Clinical and Molecular Hepatology

"Carcinoma, Hepatocellular"

Correspondence

Correspondence to editorial on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway”: Tomoko Aoki, Naoshi Nishida, Masatoshi Kudo; Clin Mol Hepatol 2026;32(1):e79-e82.
Published online April 28, 2025; DOI: https://doi.org/10.3350/cmh.2025.0435

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Reply to correspondence on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway”
Eun Ji Jang, Pil Soo Sung
Clinical and Molecular Hepatology.2026; 32(1): e115. CrossRef
Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography: A Potential Imaging Biomarker for Predicting Response to Combination Immunotherapy in Hepatocellular Carcinoma
Masatoshi Kudo
Liver Cancer.2025; 14(5): 511. CrossRef

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Editorial

Regulation of hepatitis B virus cccDNA by metabolic pathways: Editorial on “GDH1-dependent α-ketoglutarate promotes HBV transcription by modulating histone methylations on the cccDNA minichromosome”: Hyeong-Jin Cho, Sung-Gyoo Park; Clin Mol Hepatol 2026;32(1):381-384.
Published online March 12, 2025; DOI: https://doi.org/10.3350/cmh.2025.0255

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Establishment and evaluation of an immortalized dzo kidney cell line
Wenkai Liu, Cong Xu, Jiamin Wang, Na Sun, Zhongren Ma, Jin Zhao, Jianguo Chen, You Li, Zilin Qiao
Scientific Reports.2025;[Epub] CrossRef

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Original Article

Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway: Tomoko Aoki, Naoshi Nishida, Yutaka Kurebayashi, Kazuko Sakai, Naoto Fujiwara, Masakatsu Tsurusaki, Kohei Hanaoka, Masahiro Morita, Hirokazu Chishina, Masahiro Takita, Satoru Hagiwara, Hiroshi Ida, Kazuomi Ueshima, Yasunori Minami, Atsushi Takebe, Takaaki Murase, Keiko Kamei, Takuya Nakai, Ippei Matsumoto, Kazuto Nishio, Masatoshi Kudo; Clin Mol Hepatol 2025;31(3):981-1002.
Published online March 11, 2025; DOI: https://doi.org/10.3350/cmh.2024.1088

Background/Aims
Previously, we advocated the importance of classifying hepatocellular carcinoma (HCC) based on physiological functions. This study aims to classify HCC by focusing on liver-intrinsic metabolism and glycolytic pathway in cancer cells.
Methods
Comprehensive RNA/DNA sequencing, immunohistochemistry, and radiological evaluations were performed on HCC tissues from the training cohort (n=136) and validated in 916 public samples. HCC was classified using hierarchical clustering and compared with previous molecular, histopathological, and hemodynamic classifications.
Results
Liver-specific metabolism and glycolysis are mutually exclusive and were divided into two major subclasses: The “rich metabolism” subclass (60.3%) is characterized by enhanced bile acid and fatty acid metabolism, wellto-moderate differentiation, microtrabecular or pseudoglandular pattern, and homogeneous arterial-phase hyperenhancement (APHE), corresponding to Hoshida S3 with favorable prognosis. In IL6-JAK-STAT3-high (25.0%) conditions, upregulated ALB expression, enhanced gluconeogenesis and urea cycle activity, and an inflammatorymicroenvironment are observed. Conversely, the Wnt/β-catenin-high environment (19.9%) features elevated GLUL, APOB and CYP3A4 expression, frequent CTNNB1 (D32–S37) mutations, and an immune-desert/excluded phenotype. The “glycolysis” subclass (39.7%), characterized by histopathological dedifferentiation and downregulated liver-specific metabolism, encompasses subclasses with PI3K/mTOR (20.6%) and NOTCH/TGF-β (19.1%) signaling. These often exhibit TP53 mutations, macrotrabecular massive or compact patterns, inhomogeneous/rim-APHE, and high expression of hypoxia-inducible factors and glucose transporters, corresponding to Hoshida S1/2 with poor prognosis.
Conclusions
The loss of liver-specific metabolism correlates with morphological dedifferentiation, indicating cellular dedifferentiation may exhibit both physiological and pathological duality. Key signaling pathways involved in the maturation process from fetal to adult liver and zonation program may play a critical role in defining HCC diversity.

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Correspondence to editorial on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway”
Tomoko Aoki, Naoshi Nishida, Masatoshi Kudo
Clinical and Molecular Hepatology.2026; 32(1): e79. CrossRef
Molecular stratification of hepatocellular carcinoma by metabolic-signaling pathways guides precision immunotherapy and TACE therapy
Binghua Li, Yanchao Xu, Yican Zhu, Yukun Zhang, Zijie Wu, Tianci Luo, Laizhu Zhang, Weiwei Hu, Decai Yu
Clinical and Molecular Hepatology.2026; 32(1): e16. CrossRef
Reply to correspondence on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway”
Eun Ji Jang, Pil Soo Sung
Clinical and Molecular Hepatology.2026; 32(1): e115. CrossRef
A novel link between tumor cell metabolism and patient prognosis: Editorial on “Molecular classification of hepatocellular carcinoma based on zoned metabolic feature and oncogenic signaling pathway”
Eun Ji Jang, Pil Soo Sung
Clinical and Molecular Hepatology.2026; 32(1): 420. CrossRef
Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography: A Potential Imaging Biomarker for Predicting Response to Combination Immunotherapy in Hepatocellular Carcinoma
Masatoshi Kudo
Liver Cancer.2025; 14(5): 511. CrossRef

11,733 View
310 Download
5 Web of Science
Crossref

Review

Hepatic neoplasm

Current evidence and the potential role of proton beam therapy for hepatocellular carcinoma: Sung Uk Lee, Tae Hyun Kim; Clin Mol Hepatol 2023;29(4):958-968.
Published online August 29, 2023; DOI: https://doi.org/10.3350/cmh.2023.0274

Abstract
PDF

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, and external beam radiation therapy has emerged as a promising approach for managing HCC. Proton beam therapy (PBT) offers dosimetric advantages over X-ray therapy, with superior physical properties known as the Bragg peak. PBT holds promise for reducing hepatotoxicity and allowing safe dose-escalation to the tumor. It has been tried in various clinical conditions and has shown promising local tumor control and survival outcomes. A recent phase III trial demonstrated the non-inferiority of PBT in local tumor control compared to current standard radiofrequency ablation in early-stage HCC. PBT also tended to show more favorable outcomes compared to transarterial chemoembolization in the intermediate stage, and has proven effective in-field disease control and safe toxicity profiles in advanced HCC. In this review, we discuss the rationale, clinical studies, optimal indication, and future directions of PBT in HCC treatment.

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Takuto Nosaka, Ryotaro Sugata, Yosuke Murata, Yu Akazawa, Tomoko Tanaka, Kazuto Takahashi, Tatsushi Naito, Masahiro Ohtani, Kenji Takata, Tetsuya Tsujikawa, Yoshitaka Sato, Yoshikazu Maeda, Hiroyasu Tamamura, Yasunari Nakamoto
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Jingwen Zhang, Han Zhou, Benxin Zhao, Tian Liu, Chang Guo, Wenjing Fei, Zetian Shen
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Bo Liu, Yuan Xu, Xijie Zhang, Wei Qi, Bo Ren, Wenjia Kong, Wence Zhou
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Yidan Shen, Yiyang Sun, Yangla Xie, Yanpeng Liu, Zile Shao, Siyu Chen, Zhengxing Lian, Chang Xu, Fei Lv, Jinyi Tong, Youqing Shen, Nasha Qiu
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Original Article

Viral hepatitis

Hepatocellular carcinoma prediction model performance decreases with long-term antiviral therapy in chronic hepatitis B patients: Xiaoning Wu, Xiaoqian Xu, Jialing Zhou, Yameng Sun, Huiguo Ding, Wen Xie, Guofeng Chen, Anlin Ma, HongXin Piao, Bingqiong Wang, Shuyan Chen, Tongtong Meng, Xiaojuan Ou, Hwai-I Yang, Jidong Jia, Yuanyuan Kong, Hong You; Clin Mol Hepatol 2023;29(3):747-762.
Published online May 10, 2023; DOI: https://doi.org/10.3350/cmh.2023.0121

Background/Aims
Existing hepatocellular carcinoma (HCC) prediction models are derived mainly from pretreatment or early on-treatment parameters. We reassessed the dynamic changes in the performance of 17 HCC models in patients with chronic hepatitis B (CHB) during long-term antiviral therapy (AVT).
Methods
Among 987 CHB patients administered long-term entecavir therapy, 660 patients had 8 years of follow-up data. Model scores were calculated using on-treatment values at 2.5, 3, 3.5, 4, 4.5, and 5 years of AVT to predict threeyear HCC occurrence. Model performance was assessed with the area under the receiver operating curve (AUROC). The original model cutoffs to distinguish different levels of HCC risk were evaluated by the log-rank test.
Results
The AUROCs of the 17 HCC models varied from 0.51 to 0.78 when using on-treatment scores from years 2.5 to 5. Models with a cirrhosis variable showed numerically higher AUROCs (pooled at 0.65–0.73 for treated, untreated, or mixed treatment models) than models without (treated or mixed models: 0.61–0.68; untreated models: 0.51–0.59). Stratification into low, intermediate, and high-risk levels using the original cutoff values could no longer reflect the true HCC incidence using scores after 3.5 years of AVT for models without cirrhosis and after 4 years of AVT for models with cirrhosis.
Conclusions
The performance of existing HCC prediction models, especially models without the cirrhosis variable, decreased in CHB patients on long-term AVT. The optimization of existing models or the development of novel models for better HCC prediction during long-term AVT is warranted.

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Yaru Shi, Rong Fan
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Canadian Liver Journal.2025; 8(2): 402. CrossRef
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Carla Osiowy, Fernando Alvarez, Carla S Coffin, Curtis L Cooper, Scott K Fung, Hin Hin Ko, Sébastien Poulin, Jennifer van Gennip
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Reviews

Hepatic neoplasm

Utility of combining PIVKA-II and AFP in the surveillance and monitoring of hepatocellular carcinoma in the Asia-Pacific region: Do Young Kim, Bao Nguyen Toan, Chee-Kiat Tan, Irsan Hasan, Lyana Setiawan, Ming-Lung Yu, Namiki Izumi, Nguyen Nguyen Huyen, Pierce Kah-Hoe Chow, Rosmawati Mohamed, Stephen Lam Chan, Tawesak Tanwandee, Teng-Yu Lee, Thi Thanh Nguyen Hai, Tian Yang, Woo-Chang Lee, Henry Lik Yuen Chan; Clin Mol Hepatol 2023;29(2):277-292.
Published online January 30, 2023; DOI: https://doi.org/10.3350/cmh.2022.0212

Abstract
PDF

Even though the combined use of ultrasound (US) and alpha-fetoprotein (AFP) is recommended for the surveillance of hepatocellular carcinoma (HCC), the utilization of AFP has its challenges, including accuracy dependent on its cut-off levels, degree of liver necroinflammation, and etiology of liver disease. Though various studies have demonstrated the utility of protein induced by vitamin K absence II (PIVKA-II) in surveillance, treatment monitoring, and predicting recurrence, it is still not recommended as a routine biomarker test. A panel of 17 experts from Asia-Pacific, gathered to discuss and reach a consensus on the clinical usefulness and value of PIVKA-II for the surveillance and treatment monitoring of HCC, based on six predetermined statements. The experts agreed that PIVKA-II was valuable in the detection of HCC in AFP-negative patients, and could potentially benefit detection of early HCC in combination with AFP. PIVKA-II is clinically useful for monitoring curative and intra-arterial locoregional treatments, outcomes, and recurrence, and could potentially predict microvascular invasion risk and facilitate patient selection for liver transplant. However, combining PIVKA-II with US and AFP for HCC surveillance, including small HCC, still requires more evidence, whilst its role in detecting AFP-negative HCC will potentially increase as more patients are treated for hepatitis-related HCC. PIVKA-II in combination with AFP and US has a clinical role in the Asia-Pacific region for surveillance. However, implementation of PIVKA-II in the region will have some challenges, such as requiring standardization of cut-off values, its cost-effectiveness and improving awareness among healthcare providers.

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Crosstalk between tumor-associated macrophages and neighboring cells in hepatocellular carcinoma: Pil Soo Sung; Clin Mol Hepatol 2022;28(3):333-350.
Published online October 19, 2021; DOI: https://doi.org/10.3350/cmh.2021.0308

Abstract
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The tumor microenvironment generally shows a substantial immunosuppressive activity in hepatocellular carcinoma (HCC), accounting for the suboptimal efficacy of immune-based treatments for this difficult-to-treat cancer. The crosstalk between tumor cells and various cell types in the tumor microenvironment is strongly related to HCC progression and treatment resistance. Monocytes are recruited to the HCC tumor microenvironment by various factors and become tumor-associated macrophages (TAMs) with distinct phenotypes. TAMs often contribute to weakened tumor-specific immune responses and a more aggressive phenotype of malignancy. Recent single-cell RNA-sequencing data have demonstrated the central roles of specific TAMs in tumorigenesis and treatment resistance by their interactions with various cell populations in the HCC tumor microenvironment. This review focuses on the roles of TAMs and the crosstalk between TAMs and neighboring cell types in the HCC tumor microenvironment.

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Letter to the Editor

Hepatic neoplasm

Impact of branched-chain amino acids and frailty on the management of lenvatinib-related fatigue in patients with hepatocellular carcinoma: Shigeo Shimose, Shunji Koya, Takumi Kawaguchi, Keisuke Hirota, Sachiyo Yoshio, Takashi Niizeki, Hiroo Matsuse, Takuji Torimura; Clin Mol Hepatol 2021;27(4):616-619.
Published online September 13, 2021; DOI: https://doi.org/10.3350/cmh.2021.0258

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Editorial

Hepatic neoplasm

Microwave thermosphere versus radiofrequency ablation for hepatocellular carcinoma: Are we approaching the time to end the debate?: Man-Deuk Kim; Clin Mol Hepatol 2021;27(4):560-561.
Published online September 8, 2021; DOI: https://doi.org/10.3350/cmh.2021.0279

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Original Article

Hepatic neoplasm

New next-generation microwave thermosphere ablation for small hepatocellular carcinoma: Hideyuki Tamai, Jumpei Okamura; Clin Mol Hepatol 2021;27(4):564-574.
Published online August 2, 2021; DOI: https://doi.org/10.3350/cmh.2021.0136

Abstract
PDF

Background/Aims
In July 2017, the Emprint™ next-generation microwave ablation system using thermosphere technology (Covidien, Boulder, CO, USA) was approved for use in Japan. This system can produce a predictable spherical ablation zone at higher temperatures than radiofrequency ablation (RFA). The aim of the present study was to elucidate whether this new microwave thermosphere ablation (MTA) could safely improve outcome compared to RFA, which is the standard of care for small hepatocellular carcinoma (HCC).
Methods
This retrospective study analyzed 513 patients with 630 HCCs (≤3 cm) who were performed by percutaneous RFA (174 patients, 214 HCCs) or MTA (339 patients, 416 HCCs) between January 2016 and March 2020.
Results
Median ablation time was significantly shorter for MTA (240 seconds) than for RFA (721 seconds; P<0.001). A significant difference in 3-year local tumor progression rate was evident between the RFA group (22%) and MTA group (8%; P<0.001). Multivariable analysis revealed ablation procedure and tumor diameter as independent factors contributing to local tumor progression (MTA; P<0.001; hazard ratio, 0.565; 95% confidence interval, 0.437–0.731). In patients with primary HCC, a significant difference in overall survival was evident (RFA vs. MTA, 3-year, 77% vs. 95%, P=0.029). Ablation procedure and Child-Pugh score were independent factors contributing to survival. The total complication rate was significantly lower for MTA (8%) than for RFA (14%, P<0.05), particularly for bile duct injury (3% vs. 9%, respectively; P<0.05).
Conclusions
Next-generation MTA for small HCC could provide safer, more curative treatment in a shorter ablation time than RFA.

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Review

Viral hepatitis

Entecavir versus tenofovir in patients with chronic hepatitis B: Enemies or partners in the prevention of hepatocellular carcinoma: Sung Won Lee, Jonggi Choi, Seung Up Kim, Young-Suk Lim; Clin Mol Hepatol 2021;27(3):402-412.
Published online June 23, 2021; DOI: https://doi.org/10.3350/cmh.2021.0179

Abstract
PDF

Over the past several decades, entecavir (ETV) and tenofovir disoproxil fumarate (TDF) have remained the first-line antiviral agents in several international guidelines. These two antiviral agents have shown similar short to intermediateterm efficacy, including virologic, biochemical, serologic, and histologic responses. However, huge controversies regarding the antiviral efficacy of ETV and TDF in preventing the development of hepatocellular carcinoma (HCC) still exist. In this review, we summarized recent studies that compared the treatment efficacy of ETV and TDF in terms of HCC development.

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Bao‐Hong Yuan, Ru‐Hong Li, Rong‐Rui Huo, Min‐Jun Li, George Papatheodoridis, Jian‐Hong Zhong
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Hyung Joon Kim, Ju Hyun Kim, Jong Eun Yeon, Yeon Seok Seo, Jeong Won Jang, Yong Kyun Cho, Byoung Kuk Jang, Byung Hoon Han, Changhyeong Lee, Joon Hyeok Lee, Jung-Hwan Yoon, Kang Mo Kim, Moon Young Kim, Do Young Kim, Neung Hwa Park, Eun Young Cho, June Sung
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Byungyoon Yun, Sang Hoon Ahn, Juyeon Oh, Jin-Ha Yoon, Beom Kyung Kim
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Hankil Lee, Beom Kyung Kim
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Hye Yeon Chon, Sang Hoon Ahn, Yoon Jun Kim, Jung-Hwan Yoon, Jeong-Hoon Lee, Dong Hyun Sinn, Seung Up Kim
Hepatology International.2021; 15(6): 1328. CrossRef
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Jung Hyun Lim, Jung Hwan Yu, Young Ju Suh, Jin-Woo Lee, Young-Joo Jin
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Jae Seung Lee, Hyun Woong Lee, Tae Seop Lim, Hye Jung Shin, Hye Won Lee, Seung Up Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Beom Kyung Kim
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39 Web of Science
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Editorial

Viral hepatitis

Risk of hepatocellular carcinoma in untreated patients with chronic hepatitis B: Independent of HBeAg status?: Ho Soo Chun, Minjong Lee; Clin Mol Hepatol 2021;27(3):448-450.
Published online June 23, 2021; DOI: https://doi.org/10.3350/cmh.2021.0130

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Association of HBV serological markers with host antiviral immune response relevant hepatic inflammatory damage in chronic HBV infection
Bei Jiang, Leijie Wang, Huan Liu, Lin Wang, Rui Su, Liang Xu, Guochao Wei, Jia Li, Fengmin Lu, Xiangmei Chen
Journal of Medical Virology.2024;[Epub] CrossRef

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Original Article

Hepatic neoplasm

Serum fibrosis index-based risk score predicts hepatocellular carcinoma in untreated patients with chronic hepatitis B: Lilian Yan Liang, Hye Won Lee, Vincent Wai-Sun Wong, Terry Cheuk-Fung Yip, Yee-Kit Tse, Vicki Wing-Ki Hui, Grace Chung-Yan Lui, Henry Lik-Yuen Chan, Grace Lai-Hung Wong; Clin Mol Hepatol 2021;27(3):499-509.
Published online February 26, 2021; DOI: https://doi.org/10.3350/cmh.2020.0333

Background/Aims
Serum fibrosis scores comprised of common laboratory tests have high utility to assess severity of liver fibrosis. We aimed to derive and validate a hepatocellular carcinoma (HCC) risk score based on serum fibrosis scores to predict HCC in treatment-naïve chronic hepatitis B (CHB) patients.
Methods
Fifteen thousand one hundred eighty-seven treatment-naïve adult CHB patients were identified to form the training cohort in this retrospective study. Individual fibrosis score was included to construct a new HCC prediction score. The score was externally validated in an independent treatment-naïve Korean CHB cohort.
Results
180/15,187 patients (1.2%) in training cohort and 47/4,286 patients (1.1%) in validation cohort developed HCC during a mean follow-up of 52 and 50 months, respectively. The newly developed HCC risk score, Liang score, is composed of gender, age, hepatitis B virus DNA, fibrosis-4 (FIB-4) index, and ranges from 0 to 22. Area under the time-dependent receiver operating characteristic curve of Liang score was 0.79 (95% confidence interval, 0.70–0.89). A cutoff value of nine provided an extremely high negative predictive value of 99.9% and high sensitivity of 90.0% at 5 years in the validation cohort. Patients with Liang score ≤9 had HCC incidence <0.2% per year in both training and validation cohorts, in whom HCC surveillance might be exempted.
Conclusion
A novel HCC risk score, Liang score, based on FIB-4 index, is applicable and accurate to identify treatment-naïve CHB patients with very low risk of HCC to be exempted from HCC surveillance.

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Yixin Hou, Jianguo Yan, Ke Shi, Xiaoli Liu, Fangyuan Gao, Tong Wu, Peipei Meng, Min Zhang, Yuyong Jiang, Xianbo Wang
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Xue Cong, Shuyao Song, Yingtao Li, Kaiyang Song, Cameron MacLeod, Yujie Cheng, Jun Lv, Canqing Yu, Dianjianyi Sun, Pei Pei, Ling Yang, Yiping Chen, Iona Millwood, Shukuan Wu, Xiaoming Yang, Rebecca Stevens, Junshi Chen, Zhengming Chen, Liming Li, Christia
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Post-operative recurrence of liver cancer according to antiviral therapy for detectable hepatitis B viremia: A nationwide study
Byungyoon Yun, Sang Hoon Ahn, Juyeon Oh, Jin-Ha Yoon, Beom Kyung Kim
European Journal of Internal Medicine.2023; 107: 66. CrossRef
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Byungyoon Yun, Juyeon Oh, Sang Hoon Ahn, Jin-Ha Yoon, Beom Kyung Kim
American Journal of Gastroenterology.2023; 118(6): 1001. CrossRef
Statin use is associated with better post‐operative prognosis among patients with hepatitis B virus‐related hepatocellular carcinoma
Byungyoon Yun, Sang Hoon Ahn, Juyeon Oh, Jin‐Ha Yoon, Beom Kyung Kim
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Han Ah Lee, Seung Up Kim, Yeon Seok Seo, Sang Hoon Ahn, Chai Hong Rim
Hepatology Communications.2023; 7(2): e0011. CrossRef
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Hepatology.2023; 77(5): 1746. CrossRef
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Beom Kyung Kim, Sang Hoon Ahn
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Supinya Sono, Jirayu Sae-Chan, Apichat Kaewdech, Naichaya Chamroonkul, Pimsiri Sripongpun, Jason T. Blackard
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Kai Liu, Zeyu Huang, Suhua Yang, Lin Lin, Shuqin Zheng, Xiujun Zhang, Yuan Xue, Weibin Xie
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Bo Hyun Kim, Yuri Cho, Joong-Won Park
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Jae Lee, Tae Lim, Hye Lee, Seung Kim, Jun Park, Do Kim, Sang Ahn, Hyun Lee, Jung Lee, Ja Kim, In Min, Beom Kim
Diagnostics.2022; 13(1): 3. CrossRef
Risk of hepatocellular carcinoma in untreated patients with chronic hepatitis B: Independent of HBeAg status?
Ho Soo Chun, Minjong Lee
Clinical and Molecular Hepatology.2021; 27(3): 448. CrossRef

8,871 View
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Editorials

Viral hepatitis

Old hepatitis B virus never dies: It just hides itself within the host genome: Jeong-Hoon Lee; Clin Mol Hepatol 2021;27(1):107-109.
Published online December 23, 2020; DOI: https://doi.org/10.3350/cmh.2020.0324

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A machine learning model for predicting hepatocellular carcinoma risk in patients with chronic hepatitis B
Hye Won Lee, Hwiyoung Kim, Taeyun Park, Soo Young Park, Young Eun Chon, Yeon Seok Seo, Jae Seung Lee, Jun Yong park, Do Young Kim, Sang Hoon Ahn, Beom Kyung Kim, Seung Up Kim
Liver International.2023; 43(8): 1813. CrossRef
Translational Strategies to Eliminate Chronic Hepatitis B in Children: Prophylaxis and Management in East Asian Countries
Ben Kang, Dae Yong Yi, Byung-Ho Choe
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Association of Physical Activity with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B
Ho Soo Chun, Sojeong Park, Minjong Lee, Yuri Cho, Ha Sung Kim, A Reum Choe, Hwi Young Kim, Kwon Yoo, Tae Hun Kim
Cancers.2021; 13(14): 3424. CrossRef

6,677 View
122 Download
5 Web of Science
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Hepatic neoplasm

Exploring the mythical abscopal effect: Radiation and programmed cell death protein 1 (PD-1) blockade for hepatocellular carcinoma: Jun Won Kim, Ik Jae Lee; Clin Mol Hepatol 2021;27(1):103-106.
Published online December 14, 2020; DOI: https://doi.org/10.3350/cmh.2020.0297

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Exploiting the immune system in hepatic tumor targeting: Unleashing the potential of drugs, natural products, and nanoparticles
Chou-Yi Hsu, Mohammed Ahmed Mustafa, Ashwani Kumar, Atreyi Pramanik, Rajiv Sharma, Faraj Mohammed, Israa Abed Jawad, Imad Jasim Mohammed, Mohammad Y. Alshahrani, Noor Alhuda Mohammad Ali khalil, Ali Turki Shnishil, Munther Kadhim Abosaoda
Pathology - Research and Practice.2024; 256: 155266. CrossRef

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Original Articles

Significant down-regulation of growth hormone receptor expression revealed as a new unfavorable prognostic factor in hepatitis C virus-related hepatocellular carcinoma: Ching-Chih Lin, Ta-Wei Liu, Ming-Lun Yeh, Yi-Shan Tsai, Pei-Chien Tsai, Chung-Feng Huang, Jee-Fu Huang, Wan-Long Chuang, Chia-Yen Dai, Ming-Lung Yu; Clin Mol Hepatol 2021;27(2):313-328.
Published online December 14, 2020; DOI: https://doi.org/10.3350/cmh.2020.0247

Background/Aims
Growth hormone (GH) is the main regulator of somatic growth, metabolism, and gender dimorphism in the liver. GH receptor (GHR) signaling in cancer is derived from a large body of evidence, although the GHR signaling pathway involved in the prognosis of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related HCC, remains unclear. We aimed to explore the expression of GHR and analyze its association with clinicopathologic features and prognosis of patients with chronic hepatitis C and HCC.
Methods
The expression of GHR mRNA was investigated by quantitative real-time polymerase chain reaction in paired tumors and adjacent non-tumorous (ANT) liver tissues of 200 patients with chronic hepatitis C and HCC. Western blotting and immunofluorescence assays using the HCV-infected Huh7.5.1 cell model was performed.
Results
GHR mRNA was significantly lower in HCV-HCC tissues than in corresponding ANT liver tissues. GHR mRNA and protein levels also decreased in the HCV-infected Huh7.5.1 cell model. Notably, lower GHR expression was associated with age of >60 years (P=0.0111) and worse clinicopathologic characteristics, including alpha-fetoprotein >100 ng/mL (P=0.0403), cirrhosis (P=0.0075), vascular invasion (P=0.0052), pathological stage II–IV (P=0.0002), and albumin ≤4.0 g/dL (P=0.0055), which were linked with poor prognosis of HCC. Most importantly, the high incidence of recurrence and poor survival rates in patients with a low ratio of tumor/ANT GHR (≤0.1) were observed, indicating that low expression levels of GHR had great risk for development of HCC in patients with chronic hepatitis C.
Conclusions
Our study demonstrates a significant down-regulation of GHR expression as a new unfavorable independent prognostic factor in patients with chronic hepatitis C and HCC.

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Mo-Han Liu, Fu-Yong Zhang, Yuan-Jun Huang, Zhi-Hua Jiang, Qin-Yan Chen, Lu-Juan Zhang, Li-Ping Hu, Zhong-Liao Fang
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Jialin Qu, Fenghao Sun, Yichen Hou, Haoran Qi, Xiaorong Sun, Ligang Xing
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Yue Wang, Minah Kim, Chantal Buckley, Heather D. Maynard, Ries J. Langley, Jo K. Perry
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Baozhu Zhang, Boyang Chang, Lu Wang, Yuzhong Xu
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Takahiro Kodama, Michiko Kodama, Nancy A. Jenkins, Neal G. Copeland, Huanhuan Joyce Chen, Zhubo Wei
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Yuanyuan Guo, Jing Yang, Hua Gao, Xin Tian, Xiaojian Zhang, Quancheng Kan
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Mona A. Abu El-Makarem, Mariana F. Kamel, Ahmed A. Mohamed, Hisham A. Ali, Mahmoud R. Mohamed, Alaa El-Deen M. Mohamed, Ahmed M. El-Said, Mahmoud G. Ameen, Alshymaa A. Hassnine, Hatem A. Hassan, Gianfranco D. Alpini
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Hepatic neoplasm

Radiation-induced abscopal effect and its enhancement by programmed cell death 1 blockade in the hepatocellular carcinoma: A murine model study: Gyu Sang Yoo, Won-Gyun Ahn, Shin-Yeong Kim, Wonseok Kang, Changhoon Choi, Hee Chul Park; Clin Mol Hepatol 2021;27(1):144-156.
Published online December 7, 2020; DOI: https://doi.org/10.3350/cmh.2020.0095

Background/Aims
The abscopal effect, a rare phenomenon induced by radiation, can be reinforced by immunotherapy. Although radiation therapy and immunotherapy are increasingly being utilized for the treatment of hepatocellular carcinoma (HCC), whether immunotherapy could boost the abscopal effect remains unclear. In this study, we aimed to elucidate the immunological mechanisms underlying the abscopal effect induced by the combination of irradiation and immunotherapy in a murine HCC model.
Methods
A syngeneic HCC mouse model was established by transplanting murine Hepa 1–6 HCC cells into both hind legs of immunocompetent C57BL/6 mice. The tumors on the right hind legs were irradiated, and abscopal effects were observed in the non-irradiated tumors on the left hind leg with or without the coadministration of anti-programmed cell death 1 (PD-1) antibodies. Flow cytometric analyses were performed to analyze the distributions of immune cells infiltrating both irradiated and non-irradiated tumors and the tumor-draining lymph nodes (TDLNs).
Results
Administration of 16 Gy in two fractions more effectively inhibited the growth of both irradiated and nonirradiated tumors with higher tumor infiltration of cytotoxic T cells than 8 Gy did in a single fraction. The higher dose also increased activated dendritic cells in TDLNs, which had higher expression of the programmed cell death ligand 1. Coadministration of anti-PD-1 antibodies significantly enhanced the abscopal effect and increased infiltration of activated cytotoxic T cells in both irradiated and non-irradiated tumors.
Conclusions
Our findings show that adding anti-PD-1 therapy to radiation enhanced the abscopal effect in a syngeneic murine model of HCC.

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Editorial

Hepatic neoplasm

Metabolic disease as a risk of hepatocellular carcinoma: Naoshi Nishida; Clin Mol Hepatol 2021;27(1):87-90.
Published online December 3, 2020; DOI: https://doi.org/10.3350/cmh.2020.0302

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Original Article

Negligible risks of hepatocellular carcinoma during biomarker-defined immune-tolerant phase for patients with chronic hepatitis B: Mi Young Jeon, Beom Kyung Kim, Jae Seung Lee, Hye Won Lee, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han, Seung Up Kim; Clin Mol Hepatol 2021;27(2):295-304.
Published online December 3, 2020; DOI: https://doi.org/10.3350/cmh.2020.0216

Background/Aims
The immune-tolerant (IT) phase of chronic hepatitis B (CHB) patients is not generally indicative of antiviral therapy (AVT). We assessed and compared the risk of hepatocellular carcinoma (HCC) during the IT-phase stringently defined by a low fibrosis-4 (FIB-4) index, compared to that in patients undergoing AVT.
Methods
Among 125 untreated patients that were hepatitis B e-antigen positive, hepatitis B virus-DNA >20,000 IU/mL, with normal alanine aminotransferase level from 2012 to 2018, those with a FIB-4 index of <1.45 were classified into the IT-group. The cumulative probability of HCC was estimated using Kaplan-Meier analysis. All patients were assessed until HCC development (intention-to-treat [ITT] analysis), whereas those suspected of experiencing CHB phase switch were assessed using the per-protocol (PP) and censored at the time of phase switch.
Results
The cumulative probability of HCC at 1-, 3-, and 5-years among the IT-group was zero, compared to AVT-treated patients with FIB-4 indices <1.45 during the same period: 0.2%, 0.6%, and 1.4%, respectively (P=0.264 for ITT and P=0.533 for PP). Among the initially screened 125 untreated patients, those with a FIB-4 index of ≥1.45 had a higher risk of HCC compared to the IT-group (P=0.005). Furthermore, among AVT-treated patients, those with a FIB-4 index of ≥1.45 had a higher risk of HCC compared to their counterpart (P<0.001).
Conclusions
The risk of HCC was negligible in the IT-group stringently defined by a low FIB-4 index. However, given that a higher HCC risk exists among untreated patients with higher FIB-4, appropriate criteria for AVT should be established.

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Review

Hepatic neoplasm

Optimizing the management of intermediate-stage hepatocellular carcinoma: Current trends and prospects: Takuji Torimura, Hideki Iwamoto; Clin Mol Hepatol 2021;27(2):236-245.
Published online December 3, 2020; DOI: https://doi.org/10.3350/cmh.2020.0204

Abstract
PDF

Hepatocellular carcinoma (HCC) is usually accompanied by chronic liver damage, which sometimes influences the selection of HCC treatment. The Barcelona Clinic Liver Cancer (BCLC) staging system, which was first introduced in 1999, is the most commonly used worldwide. Although the intermediate-stage (BCLC stage B) includes the largest number and heterogeneous HCC patients, the recommended treatment option is transarterial chemoembolization (TACE) only. However, recent progress in radical treatments such as hepatic resection, liver transplantation, radiation therapy, and percutaneous therapy has made it possible to treat selected patients with BCLC stage B HCC. Radical treatments are expected to prolong survival time. To-date, TACE has also progressed. In addition to conventional TACE, balloon-occluded TACE and drug-eluting beads TACE are available. These new modalities of TACE will improve therapeutic efficacy and reduce adverse events. One of the most serious concerns of TACE is that repeated TACE reduces the treatment effect and induces liver function impairment. The decision on when TACE should be interrupted is complex. Many molecular targeted agents are now available, and immune checkpoint inhibitors will soon be available for HCC patients with Child-Pugh class A worldwide. Under these circumstances, in patients with TACE unsuitability, switching to molecular targeted agents before deterioration of liver function might improve the prognosis compared to repeated TACE. We should pay attention to stop TACE in TACE-unsuitable HCC patients as it can induce the deterioration of liver function.

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Original Article

Hepatic neoplasm

Obesity and the risk of primary liver cancer: A systematic review and meta-analysis: Won Sohn, Hyun Woong Lee, Sangheun Lee, Jin Hong Lim, Min Woo Lee, Chan Hyuk Park, Seung Kew Yoon; Clin Mol Hepatol 2021;27(1):157-174.
Published online November 26, 2020; DOI: https://doi.org/10.3350/cmh.2020.0176

Background/Aims
In this systematic review and meta-analysis, we aimed to clarify the effect of obesity on the occurrence of and mortality from primary liver cancer.
Methods
This study was conducted using a systematic literature search of MEDLINE, EMBASE, and the Cochrane Library until November 2018 using the primary keywords “obesity,” “overweight,” “body mass index (BMI),” “body weight,” “liver,” “cancer,” “hepatocellular carcinoma,” “liver cancer,” “risk,” and “mortality.” Studies assessing the relationship between BMI and occurrence of or mortality from primary liver cancer in prospective cohorts and those reporting hazard ratios (HRs) or data that allow HR estimation were included.
Results
A total of 28 prospective cohort studies with 8,135,906 subjects were included in the final analysis. These included 22 studies with 6,059,561 subjects for cancer occurrence and seven studies with 2,077,425 subjects for cancerrelated mortality. In the meta-analysis, an increase in BMI was associated with the occurrence of primary liver cancer (HR, 1.69; 95% confidence interval, 1.50–1.90, I²=56%). A BMI-dependent increase in the risk of occurrence of primary liver cancer was reported. HRs were 1.36 (95% CI, 1.02–1.81), 1.77 (95% CI, 1.56–2.01), and 3.08 (95% CI, 1.21–7.86) for BMI >25 kg/m², >30 kg/m², and >35 kg/m², respectively. Furthermore, increased BMI resulted in enhanced liver cancer-related mortality (HR, 1.61; 95% CI, 1.14–2.27, I²=80%).
Conclusions
High BMI increases liver cancer mortality and occurrence of primary liver cancer. Obesity is an independent risk factor for the occurrence of and mortality from primary liver cancer.

Citations

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Editorial

Nutritional and Metabolic liver disease

Sarcopenia and blood myokine levels as prognostic biomarkers in patients with liver cirrhosis or hepatocellular carcinoma: Sooyeon Oh, Jooho Lee; Clin Mol Hepatol 2020;26(4):476-479.
Published online October 1, 2020; DOI: https://doi.org/10.3350/cmh.2020.0192

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Special topic: Alcoholic liver diseases
The 14th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis (ISALPDC)

Hepatic neoplasm

Hepatic Hippo signaling inhibits development of hepatocellular carcinoma: Yuchen Liu, Xiaohui Wang, Yingzi Yang; Clin Mol Hepatol 2020;26(4):742-750.
Published online September 28, 2020; DOI: https://doi.org/10.3350/cmh.2020.0178

Abstract
PDF

Primary liver cancer is one of the most common cancer worldwide. Hepatocellular carcinoma (HCC) in particular, is the second leading cause of cancer deaths in the world. The Hippo signaling pathway has emerged as a major oncosuppressive pathway that plays critical roles inhibiting hepatocyte proliferation, survival, and HCC formation. A key component of the Hippo pathway is the inhibition of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcription factors by the Hippo kinase cascade. Aberrant activation of YAP or TAZ has been found in several human cancers including HCC. It is also well established that YAP/TAZ activation in hepatocytes causes HCC in mouse models, indicating that YAP/TAZ are potential therapeutic targets for human liver cancer. In this review, we summarize the recent findings regarding the multifarious roles of Hippo/YAP/TAZ in HCC development, and focus on their cell autonomous roles in controlling hepatocyte proliferation, differentiation, survival and metabolism as well as their non-cell autonomous in shaping the tumor microenvironment.

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Editorial

Hepatic neoplasm

Long-term prognosis and management of hepatocellular carcinoma after curative treatment: Naoshi Nishida; Clin Mol Hepatol 2020;26(4):480-483.
Published online September 21, 2020; DOI: https://doi.org/10.3350/cmh.2020.0208

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Original Articles

Hepatic neoplasm

Substantial risk of recurrence even after 5 recurrence-free years in early-stage hepatocellular carcinoma patients: Jihye Kim, Wonseok Kang, Dong Hyun Sinn, Geum-Youn Gwak, Yong-Han Paik, Moon Seok Choi, Joon Hyeok Lee, Kwang Cheol Koh, Seung Woon Paik; Clin Mol Hepatol 2020;26(4):516-528.
Published online September 11, 2020; DOI: https://doi.org/10.3350/cmh.2020.0016

Background/Aims
Although hepatocellular carcinoma (HCC) is notorious for its high recurrence rate, some patients do not experience recurrence for more than 5 years after resection or radiofrequency ablation for early-stage HCC. For those with five recurrence-free period, the risk of HCC recurrence within the next 5 years remains unknown.
Methods
A total of 1,451 consecutive patients (median, 55 years old; males, 79.0%; hepatitis B virus-related, 79.3%) with good liver function (Child-Pugh class A) diagnosed with early-stage HCC by Barcelona Clinic Liver Cancer Staging and received radiofrequency ablation or resection as an initial treatment between 2005 and 2010 were analyzed.
Results
During a median follow-up period of 8.1 years, 961 patients (66.2%) experienced HCC recurrence. The cumulative recurrence rates increased to 39.7%, 60.3%, and 71.0% at 2, 5, and 10 years, respectively, and did not reach a plateau. Five years after HCC diagnosis, 487 patients were alive without experiencing a recurrence. Among them, during a median of 3.9 additional years of follow-up (range, 0.1–9.0 years), 127 patients (26.1%) experienced recurrence. The next 5-year cumulative recurrence rate (5–10 years from initial diagnosis) was 27.0%. Male sex, higher fibrosis-4 scores, and alpha-fetoprotein levels at 5 years were associated with later HCC recurrence among patients who did not experience recurrence for more than 5 years.
Conclusions
The HCC recurrence rate following 5 recurrence-free years after HCC treatment was high, indicating that HCC patients warrant continued HCC surveillance, even after 5 recurrence-free years.

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Hepatic neoplasm

Inhibition of PI3K/Akt signaling suppresses epithelial-to-mesenchymal transition in hepatocellular carcinoma through the Snail/GSK-3/beta-catenin pathway: Seulki Lee, Eun Ji Choi, Eun Ju Cho, Yun Bin Lee, Jeong-Hoon Lee, Su Jong Yu, Jung-Hwan Yoon, Yoon Jun Kim; Clin Mol Hepatol 2020;26(4):529-539.
Published online August 24, 2020; DOI: https://doi.org/10.3350/cmh.2019.0056n

Abstract
PDF

Background/Aims
Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis due to the lack of effective systemic therapies. Epithelial-to-mesenchymal transition (EMT) is a pivotal event in tumor progression, during which cancer cells acquire invasive properties. In this study, we investigated the effects of phosphatidylinositol 3-kinase (PI3K) inhibitors, including LY294002 and idelalisib, on the EMT features of HCC cells in vitro.
Methods
Human HCC cell lines, including Huh-BAT and HepG2, were used in this study. Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, and cell cycle distributions were evaluated using a flow cytometer by propidium iodide staining. Immunofluorescence staining, quantitative real-time polymerase chain reaction, and immunoblotting were performed to detect EMT-associated changes.
Results
PI3K inhibitors suppressed the proliferation and invasion of HCC cells and deregulated the expression of EMT markers, as indicated by increased expression of E-cadherin, an epithelial marker, and decreased expression of N-cadherin, a mesenchymal marker, and Snail, a transcription factor implicated in EMT regulation. Furthermore, LY294002 and idelalisib inhibited the phosphorylation of GSK-3β and induced the nuclear translocation of GSK-3β, which corresponded to the downregulation of Snail and β-catenin expressions in Huh-BAT and HepG2 cells.
Conclusions
The inhibition of PI3K/Akt signaling decreases Snail expression by enhancing the nuclear translocation of GSK-3β, which suppresses EMT in HCC cells, suggesting the potential clinical application of PI3K inhibitors for HCC treatment.

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Hepatic neoplasm

Stereotactic body radiation therapy for small (≤5 cm) hepatocellular carcinoma not amenable to curative treatment: Results of a single-arm, phase II clinical trial: Sang Min Yoon, So Yeon Kim, Young-Suk Lim, Kang Mo Kim, Ju Hyun Shim, Danbi Lee, Jihyun An, Jinhong Jung, Jong Hoon Kim, Han Chu Lee; Clin Mol Hepatol 2020;26(4):506-515.
Published online July 10, 2020; DOI: https://doi.org/10.3350/cmh.2020.0038

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.
Conclusions
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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Hepatic neoplasm

Optimal sequence of systemic therapy after sorafenib failure in patients with hepatocellular carcinoma: Sojung Han, Do Young Kim; Clin Mol Hepatol 2020;26(3):305-308.
Published online July 1, 2020; DOI: https://doi.org/10.3350/cmh.2020.0096

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Cancers.2020; 12(11): 3347. CrossRef

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Original Articles

Hepatic neoplasm

Comparison of LI-RADS 2018 and KLCA-NCC 2018 for noninvasive diagnosis of hepatocellular carcinoma using magnetic resonance imaging: Sunyoung Lee, Seung-seob Kim, Dong ryul Chang, Hyerim Kim, Myeong-Jin Kim; Clin Mol Hepatol 2020;26(3):340-351.
Published online June 4, 2020; DOI: https://doi.org/10.3350/cmh.2020.0004

Background/Aims
This study aimed to compare the diagnostic performances of Liver Imaging Reporting and Data System (LI-RADS) 2018 and Korean Liver Cancer Association-National Cancer Center (KLCA-NCC) 2018 criteria on magnetic resonance imaging (MRI) for the noninvasive diagnosis of hepatocellular carcinoma (HCC) in high-risk patients.
Methods
This retrospective study included 273 treatment-naïve patients (71 patients with extracellular contrast agent [ECA]-MRI and 202 patients with hepatobiliary agent [HBA]-MRI; 352 lesions including 263 HCCs) with high risk of HCC who underwent contrast-enhanced MRI between 2016 and 2017. Two readers evaluated all lesions according to the criteria of LI-RADS 2018 and KLCA-NCC 2018. The per-lesion diagnostic performances were compared using the generalized estimating equation method.
Results
On ECA-MRI, the sensitivity and specificity of LI-RADS 2018 and KLCA-NCC 2018 were not significantly different (LR-5 vs. definite HCC: 75.8% vs. 69.4%, P=0.095 and 95.8% vs. 95.8%, P>0.999; LR-5/4 vs. definite/probable HCC: 87.1% vs.83.9%, P=0.313 and 87.5% vs. 91.7%, P=0.307). On HBA-MRI, definite HCC of KLCA-NCC 2018 showed significantly higher sensitivity (79.1% vs. 68.2%, P<0.001) than LR-5 of LI-RADS 2018 without a significant difference in specificity (93.9% vs. 95.4%, P=0.314). Definite/probable HCC of KLCA-NCC 2018 had higher specificity (92.3% vs. 80.0%, P=0.003) than LR-5/4 of LI-RADS 2018. The sensitivity was lower for definite/probable HCC than for LR-5/4 without statistical significance (85.6% vs. 88.1%, P=0.057).
Conclusions
On ECA-MRI, LI-RADS 2018 and KLCA-NCC 2018 showed comparable diagnostic performances. On HBA-MRI, definite HCC of KLCA-NCC 2018 provided better sensitivity than LR-5 category of LI-RADS 2018 without compromising the specificity, while definite/probable HCC of KLCA-NCC 2018 revealed higher specificity than LR-5/4 of LI-RADS 2018 for diagnosing HCC.

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Viral hepatitis

Low-level viremia and cirrhotic complications in patients with chronic hepatitis B according to adherence to entecavir: Seung Bum Lee, Joonho Jeong, Jae Ho Park, Seok Won Jung, In Du Jeong, Sung-Jo Bang, Jung Woo Shin, Bo Ryung Park, Eun Ji Park, Neung Hwa Park; Clin Mol Hepatol 2020;26(3):364-375.
Published online May 29, 2020; DOI: https://doi.org/10.3350/cmh.2020.0012

Background/Aims
Low-level viremia (LLV) after nucleos(t)ide analog treatment was presented as a possible cause of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). However, detailed information on patients’ adherence in the real world was lacking. This study aimed to evaluate the effects of LLV on HCC development, mortality, and cirrhotic complications among patients according to their adherence to entecavir (ETV) treatment.
Methods
We performed a retrospective observational analysis of data from 894 consecutive adult patients with treatment-naïve CHB undergoing ETV treatment. LLV was defined according to either persistent or intermittent episodes of <2,000 IU/mL detectable hepatitis B virus DNA during the follow-up period. Good adherence to medication was defined as a cumulative adherence ≥90% per study period.
Results
Without considering adherence in the entire cohort (n=894), multivariate analysis of the HCC incidence showed that LLV was an independent prognostic factor in addition to other traditional risk factors in the entire cohort (P=0.031). Good adherence group comprised 617 patients (69.0%). No significant difference was found between maintained virologic response and LLV groups in terms of the incidence of liver-related death or transplantation, HCC, and hepatic decompensation in good adherence group, according to multivariate analyses.
Conclusions
In patients with treatment-naïve CHB and good adherence to ETV treatment in the real world, LLV during treatment is not a predictive factor for HCC and cirrhotic complications. It may be unnecessary to adjust their antiviral agent for patients with good adherence who experience LLV during ETV treatment.

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Review

Hepatic neoplasm

Switching to systemic therapy after locoregional treatment failure: Definition and best timing: Sadahisa Ogasawara, Yoshihiko Ooka, Keisuke Koroki, Susumu Maruta, Hiroaki Kanzaki, Kengo Kanayama, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Tomoko Saito, Takayuki Kondo, Eiichiro Suzuki, Shingo Nakamoto, Akinobu Tawada, Tetsuhiro Chiba, Makoto Arai, Jun Kato, Naoya Kato; Clin Mol Hepatol 2020;26(2):155-162.
Published online January 15, 2020; DOI: https://doi.org/10.3350/cmh.2019.0021n

Abstract
PDF

In patients with unresectable hepatocellular carcinoma (HCC) without both macrovascular invasion and extrahepatic metastasis, the initial treatment choice recommended is transarterial chemoembolization (TACE). Before sorafenib came into wide use, TACE had been pointlessly carried out repeatedly. It was in the early 2010s that the concept of TACE refractory was advocated. Two retrospective studies from Japan indicated that conversion from TACE to sorafenib the day after patients were deemed as TACE refractory improved overall survival compared with continued TACE, according to the definition by the Japan Society of Hepatology. Nowadays, phase 3 trials have shown clinical benefits of several novel molecular target agents. Compared with the era of sorafenib, sequential treatments with these molecular target agents have gradually prolonged patients’ survival and have become major strategies in patients with HCC. Taking these together, conversion from TACE to systemic therapies at the time of TACE refractory, compared with before, may have a greater impact on survival and may be considered deeper in the decisions-making process in patients with unresectable HCC who are candidate for TACE. Up-to-date information on the concept of TACE refractory is summarized in this review. We believe that the survival of patients with unresectable HCC without both macrovascular invasion and extrahepatic metastasis may be dramatically improved by optimal timing of TACE refractory and switching to systemic therapies.

Citations

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Original Articles

Hepatic neoplasm

Comparisons between non-alcoholic steatohepatitis and alcohol-related hepatocellular carcinoma: Rahul Kumar, Boon-Bee George Goh, Jia-Wen Kam, Pik-Eu Chang, Chee-Kiat Tan; Clin Mol Hepatol 2020;26(2):196-208.
Published online January 9, 2020; DOI: https://doi.org/10.3350/cmh.2019.0012

Abstract
PDF

Background/Aims
Non-alcoholic liver disease and alcoholic liver disease begin as simple steatosis that may progress to steatohepatitis and ensuing liver-related complications such as cirrhosis and hepatocellular carcinoma (HCC). We explored differences in characteristics between non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis-related (ASH) HCC.
Methods
NASH and ASH patients were identified from our department’s prospective HCC database. A total of 54 and 45 patients met predefined inclusion and exclusion criteria for the NASH-HCC and ASH-HCC groups, respectively. Clinical, biochemical and tumor characteristics were studied.
Results
NASH-HCC patients were older compared to ASH-HCC patients (72±9 vs. 66±9 years, P<0.001) and less male predominant (65% vs. 98%, P<0.001). Prevalence of diabetes mellitus (78% vs. 36%, P<0.001) and hypertension (80% vs. 58%, P<0.001) were significantly higher in the NASH-HCC group. Liver function tests and Child-Pugh scores were similar. There were no differences in alpha-fetoprotein level, lesions found at diagnosis (unifocal/multifocal) or prevalence of portal vein invasion. In both groups, almost half of the patients were in TNM stage 4 at the time of diagnosis and more than 50% of patients were not suitable for any therapy. Median survival in the NASH-HCC and ASH-HCC groups were 13 and 7 months respectively (P=0.113).
Conclusions
Despite significant differences in demography of the NASH-HCC and ASH-HCC groups, liver and tumor characteristics were comparable. Most patients were diagnosed late and were not amenable to curative or locoregional therapies. Better characterization of patients with NASH and ASH at risk of HCC is necessary to optimize screening, surveillance, and management strategies.

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Hepatic neoplasm

Vimentin as a potential therapeutic target in sorafenib resistant HepG2, a HCC model cell line: Ankita Makol, Harpreet Kaur, Sakshi Sharma, Shruthi Kanthaje, Ramanpreet Kaur, Anuradha Chakraborti; Clin Mol Hepatol 2020;26(1):45-53.
Published online September 30, 2019; DOI: https://doi.org/10.3350/cmh.2019.0031

Background/Aims
Hepatocellular carcinoma (HCC) is the most common liver cancer with high mortality rate in patients suffering from liver diseases. The drug of choice used in advanced-stage of HCC is sorafenib. However, adaptive resistance has been observed in HCC patients undergoing long-term sorafenib treatment, lowering its effectiveness. Hence, it is important to overcome drug resistance to improve overall management of HCC. Here, we have identified a candidate biomarker for sorafenib resistance in a HCC model cell line, HepG2.
Methods
Initially, comparative proteomic profiling of parental HepG2 [HepG2 (P)] and sorafenib-resistant HepG2 [HepG2 (R)] cells was performed via MALDI (matrix-assisted laser desorption/ionization) which revealed the deregulation of vimentin in HepG2 (R) cells. Gene and protein level expression of vimentin was also observed through quantitative real-time polymerase chain reaction (qRT PCR) and fluorescence-activated cell sorting (FACS), respectively. Furthermore, withaferin A was used to study regulation of vimentin expression and its significance in sorafenib resistance.
Results
Both gene and protein level of vimentin expression was found to be downregulated in HepG2 (R) in comparison to HepG2 (P). Interestingly, the study demonstrated that withaferin A further lowered the expression of vimentin in HepG2 (R) cells in a dose-dependent manner. Also, inhibition of vimentin lowered ABCG2 expression and decreased cell viability in parental as well as sorafenib resistant HepG2 cells.
Conclusions
Hence, our study for the first time highlighted the probable therapeutic potential of vimentin in sorafenib resistant HepG2, a HCC model cell line.

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Hong Xiao, Hangyu Chen, Lei Zhang, Maimaitiyasen Duolikun, Baixin Zhen, Subinuer Kuerban, Xuehui Li, Yuxi Wang, Long Chen, Jian Lin
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Hepatic neoplasm

Bi-monthly hepatic arterial infusion chemotherapy as a novel strategy for advanced hepatocellular carcinoma in decompensated cirrhotic patients: Kei Moriya, Tadashi Namisaki, Shinya Sato, Masanori Furukawa, Akitoshi Douhara, Hideto Kawaratani, Kosuke Kaji, Naotaka Shimozato, Yasuhiko Sawada, Soichiro Saikawa, Hiroaki Takaya, Koh Kitagawa, Takemi Akahane, Akira Mitoro, Junichi Yamao, Hitoshi Yoshiji; Clin Mol Hepatol 2019;25(4):381-389.
Published online August 13, 2019; DOI: https://doi.org/10.3350/cmh.2019.0037

Abstract
PDF

Background and Aim
We previously reported the comparable efficacy of bi-monthly hepatic arterial infusion chemotherapy (B-HAIC) to that of sorafenib chemotherapy for the treatment of advanced hepatocellular carcinoma (aHCC) in patients with compensated cirrhosis. In this study, we demonstrate the efficacy of B-HAIC in patients with decompensated cirrhosis.
Methods
Forty-five patients with aHCC refractory to transcatheter arterial chemo-embolization (TACE) were treated with B-HAIC and were divided into two groups according to hepatic functional reserve (Child-Pugh grade). Overall survival period, treatment response, and adverse events in each group were analyzed.
Results
Efficacy and disease control rates in the Child-Pugh B group (n=24; 21% and 71%, respectively) were not significantly impaired compared the Child-Pugh A group (n=21; 38% and 67%, respectively). Median survival time and survival rate at 12 months in the Child-Pugh B group were 422 days and 58.3%, respectively, whereas those in the ChildPugh A group were 567 days and 70.8%, respectively. Importantly, the hepatic functional reserve of patients did not worsen in either group during the treatment period. Furthermore, the occurrence rate of adverse events leading to discontinuation of anti-tumor treatment was not significantly increased in the Child-Pugh B group.
Conclusions
Given the preservation of hepatic functional reserve afforded by B-HAIC chemotherapy in patients with decompensated cirrhosis, B-HAIC might be an acceptable alternative strategy for aHCC patients who do not respond to TACE.

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Yuki Zaizen, Masahito Nakano, Kazuta Fukumori, Yoichi Yano, Kota Takaki, Takashi Niizeki, Kotaro Kuwaki, Masaru Fukahori, Takahiko Sakaue, Sohei Yoshimura, Mika Nakazaki, Ryoko Kuromatsu, Shusuke Okamura, Hideki Iwamoto, Shigeo Shimose, Tomotake Shirono,
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Hepatic neoplasm

A survey on transarterial chemoembolization refractoriness and a real-world treatment pattern for hepatocellular carcinoma in Korea: Jae Seung Lee, Beom Kyung Kim, Seung Up Kim, Jun Yong Park, Sang Hoon Ahn, Jin Sil Seong, Kwang-Hyub Han, Do Young Kim; Clin Mol Hepatol 2020;26(1):24-32.
Published online May 20, 2019; DOI: https://doi.org/10.3350/cmh.2018.0065

Background/Aims
Transarterial chemoembolization (TACE) is a standard treatment for intermediate-stage hepatocellular carcinoma (HCC), but there is much controversy about TACE refractoriness. The aim of this study was to identify trends in the actual clinical application of TACE and recognition of TACE refractoriness by Korean experts.
Methods
In total, 17 questionnaires on TACE refractoriness were administered to 161 clinicians via an online survey. Multiple answers were allowed for some questions.
Results
Most clinicians agreed that there is a need for standardization of TACE application through specific scoring systems (n=124, 77.0%). TACE refractoriness was predominantly expected by participants when recurrences were detected within 1 month (n=70, 43.5%), there were 4 to 6 tumors (n=77, 47.8%), the maximal tumor size was 3–5 cm (n=49, 30.4%), and when there was insufficient tumor necrosis despite TACE being repeated more than three times (n=78, 48.4%). Overall, sorafenib therapy (n=137) and radiotherapy (n=114) were preferred when repeated TACE was considered ineffective.
Conclusions
Treatment of HCC is often based on the clinical judgment of clinicians because of the heterogeneity among individuals. Experts need to continue discussions on the standardization and sub-classification of HCC treatment guidelines in Korea.

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Review

Hepatic neoplasm

Contrast-enhanced ultrasound (CEUS) liver imaging reporting and data system (LI-RADS) 2017 – a review of important differences compared to the CT/MRI system: Tae Kyoung Kim, Seung Yeon Noh, Stephanie R Wilson, Yuko Kono, Fabio Piscaglia, Hyun-Jung Jang, Andrej Lyshchik, Christoph F. Dietrich, Juergen K. Willmann, Alexander Vezeridis, Claude B Sirlin; Clin Mol Hepatol 2017;23(4):280-289.
Published online September 15, 2017; DOI: https://doi.org/10.3350/cmh.2017.0037

Abstract
PDF

Medical imaging plays an important role in the diagnosis and management of hepatocellular carcinoma (HCC). The Liver Imaging Reporting and Data System (LI-RADS) was initially created to standardize the reporting and data collection of CT and MR imaging for patients at risk for HCC. As contrast-enhanced ultrasound (CEUS) has been widely used in clinical practice, it has recently been added to the LI-RADS. While CEUS LI-RADS shares fundamental concepts with CT/MRI LI-RADS, there are key differences between the modalities reflecting dissimilarities in the underlying methods of image acquisition and types of contrast material. This review introduces a recent update of CEUS LI-RADS and explains the key differences from CT/MRI LI-RADS.

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WFUMB Review Paper. Incidental Findings in Otherwise Healthy Subjects, How to Manage: Liver
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CT/MRI LI-RADS v2018 vs. CEUS LI-RADS v2017—Can Things Be Put Together?
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What factors predict physicians' utilization behavior of contrast-enhanced ultrasound? Evidence from the integration of the Theory of Planned Behavior and Technology Acceptance Model using a structural equation modeling approach
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Contrast-enhanced US for the Interventional Radiologist: Current and Emerging Applications
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Use of CEUS LI-RADS for the Accurate Diagnosis of Nodules in Patients at Risk for Hepatocellular Carcinoma: A Validation Study
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Contrast-enhanced US with Sulfur Hexafluoride and Perfluorobutane for the Diagnosis of Hepatocellular Carcinoma in Individuals with High Risk
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Evaluation of the Reproducibility of Bolus Transit Quantification With Contrast-Enhanced Ultrasound Across Multiple Scanners and Analysis Software Packages—A Quantitative Imaging Biomarker Alliance Study
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Original Articles

Hepatic neoplasm

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; Clin Mol Hepatol 2017;23(2):128-137.
Published online May 10, 2017; DOI: https://doi.org/10.3350/cmh.2016.0071

Background/Aims
Metronomic chemotherapy (MET) is frequently administered in comparatively low doses as a continuous chemotherapeutic agent. The aim of this study was to evaluate the feasibility and overall survival (OS) of MET compared to sorafenib for advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT).
Methods
A total of 54 patients with advanced HCC and PVTT who had undergone MET were analyzed between 2005 and 2013. A total of 53 patients who had undergone sorafenib therapy were analyzed as the control group. The primary endpoint of this study was OS.
Results
The median number of MET cycles was two (1-15). The OS values for the MET group and sorafenib group were 158 days (132-184) and 117 days (92-142), respectively (P=0.029). The Cox proportional-hazard model showed that a higher risk of death was correlated with higher serum alpha fetoprotein level (≥400 mg/dL, hazard ratio [HR]=1.680, P=0.014) and Child-Pugh class B (HR=1.856, P=0.008).
Conclusions
MET was associated with more favorable outcomes in terms of overall survival than was sorafenib in patients with advanced HCC with PVTT, especially in patients with poor liver function. Therefore, MET can be considered as a treatment option in patients with advanced HCC with PVTT and poor liver function.

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Hepatic neoplasm

A lexicon for hepatocellular carcinoma surveillance ultrasonography: benign versus malignant lesions: Chansik An, Gulbahor Rakhmonova, Kyunghwa Han, Nieun Seo, Jin Young Lee, Myeong-Jin Kim, Mi-Suk Park; Clin Mol Hepatol 2017;23(1):57-65.
Published online March 24, 2017; DOI: https://doi.org/10.3350/cmh.2016.0041

Abstract
PDF

Background/Aims
To suggest a lexicon for liver ultrasonography and to identify radiologic features indicative of benign or malignant lesions on surveillance ultrasonography.
Methods
This retrospective study included 188 nodules (benign, 101; malignant, 87) from 175 at-risk patients identified during surveillance ultrasonography for hepatocellular carcinoma. We created a lexicon for liver ultrasonography by reviewing relevant literature regarding the ultrasonographic features of hepatic lesions. Using this lexicon, two abdominal radiologists determined the presence or absence of each ultrasonographic feature for the included hepatic lesions. Independent factors associated with malignancy and interobserver agreement were determined by logistic regression analysis and kappa statistics, respectively.
Results
Larger tumor size (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.06-1.183; P<0.001), multinodular confluent morphology (OR, 7.712; 95% CI, 1.053-56.465; P=0.044), thick hypoechoic rim (OR, 5.878; 95% CI, 2.681-12.888; P<0.001), and posterior acoustic enhancement (OR, 3.077; 95% CI, 1.237-7.655; P=0.016) were independently associated with malignant lesions. In a subgroup analysis of lesions <2 cm, none of the ultrasonographic features were significantly associated with malignancy or benignity. Interobserver agreement for morphology was fair (κ=0.36), while those for rim (κ=0.427), echogenicity (κ=0.549), and posterior acoustic enhancement (κ=0.543) were moderate.
Conclusions
For hepatic lesions larger than 2 cm, some ultrasonography (US) features might be suggestive of malignancy. We propose a lexicon that may be useful for surveillance US.

Citations

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Focal Hyperechoic Hepatic Lesions in Northern Region of Saudi Arabia: Prevalence, Radiologic Features, and Clinical Relevance
Fatimah M. Alonzi, Mohammed J. Alsaadi, Khaled Said Karam, Essa M. Alanzi, Noura K. Alhathal, Maram F. Alreshidi, Abdulrahman M. Alfuraih
Journal of Clinical Medicine.2025; 14(19): 6987. CrossRef
Sonographic appearance of focal liver lesions and likelihood of hepatocellular carcinoma in adult Thais with chronic hepatitis B virus infection
Sarana Suttivanich, Kamonwan Soonklang, Pantajaree Hiranrat, Surachate Siripongsakun
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Direct comparison of biopsy techniques for hepatic malignancies
Shang-Chin Huang, Ja-Der Liang, Shih-Jer Hsu, Tzu-Chan Hong, Hung-Chih Yang, Jia-Horng Kao
Clinical and Molecular Hepatology.2021; 27(2): 305. CrossRef

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Hepatic neoplasm

The role of scheduled second TACE in early-stage hepatocellular carcinoma with complete response to initial TACE: Jung Hee Kim, Dong Hyun Sinn, Sung Wook Shin, Sung Ki Cho, Wonseok Kang, Geum-Youn Gwak, Yong-Han Paik, Joon Hyeok Lee, Kwang Cheol Koh, Seung Woon Paik, Moon Seok Choi; Clin Mol Hepatol 2017;23(1):42-50.
Published online March 7, 2017; DOI: https://doi.org/10.3350/cmh.2016.0058

Background/Aims
We investigated the outcomes of early-stage hepatocellular carcinoma (HCC) patients who showed a complete response (CR) to initial transarterial chemoembolization (TACE), with a focus on the role of scheduled TACE repetition.
Methods
A total of 178 patients with early-stage HCC who were initially treated with TACE and showed a CR based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria on one month follow-up computed tomography (CT) were analyzed. Among them, 90 patients underwent scheduled repetition of TACE in the absence of viable tumor on CT.
Results
During a median follow-up period of 4.6 years (range: 0.4-8.8 years), mortality was observed in 71 patients (39.9%). The overall recurrence-free and local recurrence-free survival rates at 1 year were 44.4% and 56.2%. In the multivariable model, scheduled repetition of TACE was an independent factor associated with survival (hazard ratio [95% confidence interval]: 0.56 [0.34-0.93], P=0.025). When stratified using Barcelona clinic liver cancer (BCLC) stage, scheduled repetition of TACE was associated with a favorable survival rate in BCLC stage A patients, but not in BCLC 0 patients.
Conclusions
Scheduled repetition of TACE was associated with better survival for early-stage HCC patients showing a CR after initial TACE, especially in BCLC stage A patients.

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Review

Hepatic neoplasm

Imaging findings of mimickers of hepatocellular carcinoma: Tae Kyoung Kim, Eunchae Lee, Hyun-Jung Jang; Clin Mol Hepatol 2015;21(4):326-343.
Published online December 24, 2015; DOI: https://doi.org/10.3350/cmh.2015.21.4.326

Abstract
PDF

Radiological imaging plays a crucial role in the diagnosis of hepatocellular carcinoma (HCC) as the noninvasive diagnosis of HCC in high-risk patients by typical imaging findings alone is widely adopted in major practice guidelines for HCC. While imaging techniques have markedly improved in detecting small liver lesions, they often detect incidental benign liver lesions and non-hepatocellular malignancy that can be misdiagnosed as HCC. The most common mimicker of HCC in cirrhotic liver is nontumorous arterioportal shunts that are seen as focal hypervascular liver lesions on dynamic contrast-enhanced cross-sectional imaging. Rapidly enhancing hemangiomas can be easily misdiagnosed as HCC especially on MR imaging with liver-specific contrast agent. Focal inflammatory liver lesions mimic HCC by demonstrating arterial-phase hypervascularity and subsequent washout on dynamic contrast-enhanced imaging. It is important to recognize the suggestive imaging findings for intrahepatic cholangiocarcinoma (CC) as the management of CC is largely different from that of HCC. There are other benign mimickers of HCC such as angiomyolipomas and focal nodular hyperplasia-like nodules. Recognition of their typical imaging findings can reduce false-positive HCC diagnosis.

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Original Article

Hepatic neoplasm

Efficacy and safety of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma as first-line therapy: Myung Jin Oh, Heon Ju Lee, Si Hyung Lee; Clin Mol Hepatol 2013;19(3):288-299.
Published online September 30, 2013; DOI: https://doi.org/10.3350/cmh.2013.19.3.288

Abstract
PDF

Background/Aims

Hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil and cisplatin for intractable advanced hepatocellular carcinoma (HCC) may have survival benefits. We aimed to determine the efficacy and safety of HAIC for advanced HCC as first-line therapy.

Methods

A total of 54 patients who received only HAIC with 5-fluorouracil (750 mg/m² on days 1-4) and cisplatin (25 mg/m² on days 1-4) for advanced HCC from Jan. 2009 to Dec. 2011 were selected. According to Child-Pugh class, the overall survival (OS), progression-free survival (PFS), and adverse events after HAIC were investigated retrospectively.

Results

Median OS and PFS between the Child-Pugh A group (n=24) and the Child-Pugh B/C group (n=30) were 8.7 (95% confidence interval [CI]: 4.7-12.7) vs. 3.7 months (95% CI: 2.0-5.3), and 7.1 (95% CI: 3.8-10.4) vs. 3.6 months (95% CI: 2.0-5.2), respectively. Although median OS and PFS were not statistically significant between the two groups (P=0.079, P=0.196), the Child-Pugh class B/C tended to influence poor OS. Serious adverse events ≥ grade 3 occurred frequently in both groups (83.3 vs. 96.7%, P=0.159). Responders (22.2%, complete or partial response) significantly differed in median OS, compared to non-responders (13.1 vs. 4.4 months, P=0.019). Achievement of complete or partial response was an independent prognostic factor of OS (hazard ratio: 0.4, 95% CI: 0.2-0.8, P=0.011).

Conclusions

Achievement of response after HAIC provide a survival benefit in patients with advanced HCC, but HAIC should be administered cautiously in patients with Child-Pugh class B/C, because of a relatively low survival and high incidence of serious adverse events.

Citations

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Predictive factors and prognostic models for Hepatic arterial infusion chemotherapy in Hepatocellular carcinoma: a comprehensive review
Xing Lv, Peng-Bo Zhang, Er-lei Zhang, S. Yang
World Journal of Surgical Oncology.2025;[Epub] CrossRef
Arterial chemotherapy for hepatocellular carcinoma in China: consensus recommendations
Ming Zhao, Zhi Guo, Ying-Hua Zou, Xiao Li, Zhi-Ping Yan, Min-Shan Chen, Wei-Jun Fan, Hai-Liang Li, Ji-Jin Yang, Xiao-Ming Chen, Lin-Feng Xu, Yue-Wei Zhang, Kang-Shun Zhu, Jun-Hui Sun, Jia-Ping Li, Yong Jin, Hai-Peng Yu, Feng Duan, Bin Xiong, Guo-Wen Yin,
Hepatology International.2024; 18(1): 4. CrossRef
Comparison of Sorafenib versus Hepatic Arterial Infusion Chemotherapy-Based Treatment for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis
Young Eun Ahn, Sang Jun Suh, Hyung Joon Yim, Yeon Seok Seo, Eileen L. Yoon, Tae Hyung Kim, Young Sun Lee, Sun Young Yim, Hae Rim Kim, Seong Hee Kang, Young Kul Jung, Ji Hoon Kim, Jong Eun Yeon, Soon Ho Um, Kwan Soo Byun
Gut and Liver.2021; 15(2): 284. CrossRef
High-dose versus Low-dose 5-Fluorouracil and Cisplatin Based Hepatic Arterial Infusion Chemotherapy for Advanced Hepatocellular Carcinoma
Chae-June Lim, Ji-Yun Hong, Yang-Seok Ko, Min-Woo Chung, Chung-Hwan Jun, Sung-Kyu Choi, Sung-Bum Cho
Journal of Liver Cancer.2019; 19(1): 38. CrossRef
Bi-monthly hepatic arterial infusion chemotherapy as a novel strategy for advanced hepatocellular carcinoma in decompensated cirrhotic patients
Kei Moriya, Tadashi Namisaki, Shinya Sato, Masanori Furukawa, Akitoshi Douhara, Hideto Kawaratani, Kosuke Kaji, Naotaka Shimozato, Yasuhiko Sawada, Soichiro Saikawa, Hiroaki Takaya, Koh Kitagawa, Takemi Akahane, Akira Mitoro, Junichi Yamao, Hitoshi Yoshij
Clinical and Molecular Hepatology.2019; 25(4): 381. CrossRef
Objective Response by mRECIST Is an Independent Prognostic Factor for Overall Survival in Hepatocellular Carcinoma Treated with Sorafenib in the SILIUS Trial
Masatoshi Kudo, Kazuomi Ueshima, Yasutaka Chiba, Sadahisa Ogasawara, Shuntaro Obi, Namiki Izumi, Hiroshi Aikata, Hiroaki Nagano, Etsuro Hatano, Yutaka Sasaki, Keisuke Hino, Takashi Kumada, Kazuhide Yamamoto, Yasuharu Imai, Shouta Iwadou, Chikara Ogawa, Ta
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Conditional survival estimate in patients with Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy with/without concurrent radiotherapy
In Rae Cho, Hye Won Lee, Ki Jun Song, Beom Kyung Kim, Seung Up Kim, Do Young Kim, Sang Hoon Ahn, Jinsil Seong, Kwang-Hyub Han, Jun Yong Park
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Kichang Han
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Kazuto Tajiri, Kengo Kawai, Masami Minemura, Satoshi Yasumura, Ayumu Hosokawa, Hideto Kawabe, Gakuto Tomizawa, Toshiro Sugiyama
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Case Report

Hepatic neoplasm

A case of necrotizing pancreatitis subsequent to transcatheter arterial chemoembolization in a patient with hepatocellular carcinoma: Song-I Bae, Jong Eun Yeon, Jong Mee Lee, Ji Hoon Kim, Hyun Jung Lee, Sun Jae Lee, Sang Jun Suh, Eileen L. Yoon, Hae Rim Kim, Kwan Soo Byun, Tae-Seok Seo; Korean J Hepatol 2012;18(3):321-325.
Published online September 25, 2012; DOI: https://doi.org/10.3350/cmh.2012.18.3.321

Abstract
PDF

Necrotizing pancreatitis is one of the rare complications of transcatheter arterial chemoembolization (TACE). Necrotizing pancreatitis after TACE may result from the development of ischemia caused by regurgitation of embolic materials into the vessels supplying the pancreas. We report a case of post-TACE necrotizing pancreatitis with abscess formation in a patient with hepatocellular carcinoma. The patient had suffered hepatic artery injury due to repetitive TACE; during his 25th TACE procedure he had submitted to selective catheterization of the feeding vessel from the dorsal pancreatic artery with a cytotoxic agent and Gelfoam particles. The patient complained of abdominal pain after the TACE procedure, and a CT scan led to a diagnosis of necrotizing pancreatitis with abscess formation. The pancreatic abscess progressed despite general management of the pancreatitis, including antibiotics. Percutaneous catheter drainage was performed, and the symptoms of the patient improved.

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ACUTE NECROTIZING PANCREATITIS AFTER TRANSARTERIAL CHEMOEMBOLIZATION IN A PATIENT WITH HEPATOCELLULAR CANCER: CASE REPORT AND REVIEW OF THE LITERATURE
Serkan Öcal, Nuretdin Suna, Digdem Özer Etik, Fatih Boyvat, Haldun Selcuk
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Xiao Jing Wang, Navtej Buttar, Andrew C. Storm
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Pancreas lipiodol embolism induced acute necrotizing pancreatitis following transcatheter arterial chemoembolization for hepatocellular carcinoma
Youwen Tan, Jianhui Sheng, Huiying Tan, Jianzhong Mao
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Gastric and duodenal ischaemia after transarterial chemoembolisation for hepatocellular carcinoma: an unexpected but significant complication
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Doxorubicin/ethiodized oil/gelatin

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Original Article

Treatment and clinical outcome of needle-track seeding from hepatocellular carcinoma: Dong-Won Ahn, Ju Hyun Shim, Jung-Hwan Yoon, Chung Yong Kim, Hyo-Suk Lee, Yeong Tae Kim, Yoon Jun Kim; Korean J Hepatol 2011;17(2):106-112.
Published online June 23, 2011; DOI: https://doi.org/10.3350/kjhep.2011.17.2.106

Abstract
PDF

Background/Aims

Needle-track seeding is a rare but important complication of diagnostic and therapeutic ultrasound (US)-guided procedures in hepatocellular carcinoma (HCC). We examined the frequency of needle-track seeding after US-guided percutaneous ethanol injection (PEI), fine-needle aspiration biopsy (FNAB), and percutaneous transhepatic biliary drainage (PTBD) in order to determine the appropriate treatment for needle-track seeding and its clinical outcome.

Methods

We analyzed the clinical characteristics and treatment outcomes in eight patients who experienced needle-track seeding from HCC after an US-guided procedure (FNAB, PEI, or PTBD) between January 1990 and July 2004.

Results

Seven (0.14%) of 5,092 patients who experienced needle-track seeding (2 after PEI, 4 after FNAB, and 1 after PTBD) during the study period and 1 other patient who experienced needle-track seeding recently were recruited for this study. Two of the eight patients underwent mass excision and the other six patients underwent en-bloc wide excision for the needle-track seeding. Tumors recurred in the needle-tracks in both patients who underwent mass excision but not in the six patients who underwent en-bloc wide excision. Mortality occurred in three patients who experienced the recurrence and progression of intrahepatic HCC.

Conclusions

The incidence of needle-track seeding after US-guided procedures in HCC was 0.14%. En-bloc wide excision seems to be the optimal treatment for minimizing the probability of tumor recurrence due to needle-track seeding.

Citations

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Cureus.2024;[Epub] CrossRef
Tumor seeding across specialties: a systematic review
Pavel Kipnis, Diya Ramanathan, Richard Hoehn, Ashok R. Jethwa, Daniel W. Karakla, Bethany Rohr, Christopher M. Sutter, Jonathan R. Mark, Sobia F. Khaja, Shawn Li, Jason Thuener, Bryan T. Carroll
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Justin R. Tse, Kevin Terashima, Luyao Shen, Justin P. McWilliams, David S. K. Lu, Steven S. Raman
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Anastasia Murtha-Lemekhova, Juri Fuchs, Emil Ritscher, Katrin Hoffmann
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Qi-wen Chen, Chien-shan Cheng, Hao Chen, Zhou-yu Ning, Shi-feng Tang, Xun Zhang, Xiao-yan Zhu, Sonya Vargulick, Ye-hua Shen, Yong-qiang Hua, Jing Xie, Wei-dong Shi, Hui-feng Gao, Li-tao Xu, Lan-yun Feng, Jun-hua Lin, Zhen Chen, Lu-ming Liu, Bo Ping, Zhi-q
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Case Report

A case of hepatocellular carcinoma in the caudate lobe successfully treated by transcatheter arterial chemoembolization using drug-eluting beads: Dong Hoo Joh, Jin Dong Kim, Young Nam Kim, Ha Hun Song, Hyun Kim, Kyung Ho Song, Sang Jin Lee, Jeong Rok Lee, Won Joong Jeon, Byung Hyo Cha; Korean J Hepatol 2010;16(4):405-409.
Published online December 31, 2010; DOI: https://doi.org/10.3350/kjhep.2010.16.4.405

Abstract
PDF

Hepatocellular carcinoma (HCC) in the caudate lobe remains one of the most intricate locations where various treatments tend to pose problems with regard to the optimal approach. Surgical resection has been regarded as the most effective treatment; however, isolated resection of the caudate lobe is strenuous and associated with a high rate of early recurrence. Percutaneous ablation might be technically difficult or impossible to perform due to the deep location of tumors and adjacent large vessels. Treatment with drug-eluting beads (DEB) can potentially enhance the therapeutic efficacy for patients with unresectable HCC by drawing on the slower, more consistent drug delivery process. We described a case of a 62-year-old man with HCC in the caudate lobe who was successfully treated by DEB.

Citations

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Darrel Ceballos, Albert Tine, Rakesh Varma, Husameddin El Khudari
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Current status of Liver diseases in Korea: Toxic and alcoholic Liver diseases: Kyung Ah Kim; Korean J Hepatol 2009;15(60):29-33.
Published online December 31, 2009; DOI: https://doi.org/10.3350/kjhep.2009.15.S6.S29

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Sebastian Mueller
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Jong Joon Lee, Soo Kyung Park, Oh Sang Kwon, In Sik Won, Dong Kyu Kim, Young Kul Jung, Yang Suh Ku, Yun Soo Kim, Duck Joo Choi, Ju Hyun Kim
The Korean Journal of Hepatology.2011; 17(1): 37. CrossRef

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Original Articles

Comparison of radiofrequency ablation and transarterial chemoembolization for the treatment of a single hepatocellular carcinoma smaller than 4 cm: Min Jae Yang, M.D., So Yun An, M.D., Eun Joon Moon, M.D., Min Suk Lee, M.D., Joo An Hwang, M.D., Jae Youn Cheong, M.D., Je Hwan Won, M.D.1, Jai Keun Kim, M.D.1, Hee Jung Wang, M.D.2, Sung Won Cho, M.D.; Korean J Hepatol 2009;15(4):474-485.
Published online December 31, 2009; DOI: https://doi.org/10.3350/kjhep.2009.15.4.474

Abstract
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Background/Aims
Radiofrequency ablation (RFA) is an established curative therapeutic modality for unresectable hepatocellular carcinoma (HCC), and transarterial chemoembolization (TACE) has been used as a palliative treatment for inoperable HCC. It is still unknown whether RFA and TACE are equally effective for improving the survival of patients with unresectable HCC that is amenable to either treatment. The aim of this retrospective study was to compare the clinical impacts of two treatments, and analyze the prognostic factors for recurrence and survival. Methods: Ninety-three patients with a single HCC smaller than 4 cm who showed complete responses (complete ablation or complete lipiodol tagging) after treatment with RFA (n=43) or TACE (n=50) between January 2002 and February 2009 were investigated. Univariate and multivariate analyses were performed for 13 potential prognostic factors using the Cox proportional-hazards model. Results: The time-to-recurrence rates at 1, 2, and 3 years after treatment were 32.9%, 44.3%, and 55.4%, respectively, for the RFA group, and 42%, 68.3%, 71.7% for the TACE group. The probability of survival at 1, 2, and 3 years was 97.7%, 77.4%, and 63.1%, respectively, for the RFA group, and 95.9%, 76.1%, and 60.2% for the TACE group. The time-to-recurrence and overall survival rates did not differ significantly between the two treatment groups. A multivariate Cox proportional-hazards model revealed that a tumor size larger than 3 cm and lower serum albumin levels were independent risk factors for recurrence, and that being male, being seropositive for hepatitis B surface antigen, and having a higher serum albumin level were independent favorable prognostic factors for survival. Conclusions: TACE and RFA exhibited similar therapeutic effects in terms of recurrence and survival for patients with a single HCC smaller than 4 cm, if they could exhibited complete responses. (Korean J Hepatol 2009;15:474-485)

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Prognostic value of aspartate aminotransferase/alanine aminotransferase ratio in hepatocellular carcinoma after hepatectomy
Rong-Rui Huo, Li-Xin Pan, Pei-Sheng Wu, Xiu-Mei Liang, Xue-Mei You, Liang Ma, Jian-Hong Zhong
BJS Open.2024;[Epub] CrossRef
Risk factors of secondary infection/recurrence after ablation for liver cancers: A systemic review and meta-analysis
Gang Yin, Nengwei Zhang, AMin BuHe, Wei Yan, Tianxiong Li, Jirun Peng
Journal of Cancer Research and Therapeutics.2022; 18(5): 1352. CrossRef
Clinical feasibility and efficacy of stereotactic body radiotherapy for hepatocellular carcinoma: A systematic review and meta-analysis of observational studies
Chai Hong Rim, Hyun Ju Kim, Jinsil Seong
Radiotherapy and Oncology.2019; 131: 135. CrossRef
Efficacy and safety of radiofrequency ablation and transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma: A meta‐analysis
Yulan Wang, Tianxing Deng, Li Zeng, Weiqing Chen
Hepatology Research.2016; 46(1): 58. CrossRef
Transarterial Chemoembolization vs. Radiofrequency Ablation for the Treatment of Single Hepatocellular Carcinoma 2 cm or Smaller
Jong Woo Kim, Jin Hyoung Kim, Kyu-Bo Sung, Heung-Kyu Ko, Ji Hoon Shin, Pyo Nyun Kim, Hyun-Kyung Choi, Gi-Young Ko, Hyun-Ki Yoon, Seng-Yong Chun, Dong Il Gwon
American Journal of Gastroenterology.2014; 109(8): 1234. CrossRef

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Prognostic value of serum osteopontin in hepatocellular carcinoma patients treated with transarterial chemoembolization: Sung Hoon Kim, M.D., Young-Hwa Chung, M.D.1, Soo Hyun Yang, M.D., Jeong A Kim, M.S.1, Myoung Kuk Jang, M.D.2, Sung Eun Kim, M.D.1, Danbi Lee, M.D.1, Sae Hwan Lee, M.D.1, Don Lee, M.D.1, Kang Mo Kim, M.D.1, Young Suk Lim, M.D.1, Han Chu Lee, M.D.1, Yung Sang Lee, M.D.1, Dong Jin Suh, M.D.1; Korean J Hepatol 2009;15(3):320-330.
Published online September 30, 2009; DOI: https://doi.org/10.3350/kjhep.2009.15.3.320

Abstract
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Background/Aims
Osteopontin (OPN) is overexpressed in hepatocellular carcinoma (HCC) with postoperative recurrence or extrahepatic metastasis. However, its prognostic value in patients treated with transarterial chemoembolization (TACE) is unclear. We investigated the utility of serum OPN levels and changes therein as prognostic markers in HCC patients who have received TACE. Methods: Forty-six patients with HCC were enrolled. Serum OPN levels were measured before and 4 weeks after TACE. Serum biochemistry and computed tomography (CT) scans were analyzed. We evaluated baseline serum OPN levels and subsequent changes therein in relation to tumor responses and cumulative survival rates following TACE. A decreasing pattern was defined as a decrease after TACE of more than 10% relative to baseline levels. A "responder" was defined as a patient who exhibited a tumor necrosis rate of higher than 50% on the follow-up CT scan. Results: Higher initial serum OPN levels were associated with a large tumor, portal vein invasion, and an advanced tumor stage. Patients who had lower initial serum OPN levels and those who exhibited decreasing patterns after TACE tended to have more favorable tumor responses (P=0.043 and 0.055, respectively) and exhibited better cumulative survival rates (P=0.036 and 0.030, respectively). However, the initial serum OPN level and subsequent changes in serum OPN levels were not independent predictors for survival on multivariate analysis. Conclusions: Serum OPN levels were significantly higher in patients with advanced HCC. In addition, HCC patients with low pretreatment serum OPN levels and those for whom serum OPN declined following TACE exhibited better tumor responses and survived for longer. (Korean J Hepatol 2009,15:320-330)

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European Journal of Radiology.2023; 167: 111086. CrossRef
Tumor Biomarkers and Interventional Oncology: Impact on Local Outcomes for Liver and Lung Malignancy
Yuan-Mao Lin, Ryosuke Taiji, Marco Calandri, Bruno C. Odisio
Current Oncology Reports.2021;[Epub] CrossRef
Prognostic Value of Serum Apolipoprotein B to Apolipoprotein A-I Ratio in Hepatocellular Carcinoma Patients Treated with Transcatheter Arterial Chemoembolization: A Propensity Score-Matched Analysis
Meng-Meng Liu, Zhan-Hong Chen, Li-Yun Zhao, Jing-Yuan Zhao, Dai-Lin Rong, Xiao-Kun Ma, Dan-Yun Ruan, Jin-Xiang Lin, Jing-Jing Qi, Pei-Shan Hu, Jing-Yun Wen, Jie Chen, Qu Lin, Xiang-Yuan Wu, Li Wei, Min Dong
Oncology Research and Treatment.2021; 44(9): 450. CrossRef
ARD1/NAA10 in hepatocellular carcinoma: pathways and clinical implications
Danbi Lee, Myoung-Kuk Jang, Ji Hae Seo, Soo Hyung Ryu, Jeong A. Kim, Young-Hwa Chung
Experimental & Molecular Medicine.2018; 50(7): 1. CrossRef
Prognostic value of osteopontin in patients with hepatocellular carcinoma
Tingting Sun, Peng Li, Diwen Sun, Qingao Bu, Guoqiang Li
Medicine.2018; 97(43): e12954. CrossRef
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James Ronald, Andrew B. Nixon, Daniele Marin, Rajan T. Gupta, Gemini Janas, Willa Chen, Paul V. Suhocki, Waleska Pabon-Ramos, David R. Sopko, Mark D. Starr, John C. Brady, Herbert I. Hurwitz, Charles Y. Kim
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ATX–LPA Axis Induces Expression of OPN in Hepatic Cancer Cell SMMC7721
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Osteopontin as a Key Mediator for Vasculogenic Mimicry in Hepatocellular Carcinoma
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Hepatology Elsewhere

The Korean Journal of Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: Jeong Heo; Korean J Hepatol 2009;15(2):227-230.
Published online June 30, 2009; DOI: https://doi.org/10.3350/kjhep.2009.15.2.227

Abstract
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Background
Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebocontrolled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. Methods: Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with Clinical- Trials.gov, number NCT00492752. Findings: 271 patients from 23 centers in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% CI 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; P=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.79]; P=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation. Interpretation: Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.

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Phase II, Open-Label Study of Brivanib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma
Joong-Won Park, Richard S. Finn, Jun Suk Kim, Mark Karwal, Ruby K. Li, Fuad Ismail, Melanie Thomas, Rosemarie Harris, Christine Baudelet, Ian Walters, Jean-Luc Raoul
Clinical Cancer Research.2011; 17(7): 1973. CrossRef

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Case Report

A case of hypervascular hyperplastic nodules mimicking hepatocellular carcinoma in alcoholic Liver cirrhosis: Jae Eun Park, M.D., Byung Seok Kim, M.D., Chang Hyeong Lee, M.D., Joon Hyuck Choi, M.D., Young Chan Park, M.D.1, Kwan Kyu Park, M.D.2; Korean J Hepatol 2009;15(2):193-200.
Published online June 30, 2009; DOI: https://doi.org/10.3350/kjhep.2009.15.2.193

Abstract
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Benign hypervascular hyperplastic nodules (HHN) in liver cirrhosis are very rare. It is important to distinguish between regenerative nodules (hyperplastic nodules) and tumorous nodules (dysplastic or neoplastic nodules) in hepatocellular nodular lesions. The differential diagnosis between HHN and hepatocellular carcinoma on the basis of radiologic imaging is often difficult, and is clinically important when determining the therapeutic plan. Therefore, histological confirmation by needle biopsy sampling of the liver is necessary for a correct diagnosis of HHN. We report herein a case of benign HHN mimicking hepatocellular carcinoma in a 32-year-old male alcoholic liver cirrhosis patient without viral hepatitis infection. (Korean J Hepatol 2009; 15:193-200)

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A Case of Multiple Hypervascular Hyperplastic Liver Nodules in a Patient with No History of Alcohol Abuse or Chronic Liver Diseases
Byoung Joo Do, In Young Park, So Yon Rhee, Jin Kyung Song, Myoung Kuk Jang, Seong Jin Cho, Eun Sook Nam, Eun Joo Yun
The Korean Journal of Gastroenterology.2015; 65(5): 321. CrossRef

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