial. In this study, we investigated whether the response to lenvatinib was affected by tumor immunogenicity.
Methods
Between May 2019 and April 2020, nine patients with intermediate-to-advanced HCC, who were treated with lenvatinib after liver biopsy, were enrolled. Immunohistochemical staining and multi-color flow cytometry were performed on specimens obtained from liver biopsy.
Results
Among the nine patients enrolled, four showed objective responses (complete responses+partial responses). Immunohistochemical staining for CD3, CD68, and programmed cell death ligand 1 (PD-L1) demonstrated that patients with objective responses showed marked infiltration of T cells and PD-L1-expressing macrophages in intra-tumoral and peri-tumoral tissues compared to those without objective responses. A significant difference in the numbers of infiltrated T cells, both in the intra-tumoral (P<0.01) and peri-tumoral regions (P<0.05), were identified between responders and non-responders. Regarding the number of infiltrated macrophages, no significant difference was found between the responders and non-responders, although the number of PD-L1-expressing tumor-associated macrophages was significantly higher in responders than that in non-responders (P<0.05).
Conclusions
Tumor immunogenicity, as indicated by T cell and PD-L1-positive macrophage infiltration, affects lenvatinib response in unresectable HCC.

Citations

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Roles of clinical application of lenvatinib and its resistance mechanism in advanced hepatocellular carcinoma (Review)
Ganghui Ye
American Journal of Cancer Research.2024; 14(9): 4113. CrossRef
Recent Advances in Immune-based Therapy for Hepatocellular Carcinoma
Kyung Won Park, Tae Hoon Park, Eun Ji Jang, Pil Soo Sung
Journal of Digestive Cancer Research.2024; 12(2): 115. CrossRef
Higher Number of Tumor-Infiltrating PD-L1+ Cells Is Related to Better Response to Multikinase Inhibitors in Hepatocellular Carcinoma
Ji Won Han, Ji Hoon Kim, Dong Hyun Kim, Jeong Won Jang, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon, Jaegyoon Ahn, Hyun Yang, Pil Soo Sung
Diagnostics.2023; 13(8): 1453. CrossRef
Intrahepatic inflammatory IgA+PD-L1high monocytes in hepatocellular carcinoma development and immunotherapy
Pil Soo Sung, Dong Jun Park, Pu Reun Roh, Kyoung Do Mun, Sung Woo Cho, Gil Won Lee, Eun Sun Jung, Sung Hak Lee, Jeong Won Jang, Si Hyun Bae, Jong Young Choi, Jonghwan Choi, Jaegyoon Ahn, Seung Kew Yoon
Journal for ImmunoTherapy of Cancer.2022; 10(5): e003618. CrossRef
Crosstalk between tumor-associated macrophages and neighboring cells in hepatocellular carcinoma
Pil Soo Sung
Clinical and Molecular Hepatology.2022; 28(3): 333. CrossRef
Blood-based biomarkers for immune-based therapy in advanced HCC: Promising but a long way to go
Pil Soo Sung, Isaac Kise Lee, Pu Reun Roh, Min Woo Kang, Jaegyoon Ahn, Seung Kew Yoon
Frontiers in Oncology.2022;[Epub] CrossRef
Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection
Pil Soo Sung, Eui-Cheol Shin
Journal of Clinical Medicine.2021; 10(2): 221. CrossRef
Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma
Dong-Jun Park, Pil-Soo Sung, Gil-Won Lee, Sung-Woo Cho, Sung-Min Kim, Byung-Yoon Kang, Won-Hee Hur, Hyun Yang, Soon-Kyu Lee, Sung-Hak Lee, Eun-Sun Jung, Chang-Ho Seo, Joseph Ahn, Ho-Joong Choi, Young-Kyoung You, Jeong-Won Jang, Si-Hyun Bae, Jong-Young Cho
International Journal of Molecular Sciences.2021; 22(9): 4710. CrossRef

Case Report

Early Onset Polymorphic Post-transplant Lymphoproliferative Disease Mimicking a Solitary Necrotizing Abscess in a Graft Liver: Pil Soo Sung, Jaejun Lee, Joon Lee, Hee Chul Nam, Si Hyun Bae, Seung Kew Yoon; J Liver Cancer. 2019;19(2):165-170. Published online September 30, 2019; DOI: https://doi.org/10.17998/jlc.19.2.165

7,480 Views
84 Downloads
1 Citation

Abstract PDF

Although post-transplantation lymphoproliferative disease (PTLD) after liver transplantation is very rare, its prognosis is worse than that of PTLD following other types of solid organ transplantation. Here, we report a rare case of early onset polymorphic PTLD in a graft liver occurring five months after deceased-donor liver transplantation due to hepatocellular carcinoma and hepatitis C virus infection. Initially, findings from contrast-enhanced magnetic resonance imaging mistakenly suspected the lesion was a necrotizing abscess with central necrosis. However, ¹⁸F-fluorodeoxyglucose positron emission tomography and biopsy findings confirmed an Epstein-Barr virus (EBV)-associated, B cell type polymorphic PTLD with central necrosis. Our case suggests regular monitoring of EBV serologic status for liver transplant recipients who were initially in an EBV seronegative state. Although early-onset PTLD is very rare after liver transplantation, PTLD should be suspected when recipients show the seroconversion for EBV proteins and the development of new tumors with various clinical presentations.

Citations

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The ‘Oma’s of the Gammas—Cancerogenesis by γ-Herpesviruses
Anwesha Banerjee, Debashree Dass, Soumik Mukherjee, Mollina Kaul, R. Harshithkumar, Parikshit Bagchi, Anupam Mukherjee
Viruses.2024; 16(12): 1928. CrossRef

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