Journal of Liver Cancer

Original Article

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.

Special Contributions

Impact of the 2024 medical-policy conflict on hepatocellular carcinoma management in Korea: Soon Sun Kim, Hyun Yang, Jieun Kwon, Eunju Kim, Jeong Il Yu, Janghan Jung, Woosun Choi, Ji Eun Han, Moon Haeng Hur, Bo Hyun Kim, Sung Hyun Kim, Jeong Han Kim, Haeryoung Kim, Pyoung-Jae Park, Hyun Phil Shin, Su Jong Yu, Ki Tae Yoon, Sang Min Yoon, Minjong Lee, Jai Young Cho, Jin-Young Choi, Do Young Kim, June Sung Lee, Mi-Sook Kim, Kyung Sik Kim; J Liver Cancer. 2025;25(2):169-177. Published online September 2, 2025; DOI: https://doi.org/10.17998/jlc.2025.09.01

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Abstract PDF: In 2024, a nationwide conflict between the South Korean government and the medical community, the medical-policy conflict, profoundly impacted healthcare delivery. This study aimed to evaluate the changes in the management of hepatocellular carcinoma (HCC) following this crisis. We analyzed retrospective real-world data from university hospitals in the Seoul Metropolitan Area, supplemented with national healthcare data from the Health Insurance Review and Assessment Service. The analytical variables included changes in workforce composition, initial treatment modalities, HCC stage distribution, quality indicators for HCC care, regional and institutional variations in care delivery, and liver transplantation (LT) volume. A comparison between 2023 and 2024 revealed a marked decline in the number of medical trainees, a rise in the proportion of physician assistants, a 28.9% reduction in newly initiated HCC treatments, and an increased rate of stage IV diagnoses. Several quality indicators, including rates of multidisciplinary care and patient education, declined. The volume of LTs decreased by approximately 20% nationwide, with some regions ceasing LT procedures. The results suggest that serious disruptions occurred in HCC care following the conflict. The significant decrease in initial treatment and number of LT procedures, more advanced stages at diagnosis, and declining quality metrics indicate the emergence of healthcare gaps. Without the recovery of the clinical workforce and the reestablishment of a stable healthcare delivery system, the management of serious diseases such as HCC will remain structurally vulnerable. National-level efforts are urgently required to address regional disparities and restore essential medical services.

Expert survey on systemic therapy indications for hepatocellular carcinoma in Korea: bridging clinical practice and reimbursement criteria: Hyun Yang, Soon Sun Kim, Seong Hee Kang, Jieun Kwon, Do Young Kim, Eunju Kim, Hyun Phil Shin, Jeong Il Yu, Jeong-Ju Yoo, Eileen L. Yoon, Sangheun Lee, Young Eun Chon, Janghan Jung, Jaekyung Cheon, Woosun Choi, Seul Ki Han, Ji Eun Han, Moon Haeng Hur, Hyun Woong Lee, Hyung Joon Kim; J Liver Cancer. 2025;25(2):160-168. Published online July 7, 2025; DOI: https://doi.org/10.17998/jlc.2025.07.02

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Abstract PDF: This survey aimed to collect expert opinions from multidisciplinary specialists involved in the management of hepatocellular carcinoma (HCC) in Korea regarding real-world criteria for systemic therapy indications. In response to discrepancies between national reimbursement policies and clinical decision-making, members of the Korean Liver Cancer Association and Korean Association for the Study of the Liver participated in a web-based survey from February 4 to 14, 2025. A total of 89 respondents, primarily experienced clinicians, provided their views on major clinical scenarios including infiltrative HCC, bilobar multifocal disease, huge tumors, vascular invasion, extrahepatic metastasis, and transarterial chemoembolization (TACE) refractoriness. There was high agreement for including infiltrative HCC (69.7%), suspected portal vein invasion (70.8%), and TACE refractoriness (82.0%) as systemic therapy indications. TACE refractoriness, in particular, aligns with current guideline definitions. Additionally, over half of respondents (51.7%) supported extrahepatic metastasis under similar conditions. Notably, multidisciplinary discussion was emphasized across scenarios, but many respondents also favored allowing primary physician discretion in select cases. This report provides consolidated expert input to inform future updates to reimbursement policies and promote alignment with real-world clinical practice. These findings may help bridge the gap between national coverage criteria and clinical decision in systemic therapy for HCC.

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

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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

Citations to this article as recorded by

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

6,232 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

Citations to this article as recorded by

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

A Case of Complete Response by Multidisciplinary Management in a Patient with Solitary Bone Metastasis after Curative Resection of Hepatocellular Carcinoma: Seawon Hwang, Hyun Yang, Hae Lim Lee, Jeong Won Jang, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon; J Liver Cancer. 2016;16(1):52-56. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.52

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15 Downloads

Abstract PDF: Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of patients with extrahepatic metastasis from HCC still remains dismal. The current study presents a case of HCC that was metastatic to the pelvis and describes successful treatment with multidisciplinary approach to the skeletal metastasis. The patient was a 67-year-old male who presented with right pelvic pain 28 months following right hepatectomy for HCC. Computed tomography and magnetic resonance imaging indicated a solitary bone metastasis without intrahepatic recurrence. Complete response was achieved with multidisciplinary management including sorafenib, transarterial embolization, surgery to remove the metastatic mass and radiotherapy after surgery. A post-operative follow-up 15 months later found that the patient remained in good health with maintained complete response. This case suggests that a multidisciplinary approach can achieve long-term cancer-free survival and prolonged life expectancy beyond palliative care for patients with solitary bone metastasis after curative surgery for HCC.

Original Article

Comparative Study between Metronomic Chemotherapy and Transarterial Chemoembolization in Patients with Child-Pugh Class B Advanced Hepatocellular Carcinoma: Hyun Yang, Myeong Jun Song, Hee Chul Nam, Hae Lim Lee, Sung Won Lee, Do Seon Song, Jeong Won Jang, Si Hyun Bae, Jong Yong Choi, Seung Kew Yoon; J Liver Cancer. 2015;15(2):92-99. Published online September 30, 2015; DOI: https://doi.org/10.17998/jlc.15.2.92

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1 Citation

Abstract PDF

Background/Aims
Metronomic (MET) chemotherapy is a treatment characterized by frequent infusion of low doses of chemotherapeutic agent without extended break. The aim of this study is to evaluate the efficacy of MET chemotherapy compared with transarterial chemoembolization (TACE) in patients with child B class advanced hepatocellular carcinoma (HCC).
Methods
Seventy-three patients with child B class advanced HCC were analyzed between April, 2007 and August, 2013 according to two treatment groups: (i) MET chemotherapy group (n=43, Epirubicin 35 mg/body surface area [BSA] every 4 weeks, and cisplatin 15 mg/BSA and 5-fluorouracil 50 mg/BSA weekly for 3 weeks) via an implantable port system with 1 week break. (ii) TACE group (n=30, Adriamycin 20-50 mg) every 4 weeks. Primary endpoint was overall survival (OS).
Results
The median survival times in the MET and TACE groups were 4.5 months and 3.1 months, respectively. The overall survival rate showed significantly better in the MET treatment group than in the TACE group (P=0.039). When the factors affecting patient OS were analyzed, MET chemotherapy (P=0.038, hazard ratio {HR} 0.538 [95% confidence interval {CI} 0.299-0.967]) was independently associated with OS. Larger maximal tumor size, extrahepatic metastasis and advanced stage also were significant factors for OS (P=0.009, HR 1.064 [95% CI 1.014-16.064]; P=0.014, HR 2.120 [95% CI 1.164-3.861]; P=0.019, HR 2.046 [95% CI 1.125-3.720], respectively).
Conclusions
MET chemotherapy showed survival benefit than TACE in patients with child class B advanced HCC. Therefore, MET chemotherapy may be considered as a treatment option for advanced HCC with poor liver function. (J Liver Cancer 2015;15:92-99)

Citations

Citations to this article as recorded by

A comparative study of sorafenib and metronomic chemotherapy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma with poor liver function
Hyun Yang, Hyun Young Woo, Soon Kyu Lee, Ji Won Han, Bohyun Jang, Hee Chul Nam, Hae Lim Lee, Sung Won Lee, Do Seon Song, Myeong Jun Song, Jung Suk Oh, Ho Jong Chun, Jeong Won Jang, Angelo Lozada, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon
Clinical and Molecular Hepatology.2017; 23(2): 128. CrossRef

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