Journal of Liver Cancer

Volume 25(1); March 2025

Editorials

Antitumor role of L-arginine and argininosuccinate synthetase 1 in hepatocellular carcinoma: direct and immunological mechanisms: Hyuk Soo Eun; J Liver Cancer. 2025;25(1):1-3. Published online March 11, 2025; DOI: https://doi.org/10.17998/jlc.2025.03.07

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Evolving trends in epidemiology, etiology, and treatment patterns for hepatocellular carcinoma in South Korea: Soo Young Hwang, Ju Dong Yang; J Liver Cancer. 2025;25(1):4-6. Published online December 5, 2024; DOI: https://doi.org/10.17998/jlc.2024.12.04

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Correspondence to editorial on “Evolving trends in epidemiology, etiology, and treatment patterns for hepatocellular carcinoma in South Korea”
Ji Won Han, Bo Hyun Kim
Journal of Liver Cancer.2025; 25(1): 7. CrossRef

Correspondence

Correspondence to editorial on “Evolving trends in epidemiology, etiology, and treatment patterns for hepatocellular carcinoma in South Korea”: Ji Won Han, Bo Hyun Kim; J Liver Cancer. 2025;25(1):7-8. Published online February 27, 2025; DOI: https://doi.org/10.17998/jlc.2025.02.17

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Review Articles

Molecular and immune landscape of hepatocellular carcinoma for therapeutic development: Hiroyuki Suzuki, Sumit Mishra, Subhojit Paul, Yujin Hoshida; J Liver Cancer. 2025;25(1):9-18. Published online December 6, 2024; DOI: https://doi.org/10.17998/jlc.2024.12.02

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Abstract PDF

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with an estimated 750,000 deaths in 2022. Recent emergence of molecular targeted agents and immune checkpoint inhibitors and their combination therapies have been transforming HCC care, but their prognostic impact in advanced-stage disease remains unsatisfactory. In addition, their application to early-stage disease is still an unmet need. Omics profiling studies have elucidated recurrent and heterogeneously present molecular aberrations involved in pro-cancer tumor (immune) microenvironment that may guide therapeutic strategies. Recurrent aberrations such somatic mutations in TERT promoter and TP53 have been regarded undruggable, but recent studies have suggested that these may serve as new classes of therapeutic targets. HCC markers such as alpha-fetoprotein, glypican-3, and epithelial cell adhesion molecule have also been explored as therapeutic targets. These molecular features may be utilized as biomarkers to guide the application of new approaches as companion biomarkers to maximize therapeutic benefits in patients who are likely to benefit from the therapies, while minimizing unnecessary harm in patients who will not respond. The explosive number of new agents in the pipelines have posed challenges in their clinical testing. Novel clinical trial designs guided by predictive biomarkers have been proposed to enable their efficient and cost-effective evaluation. These new developments collectively facilitate clinical translation of personalized molecular-targeted therapies in HCC and substantially improve prognosis of HCC patients.

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Paracancerous binuclear hepatocytes assessed by computer program is a novel biomarker for short term recurrence of hepatocellular carcinoma after surgery
Yifan Zhang, Yiquan Lu, Nan Wang, Fengjie Hao, Yongjun Chen, Xiaochun Fei, Junqing Wang
Scientific Reports.2025;[Epub] CrossRef

A concise review of updated global guidelines for the management of hepatocellular carcinoma: 2017-2024: Hyunjae Shin, Su Jong Yu; J Liver Cancer. 2025;25(1):19-30. Published online February 10, 2025; DOI: https://doi.org/10.17998/jlc.2025.02.03

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Abstract PDF: Many guidelines for hepatocellular carcinoma (HCC) have been published and are regularly updated worldwide. HCC management involves a broad range of treatment options and requires multidisciplinary care, resulting in significant heterogeneity in management practices across international communities. To support standardized care for HCC, we systematically appraised 13 globally recognized guidelines and expert consensus statements, including five from Asia, four from Europe, and four from the United States. These guidelines share similarities but reveal notable discrepancies in surveillance strategies, treatment allocation, and other recommendations. Geographic differences in tumor biology (e.g., prevalence of viral hepatitis, alcohol-related liver disease, or metabolic dysfunction-associated steatotic liver disease) and disparities in available medical resources (e.g., organ availability, healthcare infrastructure, and treatment accessibility) complicate the creation of universally applicable guidelines. Previously, significant gaps existed between Asian and Western guidelines, particularly regarding treatment strategies. However, these differences have diminished over the years. Presently, variations are often more attributable to publication dates than to regional differences. Nonetheless, Asia-Pacific experts continue to diverge from the Barcelona Clinic Liver Cancer system, particularly with respect to surgical resection and locoregional therapies, which are viewed as overly conservative in Western guidelines. Advancements in systemic therapies have prompted ongoing updates to these guidelines. Given that each set of guidelines reflects distinct regional characteristics, strengths, and limitations, fostering collaboration and mutual complementarity is essential for addressing discrepancies and advancing global HCC care.

Recent advances and issues in imaging modalities for hepatocellular carcinoma surveillance: Dong Ho Lee; J Liver Cancer. 2025;25(1):31-40. Published online February 26, 2025; DOI: https://doi.org/10.17998/jlc.2025.02.16

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Abstract PDF: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Early detection via surveillance plays a crucial role in enabling curative treatment and improving survival rates. Since the initial randomized controlled trial, biannual ultrasound (US) has been established as the standard surveillance method because of its accessibility, safety, and low cost. However, US has some limitations, including operator dependency, suboptimal sensitivity for early-stage HCC, and challenges such as a limited sonic window that may result in inadequate examination. Alternative imaging modalities, including contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI), have demonstrated higher sensitivity for detecting very early-stage HCC. Recent advancements, such as low-dose CT with deep learning-based reconstruction, have enhanced the safety and feasibility of CT-based surveillance by reducing radiation exposure and amount of contrast media. MRI, particularly with gadoxetic acid or abbreviated protocols, offers superior tissue contrast and sensitivity, although its accessibility and cost remain challenges. Tailored surveillance strategies based on individual risk profiles and integration of advanced imaging technologies have the potential to enhance the detection performance and cost-effectiveness. This review highlights the recent developments in imaging technologies for HCC surveillance, focusing on their respective strengths and limitations.

Epidemiology and genomic features of biliary tract cancer and its unique features in Korea: Seonjeong Woo, Youngun Kim, Sohyun Hwang, Hong Jae Chon; J Liver Cancer. 2025;25(1):41-51. Published online March 4, 2025; DOI: https://doi.org/10.17998/jlc.2025.02.27

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Abstract PDF Supplementary Material: Biliary tract cancer (BTC) is a rare but highly aggressive malignancy that includes intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma, and gallbladder cancer (GBC). While BTC has a low global incidence, its regional variations are notable. Among nations, Korea has the second-highest incidence of BTC globally, with the highest mortality rate worldwide, underscoring the need for a deeper understanding of this cancer. Liver fluke infection and hepatitis B virus infection are key risk factors unique to Korea, contributing to regional differences in BTC incidence. Additionally, genomic alterations in Korean patients with BTC differ from those in other populations, including lower frequencies of IDH1 mutations and FGFR2 fusions in ICC and a higher prevalence of ERBB2 amplification in GBC. Recognizing the clinical significance of these alterations, ivosidenib and pemigatinib have been approved in Korea for BTC patients with IDH1 mutations and FGFR2 fusions, respectively. This review explores the epidemiology, risk factors, and molecular features of BTC, along with corresponding targeted therapies. Furthermore, we compare the unique characteristics of BTC in Korea with global data to inform future research and clinical practice.

Management of hepatocellular carcinoma in elderly and adolescent/young adult populations: Han Ah Lee; J Liver Cancer. 2025;25(1):52-66. Published online March 20, 2025; DOI: https://doi.org/10.17998/jlc.2025.02.28

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Abstract PDF: Hepatocellular carcinoma (HCC) presents unique challenges in both the elderly and adolescent/young adult (AYA) populations, requiring distinct management approaches. Recent epidemiological data show an increasing incidence of HCC in both age groups, with elderly cases rising significantly and AYA cases showing trends in specific regions. The clinical characteristics and treatment considerations vary substantially among these populations. Elderly patients with HCC typically present with hepatitis C virus infection, metabolic dysfunction-associated steatotic liver disease, well-differentiated tumors, and multiple comorbidities. In contrast, AYA patients with HCC often present with more aggressive tumor characteristics and predominantly with hepatitis B virus-related diseases. Treatment decisions for elderly patients with HCC require careful consideration of physiological reserves, comprehensive geriatric assessments, and potential complications. Recent studies have demonstrated that elderly patients can achieve outcomes comparable to younger patients across various treatment modalities when properly selected. While surgical outcomes are comparable to those of younger patients with proper selection, less-invasive options such as radiofrequency ablation or transarterial therapies may be more appropriate for some elderly patients. The treatment approach for AYA HCC emphasizes curative intent while considering long-term effects. AYA patients require specialized attention to their psychosocial needs, fertility preservation, and long-term health maintenance. Although data on AYA patients remain limited, they are known to have relatively favorable prognoses despite exhibiting more aggressive tumor characteristics. Management of HCC in both the elderly and AYA populations requires individualized approaches that consider age-specific factors. Both groups benefit from multidisciplinary team involvement and careful consideration of quality of life.

Insights into hepatocellular adenomas in Asia: molecular subtypes, clinical characteristics, imaging features, and hepatocellular carcinoma risks: Subin Heo, In Hye Song, Edouard Reizine, Maxime Ronot, Jean-Charles Nault, Hae Young Kim, Sang Hyun Choi, So Yeon Kim; J Liver Cancer. 2025;25(1):67-78. Published online March 7, 2025; DOI: https://doi.org/10.17998/jlc.2025.03.06

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Abstract PDF: Hepatocellular adenomas (HCAs) are benign monoclonal liver tumors. Advances in molecular studies have led to the identification of distinct subtypes of HCA with unique pathways, clinical characteristics, and complication risks, underscoring the need for precise diagnosis and tailored management. Malignant transformation and bleeding remain significant concerns. Imaging plays a crucial role in the identification of these subtypes, offering a non-invasive method to guide clinical decision-making. Most studies involving patients with HCAs have been conducted in Western populations; however, the number of studies focused on Asian population has increased in recent years. HCAs exhibit distinct features in Asian population, such as a higher prevalence among male patients and specific subtypes (e.g., inflammatory HCAs). Current clinical guidelines are predominantly influenced by Western data, which may not fully capture these regional differences in epidemiology and subtype distribution. Therefore, this review presents the updated molecular classification of HCAs and their epidemiologic differences between Asian and Western populations, and discuss the role of imaging techniques, particularly magnetic resonance imaging using hepatobiliary contrast agents, in classifying the subtypes and predicting the risk of hepatocellular carcinoma.

Original Articles

Synergistic effects of L-arginine and argininosuccinate synthetase 1 in inducing apoptosis in hepatocellular carcinoma: Jin Sun Kim, Won-Mook Choi, Ha-Il Kim, Sung Won Chung, Jonggi Choi, Danbi Lee, Kang Mo Kim; J Liver Cancer. 2025;25(1):79-90. Published online January 14, 2025; DOI: https://doi.org/10.17998/jlc.2024.12.27

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Abstract PDF

Backgrounds/Aims
Hepatocellular carcinoma (HCC) is a malignant cancer with an increasing incidence worldwide. Although numerous efforts have been made to identify effective therapies for HCC, current strategies have limitations. We present a new approach for targeting L-arginine and argininosuccinate synthetase 1 (ASS1).
Methods
ASS1 expression in HCC cell lines and primary hepatocytes was detected using polymerase chain reaction and western blotting. Proliferation, migration, signaling pathways, and nitric oxide production in HCC cell lines were measured using MTS, colony formation, wound healing, Western blot, and Griess assays.
Results
ASS1 expression varied among the HCC cell lines, and cisplatin cytotoxicity was ASS1-dependent. L-arginine alone induced apoptosis in HCC cell lines, regardless of ASS1 expression; however, its effect was enhanced in ASS1-expressing HCC cell lines. Cisplatin cytotoxicity also increased, suggesting that L-arginine acts as a sensitizer to cisplatin in HCC cell lines. ASS1 and L-arginine produced nitric oxide and inhibited key proliferation- and survival-related signaling pathways such as PI3K/Akt and MAPK. Additionally, ASS1 and L-arginine reduced the expression of PKM1 and PKM2 in the glycolysis pathway.
Conclusions
Our study revealed that ASS1 and L-arginine exhibited anticancer effects in HCC and sensitized cisplatin-resistant HCC cells to chemotherapy. The combination of ASS1 and L-arginine significantly enhanced the anticancer effects, even in HCC cell lines with low or absent ASS1 expression. These findings highlight the critical roles of arginine and ASS1 in HCC and suggest that increasing arginine availability could be a promising therapeutic strategy.

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Antitumor role of L-arginine and argininosuccinate synthetase 1 in hepatocellular carcinoma: direct and immunological mechanisms
Hyuk Soo Eun
Journal of Liver Cancer.2025; 25(1): 1. CrossRef

Enhanced radiofrequency ablation for recurrent hepatocellular carcinoma post-transarterial chemoembolization: a prospective study utilizing twin internally cooled-perfusion electrodes: Sungjun Hwang, Jae Hyun Kim, Sae-Jin Park, Su Jong Yu, Yoon Jun Kim, Jung-Hwan Yoon, Jeong Min Lee; J Liver Cancer. 2025;25(1):91-98. Published online February 7, 2025; DOI: https://doi.org/10.17998/jlc.2025.01.25

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Abstract PDF: Backgrounds/Aims
Radiofrequency ablation (RFA) is widely employed for managing recurrent hepatocellular carcinoma (HCC) following transarterial chemoembolization (TACE). However, local tumor progression (LTP) after treatment remains a significant challenge. This study evaluates the efficacy of saline-perfused bipolar RFA using twin internally cooled-perfusion (TICP) electrodes in managing recurrent HCC post-TACE.
Methods
Between September 2017 and January 2019, 100 patients with 105 nodules (mean diameter, 1.6±0.5 cm) were prospectively enrolled. Bipolar RFA with TICP electrodes was performed under ultrasound-computed tomography/magnetic resonance fusion guidance. The primary outcome was the 2-year cumulative incidence of LTP.
Results
The technical success and technique efficacy rates were 100% and 97%, respectively. During a median follow-up period of 34.0 months (range, 3-41), the estimated LTP rates were 13.3% at 1 year and 17.7% at 2 years. Progression-free survival rates were 37.8% and 27.7% at 1 year and 2 years, respectively.
Conclusions
Saline-perfused bipolar RFA using TICP electrodes demonstrates promising results for recurrent HCC after TACE, achieving high technical success and effective local tumor control rates.

Microwave ablation vs. liver resection for patients with hepatocellular carcinomas: Hyundam Gu, Yeonjoo Seo, Dong Jin Chung, Kwang Yeol Paik, Seung Kew Yoon, Jihye Lim; J Liver Cancer. 2025;25(1):99-108. Published online February 7, 2025; DOI: https://doi.org/10.17998/jlc.2025.02.02

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Abstract PDF Supplementary Material: Backgrounds/Aims
Microwave ablation (MWA) is an emerging ablative therapy that surpasses previous methods by achieving higher temperatures and creating larger ablation zones within shorter periods. This study compared the therapeutic outcomes of MWA with those of liver resection in real-world clinical practice.
Methods
A total of 178 patients with 259 nodules who underwent MWA or liver resection between January 2015 and July 2023 were enrolled. Local tumor progression (LTP)-free survival, overall progression (OP)-free survival, and overall survival (OS) were assessed based on the treatment modality for the index nodule.
Results
Of the 178 patients, 134 with 214 nodules underwent MWA, and 44 with 45 nodules underwent liver resection. The median follow-up period was 2.0±1.5 years. The annual incidence of LTP was 3.7% for MWA and 1.4% for liver resection. Treatment modality did not significantly affect LTP-free survival (hazard ratio, 0.61; 95% confidence interval, 0.14-2.69; P=0.511). For nodules larger than 3 cm, LTP-free survival was not affected by the treatment modality. Similarly, OP-free survival and OS were not influenced by treatment modality.
Conclusions
MWA and liver resection demonstrated comparable treatment outcomes in terms of local tumor control, overall recurrence, and survival. MWA may be an alternative treatment option for select patients; however, further studies are necessary to generalize these findings.

Hepatocellular carcinoma in Korea: an analysis of the 2016-2018 Korean Nationwide Cancer Registry: Jihyun An, Young Chang, Gwang Hyeon Choi, Won Sohn, Jeong Eun Song, Hyunjae Shin, Jae Hyun Yoon, Jun Sik Yoon, Hye Young Jang, Eun Ju Cho, Ji Won Han, Suk Kyun Hong, Ju-Yeon Cho, Kyu-Won Jung, Eun Hye Park, Eunyang Kim, Bo Hyun Kim; J Liver Cancer. 2025;25(1):109-122. Published online March 4, 2025; DOI: https://doi.org/10.17998/jlc.2025.02.20

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Abstract PDF Supplementary Material: Backgrounds/Aims
Hepatocellular carcinoma (HCC) is the sixth most common cancer and second leading cause of cancer-related deaths in South Korea. This study evaluated the characteristics of Korean patients newly diagnosed with HCC in 2016-2018.
Methods
Data from the Korean Primary Liver Cancer Registry (KPLCR), a representative database of patients newly diagnosed with HCC in South Korea, were analyzed. This study investigated 4,462 patients with HCC registered in the KPLCR in 2016-2018.
Results
The median patient age was 63 years (interquartile range, 55-72). 79.7% of patients were male. Hepatitis B infection was the most common underlying liver disease (54.5%). The Barcelona Clinic Liver Cancer (BCLC) staging system classified patients as follows: stage 0 (14.9%), A (28.8%), B (7.5%), C (39.0%), and D (9.8%). The median overall survival was 3.72 years (95% confidence interval, 3.47-4.14), with 1-, 3-, and 5-year overall survival rates of 71.3%, 54.1%, and 44.3%, respectively. In 2016-2018, there was a significant shift toward BCLC stage 0-A and Child-Turcotte-Pugh liver function class A (P<0.05), although survival rates did not differ by diagnosis year. In the treatment group (n=4,389), the most common initial treatments were transarterial therapy (31.7%), surgical resection (24.9%), best supportive care (18.9%), and local ablation therapy (10.5%).
Conclusions
Between 2016 and 2018, HCC tended to be diagnosed at earlier stages, with better liver function in later years. However, since approximately half of the patients remained diagnosed at an advanced stage, more rigorous and optimized HCC screening strategies should be implemented.

Identification of new biomarkers of hepatic cancer stem cells through proteomic profiling: Sung Hoon Choi, Ha Young Lee, Sung Ho Yun, Sung Jae Jang, Seung Up Kim, Jun Yong Park, Sang Hoon Ahn, Do Young Kim; J Liver Cancer. 2025;25(1):123-133. Published online March 20, 2025; DOI: https://doi.org/10.17998/jlc.2025.03.08

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Abstract PDF Supplementary Material: Backgrounds/Aims
In hepatocellular carcinoma (HCC), which exhibits high mortality and recurrence rates globally, the traits of cancer stem cells (CSCs) that significantly influence recurrence and metastasis are not well understood. CSCs are self-renewing cell types identified in most liquid and solid cancers, contributing to tumor initiation, growth, resistance, recurrence, and metastasis following chemo-radiotherapy or trans-arterial chemoembolization therapy.
Methods
CSCs are classified based on the expression of cell surface markers such as CD133, which varies depending on the tumor type. Proteomic analysis of liver cancer cell lines with cancer stem cell potential and HCC cancer cell lines lacking stem cell propensity was conducted to compare and analyze specific expression patterns.
Results
Proteomic profiling and enrichment analysis revealed higher expression of the calcium-binding protein S100 family in CD133+ Huh7 cells than in CD133- or wild-type cells. Furthermore, elevated expression of S100 family members was confirmed in an actual CD133+ liver cancer cell line via protein-protein network analysis and quantitative polymerase chain reaction (qPCR).
Conclusion
The S100 family members are not only new markers of cancer stem cells but will also assist in identifying new treatment strategies for CSC metastasis and tumor advancement.

Case Report

Durable complete response after discontinuation of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma with portal vein tumor thrombosis: the first report: Pramod Kumar, Pradeep Krishna, Rohit Maidur, Naveen Chandrashekhar, Suresh Raghavaiah; J Liver Cancer. 2025;25(1):134-137. Published online November 5, 2024; DOI: https://doi.org/10.17998/jlc.2024.09.26

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Abstract PDF: Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is associated with a dismal prognosis. Atezolizumab plus bevacizumab (atezo-bev) is the recommended palliative treatment, and approximately 10% of the patients may experience a complete response (CR), according to the mRECIST criteria. The treatment duration is until disease progression or unacceptable side effects occur. Long-term continuation can cause potential toxicities and a substantial financial burden, making early treatment discontinuation a viable option. This report describes durable CR after discontinuing atezo-bev treatment in three patients with HCC and PVTT.

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