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Original Articles

Aspirin and HCC risk in MASLD: Nationwide cohort study with genetic risk analysis
Juhee Ahn, Moon Haeng Hur, Hyunjae Shin, Min Kyung Park, Sungho Won, Jeayeon Park, Yunmi Ko, Youngsu Park, Yun Bin Lee, Eun Ju Cho, Jeong-Hoon Lee, Su Jong Yu, Jung-Hwan Yoon, Yoon Jun Kim
Received May 19, 2025  Accepted November 17, 2025  Published online November 25, 2025  
DOI: https://doi.org/10.3350/cmh.2025.0528    [Accepted]
Background
The association between aspirin use and hepatocellular carcinoma (HCC) risk in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study evaluated the effect of aspirin on HCC development in MASLD patients using Korean National Health Insurance Service (NHIS) and UK Biobank (UKB) databases.
Methods
A retrospective cohort analysis was conducted using the NHIS database with a 3-year landmark design. Baseline characteristics were balanced using inverse probability of treatment weighting (IPTW) and 1:3 propensity score matching (PSM). Additionally, Mendelian randomization (MR) analysis was performed in the UKB cohort using a genomic risk score (GRS) for salicylic acid, based on genetic variants related to aspirin metabolism, as a proxy for aspirin use.
Results
In the NHIS cohort, 6,584,155 eligible patients were included, of whom 1,723,435 had MASLD. After PSM, aspirin use was associated with a significantly lower risk of HCC compared to no aspirin use, in both the overall population (adjusted subdistribution hazard ratio [ASHR]=0.86, 95% confidence interval [CI]=0.78–0.95, P=0.002) and MASLD group (ASHR=0.86, 95% CI=0.75–0.99, P=0.036). Similar results were reproduced in the IPTW population and several sensitivity and subgroup analyses. In the UKB cohort, individuals in the top 95% of GRS had a significantly lower risk of HCC compared to those in the bottom 5%, in both the overall population (ASHR=0.61, 95% CI=0.39–0.95, P=0.028) and MASLD group (ASHR=0.47, 95% CI=0.29–0.76, P=0.002).
Conclusion
Findings from both population-based and genetic analyses suggest a possible protective association between aspirin use and HCC in patients with MASLD, which warrants further validation.
  • 521 View
  • 76 Download
Glucagon-like peptide 1 receptor agonist and reduced liver and non-liver complications in adults with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease: a target trial emulation study
Xianhua Mao, Xinrong Zhang, Rongtao Lai, Ka-Shing Cheung, Man-Fung Yuen, Ramsey Cheung, Wai-Kay Seto, Mindie H. Nguyen
Clin Mol Hepatol 2025;31(3):1084-1099.
Published online April 23, 2025
DOI: https://doi.org/10.3350/cmh.2024.1096
Background/Aims
Information about the association of glucagon-like peptide-1 receptor (GLP-1RA) with liver and non-liver complications is insufficient in patients with type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD). We conducted a target trial emulation study to evaluate whether GLP-1RA decreases the risk of liver and non-liver outcomes.
Methods
Patients with T2D and MASLD initiating GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP-4i) were included from 2013 to 2022 in Merative™ Marketscan® Research Databases. Primary outcomes included incidences of (1) hepatocellular carcinoma (HCC) and cirrhosis, and (2) cardiovascular disease (CVD), chronic kidney disease (CKD), and non-liver cancer. Inverse probability of treatment weighting was applied to balance baseline characteristics and Cox regression models were conducted to estimate hazard ratio (HR) and 95% confidence interval (CI).
Results
In the intention-to-treat design, GLP-1RA, compared with DPP-4i, had a significantly lower incidence (per 1,000 person-years) of HCC (0.8 vs. 1.7; HR 0.53, 95% CI 0.39–0.71), of cirrhosis (29.3 vs. 32.9; HR 0.91, 95% CI 0.86–0.96), of CVD (57.2 vs. 73.9; HR 0.90, 95% CI 0.86–0.95), of CKD (4.5 vs. 6.8; HR 0.73, 95% CI 0.64–0.84), and of non-liver cancer (16.9 vs. 22.9; HR 0.82, 95% CI 0.77–0.89). In the per-protocol design, significant inverse associations for these study outcomes still were observed, with HR 0.60–0.77.
Conclusions
In this emulated target trial of nationwide patients with T2D and MASLD, GLP-1RA use, when compared with DPP-4i, was associated with a significantly lower risk of liver and non-liver complications.

Citations

Citations to this article as recorded by  Crossref logo
  • Evaluating causal protective effect of dual GLP-1R/GIPR agonists on MASLD: A Mendelian randomization and colocalization study
    Yangke Cai, Siyuan Xie, Liyi Xu, Jiamin Chen, Jianting Cai
    European Journal of Pharmacology.2025; 1005: 178088.     CrossRef
  • Impaired Thyroid Hormone Sensitivity is Associated with Increased Risk of Liver Fibrosis in Euthyroid Population: A Cross-Sectional Analysis of NHANES
    Xingyu Yao, Kaiwen Xiao, Hein Ko Oo
    Hormone and Metabolic Research.2025; 57(09): 511.     CrossRef
  • 9,593 View
  • 268 Download
  • 3 Web of Science
  • Crossref

Correspondences

Revisiting unmet needs in clinical research on direct-acting antiviral therapy for HCC patients: Correspondence to letter to the editor on “Direct-acting antiviral therapy for patients with HCV-related hepatocellular carcinoma: A nationwide cohort study”
Teng-Yu Lee, Pei-Chien Tsai, Shou-Wu Lee, Ming- Lung Yu
Received April 2, 2025  Accepted April 2, 2025  Published online April 4, 2025  
DOI: https://doi.org/10.3350/cmh.2025.0362    [Epub ahead of print]
  • 3,418 View
  • 23 Download
Correspondence to letter to the editor on “GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma”
Hyung Seok Kim, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun
Received March 12, 2025  Accepted March 15, 2025  Published online March 19, 2025  
DOI: https://doi.org/10.3350/cmh.2025.0287    [Epub ahead of print]
  • 3,825 View
  • 34 Download
Emerging evidence supports direct-acting antiviral therapy for HCC patients beyond the early stage: Correspondence to editorial on “Direct-acting antiviral therapy for patients with HCV-related hepatocellular carcinoma: A nationwide cohort study”
Teng-Yu Lee, Pei-Chien Tsai, Shou-Wu Lee, Ming-Lung Yu
Received February 28, 2025  Accepted March 1, 2025  Published online March 4, 2025  
DOI: https://doi.org/10.3350/cmh.2025.0235    [Epub ahead of print]

Citations

Citations to this article as recorded by  Crossref logo
  • Revisiting unmet needs in clinical research on direct-acting antiviral therapy for HCC patients
    Teng-Yu Lee, Pei-Chien Tsai, Shou-Wu Lee, Ming- Lung Yu
    Clinical and Molecular Hepatology.2025;[Epub]     CrossRef
  • 3,409 View
  • 29 Download
  • Crossref

Editorials

Can SAFE score be utilized as a universal hepatocellular carcinoma prediction score?: Editorial on “High Steatosis-Associated Fibrosis Estimator scores predict hepatocellular carcinoma in viral and non-viral hepatitis and metabolic dysfunction-associated steatotic liver disease”
Michael Kwan-Lung Ko, Loey Lung-Yi Mak
Received February 3, 2025  Accepted February 7, 2025  Published online February 11, 2025  
DOI: https://doi.org/10.3350/cmh.2025.0118    [Epub ahead of print]
  • 3,131 View
  • 33 Download

Alcohol-related liver disease

Burden of alcohol use disorder, alcohol-related liver disease, and alcohol-related liver cancer: Editorial on “Global epidemiology of alcohol-related liver disease, liver cancer, and alcohol use disorder, 2000–2021
Youxin Wang, Noriko Oza, Jazleen Leo, Ashok Choudhury, Daniel Q. Huang
Clin Mol Hepatol 2025;31(2):654-657.
Published online February 10, 2025
DOI: https://doi.org/10.3350/cmh.2025.0133

Citations

Citations to this article as recorded by  Crossref logo
  • Correspondence to editorial on “Global epidemiology of alcohol-related liver disease, liver cancer, and alcohol use disorder, 2000-2021”
    Pojsakorn Danpanichkul, Luis Antonio Diaz, Kanokphong Suparan, Karn Wijarnpreecha, Juan Pablo Arab
    Clinical and Molecular Hepatology.2025; 31(2): e200.     CrossRef
  • 6,230 View
  • 93 Download
  • 1 Web of Science
  • Crossref

Original Articles

GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma
Hyung Seok Kim, Jung Hwan Yoon, Ji Yi Choi, Moon Gyeong Yoon, Geum Ok Baek, Minji Kang, Se Ha Jang, Won Park, Yunjin Go, Jestlin Tianthing Ng, Suk Woo Nam, Jee-Yeong Jeong, Ji Eun Han, Hyo Jung Cho, Su Bin Lim, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun
Clin Mol Hepatol 2025;31(3):914-934.
Published online February 6, 2025
DOI: https://doi.org/10.3350/cmh.2024.1038
Background/Aims
Hepatocellular carcinoma (HCC) is characterized by high recurrence and mortality, necessitating the identification of reliable biomarkers. In this study, we aimed to identify the predictive gene signatures for HCC recurrence and evaluate the efficiency of GULP PTB domain-containing engulfment adaptor 1 (GULP1) as a predictive and diagnostic marker and therapeutic target for HCC.
Methods
We analyzed genomic datasets from The Cancer Genome Atlas and Gene Expression Omnibus databases via least absolute shrinkage and selection operator Cox regression and 10-fold cross-validation, leading to the development of a 15-gene risk score model, which was validated using three independent datasets. Serum GULP1 and α-fetoprotein levels were assessed to determine the diagnostic accuracy of the model. Using clinical cohorts and patient sera, GULP1 roles were examined, and functional assays in vitro and in vivo were used to evaluate its effects on cell growth, epithelial–mesenchymal transition (EMT), ADP-ribosylation factor 6 (ARF6) activation, and β-catenin signaling.
Results
Our newly developed risk-score model accurately predicted recurrent HCC in all datasets. Among the 15 genes in the risk score model, GULP1 was overexpressed in patients with HCC and independently predicted HCC recurrence. Its expression modulation influenced cell growth and EMT, with observed effects on ARF6 activation and β-catenin signaling pathways.
Conclusions
GULP1 is a crucial biomarker for HCC, serving as a non-invasive diagnostic and predictive tool. It also plays key roles in HCC progression. Our findings highlight the potential use of GULP1 in treatment strategies targeting EMT and HCC recurrence to improve the personalized care and patient outcomes.

Citations

Citations to this article as recorded by  Crossref logo
  • The evolving landscape of biomarkers for systemic therapy in advanced hepatocellular carcinoma
    Xinyu Guo, Zhongwei Zhao, Lingyi Zhu, Shuang Liu, Lingling Zhou, Fazong Wu, Shiji Fang, Minjiang Chen, Liyun Zheng, Jiansong Ji
    Biomarker Research.2025;[Epub]     CrossRef
  • Advances in research regarding epithelial-mesenchymal transition and prostate cancer
    Xi Wei, Rui Liu, Wei Li, Qi Yu, Qing Tao Yang, Tao Li
    Frontiers in Cell and Developmental Biology.2025;[Epub]     CrossRef
  • Correspondence: Response to the Letter Regarding "GULP1 as a Novel Diagnostic and Predictive Biomarker in Hepatocellular Carcinoma"
    Hyung Seok Kim, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun
    Clinical and Molecular Hepatology.2025;[Epub]     CrossRef
  • Serum Proteomic Profile Based on the TGF‐β Pathway Stratifies Risk of Hepatocellular Carcinoma
    Xiyan Xiang, Kirti Shetty, Herbert Yu, Bibhuti Mishra, Linda L. Wong, Xianghong Jasmine Zhou, Sanjaya K. Satapathy, James M. Crawford, Patricia S. Latham, Steven‐Huy Han, Brandon Mathew, Nabil N. Dagher, Lawrence Lau, Fellanza Cacaj, Anil K. Vegesna, Srin
    Liver International.2025;[Epub]     CrossRef
  • Systematic analysis of the expression profiles and prognostic values of the FAM72 family in liver cancer
    Weihao Kong, Long Teng, Kangjie Zhang, Yajun Zou, Xingyu Wang, Jianlin Zhang
    Biochemistry and Biophysics Reports.2025; 44: 102358.     CrossRef
  • 11,052 View
  • 974 Download
  • 4 Web of Science
  • Crossref
Direct-acting antiviral therapy for patients with hepatitis C virus-related hepatocellular carcinoma: A nationwide cohort study
Shou-Wu Lee, Sheng-Shun Yang, Pei-Chien Tsai, Chung-Feng Huang, Chi-Yi Chen, Chao-Hung Hung, Chien-Hung Chen, Chi-Ming Tai, Pin-Nan Cheng, Hsing-Tao Kuo, Kuo-Chih Tseng, Lein-Ray Mo, Ching-Chu Lo, Yi-Hsiang Huang, Han-Chieh Lin, Pei-Lun Lee, Ming-Jong Bair, Te-Sheng Chang, Chun-Yen Lin, Szu-Jen Wang, Tsai-Yuan Hsieh, Tzeng-Hue Yang, Cheng-Yuan Peng, Chi-Chieh Yang, Lee-Won Chong, Chien-Wei Huang, Chih-Wen Lin, Cheng-Hsin Chu, Ming-Chang Tsai, Jia-Horng Kao, Chun-Jen Liu, Wan-Long Chuang, Teng-Yu Lee, Ming-Lung Yu, on behalf of TACR investigators
Clin Mol Hepatol 2025;31(3):899-913.
Published online February 5, 2025
DOI: https://doi.org/10.3350/cmh.2024.1015
Background/Aims
The survival benefit of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection in patients with hepatocellular carcinoma (HCC), particularly in Barcelona Clinic Liver Cancer (BCLC) stages B/C, remains largely uncertain. We aimed to explore the impact of DAA therapy on overall survival (OS) in HCC patients using a nationwide cohort study.
Methods
We utilized the nationwide Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) database to include all adults receiving a DAA therapy for HCV, excluding those with other viral infections, liver transplantation, non-HCC malignancies, and terminal-staged HCC. We respectively analyzed the adjusted odds ratio (aOR) for sustained virological response (SVR) and adjusted hazard ratio (aHR) for OS.
Results
Between December 2013 and December 2020, 2,205 (9.3%) patients with HCC and 21,569 (90.7%) patients without HCC were include. The SVR rates were 96.6% in the HCC group and 98.8% in the non-HCC group (P<0.001), with HCC being an independent risk factor affecting SVR (aOR 0.41; 95% CI 0.31–0.54; P<0.001). In the whole patient cohort, SVR was independently associated with improved OS (aHR 0.46; 95% CI 0.35–0.60; P<0.001). Among patients with baseline HCC, SVR remained an independent factor related to OS (aHR 0.41; 95% CI 0.28–0.59; P<0.001). The impact of SVR on OS persisted significantly across BCLC stages 0/A and stages B/C.
Conclusions
High SVR rates among HCC patients underscore the importance of DAA therapy in enhancing OS, reaffirming its efficacy across various HCC stages.

Citations

Citations to this article as recorded by  Crossref logo
  • Survival impact of hepatitis C virus eradication in patients with or without active hepatocellular carcinoma: A nationwide cohort study
    Teng-Yu Lee, Sheng-Shun Yang, Pei-Chien Tsai, Chung-Feng Huang, Chi-Yi Chen, Chao-Hung Hung, Chien-Hung Chen, Chi-Ming Tai, Pin-Nan Cheng, Hsing-Tao Kuo, Kuo-Chih Tseng, Lein-Ray Mo, Ching-Chu Lo, Yi-Hsiang Huang, Han-Chieh Lin, Pei-Lun Lee, Ming-Jong Bai
    European Journal of Cancer.2026; 232: 116109.     CrossRef
  • Revisiting unmet needs in clinical research on direct-acting antiviral therapy for HCC patients
    Teng-Yu Lee, Pei-Chien Tsai, Shou-Wu Lee, Ming- Lung Yu
    Clinical and Molecular Hepatology.2025;[Epub]     CrossRef
  • Emerging evidence supports direct-acting antiviral therapy for HCC patients beyond the early stage
    Teng-Yu Lee, Pei-Chien Tsai, Shou-Wu Lee, Ming- Lung Yu
    Clinical and Molecular Hepatology.2025;[Epub]     CrossRef
  • HIV, Viral Hepatitis, and Schistosomiasis Association with Liver Cancer: A Systematic Review
    Khumbuzile Canham, Pragalathan Naidoo, Sibusiso Senzani, Sayed Shakeel Kader, Zilungile L. Mkhize-Kwitshana
    Microorganisms.2025; 13(12): 2753.     CrossRef
  • 10,050 View
  • 205 Download
  • 1 Web of Science
  • Crossref

Review

Unveiling the intratumor microbiome in liver cancer: Current insights and prospective applications
Xindi Ke, Shangze Jiang, Qiaoxin Wei, Minghao Sun, Hang Sun, Mingchang Pang, Mei Liu, Lejia Sun, Huayu Yang, Yilei Mao
Clin Mol Hepatol 2025;31(3):685-705.
Published online January 22, 2025
DOI: https://doi.org/10.3350/cmh.2024.1039
The role of the gut microbiome in the development and progression of liver cancer has long been recognized. However, the presence of microbes in tumors that were previously considered sterile has only recently been discovered. The intratumor microbiome in liver cancer likely originates from various sources, including the gut, hematogenous spread from other mucosal locations, adjacent non-cancerous tissues, and co-metastasis with the tumor cells. As a newly discovered component of the tumor microenvironment, it regulates host immune responses, promotes chronic inflammation, modulates metabolic pathways, and exerts other influences in liver cancer. These unique features offer potential new biomarkers for liver cancer prognosis and treatment response. Exploring the complex interactions between intratumor microbiome and the host to modulate or target the intratumor microbiome may provide new avenues for liver cancer treatment. This article provides a comprehensive review of our current understanding regarding the potential origins of the intratumor microbiome in liver cancer, its unique characteristics, and the underlying mechanisms by which it affects liver cancer. Furthermore, we discuss the promising clinical implications and potential challenges that remain before this knowledge can be fully integrated into clinical practice.

Citations

Citations to this article as recorded by  Crossref logo
  • RNA modifications in the tumor microenvironment: insights into the cancer-immunity cycle and beyond
    You-Peng Ding, Cui-Cui Liu, Ke-Da Yu
    Experimental Hematology & Oncology.2025;[Epub]     CrossRef
  • Intratumoral Microbe Correlated with Expression of DNA Methylation Genes in Hepatocellular Carcinoma
    Ashish Kumar, Ajeet Raj, Karan Chaman Lal, Puja
    Digestive Diseases and Sciences.2025;[Epub]     CrossRef
  • 8,739 View
  • 277 Download
  • 2 Web of Science
  • Crossref

Original Article

High Steatosis-Associated Fibrosis Estimator scores predict hepatocellular carcinoma in viral and non-viral hepatitis and metabolic dysfunction-associated steatotic liver disease
Tung-Hung Su, Sheng-Shun Yang, Mei-Hsuan Lee, Wei-Yu Kao, Shang-Chin Huang, Fen-Fang Chen, Francis SK Poon, Lung-Wen Tsai, Yi-Ting Chen, Che Lin, Weichung Wang, W Ray Kim, Jia-Horng Kao
Clin Mol Hepatol 2025;31(3):796-809.
Published online January 6, 2025
DOI: https://doi.org/10.3350/cmh.2024.0822
Background/Aims
There are no hepatocellular carcinoma (HCC) surveillance recommendations for non-viral chronic liver diseases (CLD), such as metabolic dysfunction-associated steatotic liver disease (MASLD). We explored the Steatosis-Associated Fibrosis Estimator (SAFE) score to predict HCC in MASLD and other CLD etiologies.
Methods
Patients with various CLDs were included from medical centers in Taiwan. The SAFE score, consisting of age, body mass index, diabetes, and laboratory data, was calculated at baseline, and patients were traced for new development of HCC. The predictability of the SAFE score for HCC was analyzed using the sub-distribution hazard model with adjustments for competing risks.
Results
Among 12,963 CLD patients with a median follow-up of 4 years, 258 developed HCC. The SAFE score classifies 1-, 3-, and 5-year HCC risk regardless of CLD etiologies. High (≥100) and intermediate (0–100) SAFE scores increased 11 and 2 folds HCC risks compared to low (<0) SAFE scores. Combining two lower risk tiers (SAFE<100), a high SAFE score (≥100) was associated with a 7.5-fold risk of HCC (adjusted sub-distributional hazard ratio [aSHR] 7.54; 95% confidence interval (CI) 5.38–10.60). A high SAFE score increased the risks of HCC in subgroups of viral hepatitis, non-viral hepatitis (aSHR 11.10; 95% CI 3.97–31.30) and MASLD (aSHR 4.23; 95% CI 1.43–12.50). A hospital cohort (n=8,103) and a community MASLD cohort (n=120,166) validated the high SAFE score (≥100) for HCC risk prediction.
Conclusions
The SAFE score stratifies high risks for HCC in CLD patients regardless of etiologies and helps to select at-risk candidates for HCC surveillance.
  • 9,631 View
  • 355 Download

Reviews

Hepatic neoplasm

Gut microbiota-mediated gut-liver axis: a breakthrough point for understanding and treating liver cancer
Chenyang Li, Chujun Cai, Chendong Wang, Xiaoping Chen, Bixiang Zhang, Zhao Huang
Clin Mol Hepatol 2025;31(2):350-381.
Published online December 11, 2024
DOI: https://doi.org/10.3350/cmh.2024.0857
The trillions of commensal microorganisms living in the gut lumen profoundly influence the physiology and pathophysiology of the liver through a unique gut-liver axis. Disruptions in the gut microbial communities, arising from environmental and genetic factors, can lead to altered microbial metabolism, impaired intestinal barrier and translocation of microbial components to the liver. These alterations collaboratively contribute to the pathogenesis of liver disease, and their continuous impact throughout the disease course plays a critical role in hepatocarcinogenesis. Persistent inflammatory responses, metabolic rearrangements and suppressed immunosurveillance induced by microbial products underlie the pro-carcinogenic mechanisms of gut microbiota. Meanwhile, intrahepatic microbiota derived from the gut also emerges as a novel player in the development and progression of liver cancer. In this review, we first discuss the causes of gut dysbiosis in liver disease, and then specify the pivotal role of gut microbiota in the malignant progression from chronic liver diseases to hepatobiliary cancers. We also delve into the cellular and molecular interactions between microbes and liver cancer microenvironment, aiming to decipher the underlying mechanism for the malignant transition processes. At last, we summarize the current progress in the clinical implications of gut microbiota for liver cancer, shedding light on microbiota-based strategies for liver cancer prevention, diagnosis and therapy.

Citations

Citations to this article as recorded by  Crossref logo
  • Gut Microbiota and the Gut–Liver Axis in Liver Disease: From Chronic Viral Hepatitis to Cirrhosis, Hepatocellular Carcinoma, and Microbiome-Based Therapies
    Sniedze Laivacuma, Olga Oblate, Aleksejs Derovs
    Microorganisms.2025; 13(5): 1053.     CrossRef
  • Deciphering the circadian rhythm in colorectal cancer: a bibliometric analysis of research landscape and trends
    Linzi Chen, Zhongjie Wang, Ningkun Xiao, Jinhui Liu, Yuhan Tao, Sifang Zhang
    Frontiers in Oncology.2025;[Epub]     CrossRef
  • Mechanism of activation of the Nrf2-Keap1 pathway by fermented Chinese herbal medicines via the gut-liver axis to alleviate cadmium-induced hepatotoxicity
    Li Jiang, Qiuhong Wu, Yilei Liang, Zhiwen Yang, Guang Fan, Pan Zhou, Xinyue Liu, Yachao Wang
    Environmental Chemistry and Ecotoxicology.2025; 7: 1300.     CrossRef
  • Associations between the effectiveness of sleeve gastrectomy and the composition and function of gut microbiome in obese rats
    Yifan Cao, Songhan Qin, Dandan Liu, Tao Zhang, Yin Wu, Ming Xie, Jiwei Wang
    Journal of Gastrointestinal Surgery.2025; 29(9): 102153.     CrossRef
  • Exploring the Epidemiologic Burden, Pathogenetic Features, and Clinical Outcomes of Primary Liver Cancer in Patients with Type 2 Diabetes Mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Scoping Review
    Mario Romeo, Fiammetta Di Nardo, Carmine Napolitano, Claudio Basile, Carlo Palma, Paolo Vaia, Marcello Dallio, Alessandro Federico
    Diabetology.2025; 6(8): 79.     CrossRef
  • The microbiome–cancer axis as a hidden contributor to early-onset tumorigenesis
    Azfar Jamal, Mohammad Azhar Kamal, Yaser E. Alqurashi, Esam S. Al-Malki, Mohammed M. Naiyer, Syed Arif Hussain, Haroonrashid M. Hattiwale
    Medical Oncology.2025;[Epub]     CrossRef
  • Probiotic-Derived Strain-Specific Metabolites Ameliorate Metabolic Dysfunction–Associated Steatotic Liver Disease through Modulation of the Gut-Liver Axis
    Sang Jun Yoon, Jieun Choi, Sung-Min Won, Jeong Seok Yu, Hee Young Kim, Hyun Chae Joung, In Gyu Park, Jung A Eom, Sang Hak Han, Do Yup Lee, Ki Tae Suk
    Probiotics and Antimicrobial Proteins.2025;[Epub]     CrossRef
  • Tumor microenvironment and macroenvironment: A new perspective on holistic oncology
    Qun Chen, Kuirong Jiang, Michael S. Bronze, Min Li, Courtney W. Houchen, Yuqing Zhang
    Cancer Letters.2025; 634: 218076.     CrossRef
  • Gut–liver axis dysregulation and microbial dysbiosis in invasive liver abscess: a narrative review
    Xiaoshuai Bai, Zhen Wang, Kai Guo, Ping Zhou, Lei Shi
    Frontiers in Immunology.2025;[Epub]     CrossRef
  • The role of hypothyroidism in cirrhosis pathogenesis: A retrospective cohort study and multi-omics integration analysis
    Ziyang Yang, Weixuan Liang, Qi Zhang, Can Weng, Hao Deng, Zhuofeng Wen, Jingyi Wu, Jingwen Deng, Zhixin Xie, Yiwei Lin, Xiuling Fu, Chengxin Gu, Tao Yang, Hui Yang, Jiyuan Zhou, Renato Polimanti
    PLOS Genetics.2025; 21(11): e1011947.     CrossRef
  • Recent Advancements in Known and Emerging Risk Factors of Hepatocellular Carcinoma
    Muhammad Masroor Hussain, Bi Feng, Ju‐Mei Wang, Ao‐Qiang Zhai, Fu‐yu Li, Hai‐jie Hu
    Cancer Medicine.2025;[Epub]     CrossRef
  • Harnessing the microbiota-gut–brain axis to prevent and treat pediatric neurodevelopmental disorders: translational insights and strategies
    Shamma H. Alkuwaiti, Jurga Skrabulyte-Barbulescu, Lidya K. Yassin, Saif Almazrouei, Dana Aldhaheri, Mahra Alderei, Shamsa BaniYas, Shamsa H. Alshamsi, Abeer Alnuaimi, Sara Saeed, Mohammad Alawadhi, Paulina Rutkowska-Gauvry, Fatima Y. Ismail, Mohammad I. K
    Journal of Translational Medicine.2025;[Epub]     CrossRef
  • Gut microbiota–derived metabolites in immunomodulation and gastrointestinal cancer immunotherapy
    Wenbin Luo, Ruoyun Li, Chaofan Pan, Changjiang Luo
    Frontiers in Immunology.2025;[Epub]     CrossRef
  • 8,937 View
  • 359 Download
  • 12 Web of Science
  • Crossref

Hepatic neoplasm

Liquid biopsy in hepatocellular carcinoma: Challenges, advances, and clinical implications
Jaeho Park, Yi-Te Lee, Vatche G. Agopian, Jessica S Liu, Ekaterina K. Koltsova, Sungyong You, Yazhen Zhu, Hsian-Rong Tseng, Ju Dong Yang
Clin Mol Hepatol 2025;31(Suppl):S255-S284.
Published online November 28, 2024
DOI: https://doi.org/10.3350/cmh.2024.0541
Hepatocellular carcinoma (HCC) is an aggressive primary liver malignancy often diagnosed at an advanced stage, resulting in a poor prognosis. Accurate risk stratification and early detection of HCC are critical unmet needs for improving outcomes. Several blood-based biomarkers and imaging tests are available for early detection, prediction, and monitoring of HCC. However, serum protein biomarkers such as alpha-fetoprotein have shown relatively low sensitivity, leading to inaccurate performance. Imaging studies also face limitations related to suboptimal accuracy, high cost, and limited implementation. Recently, liquid biopsy techniques have gained attention for addressing these unmet needs. Liquid biopsy is non-invasive and provides more
objective
readouts, requiring less reliance on healthcare professional’s skills compared to imaging. Circulating tumor cells, cell-free DNA, and extracellular vesicles are targeted in liquid biopsies as novel biomarkers for HCC. Despite their potential, there are debates regarding the role of these novel biomarkers in the HCC care continuum. This review article aims to discuss the technical challenges, recent technical advancements, advantages and disadvantages of these liquid biopsies, as well as their current clinical application and future directions of liquid biopsy in HCC.

Citations

Citations to this article as recorded by  Crossref logo
  • Therapeutic effects of the n-butanol extract of Potentilla freyniana Bornm. in hepatocellular carcinoma cells
    Yan Wang, Zaiqi Zhang, Liang Cao, Sisi Huang, Xi Huang, Ziyang Zhang, Yanbin Zhang, Xiang Li
    Journal of Ethnopharmacology.2026; 354: 120492.     CrossRef
  • Liquid biopsy: Fundamental principles and clinical value in hepatocellular carcinoma
    Anil Chandra Anand, Dibyalochan Praharaj, Preetam Nath
    Journal of Integrative Medicine and Research.2025; 3(3): 148.     CrossRef
  • Prognostic Significance of Liquid Biopsy-Detected Genetic Alterations in Hepatocellular Carcinoma
    Ahmet Gökhan Sarıtaş, Burak Yavuz, İshak Aydın, Harun Ağca, Uğur Topal, Tuğsan Ballı, Atil Bisgin, Abdullah Ülkü, Atılgan Tolga Akçam
    Journal of Hepatocellular Carcinoma.2025; Volume 12: 2035.     CrossRef
  • Electrochemical Biosensor Based on a Tetrahedral DNA Nanostructure and an “AND” Logic Gate-Regulated Cascade Amplification System for Parallel Detection of Dual Disease Biomarkers
    Li Yang, Ya Zhou, Huimin Li, Yao Gao, Xiaoli Xiong, Tao Zhang, Liping Zhu, Xiurong Yang
    ACS Sensors.2025; 10(10): 7744.     CrossRef
  • Machine Learning-based Gene Biomarker Identification for Improving Prognosis and Therapy in Hepatocellular Carcinoma
    Lingyan Deng, Lei Dou, Xinyu Huang, Peng Wang, Na Shen
    Current Medicinal Chemistry.2025; 32(39): 8975.     CrossRef
  • Preclinical Studies on the Photothermal Therapy of NIR‐II AIEgens: Across Tumor Types
    Zijuan Meng, Xiaohua Ji, Shengyan Yin, Zhen Zhang, Ruihua Dong, Zheng Zhao, Ben Zhong Tang
    Small.2025;[Epub]     CrossRef
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Correspondences

Hepatic neoplasm

Correspondence to letter to the editor on “Transarterial radioembolization versus tyrosine kinase inhibitor in hepatocellular carcinoma with portal vein thrombosis”
Moon Haeng Hur, Yoon Jun Kim
Clin Mol Hepatol 2025;31(1):e93-e95.
Published online November 6, 2024
DOI: https://doi.org/10.3350/cmh.2024.0943
  • 3,924 View
  • 50 Download

Hepatic neoplasm

Correspondence to editorial 2 on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 trial”
Sun Young Yim, Sung Hwan Lee, Ji Hoon Kim, Sunyoung S Lee, Ahmed O Kaseb, Ju-Seog Lee
Clin Mol Hepatol 2025;31(1):e84-e86.
Published online October 7, 2024
DOI: https://doi.org/10.3350/cmh.2024.0830
  • 4,014 View
  • 46 Download

Hepatic neoplasm

Correspondence to editorial 1 on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: insights from the IMbrave150 Trial”
Sung Hwan Lee, Sun Young Yim, Ji Hoon Kim, Sunyoung S. Lee, Ahmed O. Kaseb, Ju-Seog Lee
Clin Mol Hepatol 2025;31(1):e81-e83.
Published online October 7, 2024
DOI: https://doi.org/10.3350/cmh.2024.0829

Citations

Citations to this article as recorded by  Crossref logo
  • Reply to correspondence on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”
    Hiroaki Kanzaki, Yujin Hoshida
    Clinical and Molecular Hepatology.2025; 31(1): e121.     CrossRef
  • 4,193 View
  • 43 Download
  • Crossref

Hepatic neoplasm

Correspondence to letter to the editor on “Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial”
Sung Hwan Lee, Sun Young Yim, Ji Hoon Kim, Sunyoung S Lee, Ahmed O Kaseb, Peng Wei, Ju-Seog Lee
Clin Mol Hepatol 2025;31(1):e110-e112.
Published online October 2, 2024
DOI: https://doi.org/10.3350/cmh.2024.0828
  • 3,978 View
  • 57 Download

Viral hepatitis

Correspondence to letter to the editor on “Non-linear association between liver fibrosis scores and viral load in patients with chronic hepatitis B”
Gi-Ae Kim, Seung Won Choi, Young-Suk Lim
Clin Mol Hepatol 2025;31(1):e108-e109.
Published online August 5, 2024
DOI: https://doi.org/10.3350/cmh.2024.0619
  • 4,258 View
  • 40 Download

Editorial

From past to pandemic: Health disparities in US hepatobiliary cancer mortality before and during COVID-19: Editorial on “Burden of mortality from hepatocellular carcinoma and biliary tract cancers by race and ethnicity and sex in US, 2018–2023”
Ilona Argirion
Clin Mol Hepatol 2025;31(1):286-289.
Published online August 5, 2024
DOI: https://doi.org/10.3350/cmh.2024.0597
  • 5,574 View
  • 41 Download

Original Article

Viral hepatitis

Non-linear association between liver fibrosis scores and viral load in patients with chronic hepatitis B
Gi-Ae Kim, Seung Won Choi, Seungbong Han, Young-Suk Lim
Clin Mol Hepatol 2024;30(4):793-806.
Published online July 19, 2024
DOI: https://doi.org/10.3350/cmh.2024.0252
Background/Aims
Serum hepatitis B virus (HBV) DNA levels and non-invasive liver fibrosis scores are significantly associated with hepatocellular carcinoma (HCC) risk in chronic hepatitis B (CHB) patients. Nonetheless, the relationship between HBV DNA levels and liver fibrosis scores is unclear.
Methods
A historical cohort comprising 6,949 non-cirrhotic Korean CHB patients without significant alanine aminotransferase elevation was investigated. The association of HBV DNA levels with the aspartate aminotransferase to platelet ratio index (APRI) and fibrosis (FIB)-4 score at baseline was analyzed using general linear models.
Results
In HBeAg-negative patients (n=4,868), HBV DNA levels correlated linearly with both APRI and FIB-4 scores. In contrast, in HBeAg-positive patients (n=2,081), HBV DNA levels correlated inversely with both APRI and FIB-4 scores. Across the entire cohort, a significant non-linear parabolic relationship was identified between HBV DNA levels and fibrosis scores, independent of age and other covariates. Notably, moderate viral loads (6–7 log10 IU/mL) corresponded to the highest APRI and FIB-4 scores (p<0.001). Over a median 10-year follow-up, 435 patients (6.3%) developed HCC. Higher APRI scores ≥0.5 and FIB-4 scores ≥1.45 were significantly associated with elevated HCC risk (p<0.001 for both). HBV DNA level remained a significant predictive factor for HCC development, even after adjusting for APRI or FIB-4 scores.
Conclusions
HBV viral load is significantly correlated with APRI and FIB-4 scores, and is also associated with HCC risk independent of those scores in CHB patients. These findings suggest that HBV DNA level is associated with hepatocarcinogenesis through both direct and indirect pathways.

Citations

Citations to this article as recorded by  Crossref logo
  • Presence of liver fibrosis in chronic hepatitis B patients with varying serum hepatitis B virus DNA levels: Letter to the editor on “Non-linear association between liver fibrosis scores and viral load in patients with chronic hepatitis B”
    Jian Wang, Shaoqiu Zhang, Chuanwu Zhu, Yuanwang Qiu, Chao Wu, Rui Huang
    Clinical and Molecular Hepatology.2025; 31(1): e27.     CrossRef
  • Correspondence to letter to the editor on “Non-linear association between liver fibrosis scores and viral load in patients with chronic hepatitis B”
    Gi-Ae Kim, Seung Won Choi, Young-Suk Lim
    Clinical and Molecular Hepatology.2025; 31(1): e108.     CrossRef
  • Early antiviral treatment with tenofovir alafenamide to prevent serious clinical adverse events in adults with chronic hepatitis B and moderate or high viraemia (ATTENTION): interim results from a randomised controlled trial
    Young-Suk Lim, Ming-Lung Yu, Jonggi Choi, Chi-Yi Chen, Won-Mook Choi, Wonseok Kang, Gi-Ae Kim, Hyung Joon Kim, Yun Bin Lee, Jeong-Hoon Lee, Neung Hwa Park, So Young Kwon, Soo Young Park, Ji Hoon Kim, Gwang Hyeon Choi, Eun Sun Jang, Chien-Hung Chen, Yao-Ch
    The Lancet Gastroenterology & Hepatology.2025; 10(4): 295.     CrossRef
  • Aspartate aminotransferase-to-platelet ratio index as a novel predictor of early mortality in heat stroke patients: a multi-centre retrospective study
    Min Wang, Yun Li, Yuan Cao, Meng-Meng Yang, Fu-Jing Liu, Jie Jiao, Sheng-Yuan Wang, Bin Song, Lu Wang, Yi-Qi Wu, Hong-Jun Kang
    Annals of Medicine.2025;[Epub]     CrossRef
  • Head‐to‐Head Comparison of Long‐Term HCC Risk of Antivirals‐Treated Versus Untreated Low‐Level Viremia in HBV‐Compensated Cirrhosis
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    Journal of Gastroenterology and Hepatology.2025; 40(6): 1595.     CrossRef
  • HBV activates hepatic stellate cells through RUNX2/ITGBL1 axis
    Fengchun Shi, Wei Tan, Wei Huang, Fei Ye, Mingjie Wang, Yongxiang Wang, Xinxin Zhang, Demin Yu
    Virology Journal.2025;[Epub]     CrossRef
  • EASL Clinical Practice Guidelines on the management of hepatitis B virus infection
    Markus Cornberg, Lisa Sandmann, Jerzy Jaroszewicz, Patrick Kennedy, Pietro Lampertico, Maud Lemoine, Sabela Lens, Barbara Testoni, Grace Lai-Hung Wong, Francesco Paolo Russo
    Journal of Hepatology.2025; 83(2): 502.     CrossRef
  • Geospatial patterns and socioeconomic determinants of the global acute viral hepatitis burden
    Ke-Jie He, Guoyu Gong
    Frontiers in Public Health.2025;[Epub]     CrossRef
  • Reevaluating antiviral thresholds in HBV DNA-negative inactive HBsAg carriers: a multicenter histopathological analysis
    Shan Ren, Sujun Zheng, Xinyang Zhang, Junliang Fu, Rongshan Fan, Qingfa Ruan, Wenqi Huang, Haibing Gao, Xiulan Xue, Fang Yang, Yao Xie, Minghui Li, Xinyue Chen
    Virology Journal.2025;[Epub]     CrossRef
  • Evaluating Non-Invasive Biomarkers and Composite Scores for Liver Fibrosis Diagnosis in Hepatitis B and C Infections
    Tamer A. Addissouky, Ibrahim El Tantawy El Sayed, Ayman E. El Agroudy, Yuliang Wang
    SN Comprehensive Clinical Medicine.2025;[Epub]     CrossRef
  • Viral Load–Based Prediction of Hepatocellular Carcinoma Risk in Noncirrhotic Patients With Chronic Hepatitis B
    Gi-Ae Kim, Young-Suk Lim
    Annals of Internal Medicine.2025; 178(9): 1365.     CrossRef
  • Revised REACH-B Model for Hepatocellular Carcinoma Risk Prediction in Patients With Chronic Hepatitis B
    Ju Dong Yang, Patrick S. Kamath
    Annals of Internal Medicine.2024; 177(10): 1435.     CrossRef
  • Decrease in HBsAg After TAF Switching from Entecavir During Long-Term Treatment of Chronic Hepatitis B Virus Infection
    Kazuto Tajiri, Yuka Hayashi, Aiko Murayama, Nozomu Muraishi, Masami Minemura, Ichiro Yasuda
    Viruses.2024; 17(1): 44.     CrossRef
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  • Crossref

Letter to the Editor

Hepatic neoplasm

Dipeptidyl peptidase-4 inhibitors are associated with improved survival of patients with diabetes mellitus and hepatocellular carcinoma receiving immunotherapy: Letter to the editor on “Statin and aspirin for chemoprevention of hepatocellular carcinoma: Time to use or wait further?”
Dorothy Cheuk-Yan Yiu, Huapeng Lin, Vincent Wai-Sun Wong, Grace Lai-Hung Wong, Ken Liu, Terry Cheuk-Fung Yip
Clin Mol Hepatol 2024;30(4):970-973.
Published online July 4, 2024
DOI: https://doi.org/10.3350/cmh.2024.0280

Citations

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  • CXCL12 as a Potential Hub Gene for N-Acetylcysteine Treatment of T1DM Liver Disease
    Menglong Zhao, Mingzheng Han, Shuaihao Guo, Zhaoxin Tang
    Biomolecules.2025; 15(2): 176.     CrossRef
  • Comparative Risk of Hepatitis B Virus Reactivation in Patients Receiving Immune Checkpoint Inhibitors or Tyrosine Kinase Inhibitors for Liver Cancer
    Dorothy Cheuk‐Yan Yiu, Jimmy Che‐To Lai, Landon Long Chan, Grace Lai‐Hung Wong, Mandy Sze‐Man Lai, Vincent Wai‐Sun Wong, Yee‐Kit Tse, Henry Lik‐Yuen Chan, Stephen Lam Chan, Terry Cheuk‐Fung Yip
    Alimentary Pharmacology & Therapeutics.2025;[Epub]     CrossRef
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    Shuhei Kamada, Sachi Kitayama, Ryosuke Yamase, Kazuhiro Ikeda, Wataru Sato, Tomokazu Sazuka, Hideki Takeshita, Shinichi Sakamoto, Akihiro Yano, Kuniko Horie, Tomohiko Ichikawa, Satoru Kawakami, Satoshi Inoue
    Cancer Science.2025;[Epub]     CrossRef
  • 3,930 View
  • 71 Download
  • 3 Web of Science
  • Crossref

Editorial

Hepatic neoplasm

Engineering HBV-specific T cells for the treatment of HBV-related HCC and HBV infection: Past, Present, and Future. Editorial on “Genetically-modified, redirected T cells target hepatitis B surface antigen-positive hepatocytes and hepatocellular carcinoma lesions in a clinical setting”
Antonio Bertoletti, Anthony T Tan
Clin Mol Hepatol 2024;30(4):728-734.
Published online June 27, 2024
DOI: https://doi.org/10.3350/cmh.2024.0469

Citations

Citations to this article as recorded by  Crossref logo
  • Reply to correspondence on “Genetically-modified, redirected T cells target hepatitis B surface antigen-positive hepatocytes and hepatocellular carcinoma lesions in a clinical setting”
    Antonio Bertoletti, Anthony T Tan
    Clinical and Molecular Hepatology.2025; 31(1): e113.     CrossRef
  • Correspondence to editorial on “Genetically-modified, redirected T cells target hepatitis B surface antigen-positive hepatocytes and hepatocellular carcinoma lesions in a clinical setting”
    Shunda Du, Karin Wisskirchen, Ke Zhang, Ulrike Protzer
    Clinical and Molecular Hepatology.2025; 31(1): e44.     CrossRef
  • Viral oncogenesis in cancer: from mechanisms to therapeutics
    Qing Xiao, Yi Liu, Tingting Li, Chaoyu Wang, Sanxiu He, Liuyue Zhai, Zailin Yang, Xiaomei Zhang, Yongzhong Wu, Yao Liu
    Signal Transduction and Targeted Therapy.2025;[Epub]     CrossRef
  • M1‐Like Macrophage May Contribute to the Inflammation and Fibrosis Process of Chronic Hepatitis B
    Yuxue Gao, Pengxiang Yang, Yuanyue Guan, Pengxiang Liu, Dexi Chen, Qiqi Ning
    Journal of Viral Hepatitis.2025;[Epub]     CrossRef
  • Viral oncogenesis and immune remodeling: Decoding the therapeutic potential of immune checkpoint inhibitors in virus-associated cancers
    Lihua Qi, Bai Hu, Canhui Cao, Ting Peng, Miaochun Xu, Shiyi Liu, Yashi Xu, Xiaojie Liu, Wencheng Ding, Li Li, Shitong Lin
    Biomedicine & Pharmacotherapy.2025; 191: 118515.     CrossRef
  • T cells engineered to carry a high-affinity HBV-specific T cell receptor: a potent weapon against advanced HBV-related HCC
    Robert Thimme, Christoph Neumann-Haefelin
    Gut.2025; : gutjnl-2025-336452.     CrossRef
  • Adoptive T-cell therapy for virus-associated diseases
    Corey Smith, Rajiv Khanna, Graeme N. Forrest
    Clinical Microbiology Reviews.2025;[Epub]     CrossRef
  • HBV-Specific TCR–T Cell Therapy Combining mRNA Electroporation and Lentiviral Transduction: Treatment Regimen for Recurrent HBV-Related HCC after Liver Transplantation
    Qiang Zhao, Jinbo Huang, Weixin Luo, Haidong Tan, Regina Wan Ju Wong, Zhiying Liu, Meiting Qin, Jiahao Li, Sarene Koh, Lu-En Wai, Tingting Wang, Jia Dan, Zhiyong Guo, Xiaoshun He
    Clinical Cancer Research.2025; 31(18): 3886.     CrossRef
  • Combination therapies for chronic hepatitis B in the era of emerging novel drugs
    Dandan Weng, Chenxi Zhang, Qunyan Wei, Lukan Zhang, Xinya Zang, Guancheng Huang, Zhujun Cao, Qing Xie
    Hepatology International.2025;[Epub]     CrossRef
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    Shan He, Anthony T. Tan, Antonio Bertoletti
    Seminars in Immunology.2025; 80: 102004.     CrossRef
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  • 109 Download
  • 10 Web of Science
  • Crossref

Original Article

Hepatic neoplasm

Burden of mortality from hepatocellular carcinoma and biliary tract cancers by race and ethnicity and sex in US, 2018–2023
Donghee Kim, Richie Manikat, Karn Wijarnpreecha, George Cholankeril, Aijaz Ahmed
Clin Mol Hepatol 2024;30(4):756-770.
Published online June 24, 2024
DOI: https://doi.org/10.3350/cmh.2024.0318
Backgrounds/Aims
The trends in mortality of hepatocellular carcinoma (HCC) and biliary tract cancers stratified by sex and race/ethnicity in the US continue to evolve. We estimated the sex- and race/ethnicity-based trends in HCC and biliary tract cancers-related mortality in US adults with a focus on disease burden.
Methods
We performed a population-based analysis using the US national mortality records from 2018 to 2023. We identified HCC and biliary tract cancer using appropriate ICD-10 codes. Temporal trends in mortality were calculated by joinpoint analysis with annual percentage change (APC).
Results
Annual age-standardized mortality from HCC decreased steadily with an APC of –1.4% (95% confidence interval [CI]: –2.0% to –0.7%). While there was a linear increase in intrahepatic cholangiocarcinoma-related mortality (APC: 3.1%, 95% CI: 1.2–4.9%) and ampulla of Vater cancer-related mortality (APC: 4.1%, 95% CI: 0.5–7.9%), gallbladder cancer-related mortality decreased (APC: –1.9%, 95% CI: –3.8% to –0.0%). Decreasing trends in mortality from HCC were noted in males, not females. HCC-related mortality decreased more steeply in racial and ethnic minority individuals compared with non-Hispanic White individuals. Racial and ethnic differences in trends in mortality for biliary tract cancers depended on the malignancy’s anatomical site.
Conclusions
While the annual mortality for HCC and gallbladder cancer demonstrated declining trends, ICC- and AVC-related mortality continued to increase from 2018 to 2023. Although racial and ethnic minority individuals in the US experienced disproportionately higher HCC and biliary tract cancer, recent declines in HCC may be primarily due to declines among racial and ethnic minority individuals and males.

Citations

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  • Global Burden, Trends, and Inequalities of Gallbladder and Biliary Tract Cancer, 1990–2021: A Decomposition and Age–Period–Cohort Analysis
    Sen Lei, Guizhong Huang, Xiaohui Li, Pu Xi, Zehui Yao, Xiaojun Lin
    Liver International.2025;[Epub]     CrossRef
  • Alcohol–Related Liver Disease, Followed by Metabolic Dysfunction–Associated Steatotic Liver Disease, Emerges as the Fastest‐Growing Aetiologies for Primary Liver Cancer in the United States
    Pojsakorn Danpanichkul, Kwanjit Duangsonk, Markos Kalligeros, Michael B. Fallon, Chawinthorn Vuthithammee, Chun Wei Pan, Preenapun Saokhieo, William Derrick, Yanfang Pang, Vincent L. Chen, Donghee Kim, Amit G. Singal, Ju Dong Yang, Karn Wijarnpreecha
    Alimentary Pharmacology & Therapeutics.2025; 61(6): 959.     CrossRef
  • Increased MASH-associated liver cancer in younger demographics
    Pojsakorn Danpanichkul, Yanfang Pang, Kanokphong Suparan, Thanida Auttapracha, Supapitch Sirimangklanurak, Abdelrahman M. Attia, Chanattha Thimphitthaya, Michelle Shi Ni Law, Zhenning Yu, Mostafa A. Soliman, Natchaya Polpichai, Chanakarn Kanitthamniyom, D
    Hepatology Communications.2025;[Epub]     CrossRef
  • Contemporary awareness of viral hepatitis between 2012 and 2022 among Korean adults
    Donghee Kim, Won Kim, Aijaz Ahmed
    Clinical and Molecular Hepatology.2025; 31(1): e5.     CrossRef
  • Long-term outcomes and risk modifiers of metabolic dysfunction-associated steatotic liver disease between lean and non-lean populations
    Pojsakorn Danpanichkul, Kanokphong Suparan, Vitchapong Prasitsumrit, Aijaz Ahmed, Karn Wijarnpreecha, Donghee Kim
    Clinical and Molecular Hepatology.2025; 31(1): 74.     CrossRef
  • From past to pandemic: Health disparities in US hepatobiliary cancer mortality before and during COVID-19: Editorial on “Burden of mortality from hepatocellular carcinoma and biliary tract cancers by race and ethnicity and sex in US, 2018–2023”
    Ilona Argirion
    Clinical and Molecular Hepatology.2025; 31(1): 286.     CrossRef
  • The burden of steatotic liver disease before and during the COVID-19 pandemic: Correspondence to editorial on “Current burden of steatotic liver disease and fibrosis among adults in the United States, 2017-2023”
    Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Rohit Loomba, Aijaz Ahmed
    Clinical and Molecular Hepatology.2025; 31(2): e183.     CrossRef
  • Integrating expert knowledge with machine learning for AI-based stroke identifications and treatment systems
    Taddesse kassu Yimenu, Abebe Belay Adege, Sofonias Yitagesu Techan
    DIGITAL HEALTH.2025;[Epub]     CrossRef
  • Contemporary burden of mortality from chronic liver disease by sex and race/ethnicity in the United States
    Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Aijaz Ahmed
    Clinical and Molecular Hepatology.2025; 31(3): e268.     CrossRef
  • Rising drug overdose deaths in chronic liver disease in the United States, 2015–2023
    Donghee Kim, Brittany B Dennis, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Aijaz Ahmed
    Clinical and Molecular Hepatology.2025; 31(3): e277.     CrossRef
  • Epidemiological trends and burden of gallbladder and biliary tract cancer in Belt and Road Initiative countries: A comprehensive analysis from the Global Burden of Disease 2021 database
    Hao Wu, Qian-Qian Feng, Jian-Hui Li, Hai-Yang Xie, Shi-Gui Yang, Shu-Sen Zheng
    Hepatobiliary & Pancreatic Diseases International.2025;[Epub]     CrossRef
  • Extrahepatic manifestation of metabolic dysfunction-associated steatotic liver disease
    Anoushka Shenoy, Aijaz Ahmed, Donghee Kim
    Metabolism and Target Organ Damage.2025;[Epub]     CrossRef
  • Paired snRNA-seq and scRNA-seq analysis of MASLD patients to identify early-stage markers for disease progression
    Suebin Park, Su-Hyeon Lee, Se-eun Han, Beom Kyung Kim, Byungjin Hwang
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  • Construction and validation of a novel prognostic model for postoperative patients with stage I intrahepatic cholangiocarcinoma: a population-based study
    Xiaomeng Yao, Xinru Fan, Qing Wang, Huabang Zhou, Hui Wang, Heping Hu
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  • Even Lower Alcohol Intake Might Be Harmful for East Asian Males With MASLD Spectrum
    Byungyoon Yun, Juyeon Oh, Heejoo Park, Jian Lee, Beom Kyung Kim, Jin-Ha Yoon
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  • Multi-omic analysis reveals elevated BRI3BP expression associated with hepatocellular carcinoma progression and poor prognosis
    Ling Liu, Ye Wang, Jintao Zheng, Lixin Zhou, Chenao Yang, Jiachen Zhang, Changku Jia
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    Yang Zhang, Yixiang Gu, Ming Zhan, Linhua Yang, Hui Wang
    Molecular Biomedicine.2025;[Epub]     CrossRef
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  • Crossref

Editorial

Hepatic neoplasm

Unveiling etiology-specific blood biomarkers in hepatocellular carcinoma: A gateway to personalized medicine: Editorial on “Multiomics profiling of buffy coat and plasma unveils etiology-specific signatures in hepatocellular carcinoma”
Joseph C. Ahn, Ju Dong Yang
Clin Mol Hepatol 2024;30(4):689-691.
Published online May 14, 2024
DOI: https://doi.org/10.3350/cmh.2024.0348

Citations

Citations to this article as recorded by  Crossref logo
  • Correspondence: Response to the Letter Regarding "GULP1 as a Novel Diagnostic and Predictive Biomarker in Hepatocellular Carcinoma"
    Hyung Seok Kim, Soon Sun Kim, Jae Youn Cheong, Jung Woo Eun
    Clinical and Molecular Hepatology.2025;[Epub]     CrossRef
  • Metabolites involvement in the growth and spread of liver cancer
    Anurag Kumar Gautam, Vipin Kumar, Archana Bharti Sonkar, Amita Singh, Deepankar Yadav, Nitin Rajan, Pranesh Kumar, Sanjay Singh, Sudipta Saha, Vijayakumar Mahalingam Rajamanickam
    Liver Research.2025;[Epub]     CrossRef
  • Correspondence to editorial on “Multiomics profiling of buffy coat and plasma unveils etiology-specific signatures in hepatocellular carcinoma”
    Su Bin Lim, Hyo Jung Cho
    Clinical and Molecular Hepatology.2024; 30(4): 1009.     CrossRef
  • 4,219 View
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  • 1 Web of Science
  • Crossref

Original Article

Viral hepatitis

Extrahepatic malignancies and antiviral drugs for chronic hepatitis B: A nationwide cohort study
Moon Haeng Hur, Dong Hyeon Lee, Jeong-Hoon Lee, Mi-Sook Kim, Jeayeon Park, Hyunjae Shin, Sung Won Chung, Hee Jin Cho, Min Kyung Park, Heejoon Jang, Yun Bin Lee, Su Jong Yu, Sang Hyub Lee, Yong Jin Jung, Yoon Jun Kim, Jung-Hwan Yoon
Clin Mol Hepatol 2024;30(3):500-514.
Published online May 10, 2024
DOI: https://doi.org/10.3350/cmh.2024.0055
Background/Aims
Chronic hepatitis B (CHB) is related to an increased risk of extrahepatic malignancy (EHM), and antiviral treatment is associated with an incidence of EHM comparable to controls. We compared the risks of EHM and intrahepatic malignancy (IHM) between entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment.
Methods
Using data from the National Health Insurance Service of Korea, this nationwide cohort study included treatment-naïve CHB patients who initiated ETV (n=24,287) or TDF (n=29,199) therapy between 2012 and 2014. The primary outcome was the development of any primary EHM. Secondary outcomes included overall IHM development. E-value was calculated to assess the robustness of results to unmeasured confounders.
Results
The median follow-up duration was 5.9 years, and all baseline characteristics were well balanced after propensity score matching. EHM incidence rate differed significantly between within versus beyond 3 years in both groups (P<0.01, Davies test). During the first 3 years, EHM risk was comparable in the propensity score-matched cohort (5.88 versus 5.84/1,000 person-years; subdistribution hazard ratio [SHR]=1.01, 95% confidence interval [CI]=0.88–1.17, P=0.84). After year 3, however, TDF was associated with a significantly lower EHM incidence compared to ETV (4.92 versus 6.91/1,000 person-years; SHR=0.70, 95% CI=0.60–0.81, P<0.01; E-value for SHR=2.21). Regarding IHM, the superiority of TDF over ETV was maintained both within (17.58 versus 20.19/1,000 person-years; SHR=0.88, 95% CI=0.81–0.95, P<0.01) and after year 3 (11.45 versus 16.20/1,000 person-years; SHR=0.68, 95% CI=0.62–0.75, P<0.01; E-value for SHR=2.30).
Conclusions
TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.

Citations

Citations to this article as recorded by  Crossref logo
  • Chronic hepatitis B, extrahepatic malignancies and the use of antiviral drugs
    Meng-Che Wu, Shih-Chi Yang, Shuo-Yan Gau
    Clinical and Molecular Hepatology.2025; 31(1): e19.     CrossRef
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    Miao Miao, Yuelei Chen, Xuehan Wang, Shengyang Li, Rong Hu
    Virulence.2025;[Epub]     CrossRef
  • Antiviral Therapy Reduces Dyslipidemia and Cardiovascular Risk in Chronic Hepatitis B: TDF as the Most Effective Agent
    Hyuk Kim, Jae‐Young Kim, Hyun Bin Choi, Ji‐Soo Lee, Yoon E. Shin, Jeong‐Ju Yoo, Sang Gyune Kim, Young‐Seok Kim
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Editorial

Hepatic neoplasm

Unlocking the future: Machine learning sheds light on prognostication for early-stage hepatocellular carcinoma: Editorial on “Conventional and machine learning-based risk scores for patients with early-stage hepatocellular carcinoma”
Junlong Dai, Jimmy Che-To Lai, Grace Lai-Hung Wong, Terry Cheuk-Fung Yip
Clin Mol Hepatol 2024;30(4):698-701.
Published online May 7, 2024
DOI: https://doi.org/10.3350/cmh.2024.0327

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Original Article

Hepatic neoplasm

Prognostic value of ultra-low-pass whole-genome sequencing of circulating tumor DNA in hepatocellular carcinoma under systemic treatment
Miguel Sogbe, Idoia Bilbao, Francesco P. Marchese, Jon Zazpe, Annarosaria De Vito, Marta Pozuelo, Delia D’Avola, Mercedes Iñarrairaegui, Carmen Berasain, Maria Arechederra, Josepmaria Argemi, Bruno Sangro
Clin Mol Hepatol 2024;30(2):177-190.
Published online December 29, 2023
DOI: https://doi.org/10.3350/cmh.2023.0426
Background/Aims
New prognostic markers are needed to identify patients with hepatocellular carcinoma (HCC) who carry a worse prognosis. Ultra-low-pass whole-genome sequencing (ULP-WGS) (≤0.5× coverage) of cell-free DNA (cfDNA) has emerged as a low-cost promising tool to assess both circulating tumor DNA (ctDNA) fraction and large structural genomic alterations. Here, we studied the performance of ULP-WGS of plasma cfDNA to infer prognosis in patients with HCC.
Methods
Plasma samples were obtained from patients with HCC prior to surgery, locoregional or systemic therapy, and were analyzed by ULP-WGS of cfDNA to an average genome-wide fold coverage of 0.3x. ctDNA and copy number alterations (CNA) were estimated using the software package ichorCNA.
Results
Samples were obtained from 73 HCC patients at different BCLC stages (BCLC 0/A: n=37, 50.7%; BCLC B/C: n=36, 49.3%). ctDNA was detected in 18 out of 31 patients who received systemic treatment. Patients with detectable ctDNA showed significantly worse overall survival (median, 13.96 months vs not reached). ctDNA remained an independent predictor of prognosis after adjustment by clinical-pathologic features and type of systemic treatment (hazard ratio 7.69; 95%, CI 2.09–28.27). Among ctDNA-positive patients under systemic treatments, the loss of large genomic regions in 5q and 16q arms was associated with worse prognosis after multivariate analysis.
Conclusions
ULP-WGS of cfDNA provides clinically relevant information about the tumor biology. The presence of ctDNA and the loss of 5q and 16q arms in ctDNA-positive patients are independent predictors of worse prognosis in patients with advanced HCC receiving systemic therapy.

Citations

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Review

Hepatic neoplasm

Recent advances in the management of hepatocellular carcinoma
Kamya Sankar, Jun Gong, Arsen Osipov, Steven A. Miles, Kambiz Kosari, Nicholas N. Nissen, Andrew E. Hendifar, Ekaterina K. Koltsova, Ju Dong Yang
Clin Mol Hepatol 2024;30(1):1-15.
Published online July 21, 2023
DOI: https://doi.org/10.3350/cmh.2023.0125
Liver cancer remains a challenge of global health, being the 4th leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and is usually precipitated by chronic viral infections (hepatitis B and C), non-alcoholic steatohepatitis, heavy alcohol use, and other factors which may lead to chronic inflammation and cirrhosis of the liver. There have been significant advances in the systemic treatment options for HCC over the past decades, with several approvals of both immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with preserved liver function. These advances have led to improvement in survival outcomes, with expected survival of greater than 18 months, in those with sensitive tumors, adequate liver function, and those functionally fit to receive sequential therapies. Several ongoing and promising trials are now evaluating combinational strategies with novel systemic agents and combinations of systemic therapy with locoregional therapy. In view of these trials, further advances in the treatment of HCC are foreseen in the near future.

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Snapshot

Hepatic neoplasm

Systemic therapy in advanced hepatocellular carcinoma
Joseph C. Ahn, Nguyen H. Tran, Ju Dong Yang
Clin Mol Hepatol 2023;29(2):516-519.
Published online February 20, 2023
DOI: https://doi.org/10.3350/cmh.2023.0051

Citations

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Review

Hepatic neoplasm

Clinical practice guidelines and real-life practice in hepatocellular carcinoma: A Taiwan perspective
Tung-Hung Su, Chih-Horng Wu, Tsung-Hao Liu, Cheng-Maw Ho, Chun-Jen Liu
Clin Mol Hepatol 2023;29(2):230-241.
Published online January 30, 2023
DOI: https://doi.org/10.3350/cmh.2022.0421
Hepatocellular carcinoma (HCC) is the fourth most common cancer and the second leading cause of cancer-related death in Taiwan. The Taiwan Liver Cancer Association and the Gastroenterological Society of Taiwan developed and updated the guidelines for HCC management in 2020. In clinical practice, we follow these guidelines and the reimbursement policy of the government. In Taiwan, abdominal ultrasonography, alpha-fetoprotein, and protein induced by vitamin K absence or antagonist-II (PIVKA-II) tests are performed for HCC surveillance every 6 months or every 3 months for high-risk patients. Dynamic computed tomography, magnetic resonance imaging, and contrast-enhanced ultrasound have been recommended for HCC surveillance in extremely high-risk patients or those with poor ultrasonographic visualization results. HCC is usually diagnosed through dynamic imaging, and pathological diagnosis is recommended. Staging of HCC is based on a modified version of the Barcelona Clinic Liver Cancer (BCLC) system, and the HCC management guidelines in Taiwan actively promote curative treatments including surgery and locoregional therapy for BCLC stage B or C patients. Transarterial chemoembolization (TACE), drug-eluting bead TACE, transarterial radioembolization, and hepatic artery infusion chemotherapy may be administered for patients with BCLC stage B or C HCC. Sorafenib and lenvatinib are reimbursed as systemic therapies, and regorafenib and ramucirumab may be reimbursed in cases of sorafenib failure. First-line atezolizumab with bevacizumab is not yet reimbursed but may be administered in clinical practice. Systemic therapy and external beam radiation therapy may be used in specific patients. Early switching to systemic therapy in TACE-refractory patients is a recent paradigm shift in HCC management.

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Original Article

Hepatic neoplasm

Global burden of primary liver cancer and its association with underlying aetiologies, sociodemographic status, and sex differences from 1990–2019: A DALY-based analysis of the Global Burden of Disease 2019 study
Sungchul Choi, Beom Kyung Kim, Dong Keon Yon, Seung Won Lee, Han Gyeol Lee, Ho Hyeok Chang, Seoyeon Park, Ai Koyanagi, Louis Jacob, Elena Dragioti, Joaquim Radua, Jae Il Shin, Seung Up Kim, Lee Smith
Clin Mol Hepatol 2023;29(2):433-452.
Published online January 4, 2023
DOI: https://doi.org/10.3350/cmh.2022.0316
Background/Aims
Global distribution of dominant liver cancer aetiologies has significantly changed over the past decades. This study analyzed the updated temporal trends of liver cancer aetiologies and sociodemographic status in 204 countries and territories from 1990 to 2019.
Methods
The Global Burden of Disease 2019 report was used for statistical analysis. In addition, we performed stratification analysis to five quintiles using sociodemographic index and 21 geographic regions.
Results
The crude numbers of liver cancer disease-adjusted life years (DALYs) and deaths significantly increased during the study period (DALYs; 11,278,630 in 1990 and 12,528,422 in 2019, deaths; 365,215 in 1990 and 484,577 in 2019). However, the Age-standardized DALY and mortality rates decreased. Hepatitis B virus (HBV) remains the leading cause of liver cancer DALYs and mortality, followed by hepatitis C virus (HCV), alcohol consumption, and non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (NASH/NAFLD). Although Age-standardized DALY and mortality rates of liver cancer due to HBV and HCV have decreased, the rates due to alcohol consumption and NASH/NAFLD have increased. In 2019, the population of the East Asia region had the highest Age-standardized DALY and mortality rates, followed by high-income Asia-Pacific and Central Asia populations. Although East Asia and high-income Asia-Pacific regions showed a decrease during the study period, Age-standardized DALY rates increased in Central Asia. High-income North American and Australasian populations also showed a significant increase in Age-standardized DALY.
Conclusions
Liver cancer remains an ongoing global threat. The burden of liver cancer associated with alcohol consumption and NASH/NAFLD is markedly increasing and projected to continuously increase.

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Reviews

Steatotic liver disease

Non-invasive biomarkers for liver inflammation in non-alcoholic fatty liver disease: present and future
Terry Cheuk-Fung Yip, Fei Lyu, Huapeng Lin, Guanlin Li, Pong-Chi Yuen, Vincent Wai-Sun Wong, Grace Lai-Hung Wong
Clin Mol Hepatol 2023;29(Suppl):S171-S183.
Published online December 12, 2022
DOI: https://doi.org/10.3350/cmh.2022.0426
Inflammation is the key driver of liver fibrosis progression in non-alcoholic fatty liver disease (NAFLD). Unfortunately, it is often challenging to assess inflammation in NAFLD due to its dynamic nature and poor correlation with liver biochemical markers. Liver histology keeps its role as the standard tool, yet it is well-known for substantial sampling, intraobserver, and interobserver variability. Serum proinflammatory cytokines and apoptotic markers, namely cytokeratin-18, are well-studied with reasonable accuracy, whereas serum metabolomics and lipidomics have been adopted in some commercially available diagnostic models. Ultrasound and computed tomography imaging techniques are attractive due to their wide availability; yet their accuracies may not be comparable with magnetic resonance imaging-based tools. Machine learning and deep learning models, be they supervised or unsupervised learning, are promising tools to identify various subtypes of NAFLD, including those with dominating liver inflammation, contributing to sustainable care pathways for NAFLD.

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Intrahepatic cholangiocarcinoma: Tumour heterogeneity and its clinical relevance
Mina Komuta
Clin Mol Hepatol 2022;28(3):396-407.
Published online January 14, 2022
DOI: https://doi.org/10.3350/cmh.2021.0287
Treatment of intrahepatic cholangiocarcinoma (iCCA) is currently at a significant turning point due to the identification of isocitrate dehydrogenase (IDH) mutations and fibroblast growth factor receptor (FGFR) fusions that can be targeted with currently available therapies. Clinical trials of these targeted therapies have been promising, and the iCCA patients who may benefit from these targeted treatments can be identified by pathological examination prior to molecular investigations. This is because IDH mutations and FGFR fusions are mainly seen in the small duct type iCCA, a subtype of iCCA defined by the 5th World Health Organization classification, which can be recognized by the pathological diagnostic process. Therefore, pathology plays an important role in precision medicine for iCCA, not only in confirming the diagnosis, but also in identifying the iCCA patients who may benefit from targeted treatments. However, caution is advised with the pathological diagnosis, as iCCA shows tumour heterogeneity, making it difficult to distinguish small duct type iCCA from hepatocellular carcinoma (HCC), and combined HCC-CCA. This review focuses on the pathological/molecular features of both subtypes of iCCA (large and small duct types), as well as their diagnostic pitfalls, clinical relevance, and future perspectives.

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Nutritional and Metabolic liver disease

MAFLD enhances clinical practice for liver disease in the Asia-Pacific region
Takumi Kawaguchi, Tsubasa Tsutsumi, Dan Nakano, Mohammed Eslam, Jacob George, Takuji Torimura
Clin Mol Hepatol 2022;28(2):150-163.
Published online November 10, 2021
DOI: https://doi.org/10.3350/cmh.2021.0310
Fatty liver is now a major cause of liver disease in the Asia-Pacific region. Liver diseases in this region have distinctive characteristics. First, fatty liver is frequently observed in lean/normal-weight individuals. However, there is no standard definition of this unique phenotype. Second, fatty liver is often observed in patients with concomitant viral hepatitis. The exclusion of viral hepatitis from non-alcoholic fatty liver disease limits its value and detracts from the investigation and holistic management of coexisting fatty liver in patients with viral hepatitis. Third, fatty liver-associated hepatocellular carcinoma (HCC) is generally categorized as non-B non-C HCC. Fourth, the population is aging rapidly, and it is imperative to develop a practicable, low-intensity exercise program for elderly patients. Fifth, most patients and nonspecialized healthcare professionals still lack an awareness of the significance of fatty liver both in terms of intrahepatic and extrahepatic disease and cancer. Recently, an international expert panel proposed a new definition of fatty liver: metabolic dysfunction-associated fatty liver disease (MAFLD). One feature of MAFLD is that metabolic dysfunction is a prerequisite for diagnosis. Pertinent to regional issues, MAFLD also provides its diagnostic criteria in lean/normal-weight individuals. Furthermore, MAFLD is independent of any concomitant liver disease, including viral hepatitis. Therefore, MAFLD may be a more suitable definition for fatty liver in the Asia-Pacific region. In this review, we introduce the regional characteristics of fatty liver and discuss the advantages of MAFLD for improving clinical practice for liver disease in the region.

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Original Articles

Hepatic neoplasm

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
Clin Mol Hepatol 2021;27(2):305-312.
Published online December 3, 2020
DOI: https://doi.org/10.3350/cmh.2020.0301
Background/Aims
The core needle biopsy (CNB), fine needle aspiration cytology (FNAC) and touch imprint cytology (TIC) are commonly used tools for the diagnosis of hepatic malignancies. However, little is known about the benefits and criteria for selecting appropriate technique among them in clinical practice. We aimed to compare the sensitivity of ultrasound-guided CNB, FNAC, TIC as well as combinations for the diagnosis of hepatic malignancies, and to determine the factors associated with better sensitivity in each technique.
Methods
From January 2018 to December 2019, a total of 634 consecutive patients who received ultrasound-guided liver biopsies at the National Taiwan University Hospital was collected, of whom 235 with confirmed malignant hepatic lesions receiving CNB, FNAC and TIC simultaneously were enrolled for analysis. The clinical and procedural data were compared.
Results
The sensitivity of CNB, FNAC and TIC for the diagnosis of malignant hepatic lesions were 93.6%, 71.9%, and 85.1%, respectively. Add-on use of FNAC or TIC to CNB provided additional sensitivity of 2.1% and 0.4%, respectively. FNAC exhibited a significantly higher diagnostic rate in the metastatic cancers (P=0.011), hyperechoic lesions on ultrasound (P=0.028), and those with depth less than 4.5 cm from the site of needle insertion (P=0.036).
Conclusions
The sensitivity of CNB is superior to that of FNAC and TIC for the diagnosis of hepatic malignancies. Nevertheless, for shallow (depth <4.5 cm) and hyperechoic lesions not typical for primary liver cancers, FNAC alone provides excellent sensitivity.

Citations

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  • Role of imaging-guided biopsy for hepatocellular carcinoma
    Roberto Cannella, Zachary T. Berman, Nikhil V. Tirukkovalur, Samer T. Tohme, Marta I. Minervini, Alessandro Furlan
    European Journal of Radiology.2025; 191: 112271.     CrossRef
  • Novel and less invasive biomarker assays to measure liver ATP7B in Wilson disease patients
    Rosanna J. Jiang, Lucy Chen, Kimberly Amburgey, Danie P. M. La, Brodie Fischbacher, Erle M. Holgersen, Lucienne Ronco, Adam J. Gehring, Jordan J. Feld, Kahlin Cheung-Ong
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  • Combined fine needle aspiration cytology and core needle biopsy in the same setting: A two‐years’ experience
    Valeria Ciliberti, Elisabetta Maffei, Angela D'Ardia, Francesco Sabbatino, Bianca Serio, Antonio D'Antonio, Pio Zeppa, Alessandro Caputo
    Cytopathology.2024; 35(1): 78.     CrossRef
  • Patient‐Derived Organoids as Therapy Screening Platforms in Cancer Patients
    Danial Khorsandi, Jia‐Wei Yang, Samuel Foster, Safoora Khosravi, Negar Hosseinzadeh Kouchehbaghi, Fahimeh Zarei, Yun Bin Lee, Farhana Runa, Ankit Gangrade, Leon Voskanian, Darbaz Adnan, Yangzhi Zhu, Zhaohui Wang, Vadim Jucaud, Mehmet Remzi Dokmeci, Xiling
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  • Risk factors of non-diagnostic percutaneous liver tumor biopsy: a single-center retrospective analysis of 938 biopsies based on cause of error
    Shintaro Kimura, Miyuki Sone, Shunsuke Sugawara, Chihiro Itou, Takumi Oshima, Mizuki Ozawa, Rakuhei Nakama, Sho Murakami, Yoshiyuki Matsui, Yasuaki Arai, Masahiko Kusumoto
    Japanese Journal of Radiology.2024;[Epub]     CrossRef
  • Usefulness of on‐site cytology of liver tumor biopsy in specimen sampling for cancer genomic profiling test
    Tasuku Nakabori, Yutaro Abe, Sena Higashi, Kaori Mukai, Risa Yoshioka, Yuki Morimoto, Yuki Koyanagi, Satoshi Tanada, Shigenori Nagata, Keiichiro Honma, Kazuyoshi Ohkawa
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  • Association between Biomarkers (VEGF-R2, VEGF-R3, VCAM-1) and Treatment Duration in Patients with Neuroendocrine Tumors Receiving Therapy with First-Generation Somatostatin Analogues
    Violetta Rosiek, Ksenia Janas, Beata Kos-Kudła
    Biomedicines.2023; 11(3): 842.     CrossRef
  • Sensitivity of cytology in liver tumor biopsy and its significance in the prompt clinical diagnosis of non‐hepatocellular carcinoma
    Tasuku Nakabori, Yutaro Abe, Sena Higashi, Kaori Mukai, Azusa Shingetsu, Sanako Nishimura, Sayoko Tsuzaki, Ayumi Ryu, Satoshi Tanada, Shigenori Nagata, Keiichiro Honma, Kazuyoshi Ohkawa
    Cancer Medicine.2023; 12(11): 12336.     CrossRef
  • Cytological diagnosis of metastatic liver carcinomas
    S.V. Smetanina, E.N. Slavnova, E.Yu. Uskova, N.Yu. Orlinskaya, M.B. Danyaeva, A.A. Khusiyanova
    P.A. Herzen Journal of Oncology.2023; 12(3): 27.     CrossRef
  • Refining Liver Biopsy in Hepatocellular Carcinoma: An In-Depth Exploration of Shifting Diagnostic and Therapeutic Applications
    Zeno Spârchez, Rareș Crăciun, Iuliana Nenu, Lavinia Patricia Mocan, Mihaela Spârchez, Tudor Mocan
    Biomedicines.2023; 11(8): 2324.     CrossRef
  • Reliability of combined fine needle aspiration and core needle biopsies in the diagnosis of liver lesions: An 8‐year institutional experience
    Yuan Shen, Evgeniya Angelova, Mariana Moreno Prats, Cecilia Clement, Vicki Schnadig, Heather Stevenson‐Lerner, Jing He
    Cytopathology.2022; 33(4): 472.     CrossRef
  • Image-guided Percutaneous Biopsy of the Liver
    Ather Adnan, Rahul A. Sheth
    Techniques in Vascular and Interventional Radiology.2021; 24(4): 100773.     CrossRef
  • Touch Imprint Intraoperative Flow Cytometry as a Complementary Tool for Detailed Assessment of Resection Margins and Tumor Biology in Liver Surgery for Primary and Metastatic Liver Neoplasms
    Georgios Markopoulos, Georgios Glantzounis, Anna Goussia, Georgios Lianos, Anastasia Karampa, George Alexiou, George Vartholomatos
    Methods and Protocols.2021; 4(3): 66.     CrossRef
  • Biopsy or cytology for diagnosing hepatic focal lesions?
    Haeryoung Kim
    Clinical and Molecular Hepatology.2021; 27(2): 278.     CrossRef
  • 8,304 View
  • 177 Download
  • 13 Web of Science
  • Crossref

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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    Lulin Yu, Jing Yuan, Mingxian Meng, Hejing Pan, Long Ge, Liaoyao Wang, Xuanlin Li
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    Si Yang, Yujiao Deng, Yi Zheng, Jing Zhang, Dongdong He, Zhijun Dai, Changcun Guo
    Hepatology International.2025; 19(2): 441.     CrossRef
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    Chendong Yuan, Xufeng Shu, Xiaoqiang Wang, Wenzheng Chen, Xin Li, Wenguang Pei, Xujie Su, Zhenzhen Hu, Zhigang Jie
    Scientific Reports.2025;[Epub]     CrossRef
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    Núria Granel, Gemma Iserte, Concepció Bartres, Neus Llarch, Anna Pla, Víctor Sapena, Zoe Mariño, Sabela Lens, Ramón Vilana, Isabel Nuñez, Anna Darnell, Ernest Belmonte, Ángeles García-Criado, Alba Díaz, Marco Sanduzzi-Zamparelli, Carla Fuster, Sergio Muño
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    Cynthia Sau Chun Yip
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    Hiroyuki Suzuki, Naoto Fujiwara, Amit G. Singal, Thomas F. Baumert, Raymond T. Chung, Takumi Kawaguchi, Yujin Hoshida
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Hepatic neoplasm

Effectiveness of nivolumab versus regorafenib in hepatocellular carcinoma patients who failed sorafenib treatment
Cheol-Hyung Lee, Yun Bin Lee, Minseok Albert Kim, Heejoon Jang, Hyunwoo Oh, Sun Woong Kim, Eun Ju Cho, Kyung-Hun Lee, Jeong-Hoon Lee, Su Jong Yu, Jung-Hwan Yoon, Tae-You Kim, Yoon Jun Kim
Clin Mol Hepatol 2020;26(3):328-339.
Published online May 28, 2020
DOI: https://doi.org/10.3350/cmh.2019.0049n
Background/Aims
Several treatment options are currently available for patients with hepatocellular carcinoma (HCC) failing previous sorafenib treatment. We aimed to compare the effectiveness of regorafenib and nivolumab in these patients.
Methods
Consecutive HCC patients who received regorafenib or nivolumab after failure of sorafenib treatment were included. Primary endpoint was overall survival (OS) and secondary endpoints were time to progression, tumor response rate, and adverse events. Inverse probability of treatment weighting (IPTW) using the propensity score was conducted to reduce treatment selection bias.
Results
Among 150 study patients, 102 patients received regorafenib and 48 patients received nivolumab. Median OS was 6.9 (95% confidence interval [CI], 3.0–10.8) months for regorafenib and 5.9 (95% CI, 3.7–8.1) months for nivolumab (P=0.77 by log-rank test). In multivariable analysis, nivolumab was associated with prolonged OS (vs. regorafenib: adjusted hazard ratio [aHR], 0.54; 95% CI, 0.30–0.96; P=0.04). Time to progression was not significantly different between groups (nivolumab vs. regorafenib: aHR, 0.82; 95% CI, 0.51–1.30; P=0.48). HRs were maintained after IPTW.
Objective
response rates were 5.9% and 16.7% in patients treated with regorafenib and nivolumab, respectively (P=0.04).
Conclusions
After sorafenib failure, the use of nivolumab may be associated with improved OS and better
objective
response rate as compared to using regorafenib.

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Hepatic neoplasm

Underlying liver disease and advanced stage liver cancer are associated with elevated neutrophil-lymphocyte ratio
Linda Wong, Kliment Bozhilov, Brenda Hernandez, Sandi Kwee, Owen Chan, Luke Ellis, Loic LeMarchand
Clin Mol Hepatol 2019;25(3):305-316.
Published online April 19, 2019
DOI: https://doi.org/10.3350/cmh.2019.0004
Background/Aims
Inflammation-based scores, such as the neutrophil-to-lymphocyte ratio (NLR), have been associated with prognosis in hepatocellular carcinoma (HCC); but variable cut-off values and potential lack of specificity have limited the utility of NLR. This study evaluates NLR in a large cohort of HCC patients.
Methods
We retrospectively reviewed 789 HCC cases (1993–2017) for demographics, tumor characteristics, treatment, and survival. NLR was stratified into NLR ≥1.5 and NLR ≥3 and analyzed for correlation with American Joint Committee on Cancer (AJCC) and Barcelona Clinic Liver Cancer (BCLC) stages. In 235 patients who underwent liver resection, survival and recurrence were evaluated by NLR.
Results
In 789 HCC cases, mean NLR was increased with advanced AJCC and BCLC stages. Hepatitis C patients were less likely to have NLR ≥1.5 and ≥3. Non-alcoholic steatohepatitis patients were more likely to have NLR ≥3. Patients with tumor size >5 cm, rupture, or macrovascular invasion were more likely to have NLR ≥3. In patients treated with resection, NLR ≥3 predicted early recurrence (odds ratio [OR] 4.14, P<0.01) and overall recurrence (OR 4.05, P<0.01). Mean NLR was 4.30 in those with recurrence and 2.75 in those without recurrence. Patients with NLR ≥3 showed significantly worse survival compared to those with NLR <3 (P<0.01 by log-rank test).
Conclusions
Elevated NLR is associated with advanced cancer stage and aggressive tumor characteristics, such as large size, rupture, and invasion. NLR ≥3 was associated with early and overall recurrence after resection but varied with etiology. NLR may be a useful biomarker in predicting recurrence for HCC patients undergoing curative resection, but further studies are required to elucidate the effect of disease etiology.

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Reviews

Hepatic neoplasm

Detect or not to detect very early stage hepatocellular carcinoma? The western perspective
Ju Dong Yang
Clin Mol Hepatol 2019;25(4):335-343.
Published online March 29, 2019
DOI: https://doi.org/10.3350/cmh.2019.0010
Very early stage hepatocellular carcinoma (HCC) is defined as a single tumor with the largest diameter of the lesion measuring 2 cm or less according to Barcelona Liver Cancer staging system. Detection of very early stage HCC is clinically important as it confers an excellent prognosis with the 5-year survival rates over 60 to 80% after patients receive curative treatments. While diagnosing HCC at a very early stage is crucial, it is technically challenging and may come with the physical or psychosocial harms related to diagnostic tests. It is further complicated by the fact that patients with very early stage HCC are not prioritized for liver transplant (LT) in the United States organ allocation system. When LT-eligible patients present with an indeterminate lesion measuring between 1 and 2 cm on the multiphasic computed tomography or magnetic resonance imaging, clinicians often observe patients carefully until the lesion grows up to 2 cm so that patients can be eligible to receive a Model for End-Stage Liver Disease (MELD) exception score for HCC in the United States. The European guideline recommends a routine biopsy of such lesion. In conclusion, attempting to detect very early stage HCC is difficult to achieve and controversial. Clinicians should take into account of the risk and the benefit of diagnostic tests, LT candidacy of patients and the local organ allocation system.

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Hepatic neoplasm

Hepatocellular carcinoma surveillance in the 21st century: Saving lives or causing harm?
Ibrahim A. Hanouneh, Naim Alkhouri, Amit G. Singal
Clin Mol Hepatol 2019;25(3):264-269.
Published online March 4, 2019
DOI: https://doi.org/10.3350/cmh.2019.1001
Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. Prognosis and treatment options largely depend on tumor stage at diagnosis, with curative treatments only available if detected at an early stage. However, two thirds of patients with HCC are diagnosed at a late stage and not eligible for cure. Therefore several liver professional societies recommend HCC surveillance using abdominal ultrasound with or without alpha fetoprotein in at-risk populations, including patients with cirrhosis and subsets of those with chronic hepatitis B. Available data suggest HCC surveillance can significantly improve early tumor detection, curative treatment eligibility, and overall survival. However, the potential benefits of HCC surveillance must be considered in light a shifting HCC demographic from a viral-mediated cancer to an increasing proportion of patients having non-alcoholic steatohepatitis, which has been shown to limit ultrasound sensitivity and may mitigate observed benefits. Further, benefits of HCC surveillance must be weighed against potential physical, financial and psychological harms. Continued data for both benefits and harms of HCC surveillance in contemporary populations are necessary. In the interim, providers should continue to strive for high quality HCC surveillance in at-risk patients.

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Original Article

Viral hepatitis

Association between hepatic steatosis and the development of hepatocellular carcinoma in patients with chronic hepatitis B
Yun Bin Lee, Yeonjung Ha, Young Eun Chon, Mi Na Kim, Joo Ho Lee, Hana Park, Kwang-il Kim, Soo-Hwan Kim, Kyu Sung Rim, Seong Gyu Hwang
Clin Mol Hepatol 2019;25(1):52-64.
Published online October 23, 2018
DOI: https://doi.org/10.3350/cmh.2018.0040
Background/Aims
Nonalcoholic fatty liver disease (NAFLD) is becoming a worldwide epidemic, and is frequently found in patients with chronic hepatitis B (CHB). We investigated the impact of histologically proven hepatic steatosis on the risk for hepatocellular carcinoma (HCC) in CHB patients without excessive alcohol intake.
Methods
Consecutive CHB patients who underwent liver biopsy from January 2007 to December 2015 were included. The association between hepatic steatosis (≥ 5%) and subsequent HCC risk was analyzed. Inverse probability weighting (IPW) using the propensity score was applied to adjust for differences in patient characteristics, including metabolic factors.
Results
Fatty liver was histologically proven in 70 patients (21.8%) among a total of 321 patients. During the median (interquartile range) follow-up of 5.3 (2.9–8.3) years, 17 of 321 patients (5.3%) developed HCC: 8 of 70 patients (11.4%) with fatty liver and 9 of 251 patients (3.6%) without fatty liver. The five-year cumulative incidences of HCC among patients without and with fatty liver were 1.9% and 8.2%, respectively (P=0.004). Coexisting fatty liver was associated with a higher risk for HCC (adjusted hazards ratio [HR], 3.005; 95% confidence interval [CI], 1.122–8.051; P=0.03). After balancing with IPW, HCC incidences were not significantly different between the groups (P=0.19), and the association between fatty liver and HCC was not significant (adjusted HR, 1.709; 95% CI, 0.404–7.228; P=0.47).
Conclusions
Superimposed NAFLD was associated with a higher HCC risk in CHB patients. However, the association between steatosis per se and HCC risk was not evident after adjustment for metabolic factors.

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Review

Hepatic neoplasm

Epidemiology of liver cancer in South Korea
Bo Hyun Kim, Joong-Won Park
Clin Mol Hepatol 2018;24(1):1-9.
Published online December 18, 2017
DOI: https://doi.org/10.3350/cmh.2017.0112
Liver cancer is the sixth most common cancer (fourth in men and sixth in women) and the second largest cause of cancer mortality in South Korea. The crude incidence rate of liver cancer was 31.9/100,000 (47.5/100,000 in men and 16.2/100,000 in women) and the age-standardized incidence rate was 19.9/100,000 (32.4/100,000 in men and 8.8/100,000 in women) in 2014. The crude incidence rate increased from 1999 to 2011 and thereafter showed a subtle decreasing tendency. The crude prevalence rate was 113.6/100,000 (170.2/100,000 in men and 57.1/100,000 in women) and the age-standardized prevalence rate was 72.6/100,000 (115.7/100,000 in men and 33.7/100,000 in women) in 2014, which increased from 2010 to 2014. Survival from liver cancer has improved over the last two decades. The 5-year relative survival rate was markedly increased from 10.7% in those diagnosed with liver cancer between 1993 and 1995 to 32.8% in those diagnosed between 2010 and 2014. The epidemiology of liver cancer is influenced by that of underlying liver diseases such as viral hepatitis. Substantial progress has been made in the prevention and treatment of viral hepatitis; however, uncontrolled alcoholic liver disease, obesity and diabetes appears to have the potential to emerge as major causes for liver cancer. Depending on the success of the control of risk factors, the epidemiology of liver cancer in Korea may change.

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Original Article

Applicability of the BCLC staging system to patients with hepatocellular carcinoma in Korea: analysis at a single center with a liver transplant center
Sung Eun Kim, Han Chu Lee, Kang Mo Kim, Young-Suk Lim, Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh
Korean J Hepatol 2011;17(2):113-119.
Published online June 23, 2011
DOI: https://doi.org/10.3350/kjhep.2011.17.2.113
Background/Aims

The Barcelona Clinic Liver Cancer (BCLC) staging system is logical for the staging and treatment of hepatocellular carcinoma (HCC) because it was based on survival data. This study evaluated the applicability of the BCLC staging system and reasons for divergence from BCLC-recommended treatments in Korean HCC patients.

Methods

One hundred and sixty consecutive HCC patients were prospectively enrolled. Treatments were generally recommended according to the guideline of the American Association for the Study of Liver Diseases, but patients were also informed about alternative treatments. The final decision was made with patient agreement, and was based on the doctor's preferences when a patient was unable to reach a decision.

Results

There were 2 (1%), 101 (64%), 20 (12.5%), 34 (21.5%), and 3 (1%) patients with very early-, early-, intermediate-, advanced-, and terminal-stage disease, respectively. Only 64 patients (40%) were treated according to BCLC recommendations. The treatment deviated from BCLC recommendations in 68% (69/101) and 79% (27/34) of patients with early and advanced stage, respectively. The main causes of deviation were refusal to undergo surgery, the presence of an indeterminate malignancy nodule, the absence of a suitable donor, or financial problems.

Conclusions

Donor shortage, financial problems, the relatively limited efficacy of molecular targeting agents, and the presence of an indeterminate nodule were the main causes of deviation from BCLC recommendations. Even after excluding cases in which decisions were made by patient preference, only 66% of the HCC patients were treated according to BCLC recommendations. Treatment guidelines that reflect the Korean situation are mandatory for HCC patients.

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Review
Recent developments in systemic chemotherapy for hepatocellular carcinoma
Chul Ju Han
Korean J Hepatol 2008;14(1):4-11.
Published online March 20, 2008
DOI: https://doi.org/10.3350/kjhep.2008.14.1.4
Despite recent developments in various chemotherapeutic agents and the performing of numerous clinical trials, chemotherapy still produces unsatisfactory results in hepatocellular carcinoma due to poor clinical benefit compared with untreated controls and its significant toxicity. The presence of liver cirrhosis, its complications, and decreased liver function increase the complexity of chemotherapy. There is recent evidence that targeted agents and antiangiogenic agents such as thalidomide are somewhat effective whilst having minimal toxicities. Some patients are cured by aggressive chemotherapy alone or in combination with other modalities. Therefore, if a patient is in good condition and the tumor shows some response to chemotherapy, aggressive chemotherapy might be considered. Although conventional chemotherapeutic agents are not very effective in many patients, their utility might be improved by lowering toxicities using reduced doses or by selecting only responsive patients if adequate chemosensitivity tests are available. Imaging studies have been conventional tools for evaluating tumor responses, but their results are not always reliable. Establishing criteria for accurately determining tumor responses is urgently needed, along with better chemotherapeutic drugs and regimens. (Korean J Hepatol 2008;14:4-11)

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