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Wu M, Yu H, Pang S, Liu A, Liu J. Application of CT-based radiomics combined with laboratory tests such as AFP and PIVKA-II in preoperative prediction of pathologic grade of hepatocellular carcinoma. BMC Med Imaging 2025; 25:51. [PMID: 39962429 PMCID: PMC11834502 DOI: 10.1186/s12880-025-01588-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 02/10/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND To investigate how effectively clinical features and CT-based radiomic features predict the pathological grade of hepatocellular carcinoma (HCC). METHODS We retrospectively analyzed 108 patients diagnosed with hepatocellular carcinoma who underwent pathological examination between May 2020 and May 2024 at the Second Hospital of Jilin University. All patients underwent laboratory tests and contrast-enhanced computed tomography (CECT) scanning of the liver within one month prior to pathological examination. First, we analyzed laboratory tests, such as alpha fetoprotein (AFP) and des-γ-carboxy prothrombin (PIVKA-II), to identify risk factors associated with the pathological grading of HCC. Then, we built and evaluated the performance of the clinical model. Next, we imported the arterial-phase and venous-phase images of the CECT images into the uAI Research Portal research platform for 'one-stop' processing, which included semiautomatic ROI outlining, feature extraction, dimensionality reduction, model construction and evaluation. To evaluate the model's diagnostic effectiveness, receiver operating characteristic (ROC) curves were produced, and the related accuracy, sensitivity, specificity, and area under the curve (AUC) were computed. The models were compared using the Delong test, and the clinical value of the predictive model was assessed via the use of calibration curves and decision curve analysis (DCA) to quantify the agreement between the model and the actual outcomes. RESULTS Poorly differentiated hepatocellular carcinoma (pHCC) is associated with risk variables such as hepatitis C virus antibodies(HCVAb), PIVKA-II, and sex. In the training and validation cohorts, the AUC values of the clinical model were 0.719 and 0.692, respectively; those of the AP model were 0.843 and 0.773; those of the VP model were 0.806 and 0.804; those of the AP + VP model were 0.953 and 0.844; and those of the AP + VP + clinical model were 0.926 (95% CI: 0.88-0.995) and 0.863 (95% CI: 0.711-1). The DCA curves revealed that the overall net benefit of the AP + VP + clinical model was greater than that of the other models and that it had the best diagnostic results. CONCLUSIONS CT-based radiomic modeling combined with clinical features (sex) and laboratory tests (e.g., AFP and PIVKA-II) can reliably predict the pathological grade of HCC patients prior to surgery.
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Affiliation(s)
- Meng Wu
- Department of Radiology, The Second Hospital of Jilin University, Changchun, China
| | - Haijia Yu
- Department of Radiology, The Second Hospital of Jilin University, Changchun, China
| | - Siwen Pang
- Department of Radiology, The Second Hospital of Jilin University, Changchun, China
| | - Aie Liu
- Department of Research and Development, Shanghai United Imaging Intelligence Co., Ltd, Shanghai, China
| | - Jianhua Liu
- Department of Radiology, The Second Hospital of Jilin University, Changchun, China.
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Zhang B, Zhu B, Yu J, Liu H, Zhou Y, Sun G, Ma Y, Luan Y, Chen M. A combined model of six serum microRNAs as diagnostic markers for hepatocellular carcinoma. Clin Chim Acta 2025; 565:119977. [PMID: 39332657 DOI: 10.1016/j.cca.2024.119977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/23/2024] [Accepted: 09/23/2024] [Indexed: 09/29/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is associated with high morbidity and mortality, and its poor prognosis is mainly due to the lack of an effective means of early diagnosis. This study aimed to identify a group of serum microRNAs (miRNAs) as potential biomarkers for the diagnosis of HCC. METHODS We collected 190 HCC cases, 109 benign lesions of the liver, 40 cases of non-HCC tumors, and 130 healthy controls. The 469 participants were divided into training and validation sets. A literature search revealed 12 miRNAs closely associated with HCC. In the training set, significantly differentially expressed miRNAs (DEmiRNAs) were screened using real-time quantitative PCR, and a diagnostic model of HCC was constructed using logistic regression analysis. An independent validation was performed using a validation set. The identified DE miRNAs were subjected to target gene prediction and functional analyses. RESULTS Compared to the controls, the levels of miR-21, miR-221, miR-801, and miR-1246 significantly decreased in HCC (P < 0.05), while the levels of miR-26a and miR-122 significantly increased (P < 0.05). A diagnostic model based on the six DE miRNAs was successfully constructed, with AUC values of 0.953 for the training set and 0.952 for the verification set. Finally, 100 target genes of the DE miRNAs were predicted and were significantly enriched in the B cell receptor, neurotrophin, ferroptosis, and EGFR tyrosine kinase inhibitor resistance signaling pathways. CONCLUSIONS The constructed diagnostic model based on six DE miRNA combinations has important clinical value for the early diagnosis of HCC.
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Affiliation(s)
- Bingqiang Zhang
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, Shandong 266111, PR China
| | - Boyang Zhu
- School of Clinical and Basic Medical Sciences, Shandong First Medical University& Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, PR China
| | - Junmei Yu
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, Shandong 266111, PR China
| | - He Liu
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, Shandong 266111, PR China
| | - Yang Zhou
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, Shandong 266111, PR China
| | - Guolong Sun
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, Shandong 266111, PR China
| | - Yongchao Ma
- School of Chemistry and Pharmacy, Qingdao Agricultural University, Qingdao, Shandong 266111, PR China
| | - Yansong Luan
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, Shandong 266111, PR China.
| | - Mengmeng Chen
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, Shandong 266111, PR China.
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Sharafeldin MA, Suef RA, Mousa AA, Ziada DH, Farag MMS. Serum miRNA-101 expression signature as non-invasive diagnostic biomarker for Hepatitis C virus-associated hepatocellular carcinoma in Egyptian patients. Sci Rep 2025; 15:645. [PMID: 39753619 PMCID: PMC11698908 DOI: 10.1038/s41598-024-81207-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Accepted: 11/25/2024] [Indexed: 01/06/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally due to HCC late diagnosis and limited treatment options. MiRNAs (miRNAs) emerged as potential biomarkers for various diseases, including HCC. However, the value of miRNA-101 as a serum biomarker for HCV-induced HCC has not been fully investigated. Our study aims to investigate the miRNA-101 differential expression in Egyptian HCV-induced HCC patients' serum versus HCV liver cirrhosis (LC) as prospective diagnostic biomarkers compared to alpha-fetoprotein (AFP). Blood samples were collected for clinical chemistry profile, liver function, and serum AFP investigations. The serum miR-101 expression levels were evaluated using real-time quantitative PCR (RT-qPCR) in 100 Egyptian subjects: 40 HCV-induced HCC, 40 HCV-induced cirrhosis, and 20 healthy controls. HCC patients showed significantly higher TB, DB, and AFP levels than those cirrhosis and control groups, whereas ALB and Total Protein exhibited significantly reduced levels. AFP sensitivity and specificity in differentiating HCC reported 60 and 67%, respectively, at the cut-off values of 7ng/dl. miR-101 shows fold change upregulation in HCC patients (P < 0.0001) compared to LC and control groups. ROC curve demonstrated miR-101 (AUC) of 0.9556, sensitivity 92.5%, and specificity 97.5%, highlighting the miR-101 diagnostic potential as a biomarker for HCC detection. Elevated miR-101 levels in HCC are significantly correlated with a higher number and larger size of focal lesions, advanced BCLC staging, and Child-Pugh score. These findings highlight the utility of miR-101 as a predictive and diagnostic non-invasive biomarker for HCV-related HCC from cirrhotic populations. More research is warranted to validate the clinical validity of miR-101 and explore underlying mechanisms in HCV-HCC progression.
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Affiliation(s)
- Mostafa A Sharafeldin
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, 11884, Egypt
| | - Reda A Suef
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, 11884, Egypt.
| | - Adel A Mousa
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, 11884, Egypt
| | - Dina H Ziada
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed M S Farag
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, 11884, Egypt.
- Biomedical Research Department, Armed Forces College of Medicine (AFCM), Cairo, Egypt.
- The Regional Centre for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt.
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Liu Y, Peng F, Wang S, Jiao H, Zhou K, Guo W, Guo S, Dang M, Zhang H, Zhou W, Guo X, Xing J. Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma. Clin Mol Hepatol 2025; 31:196-212. [PMID: 39406379 PMCID: PMC11791606 DOI: 10.3350/cmh.2024.0527] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 02/05/2025] Open
Abstract
BACKGROUND/AIMS Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provide an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA). METHODS Capture-based mtDNA sequencing was carried out in plasma cell-free DNA samples from 1168 participants, including 571 patients with HCC, 301 patients with chronic hepatitis B or liver cirrhosis (CHB/LC) and 296 healthy controls (HC). RESULTS The systematic analysis revealed significantly aberrant fragmentomic features of ccf-mtDNA in HCC group when compared with CHB/LC and HC groups. Moreover, we constructed a random forest algorithm-based HCC detection model by utilizing ccf-mtDNA fragmentomic features. Both internal and two external validation cohorts demonstrated the excellent capacity of our model in distinguishing early HCC patients from HC and highrisk population with CHB/LC, with AUC exceeding 0.983 and 0.981, sensitivity over 89.6% and 89.61%, and specificity over 98.20% and 95.00%, respectively, greatly surpassing the performance of alpha-fetoprotein (AFP) and mtDNA copy number. We also developed an HCC prognosis prediction model by LASSO-Cox regression to select 20 fragmentomic features, which exhibited exceptional ability in predicting 1-year, 2-year and 3-year survival (AUC=0.8333, 0.8145 and 0.7958 for validation cohort, respectively). CONCLUSION We have developed and validated a high-performing and low-cost approach in a large clinical cohort based on aberrant ccf-mtDNA fragmentomic features with promising clinical translational application for the early detection and prognosis prediction of HCC patients.
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Affiliation(s)
- Yang Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
- Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
| | - Fan Peng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Siyuan Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Huanmin Jiao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Kaixiang Zhou
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Wenjie Guo
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Shanshan Guo
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Miao Dang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Huanqin Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Weizheng Zhou
- Department of General Surgery, Changhai Hospital, Navy Medical University, Shanghai, China
| | - Xu Guo
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
| | - Jinliang Xing
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an, China
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Huang H, Zhang M, Lu H, Chen Y, Sun W, Zhu J, Chen Z. Identification and evaluation of plasma exosome RNA biomarkers for non-invasive diagnosis of hepatocellular carcinoma using RNA-seq. BMC Cancer 2024; 24:1552. [PMID: 39696145 DOI: 10.1186/s12885-024-13332-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 12/11/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Non-invasive diagnostic methods, including medical imaging techniques and blood biomarkers such as alpha-fetoprotein (AFP), have been crucial in detecting hepatocellular carcinoma (HCC). However, imaging techniques are only effective for tumor size larger than 2 cm. AFP measurement remains unsatisfactory due to high rate of misdiagnosis and underdiagnosis. Therefore, new reliable biomarkers and better non-invasive diagnostic approach are necessary for HCC identification. METHODS The differentially expressed genes were identified using multiple public RNA-seq data of liver tissues from healthy individuals and HCC patients including peritumoral and tumor tissues. The hub genes for HCC diagnosis were identified combining pathway enrichment analysis and protein-protein interaction network analysis. The performance of hub genes for non-invasive HCC diagnosis was analyzed in plasma of healthy individuals, HBV infected patients, and HCC patients based on exosomal RNA-seq data. A multi-layer perceptron (MLP) model based on exosomal hub genes was developed for non-invasive HCC diagnosis. RESULTS Through differential gene expression and pathway enrichment analysis on multiple public RNA-seq datasets, we first identified 30 dysregulated genes in HCC tissues. Protein-protein interaction analysis further narrowed down this list to 10 key genes: BRCA2, CDK1, MCM4, PLK1, DNA2, BLM, PCNA, POLD1, BRCA1 and FEN1. By further evaluation using additional public HCC tissue datasets, POLD1 and MCM4 were excluded from consideration as potential biomarkers due to their suboptimal performance. Notably, CDK1, FEN1, and PCNA gene were found to be significantly elevated in the plasma exosomes of HCC patients compared to non-HCC individuals, including those with HBV-infected hepatitis and healthy controls. The MLP model, based on three biomarkers, showed an area under the curve (AUC) of 0.85 and 0.84 in training and test dataset respectively, after adjusting for the covariates sex and age. CONCLUSION We identified three key genes, CDK1, FEN1, and PCNA, as exosomal biomarkers for non-invasive diagnosis of HCC. The MLP model utilizing three biomarkers showed good differentiation between non-HCC individuals and HCC patients, which exhibits promising potential as a non-invasive diagnostic tool for detecting HCC. Additional validation with a larger sample size is essential to thoroughly assess the reliability of the biomarkers and the model's performance.
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Affiliation(s)
- Heqing Huang
- Infectious Disease Department, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Min Zhang
- BamRock Research Department, Suzhou BamRock Biotechnology Ltd., Suzhou, Jiangsu Province, China
| | - Hong Lu
- Infectious Disease Department, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Yiling Chen
- Infectious Disease Department, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Weijie Sun
- Ulink College of Shanghai, Shanghai, China
| | - Jinghan Zhu
- Infectious Disease Department, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
| | - Zutao Chen
- Infectious Disease Department, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
- MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-infective Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
- Infectious Disease Department, The Fourth Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.
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Tu J, Wang B, Wang X, Huo K, Hu W, Zhang R, Li J, Zhu S, Liang Q, Han S. Current status and new directions for hepatocellular carcinoma diagnosis. LIVER RESEARCH 2024; 8:218-236. [PMID: 39958920 PMCID: PMC11771281 DOI: 10.1016/j.livres.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 10/17/2024] [Accepted: 12/01/2024] [Indexed: 02/18/2025]
Abstract
Liver cancer ranks as the sixth most common cancer globally, with hepatocellular carcinoma (HCC) accounting for approximately 75%-85% of cases. Most patients present with moderately advanced disease, while those with advanced HCC face limited and ineffective treatment options. Despite diagnostic efforts, no ideal tumor marker exists to date, highlighting the urgent clinical need for improved early detection of HCC. A key research objective is the development of assays that target specific pathways involved in HCC progression. This review explores the pathological origin and development of HCC, providing insights into the mechanistic rationale, clinical statistics, and the advantages and limitations of commonly used diagnostic tumor markers. Additionally, it discusses the potential of emerging biomarkers for early diagnosis and offers a brief overview of relevant assay methodologies. This review aims to summarize existing markers and investigate new ones, providing a basis for subsequent research.
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Affiliation(s)
- Jinqi Tu
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Bo Wang
- Animal Experimental Center, Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Xiaoming Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, Anhui, China
| | - Kugeng Huo
- Cyagen Biosciences (Guangzhou) Inc., Guangzhou, Guangdong, China
| | - Wanting Hu
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Lab of Microanalytical Methods & Instrumentation, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Rongli Zhang
- Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
| | - Shijie Zhu
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qionglin Liang
- MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Beijing Key Lab of Microanalytical Methods & Instrumentation, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, China
| | - Shuxin Han
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China
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Sun H, Liu N, Lou J. Diagnostic value of serum STIP1 in HCC and AFP-negative HCC. Lab Med 2024; 55:700-707. [PMID: 38780206 PMCID: PMC11532616 DOI: 10.1093/labmed/lmae033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2024] Open
Abstract
OBJECTIVE This study aimed to investigate the diagnostic value of stress-induced phosphoprotein 1 (STIP1) in serum for hepatocellular carcinoma (HCC) and alpha-fetoprotein (AFP)-negative HCC (ANHC). METHODS In this study, serum samples were collected from 158 HCC patients and 63 non-HCC patients. Logistic regression analysis was performed to identify independent risk factors associated with HCC and ANHC. The diagnostic values of each index for HCC and ANHC were analyzed using receiver operating characteristic (ROC) curve analysis. RESULTS The STIP1, des-γ-carboxy prothrombin (DCP), and AFP levels were higher in the HCC groups than in the non-HCC groups (P < .05). Age, DCP, STIP1, and hepatitis B virus infection were independent predictors of HCC (P < .05). The diagnostic value of STIP1 for HCC was higher than that of DCP. Additionally, age, STIP1, and hepatitis B virus infection were independent predictors for ANHC patients. The ROC curve exhibited an area under the curve value of 0.919 for STIP1, with a diagnostic cutoff value of 68.5 U/mL. Moreover, 36 ANHC patients and 19 AFP-negative non-HCC patients were included to validate the diagnostic model. A total of 20 patients had STIP1 levels greater than 68.5 U/mL, resulting in diagnostic accuracy of 67.3%, sensitivity of 55.6%, and specificity of 89.5%. CONCLUSION STIP1 demonstrates excellent diagnostic value for HCC and ANHC.
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Affiliation(s)
- Haiqing Sun
- Department of Clinical Laboratory Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Ning Liu
- Department of Clinical Laboratory Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Jinli Lou
- Department of Clinical Laboratory Center, Beijing Youan Hospital, Capital Medical University, Beijing, China
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Hatawsh A, Al-Haddad RH, Okafor UG, Diab LM, Dekanoidze N, Abdulwahab AA, Mohammed OA, Doghish AS, Moussa R, Elimam H. Mitoepigenetics pathways and natural compounds: a dual approach to combatting hepatocellular carcinoma. Med Oncol 2024; 41:302. [PMID: 39465473 DOI: 10.1007/s12032-024-02538-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 10/07/2024] [Indexed: 10/29/2024]
Abstract
Hepatocellular carcinoma (HCC) is a leading liver cancer that significantly impacts global life expectancy and remains challenging to treat due to often late diagnoses. Despite advances in treatment, the prognosis is still poor, especially in advanced stages. Studies have pointed out that investigations into the molecular mechanisms underlying HCC, including mitochondrial dysfunction and epigenetic regulators, are potentially important targets for diagnosis and therapy. Mitoepigenetics, or the epigenetic modifications of mitochondrial DNA, have drawn wide attention for their role in HCC progression. Besides, molecular biomarkers such as mitochondrial DNA alterations and non-coding RNAs showed early diagnosis and prognosis potential. Additionally, natural compounds like alkaloids, resveratrol, curcumin, and flavonoids show promise in HCC show promise in modulating mitochondrial and epigenetic pathways involved in cancer-related processes. This review discusses how mitochondrial dysfunction and epigenetic modifications, especially mitoepigenetics, influence HCC and delves into the potential of natural products as new adjuvant treatments against HCC.
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Affiliation(s)
- Abdulrahman Hatawsh
- Biotechnology School, Nile University, 26th of July Corridor, Sheikh Zayed City, Giza, 12588, Egypt
| | - Roya Hadi Al-Haddad
- Research and Technology Center of Environment, Water and Renewable Energy, Scientific Research Commission, Baghdad, Iraq
| | | | - Lamis M Diab
- Department of Medical Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | | | | | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, 61922, Bisha, Saudi Arabia
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo, 11829, Egypt.
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo, 11231, Egypt.
| | - Rewan Moussa
- Faculty of Medicine, Helwan University, Helwan, Cairo, 11795, Egypt
| | - Hanan Elimam
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Sādāt, 32897, Egypt.
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Shi Y, Yang H, Bai X, Liu X, Li Q, Du W. Female and diabetes are risk factors for alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II negative in hepatocellular carcinoma. Medicine (Baltimore) 2024; 103:e40100. [PMID: 39432605 PMCID: PMC11495763 DOI: 10.1097/md.0000000000040100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 09/26/2024] [Indexed: 10/23/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common type of tumor with a high incidence. Alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II or des-gamma-carboxy prothrombin) are proven effective biomarkers for HCC. Combining them can enhance detection rates. However, when both AFP and PIVKA-II are negative, clinical diagnosis may be missed. This study aims to explore the risk factors for AFP and PIVKA-II negativity in HCC, thereby reducing missed diagnoses. A retrospective study enrolled 609 HCC patients at Shandong Public Health Clinical Center Affiliated with Shandong University from January 2010 to March 2022. Patients with negative AFP and PIVKA-II were the observed group, and others with at least 1 positive were controls. Epidemiological, clinical, laboratory, and radiological data were collected and analyzed to identify the frequency and factors influencing AFP and PIVKA-II negativity. Receiver operating characteristic (ROC) curves were used to assess the prediction model's ability to detect negative AFP and PIVKA-II in HCC. Gender (P = .045, 95% confidence interval [95%CI] = 1.013-3.277), diabetes mellitus (P = .018, 95%CI = 1.151-4.422), tumor size (P = .000, 95%CI = 0.677-0.841), glutamate transpeptidase (P = .003, 95%CI = 0.239-0.737), total bilirubin (P = .001, 95%CI = 0.235-0.705), and hepatitis B virus-associated infections (P = .007, 95%CI = 0.077-0.661) were significantly associated with AFP and PIVKA-II negativity in HCC. The prediction model had an area under curve of 0.832 (P < .001, 95%CI = 0.786-0.877), with a sensitivity of 81.2% and specificity of 75.5% in all HCC patients. Female diabetic patients with levels closer to normal for glutamate transpeptidase and total bilirubin are more likely to develop AFP and PIVKA-II-negative HCC. Imaging is crucial for screening liver cancer in these patients.
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Affiliation(s)
- Yanhui Shi
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Hongli Yang
- Department of Gastroenterology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Xue Bai
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaoyan Liu
- Department of Liver Diseases, Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Qiang Li
- Department of Liver Diseases, Shandong Public Health Clinical Center, Shandong University, Jinan, China
| | - Wenjun Du
- Department of Liver Diseases, Shandong Public Health Clinical Center, Shandong University, Jinan, China
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10
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Mak LY. Disease modifiers and novel markers in hepatitis B virus-related hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2024; 24:145-154. [PMID: 39099070 PMCID: PMC11449577 DOI: 10.17998/jlc.2024.08.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/25/2024] [Accepted: 08/03/2024] [Indexed: 08/06/2024]
Abstract
Chronic hepatitis B (CHB) infection is responsible for 40% of the global burden of hepatocellular carcinoma (HCC) with a high case fatality rate. The risk of HCC differs among CHB subjects owing to differences in host and viral factors. Modifiable risk factors include viral load, use of antiviral therapy, co-infection with other hepatotropic viruses, concomitant metabolic dysfunctionassociated steatotic liver disease or diabetes mellitus, environmental exposure, and medication use. Detecting HCC at early stage improves survival, and current practice recommends HCC surveillance among individuals with cirrhosis, family history of HCC, or above an age cut-off. Ultrasonography with or without serum alpha feto-protein (AFP) every 6 months is widely accepted strategy for HCC surveillance. Novel tumor-specific markers, when combined with AFP, improve diagnostic accuracy than AFP alone to detect HCC at an early stage. To predict the risk of HCC, a number of clinical risk scores have been developed but none of them are clinically implemented nor endorsed by clinical practice guidelines. Biomarkers that reflect viral transcriptional activity and degree of liver fibrosis can potentially stratify the risk of HCC, especially among subjects who are already on antiviral therapy. Ongoing exploration of these novel biomarkers is required to confirm their performance characteristics, replicability and practicability.
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Affiliation(s)
- Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Liver Research, The Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
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Wen R, Peng Y, Liang Y, Wu Y, Li H, Chen Y, Qin Y, Wen Z, Cui H, He Y, Yang H. CEUS LI-RADS in Combination With the Serum Biomarker-Based ASAP Model Improves the Diagnostic Performance of HCC in High-Risk Patients. ULTRASOUND IN MEDICINE & BIOLOGY 2024:S0301-5629(24)00300-4. [PMID: 39181805 DOI: 10.1016/j.ultrasmedbio.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 07/18/2024] [Accepted: 08/02/2024] [Indexed: 08/27/2024]
Abstract
OBJECTIVE To assess the diagnostic efficacy of the CEUS LI-RADS combined with a model constructed on the basis of age, sex, AFP, and PIVKA-II (ASAP) for the diagnosis of HCC in high-risk patients. METHODS This retrospective study included 366 liver lesions from 366 patients who underwent liver CEUS. All liver lesions were characterized and categorized according to CEUS LI-RADS v2017. Two modified methods were applied: LR-3/4/M nodules accompanied by AFP > 200 ng/mL (Criterion 2) or ASAP model score > 0.5256 and CA 19-9 in the normal range (Criterion 3) were recategorized as LR-5. The reference criteria included histopathological or comprehensive imaging and the clinical follow-up results. The diagnostic performance was evaluated and compared by the sensitivity, specificity, PPV, and NPV. RESULTS The incidence of HCC in LR-3, LR-4, LR-5, and LR-M was 33.3% (4/12), 86.4% (38/44), 98.5% (191/194) and 82.7% (81/98), respectively. After using Criterion 2 compared to CEUS LI-RADS v2017, the sensitivity of the modified LR-5 for diagnosing HCC increased from 60.8% to 70.7% (p < 0.01) with little effect on its specificity (94.2% vs. 92.3%, p = 1.00) or PPV (98.5% vs. 98.2%, p = 0.86). After using Criterion 3, the sensitivity of the modified LR-5 for the diagnosis of HCC was further improved to 86.9% (p < 0.01), and its specificity and PPV were not significantly changed (92.3% and 98.6%, both p > 0.05). CONCLUSION CEUS LI-RADS combined with the serum biomarker-based ASAP model improved the sensitivity of LR-5 in diagnosing HCC with little effect on its specificity and PPV.
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Affiliation(s)
- Rong Wen
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yuting Peng
- Department of Medical Ultrasound, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yiqiong Liang
- Department of Radiology, Guangxi International Zhuang Medicine Hospital, Nanning, China
| | - Yuquan Wu
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Haiyuan Li
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yanxia Chen
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yan Qin
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhiyuan Wen
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Huanyu Cui
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yun He
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hong Yang
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
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Zheng Q, Xu X, Weng J, Li M, Li B, Cao Y. The elevated expression of serum glutathione reductase in hepatocellular carcinoma and its role in assessing the therapeutic efficacy and prognosis of transarterial chemoembolization. Free Radic Biol Med 2024; 221:225-234. [PMID: 38815771 DOI: 10.1016/j.freeradbiomed.2024.05.043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 05/22/2024] [Accepted: 05/26/2024] [Indexed: 06/01/2024]
Abstract
BACKGROUND Currently, there is a scarcity of reliable biomarkers that can accurately forecast the outcome and prognosis of transarterial chemoembolization (TACE). In this study, we assessed the diagnostic efficacy of serum glutathione reductase (GR) as a biomarker for hepatocellular carcinoma (HCC) and its practicality in predicting TACE treatment response. METHODS The baseline positive rate and level of serum GR were analyzed and compared between HCC group and control group. Serum GR levels were assessed at three specific time points in 181 patients with unresectable HCC who underwent TACE (HCC-TACE). The correlation between serum GR levels and clinical pathological factors, tumor reactivity, and prognosis was investigated. The modified Response Evaluation Criteria in Solid Tumors (mRECIST) was utilized for assessing the treatment response to TACE. A nomogram for predicting the response to TACE treatment efficacy was developed. RESULTS Serum GR demonstrated superior diagnostic performance in HCC patients. The baseline levels of serum GR were associated with the patient's age, tumor size, BCLC staging, and tumor thrombi of the portal vein (TTPV) (p < 0.05). Elevated baseline levels of serum GR were also identified as independent prognostic factors for predicting lower overall survival (OS) and shorter time to radiological progression (TTP) (p < 0.001). Moreover, it is worth noting that non-responders group exhibited a substantial increase in median GR level in the fourth week following TACE treatment (p < 0.0001), whereas the median GR level of responders group did not display a significant augmentation (p > 0.05). Lastly, the changes in serum GRt1-t3 were negatively correlated with TTP (p < 0.001). The nomogram developed to predict the risk of mRECIST responsiveness in patients with HCC-TACE demonstrated excellent discriminatory ability. CONCLUSION Serum GR can serve as a valuable biomarker for the diagnosis of HCC and for predicting the therapeutic efficacy and prognosis of TACE treatment.
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Affiliation(s)
- Qingzhu Zheng
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Xiaohong Xu
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Jiamiao Weng
- Fujian Medical University Provincial Clinical Medical College, Fuzhou, 350001, China
| | - Mingjie Li
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Bin Li
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
| | - Yingping Cao
- Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, China.
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Zeng J, Rong W, Meng B, Zheng L, Peng T, Zhai R, Jiang Y, Xiao T, Fang X, Zhang Y, Zhao Y, Dai X. Integrated plasma proteomics and N-glycoproteomics reveals alterations in the N-glycosylation in Chinese hepatocellular carcinoma patients. Proteomics Clin Appl 2024; 18:e202300029. [PMID: 38345243 DOI: 10.1002/prca.202300029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 01/11/2024] [Accepted: 01/26/2024] [Indexed: 07/19/2024]
Abstract
Hepatocellular carcinoma (HCC) is a life-threatening disease that presents diagnostic challenges due to the absence of reliable biomarkers. Recently, plasma proteomics and glycoproteomics have emerged as powerful tools for identifying potential diagnostic biomarkers for various diseases. In this study, we conducted a comprehensive proteomic and glycoproteomic analysis of plasma samples from 11 HCC patients and 11 healthy control (HC) individuals. We identified 20 differentially expressed (DE) proteins and 32 DE intact glycosylated peptides (IGPs) that can effectively differentiate between HCC patients and HC samples. Our findings demonstrate that IGP profiles had better predictive power than protein profiles for screening HCC. Pathways associated with DE proteins and IGPs were identified. It was reported that the protein expression level of galectin 3 binding protein (LGALS3BP) and its N-linked glycosylation at the N398 and N551 sites might serve as valuable candidates for HCC diagnosis. These results highlight the importance of N-glycoproteomics in advancing our understanding of HCC and suggest possible candidates for the future diagnosis of this disease.
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Affiliation(s)
- Jiaming Zeng
- Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing, China
- College of Chemical Engineering, Shenyang University of Chemical Technology, Shenyang, China
| | - Weiqi Rong
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bo Meng
- Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing, China
| | - Linlin Zheng
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tao Peng
- Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing, China
| | - Rui Zhai
- Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing, China
| | - You Jiang
- Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing, China
| | - Ting Xiao
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiang Fang
- Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing, China
| | - Yong Zhang
- Department of Nephrology and Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Zhao
- Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing, China
- College of Chemical Engineering, Shenyang University of Chemical Technology, Shenyang, China
| | - Xinhua Dai
- Technology Innovation Center of Mass Spectrometry for State Market Regulation, Center for Advanced Measurement Science, National Institute of Metrology, Beijing, China
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Jitpraphawan O, Ruamtawee W, Treewatchareekorn M, Sethasine S. Diagnostic and prognostic performances of GALAD score in staging and 1-year mortality of hepatocellular carcinoma: A prospective study. World J Gastroenterol 2024; 30:2343-2353. [PMID: 38813057 PMCID: PMC11130574 DOI: 10.3748/wjg.v30.i17.2343] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/09/2024] [Accepted: 04/11/2024] [Indexed: 04/30/2024] Open
Abstract
BACKGROUND The GALAD score has improved early hepatocellular carcinoma (HCC) detection rate. The role of the GALAD score in staging and predicting tumor characteristics or clinical outcome of HCC remains of particular interest. AIM To determine the diagnostic/prognostic performances of the GALAD score at various phases of initial diagnosis, tumor features, and 1-year mortality of HCC and compare the performance of the GALAD score with those of other serum biomarkers. METHODS This prospective, diagnostic/prognostic study was conducted among patients with newly diagnosed HCC at the liver center of Vajira Hospital. Eligible patients had HCC staging allocation using the Barcelona Clinic Liver Cancer (BCLC) categorization. Demographics, HCC etiology, and HCC features were recorded. Biomarkers and the GALAD score were obtained at baseline. The performance of the GALAD score and biomarkers were prospectively assessed. RESULTS Exactly 115 individuals were diagnosed with HCC. The GALAD score increased with disease severity. Between BCLC-0/A and BCLC-B/C/D, the GALAD score predicted HCC staging with an area under the curve (AUC) of 0.868 (95%CI: 0.80-0.93). For identifying the curative HCC, the AUC of GALAD score was significantly higher than that of Alpha-fetoprotein (AFP) (0.753) and Lens culinaris agglutinin-reactive fraction of AFP-L3 (0.706), and as good as that of Protein induced by vitamin K absence-II (PIVKA-II) (0.897). For detecting aggressive features, the GALAD score gave an AUC of 0.839 (95%CI: 0.75-0.92) and significantly outperformed compared to that of AFP (0.761) and AFP-L3 (0.697), with a trend of superiority to that of PIVKA-II (0.772). The performance to predict 1-year mortality of GALAD score (AUC: 0.711, 95%CI: 0.60-0.82) was better than that of AFP (0.541) and as good as that of PIVKA-II (0.736). The optimal cutoff value of GALAD score was ≥ 6.83, with a specificity of 72.63% for exhibiting substantial reduction in the 1-year mortality. CONCLUSION The GALAD model can diagnose HCC at the curative stage, including the characteristic of advanced disease, more than that by AFP and AFP-L3, but not PIVKA-II. The GALAD score can be used to predict the 1-year mortality of HCC.
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Affiliation(s)
- Oraphan Jitpraphawan
- Division of Gastroenterology and Hepatology, Department of Medicine, Navamindradhiraj University, Dusit 10300, Bangkok, Thailand
| | - Witchakorn Ruamtawee
- Clinical Research Center, Research Facilitation Division, Navamindradhiraj University, Dusit 10300, Bangkok, Thailand
| | - Mala Treewatchareekorn
- Division of Clinical Chemistry and Immunology, Navamindradhiraj University, Dusit 10300, Bangkok, Thailand
| | - Supatsri Sethasine
- Division of Gastroenterology and Hepatology, Department of Medicine, Navamindradhiraj University, Dusit 10300, Bangkok, Thailand
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Huang C, Xiao X, Zhou L, Chen F, Wang J, Hu X, Gao C. Chinese expert consensus statement on the clinical application of AFP/AFP-L3%/DCP using GALAD and GALAD-like algorithm in HCC. J Clin Lab Anal 2023; 37:e24990. [PMID: 38063322 PMCID: PMC10756949 DOI: 10.1002/jcla.24990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/16/2023] [Accepted: 11/01/2023] [Indexed: 12/31/2023] Open
Abstract
BACKGROUND Primary hepatocellular carcinoma (HCC) is one of the most prevalent world-wide malignancies. Half of the newly developed HCC occurs in China. Optimizing the strategies for high-risk surveillance and early diagnosis are pivotal for improving 5-year survival. Constructing the scientific non-invasive detection technologies feasible for medical and healthcare institutions is among the key routes for elevating the efficacies of HCC identification and follow-up. RESULTS Based on the Chinese and international guidelines, expert consensus statements, literatures and evidence-based clinical practice experiences, this consensus statement puts forward the clinical implications, application subjects, detection techniques and results interpretations of the triple-biomarker (AFP, AFP-L3%, DCP) based GALAD, GALAD like models for liver cancer. CONCLUSIONS The compile of this consensus statement aims to address and push the reasonable application of the triple-biomarker (AFP, AFP-L3%, DCP) detections thus to maximize the clinical benefits and help improving the high risk surveillance, early diagnosis and prognosis of HCC.
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Affiliation(s)
- Chenjun Huang
- Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Xiao Xiao
- Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Lin Zhou
- Department of Laboratory MedicineShanghai Changzheng HospitalShanghaiChina
| | - Fuxiang Chen
- Department of Laboratory Medicine, Shanghai Ninth People's HospitalShanghai JiaoTong University School of MedicineShanghaiChina
| | - Jianyi Wang
- Department of Liver Diseases, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina
| | - Xiaobo Hu
- Shanghai Clinical Laboratory CenterShanghaiChina
| | - Chunfang Gao
- Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western MedicineShanghai University of Traditional Chinese MedicineShanghaiChina
- Shanghai Eastern Hepatobiliary Surgery HospitalShanghaiChina
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Wang L, Yang X, Wang J, Yu G. Predictive value of PIVKA-II and AFP for the non-objective response of HBV-associated hepatocellular carcinoma after transarterial chemoembolization: a prospective study. Eur J Gastroenterol Hepatol 2023; 35:1410-1415. [PMID: 37942758 DOI: 10.1097/meg.0000000000002663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2023]
Abstract
BACKGROUND To determine the predictive value of serum abnormal prothrombin (PIVKA-II) and alpha-fetoprotein (AFP) for the non-objective response of HBV-associated hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE). METHODS This prospective study included HBV-associated HCC patients who underwent TACE at the Fourth People's Hospital of Qinghai Province between December 2021 and July 2022. According to contrast-enhanced ultrasound and upper abdomen contrast-enhanced MRI, the patients were divided into the objective response group and the non-objective response group 3 months after TACE. RESULTS There were 54 patients, of whom 31 experienced non-objective responses. The PIVKA-II levels in the objective response group were significantly lower than in the non-objective response group at 1 month [352.00 (142.16-722.54) vs. 528.58(241.32-1681.23) mAU/ml, P = 0.005] and 3 months [28.96 (20.01-42.49) vs. 2082.55 (52.63-10 057.30) mAU/ml, P = 0.016] after TACE. The Spearman rank correlation analysis showed no significant correlation between PIVKA-II and AFP (r = 0.315, P > 0.05). The areas under the curve (AUCs) of AFP and PIVKA-II before TACE were 0.632 and 0.529. One month after TACE, the AUC of PIVKA-II combined with AFP (AUC = 0.787) was higher than for PIVKA-II (AUC = 0.658) and AFP (AUC = 0.749). CONCLUSION PIVKA-II does not outperform AFP in predicting non-objective response after TACE in HCC patients. The combination of PIVKA-II and AFP might improve the diagnosis of HCC non-objective response after TACE.
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Affiliation(s)
- Lili Wang
- Infectious Diseases Major, Qinghai University
| | - Xiulan Yang
- Department of Medical Examination, Fourth People's Hospital of Qinghai Province
| | - Jinhuan Wang
- Department of ultrasonic electrophysiology, Fourth People's Hospital of Qinghai Province
| | - Guoying Yu
- Department of Infectious Diseases, Fourth People's Hospital of Qinghai Province, Qinghai, China
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Ren T, Hou X, Zhang X, Chen D, Li J, Zhu Y, Liu Z, Yang D. Validation of combined AFP, AFP-L3, and PIVKA II for diagnosis and monitoring of hepatocellular carcinoma in Chinese patients. Heliyon 2023; 9:e21906. [PMID: 38028013 PMCID: PMC10660169 DOI: 10.1016/j.heliyon.2023.e21906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/31/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023] Open
Abstract
Background In this study, we aimed to investigate the performance of GALAD, GALAD-C, and GAAP models in Chinese population in comparison to our newly build statistical model. Methods In this study, we built the AALP model based on age, α-fetoprotein (AFP), AFP-L3, and prothrombin induced by vitamin K absence-II (PIVKA II) to differentiate between patients with HCC and patients with CLD. We then compared the serum levels of AFP-L3 and PIVKA II in patients with HCC who were defined as remission or progression and showed the prognostic value of combined biomarkers. Results The AUC value of the AALP model for HCC detection was 0.939 and AALP model exhibited a sensitivity of 81 % and a high specificity of 95 %. AALP model also exhibited good performance in the subgroups of patients with CLD. Furthermore, we demonstrated the consistency between imaging results and serum levels of AFP-L3 and PIVKA II. Conclusions The AALP model achieved a good diagnostic performance and a high sensitivity for predicting HCC patients. Our research also showed that AFP-L3 and PIVKA II are complementary to each other but irreplaceable in the clinical detection and monitoring of HCC.
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Affiliation(s)
- Tianying Ren
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, 252000, PR China
| | - Xu Hou
- Department of Hepatobiliary Surgery, Liaocheng People's Hospital, Liaocheng, 252000, PR China
| | - Xin Zhang
- Department of Clinical Laboratory, Zibo Central Hospital, Zibo, 255036, Shandong, PR China
| | - Dongliang Chen
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, 252000, PR China
| | - Juan Li
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, 252000, PR China
| | - Yingnan Zhu
- Department of Laboratory Medicine, Liaocheng People's Hospital, Liaocheng, 252000, PR China
| | - Zhiheng Liu
- Department of Hepatobiliary Surgery, Liaocheng People's Hospital, Liaocheng, 252000, PR China
| | - Dawei Yang
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng, 252000, PR China
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Kobeissy A, Merza N, Al-Hillan A, Boujemaa S, Ahmed Z, Nawras M, Albaaj M, Dahiya DS, Alastal Y, Hassan M. Protein Induced by Vitamin K Absence or Antagonist-II Versus Alpha-Fetoprotein in the Diagnosis of Hepatocellular Carcinoma: A Systematic Review With Meta-Analysis. J Clin Med Res 2023; 15:343-359. [PMID: 37575350 PMCID: PMC10416192 DOI: 10.14740/jocmr4951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 06/09/2023] [Indexed: 08/15/2023] Open
Abstract
Background Protein induced by vitamin K absence or antagonist-II (PIVKA-II) and α-fetoprotein (AFP) are promising tumor markers for the diagnosis of hepatocellular carcinoma (HCC). Yet, their diagnostic performance differs throughout HCC investigations. The aim of this meta-analysis was to assess the effectiveness of PIVKA-II and AFP in the diagnosis of HCC. Methods A systematic literature search was performed to identify relevant studies from eight databases, which were published up to February 2023, in order to compare the diagnostic performance of PIVKA-II and AFP for HCC. Pooled sensitivity and specificity were calculated. Summary receiver operating characteristic (SROC) curve was performed to assess the diagnostic accuracy of each biomarker. Results Fifty-three studies were identified. The pooled sensitivity (95% confidence interval (CI)) of PIVKA-II and AFP was 0.71 (0.70 - 0.72) and 0.64 (0.63 - 0.65), respectively in diagnosis of HCC, and the corresponding pooled specificity (95% CI) was 0.90 (0.89 - 0.90) and 0.87 (0.87 - 0.88), respectively. The area under the ROC curve (AUC) of PIVKA-II and AFP was 0.89 (0.88 - 0.90) and 0.78 (0.77 - 0.79), respectively. Subgroup analysis demonstrated that PIVKA-II presented higher AUC values compared to AFP in terms of ethnic group (African, European, Asian, and American patients), etiology (mixed-type HCC, hepatitis C virus (HCV)-related, and hepatitis B virus (HBV)-related) and sample size of cases (≤ 100 and > 100). Conclusion This study reveals that PIVKA-II is a promising biomarker for identifying and tracking HCC, exhibiting greater accuracy than AFP. Our findings indicate that PIVKA-II outperforms AFP in detecting HCC across diverse racial groups and sample sizes, as well as in cases of HBV-related, HCV-related, or mixed-etiology HCC.
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Affiliation(s)
- Abdallah Kobeissy
- Department of Gastroenterology, The University of Toledo, Toledo, OH, USA
| | - Nooraldin Merza
- Department of Internal Medicine, The University of Toledo, Toledo, OH, USA
| | - Alsadiq Al-Hillan
- Gastroenterology Department, Corewell Health/Willam Beaumont University Hospital, Royal Oak, MI, USA
| | - Safa Boujemaa
- Biotechnology Development, Institute Pasteur De Tunis, Universite De Tunis El Manar, Tunis, Tunisia
| | - Zohaib Ahmed
- Department of Internal Medicine, The University of Toledo, Toledo, OH, USA
| | - Mohamad Nawras
- The University of Toledo, College of Medicine and Life Sciences, Toledo, OH, USA
| | - Mohammed Albaaj
- Department of Pharmacology and Experimental Therapeutics, University of Toledo, Toledo, OH, USA
| | - Dushyant Singh Dahiya
- Division of Gastroenterology, University of Kansas School of Medicine, Kansas City, KS, USA
| | - Yaseen Alastal
- Department of Gastroenterology, The University of Toledo, Toledo, OH, USA
| | - Mona Hassan
- Department of Gastroenterology, The University of Toledo, Toledo, OH, USA
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Eletreby R, Elsharkawy M, Taha AA, Hassany M, Abdelazeem A, El-Kassas M, Soliman A. Evaluation of GALAD Score in Diagnosis and Follow-up of Hepatocellular Carcinoma after Local Ablative Therapy. J Clin Transl Hepatol 2023; 11:334-340. [PMID: 36643039 PMCID: PMC9817041 DOI: 10.14218/jcth.2022.00013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 04/21/2022] [Accepted: 07/04/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND AND AIMS Strategies for detection of early hepatocellular carcinoma (HCC) are still limited. The GALAD score is a serum biomarker-based model designed to predict the probability of having HCC. We aimed to assess the ability of GALAD score to diagnose early HCC and its validity to follow patients after local ablation therapy. METHODS This multicenter prospective study included 108 patients in two groups, 58 HCC patients (67 focal lesions) with local ablative therapy (study group), and a control group of 50 patients with liver cirrhosis. The GALAD scores of the study and control groups, and of the HCC patients before and after ablative therapy were compared. RESULTS Most patients were men (74.1% in study group and 76% in controls) with hepatitis C virus infection (98.30% in the study group, and 94% in controls). GALAD scores were significantly higher in HCC patients than in those with benign cirrhosis (2.65 vs. -0.37, p=0.001). Ablative therapy was successful in 94.4% of focal lesions <2 cm, and in 86.10% of 2-5 cm lesions. The GALAD score was also significantly lower at 1 month after ablation in patients with well-ablated tumors (2.19 vs. 0.98, p=0.001). The best cutoff values of GALAD score for diagnosis of early HCC, and for prediction of well ablation of HCC were 0.74 and ≤3.31 (areas under the curve of 0.92 and 0.75, sensitivities of 84.48% and 76.19%, specificities of 89.13% and 83.33%, positive predictive values of 90.74% and 94.1%, and negative predictive values of 82% and 35.7% respectively). CONCLUSION The GALAD score was effective for the diagnosis of early HCC and for follow-up after ablative therapy.
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Affiliation(s)
- Rasha Eletreby
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Marwa Elsharkawy
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Alaa Awad Taha
- Hepatogastroenterology Department, Theodore Bilharz Research Institute, Giza, Egypt
| | - Mohamed Hassany
- Hepatogastroenterology Department, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Amr Abdelazeem
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
- Correspondence to: Mohamed El-Kassas, Endemic Medicine Department, Faculty of Medicine, Helwan University, Ain Helwan, Cairo 11795, Egypt. ORCID: https://orcid.org/0000-0002-3396-6894. Tel: +20-111-4455552, Fax: +20-235682827, E-mail:
| | - Ahmed Soliman
- Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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20
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Chen Y, Yang X, Shao Y, Zhao H, Jiang J, Huang P, Lu Y, Xuan Z. Comparison of diagnostic performance of AFP, DCP and two diagnostic models in hepatocellular carcinoma: a retrospective study. Ann Hepatol 2023; 28:101099. [PMID: 37030571 DOI: 10.1016/j.aohep.2023.101099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/15/2022] [Accepted: 10/20/2022] [Indexed: 04/10/2023]
Abstract
INTRODUCTION AND OBJECTIVES Hepatocellular carcinoma (HCC) may be diagnosed using the GAAP and ASAP models; our goal was to verify and evaluate their diagnostic effectiveness compared to AFP, DCP, and AFP & DCP for both HCC and HCC caused by the hepatitis B virus (HBV). PATIENTS AND METHODS GAAP and ASAP models were validated and compared using a retrospective investigation of 938 patients from our hospital between July 2020 and July 2021. RESULTS Both the GAAP and ASAP models had better diagnostic efficacy than AFP, DCP, AFP & DCP. The GAAP model achieved better performance in section A for the detection of HCC and in section C for the detection of HBV-HCC than the ASAP model. The Hosmer-Lemeshow test showed that the GAAP and ASAP models were well-calibrated for the diagnoses of these two groups. To be more specific, the AUC of the GAAP model for HCC detection in section A was 0.862 [95% confidence interval (CI): 0.838-0.883], and that of the ASAP model was 0.850 [95% CI: 0.826-0.872]. The AUC of the GAAP model for HBV-HCC detection in section C was 0.897 [95% CI: 0.872-0.918], and that of the ASAP model was 0.878 [95% CI: 0.852-0.902]. CONCLUSIONS The GAAP model was more accurate and reliable than the AFP, DCP, AFP and DCP, as well as the ASAP model in section A for the detection of HCC and in section C for the detection of HBV-HCC.
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Affiliation(s)
- Yongwu Chen
- Department of Pharmacy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, China
| | - Xiuli Yang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China
| | - Yanfei Shao
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China
| | - Hongying Zhao
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China
| | - Jinying Jiang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China
| | - Ping Huang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China
| | - Yi Lu
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
| | - Zixue Xuan
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.
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21
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Villalba-López F, Sáenz-Mateos LF, Sánchez-Lorencio MI, De La Orden-García V, Alconchel-Gago F, Cascales-Campos PA, García-Bernardo C, Noguera-Velasco JA, Baroja-Mazo A, Ramírez-Romero P. Usefulness of PIVKA-II for monitoring after liver transplantation in patients with hepatocellular carcinoma. Sci Rep 2023; 13:5621. [PMID: 37024609 PMCID: PMC10079651 DOI: 10.1038/s41598-023-32879-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 04/04/2023] [Indexed: 04/08/2023] Open
Abstract
The high morbidity and mortality of hepatocellular carcinoma (HCC) has encouraged the search for new biomarkers to be used alongside alpha-foetoprotein (AFP) and imaging tests. The aim of this study was to evaluate the clinical contribution of protein induced by vitamin K absence or antagonist-II (PIVKA-II) for HCC monitoring after liver transplantation (LT) and compare it with AFP, a routinely used tumour marker. A total of 46 HCC patients (Milan criteria) were enrolled in this study. Serum levels of PIVKA-II and AFP were measured before and after transplantation. Clinical features were determined for all the patients that were included. Significant correlations were found between PIVKA-II expression levels and some clinicopathological features, such as tumour size and number of pre-transplant transarterial chemoembolizations (TACEs). Serum levels of PIVKA-II and AFP decreased significantly after LT and increased in patients with tumour recurrence. Serum PIVKA-II levels may play an important role in predicting disease severity. Furthermore, monitoring PIVKA-II levels in HCC transplant recipients reflects the tumor early recurrence after transplantation and could be used, complementing AFP and imaging tests, as a novel biomarker of this pathology.
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Affiliation(s)
| | | | | | | | - Felipe Alconchel-Gago
- Liver Transplant Unit, University Hospital Virgen de la Arrixaca, 30120, Murcia, Spain
| | | | | | | | | | - Pablo Ramírez-Romero
- Liver Transplant Unit, University Hospital Virgen de la Arrixaca, 30120, Murcia, Spain
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22
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Diagnostic Performance of Extrahepatic Protein Induced by Vitamin K Absence in the Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Diagnostics (Basel) 2023; 13:diagnostics13050816. [PMID: 36899960 PMCID: PMC10001363 DOI: 10.3390/diagnostics13050816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 02/05/2023] [Accepted: 02/06/2023] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND AND OBJECTIVES the early diagnosis of hepatocellular carcinoma (HCC) benefits from the use of alpha-fetoprotein (AFP) together with imaging diagnosis using abdominal ultrasonography, CT, and MRI, leading to improved early detection of HCC. A lot of progress has been made in the field, but some cases are missed or late diagnosed in advanced stages of the disease. Therefore, new tools (serum markers, imagistic technics) are continually being reconsidered. Serum alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist II (PIVKA II) diagnostic accuracy for HCC (global and early disease) has been investigated (in a separate or cumulative way). The purpose of the present study was to determine the performance of PIVKA II compared to AFP. MATERIALS AND METHODS systematic research was conducted in PubMed, Web of Science, Embase, Medline and the Cochrane Central Register of Controlled Trials, taking into consideration articles published between 2018 and 2022. RESULTS a total number of 37 studies (5037 patients with HCC vs. 8199 patients-control group) have been included in the meta-analysis. PIVKA II presented a better diagnostic accuracy in HCC diagnostic vs. alpha-fetoprotein (global PIVKA II AUROC 0.851 vs. AFP AUROC 0.808, respectively, 0.790 vs. 0.740 in early HCC cases). The conclusion from a clinical point of view, concomitant use of PIVKA II and AFP can bring useful information, added to that brought by ultrasound examination.
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Shahini E, Pasculli G, Solimando AG, Tiribelli C, Cozzolongo R, Giannelli G. Updating the Clinical Application of Blood Biomarkers and Their Algorithms in the Diagnosis and Surveillance of Hepatocellular Carcinoma: A Critical Review. Int J Mol Sci 2023; 24:ijms24054286. [PMID: 36901717 PMCID: PMC10001986 DOI: 10.3390/ijms24054286] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
The most common primary liver cancer is hepatocellular carcinoma (HCC), and its mortality rate is increasing globally. The overall 5-year survival of patients with liver cancer is currently 10-20%. Moreover, because early diagnosis can significantly improve prognosis, which is highly correlated with tumor stage, early detection of HCC is critical. International guidelines advise using α-FP biomarker with/without ultrasonography for HCC surveillance in patients with advanced liver disease. However, traditional biomarkers are sub-optimal for risk stratification of HCC development in high-risk populations, early diagnosis, prognostication, and treatment response prediction. Since about 20% of HCCs do not produce α-FP due to its biological diversity, combining α-FP with novel biomarkers can enhance HCC detection sensitivity. There is a chance to offer promising cancer management methods in high-risk populations by utilizing HCC screening strategies derived from new tumor biomarkers and prognostic scores created by combining biomarkers with distinct clinical parameters. Despite numerous efforts to identify molecules as potential biomarkers, there is no single ideal marker in HCC. When combined with other clinical parameters, the detection of some biomarkers has higher sensitivity and specificity in comparison with a single biomarker. Therefore, newer biomarkers and models, such as the Lens culinaris agglutinin-reactive fraction of Alpha-fetoprotein (α-FP), α-FP-L3, Des-γ-carboxy-prothrombin (DCP or PIVKA-II), and the GALAD score, are being used more frequently in the diagnosis and prognosis of HCC. Notably, the GALAD algorithm was effective in HCC prevention, particularly for cirrhotic patients, regardless of the cause of their liver disease. Although the role of these biomarkers in surveillance is still being researched, they may provide a more practical alternative to traditional imaging-based surveillance. Finally, looking for new diagnostic/surveillance tools may help improve patients' survival. This review discusses the current roles of the most used biomarkers and prognostic scores that may aid in the clinical management of HCC patients.
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Affiliation(s)
- Endrit Shahini
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
- Correspondence: ; Tel.: +39-0804994249
| | - Giuseppe Pasculli
- National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Antonio Giovanni Solimando
- Guido Baccelli Unit of Internal Medicine, Department of Precision and Regenerative Medicine and Ionian Area-(DiMePRe-J), University of Bari “A. Moro”, 70121 Bari, Italy
| | | | - Raffaele Cozzolongo
- Gastroenterology Unit, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
| | - Gianluigi Giannelli
- Scientific Director, National Institute of Gastroenterology-IRCCS “Saverio de Bellis”, Castellana Grotte, 70013 Bari, Italy
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Liu L, Wang Q, Zhao X, Huang Y, Feng Y, Zhang Y, Fang Z, Li S. Establishment and validation of nomogram model for the diagnosis of AFP-negative hepatocellular carcinoma. Front Oncol 2023; 13:1131892. [PMID: 36890811 PMCID: PMC9986420 DOI: 10.3389/fonc.2023.1131892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 02/07/2023] [Indexed: 02/22/2023] Open
Abstract
Introduction As one of the most common malignant tumors in clinical practice, hepatocellular carcinoma (HCC) is a major threat to human health, where alpha-fetoprotein (AFP) is widely used for early screening and diagnoses. However, the level of AFP would not elevate in about 30-40% of HCC patients, which is clinically referred to as AFP-negative HCC, with small tumors at an early stage and atypical imaging features, making it difficult to distinguish benign from malignant by imaging alone. Methods A total of 798 patients, with the majority being HBV-positive, were enrolled in the study and were randomized 2:1 to the training and validation groups. Univariate and multivariate binary logistic regression analyses were used to determine the ability of each parameter to predict HCC. A nomogram model was constructed based on the independent predictors. Results A unordered multicategorical logistic regression analyses showed that the age, TBIL, ALT, ALB, PT, GGT and GPR help identify non-hepatic disease, hepatitis, cirrhosis, and hepatocellular carcinoma. A multivariate logistic regression analyses showed that the gender, age, TBIL, GAR, and GPR were independent predictors for the diagnosis of AFP-negative HCC. And an efficient and reliable nomogram model (AUC=0.837) was constructed based on independent predictors. Discussion Serum parameters help reveal intrinsic differences between non-hepatic disease, hepatitis, cirrhosis, and HCC. The nomogram based on clinical and serum parameters could be used as a marker for the diagnosis of AFP-negative HCC, providing an objective basis for the early diagnosis and individualized treatment of hepatocellular carcinoma patients.
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Affiliation(s)
- Long Liu
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, Zhejiang, China
| | - Qi Wang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Xiaohong Zhao
- Department of Pharmacy, Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, Zhejiang, China
| | - Yuxi Huang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yuyi Feng
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang, China
| | - Yu Zhang
- Department of Oncology, The First Hospital of the University of Science and Technology of China, Hefei, Anhui, China
| | - Zheping Fang
- Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Zhejiang University, Linhai, Zhejiang, China.,Department of Hepatobiliary Surgery, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shaowei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province, Linhai, Zhejiang, China
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25
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Liu SY, Li C, Sun LY, Guan MC, Gu LH, Yin DX, Yao LQ, Liang L, Wang MD, Xing H, Zhu H, Pawlik TM, Lau WY, Shen F, Tong XM, Yang T. ASAP Score versus GALAD Score for detection of hepatitis C-related hepatocellular carcinoma: A multicenter case-control analysis. Front Oncol 2022; 12:1018396. [PMID: 36263214 PMCID: PMC9576185 DOI: 10.3389/fonc.2022.1018396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 08/31/2022] [Indexed: 11/15/2022] Open
Abstract
Background The GALAD and ASAP scores are two well-recognized algorithms to estimate the risk of hepatocellular carcinoma (HCC) based on gender, age, alpha-fetoprotein (AFP), protein induced by vitamin K absence or Antagonist-II (PIVKA-II) and AFP-L3 (included in the GALAD score but not in the ASAP score). The current study sought to compare the diagnostic performance of each score to detect HCC among patients infected with hepatitis C virus (HCV). Methods A multicenter case-control study was undertaken in which blood samples were collected from HCVinfected patients with and without HCC. Using the area under the receiver operating characteristic curve (AUROC), ASAP and GALAD scores were compared relative to diagnostic performance to detect any stage HCV-HCC and early-stage HCV-HCC. Results The analytic cohort included 168 HCV-HCC patients and a control group of 193 HCV-infected patients. The ASAP score had a higher AUROC to detect any stage HCV-HCC versus the GALAD score, both in the overall group (0.917 vs. 0.894, P=0.057) and in the cirrhosis subgroup (0.909 vs. 0.889, P=0.132). Similar results were noted relative to the detection of early-stage HCV-HCC, whether defined by BCLC staging (stage 0-A: 0.898 vs. 0.860, P=0.026) or 8th TNM staging (stage I: 0.899 vs. 0.870, P=0.070). In subgroup analysis to detect AFP-negative HCV-HCC, the ASAP score also demonstrated a higher AUROC than the GALAD score to detect any stage HCV-HCC in the AFP-negative subgroup (0.815 vs. 0.764, P=0.063). Conclusions The ASAP score had better diagnostic performance for early detection of HCV-HCC compared with the GALAD score. The ASAP score may be preferrable to the GALAD score for HCC screening and surveillance among HCV-infected patients.
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Affiliation(s)
- Si-Yu Liu
- Department of Laboratory Medicine, Lishui Municipal Central Hospital, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China,The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Li-Yang Sun
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China
| | - Ming-Cheng Guan
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Li-Hui Gu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Dong-Xu Yin
- School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China
| | - Lan-Qing Yao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Lei Liang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China,Eastern Hepatobiliary Clinical Research Institute (EHCRI), Third Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Hao Xing
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Hong Zhu
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Timothy M. Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, OH, United States
| | - Wan Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China,Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China,Eastern Hepatobiliary Clinical Research Institute (EHCRI), Third Affiliated Hospital of Navy Medical University, Shanghai, China
| | - Xiang-Min Tong
- Department of Laboratory Medicine, Lishui Municipal Central Hospital, the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China,The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China,*Correspondence: Tian Yang, ; Xiang-Min Tong,
| | - Tian Yang
- The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China,Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, China,School of Clinical Medicine, Hangzhou Medical College, Hangzhou, China,Eastern Hepatobiliary Clinical Research Institute (EHCRI), Third Affiliated Hospital of Navy Medical University, Shanghai, China,*Correspondence: Tian Yang, ; Xiang-Min Tong,
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Lee J, Park SB, Byun S, Kim HI. Impact of ultrasonographic blind spots for early-stage hepatocellular carcinoma during surveillance. PLoS One 2022; 17:e0274747. [PMID: 36112645 PMCID: PMC9481035 DOI: 10.1371/journal.pone.0274747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 09/05/2022] [Indexed: 11/18/2022] Open
Abstract
Background
Abdominal ultrasonography (US) is the backbone of hepatocellular carcinoma (HCC) surveillance. Although previous studies have evaluated clinical factors related to surveillance failure, none have focused specifically on US blind spots.
Methods
This study included 1,289 patients who underwent 6 months intervals surveillance using US and serum alpha-fetoprotein (AFP) and were eventually diagnosed with single-nodular HCC. Patients were divided into US-detected group (n = 1,062) and US-missed group (HCC detected only by AFP ≥ 20ng/mL; n = 227). Blind spots consisted of four locations: hepatic dome, caudate lobe or around the inferior vena cava, <1 cm beneath the ribs, and the surface of the left lateral segment. Both groups were compared by HCC location, proportional distribution, treatment method, and overall survival.
Results
A higher proportion of HCCs were located within blind spots in the US-missed group than in the US-detected group (64.3% vs. 44.6%, P < 0.001). HCC ≥ 2 cm detected in blind spots was higher than in non-blind areas (60.3% vs. 47.1%, P = 0.001). Blind spot HCCs were more treated with surgery, whereas those located in a non-blind area were more treated with local ablation. Patients with an HCC located within a blind spot in the US-detected group had better overall survival than the same in the US-missed group (P = 0.008).
Conclusions
Using the current surveillance test, blind spots affected the initially detected HCC tumor size, applicability of the treatment modality, and overall survival. Physicians should pay attention to US blind spots when performing US-based HCC surveillance.
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Affiliation(s)
- Junghwan Lee
- Department of Gastroenterology, Asan Medical Center, Seoul, South Korea
| | - Su Bee Park
- Department of Gastroenterology, Asan Medical Center, Seoul, South Korea
| | - Soyoung Byun
- Department of Gastroenterology, Asan Medical Center, Seoul, South Korea
| | - Ha Il Kim
- Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, South Korea
- * E-mail:
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Seo JY, Joo I, Yoon JH, Kang HJ, Kim S, Kim JH, Ahn C, Lee JM. Deep learning-based reconstruction of virtual monoenergetic images of kVp-switching dual energy CT for evaluation of hypervascular liver lesions: Comparison with standard reconstruction technique. Eur J Radiol 2022; 154:110390. [PMID: 35724579 DOI: 10.1016/j.ejrad.2022.110390] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 01/12/2022] [Accepted: 05/31/2022] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To investigate clinical applicability of deep learning(DL)-based reconstruction of virtual monoenergetic images(VMIs) of arterial phase liver CT obtained by rapid kVp-switching dual-energy CT for evaluation of hypervascular liver lesions. MATERIALS AND METHODS We retrospectively included 109 patients who had available late arterial phase liver CT images of the liver obtained with a rapid switching kVp DECT scanner for suspicious intra-abdominal malignancies. Two VMIs of 70 keV and 40 keV were reconstructed using adaptive statistical iterative reconstruction (ASiR-V) for arterial phase scans. VMIs at 40 keV were additionally reconstructed with a vendor-agnostic DL-based reconstruction technique (ClariCT.AI, ClariPi, DL 40 keV). Qualitative, quantitative image quality and subjective diagnostic acceptability were compared according to reconstruction techniques. RESULTS In qualitative analysis, DL 40 keV images showed less image noise (4.55 vs 3.11 vs 3.95, p < 0.001), better image sharpness (4.75 vs 4.16 vs 4.3, p < 0.001), better image contrast (4.98 vs 4.72 vs 4.19, p < 0.017), better lesion conspicuity (4.61 vs 4.23 vs 3.4, p < 0.001) and diagnostic acceptability (4.59 vs 3.88 vs 4.09, p < 0.001) compared with ASiR-V 40 keV or 70 keV image sets. In quantitative analysis, DL 40 keV significantly reduced image noise relative to ASiR-V 40 keV images (49.9%, p < 0.001) and ASiR-V 70 keV images (85.2%, p = 0.012). DL 40 keV images showed significantly higher CNRlesion to the liver and SNRliver than ASiR-V 40 keV image and 70 keV images (p < 0.001). CONCLUSION DL-based reconstruction of 40 keV images using vendor-agnostic software showed greater noise reduction, better lesion conspicuity, image contrast, image sharpness, and higher overall image diagnostic acceptability than ASiR for 40 keV or 70 keV images in patients with hypervascular liver lesions.
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Affiliation(s)
- June Young Seo
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ijin Joo
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong Hee Yoon
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyo Jin Kang
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sewoo Kim
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jong Hyo Kim
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea; Center for Medical-IT Convergence Technology Research, Advanced Institutes of Convergence Technology, Suwon, Republic of Korea; Research Institute, ClariPi, Seoul, Republic of Korea
| | - Chulkyun Ahn
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea; Research Institute, ClariPi, Seoul, Republic of Korea
| | - Jeong Min Lee
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
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Nicolosi A, Pellicano R, Caviglia GP. Surveillance of cirrhotic patients using the protein induced by vitamin K absence or antagonist II (PIVKA-II). Minerva Med 2022; 113:106-108. [PMID: 35313441 DOI: 10.23736/s0026-4806.21.07952-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Aurora Nicolosi
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Rinaldo Pellicano
- Unit of Gastroenterology, Molinette Hospital, Città della Salute e della Scienza, Turin, Italy
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29
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Degasperi E, Perbellini R, D'Ambrosio R, Uceda Renteria SC, Ceriotti F, Perego A, Orsini C, Borghi M, Iavarone M, Bruccoleri M, Rimondi A, De Silvestri A, Sangiovanni A, Lampertico P. Prothrombin induced by vitamin K absence or antagonist-II and alpha foetoprotein to predict development of hepatocellular carcinoma in Caucasian patients with hepatitis C-related cirrhosis treated with direct-acting antiviral agents. Aliment Pharmacol Ther 2022; 55:350-359. [PMID: 34738664 DOI: 10.1111/apt.16685] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/05/2021] [Accepted: 10/21/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Prothrombin induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha fetoprotein (AFP) are biomarkers for hepatocellular carcinoma (HCC). However, their performance in patients with cirrhosis related to hepatitis C virus (HCV) treated with direct-acting antiviral agents (DAA) is unknown. AIM To evaluate PIVKA-II and AFP as HCC predictors in DAA-treated patients with HCV-related cirrhosis METHODS: In this single centre study, patients with cirrhosis from chronic HCV infection and with a sustained virological response (SVR) to DAA were tested for PIVKA-II and AFP (Fujirebio, Japan) at the start of DAA treatment (baseline), end of treatment (EOT) and at HCC diagnosis. RESULTS We included 400 patients with mean age 65 (24-92); 56% were men. From baseline to EOT, PIVKA-II did not change (35 vs 35 mAU/mL, P = 0.43) while AFP significantly decreased (12 vs 6 ng/mL, P < 0.0001). After 52 (3-66) months from baseline, 34 (8.5%) patients developed de novo HCC; median AFP 9 (2-12 868) ng/mL and PIVKA-II 80 (22-1813) mAU/mL. EOT-PIVKA-II (HR 3.05, P < 0.0001) and AFP (HR 2.77, P = 0.001) independently predicted HCC together with diabetes (HR 6.12, P < 0.001) and GGT (HR 1.01, P = 0.03). The 4-year cumulative probability of HCC was 24% vs 2% in patients with EOT-PIVKA-II > or ≤41 mAU/mL (P < 0.0001), and 26% vs 9% for EOT-AFP > or ≤15 ng/mL (P = 0.02). By combining EOT-PIVKA-II and AFP, the 4-year probabilities of HCC were 3% in patients testing negative for both markers, 18% in patients positive for both, and 38% in patients positive for at least one (P < 0.0001). CONCLUSIONS In patients with HCV-related cirrhosis treated with DAA, PIVKA-II and AFP independently predicted HCC, while their combination improved risk stratification.
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Affiliation(s)
- Elisabetta Degasperi
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Riccardo Perbellini
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Roberta D'Ambrosio
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Ferruccio Ceriotti
- Clinical Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | | | - Marta Borghi
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Mariangela Bruccoleri
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Alessandro Rimondi
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Annalisa De Silvestri
- Clinical Epidemiology and Biometric Unit, Foundation IRCCS Policlinico San Matteo, Pavia, Italy
| | - Angelo Sangiovanni
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.,CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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30
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Huang C, Fang M, Xiao X, Wang H, Gao Z, Ji J, Liu L, Gu E, Li Y, Wang M, Gao C. Validation of the GALAD model for early diagnosis and monitoring of hepatocellular carcinoma in Chinese multicenter study. Liver Int 2022; 42:210-223. [PMID: 34679250 DOI: 10.1111/liv.15082] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 10/18/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND GALAD is an algorithm model estimating the presence of hepatocellular carcinoma (HCC). However, the participants enrolled in the GALAD differ from those of Chinese subjects whose HCCs are mainly hepatitis B virus infection related. Therefore, the cross-sectional as well as longitudinal multicenter study was designed to assess the clinical performances of GALAD in the Chinese population. METHODS A case-control study of 602 patients with HCC (34.10% within Barcelona Clinic Liver Cancer 0-A stage) and 923 subjects without HCC from five Chinese medical centres was conducted. Longitudinally the performances of GALAD identifying HCC were assessed using receiver operating characteristic curves analyses. Furthermore, the surveillance performance of GALAD for 204 HCC patients after radical surgery and for the early detection of HCC prospectively in an independent cohort of chronic hepatitis B were analysed, respectively. RESULTS We found the GALAD identified early stage HCC at an area under the receiver operating characteristic curve (AUC) above 0.85 and outperformed significantly than AFP, PIVKAII, AFP-L3 and BALAD-2 respectively. Meanwhile the GALAD could stratify HCC into two distinct subgroups with high or low risks of overall survival and recurrence. The GALAD could detection HCC 24 (AUC: 0.848) or even 48 (AUC: 0.833) weeks before clinical diagnosis. CONCLUSIONS Our study indicates that the GALAD exhibits outstanding performance in the early diagnosis, prognosis prediction as well as risk monitoring of HCC in our cross-sectional and longitudinal multicenter study of 1561 patients. GALAD should be implanted into clinical practice early so as to improve the clinical efficacy of individual biomarkers in HCC early monitoring and prognosis prediction.
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Affiliation(s)
- Chenjun Huang
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.,Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Meng Fang
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xiao Xiao
- Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hong Wang
- Department of Hepatology and Gastroenterology, Jing'an District Centre Hospital, Fudan University, P.R. China
| | - Zhiyuan Gao
- Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jun Ji
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Lijuan Liu
- Department of Laboratory Medicine, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Erli Gu
- Department of Hepatology and Gastroenterology, Jing'an District Centre Hospital, Fudan University, P.R. China
| | - Ya Li
- Department of Laboratory Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, P.R. China
| | - Mengmeng Wang
- Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, P.R. China
| | - Chunfang Gao
- Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.,Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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31
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Han JW, Sung PS, Jang JW, Choi JY, Yoon SK. Whole blood viscosity is associated with extrahepatic metastases and survival in patients with hepatocellular carcinoma. PLoS One 2021; 16:e0260311. [PMID: 34855786 PMCID: PMC8638904 DOI: 10.1371/journal.pone.0260311] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Whole blood viscosity (WBV) is increased in cancer patients and associated with the advanced stage with systemic metastases. However, relevance of WBV in hepatocellular carcinoma (HCC) remains unclear. This pilot study included a discovery cohort of 148 treatment-naïve HCC patients with preserved liver function, and a validation cohort of 33 treatment-experienced HCC patients with nivolumab. Systolic and diastolic WBV was measured using an automated scanning capillary tube viscometer at diagnosis or before the nivolumab treatment. Extrahepatic metastases were observed in 15 treatment-naïve patients (11.3%) at diagnosis. Portal vein tumor thrombosis (PVTT), tumor size, number of tumors, and systolic/diastolic WBV were factors associated with extrahepatic metastases. Systolic WBV and diastolic WBV were significantly increased in patients with metastases compared with patients without metastases. Multivariate logistic regression showed that high diastolic WBV > 16 cP was an independent factor associated with metastases. Notably, patients who developed extrahepatic metastases during the observation period among patients without metastases at diagnosis had higher diastolic WBV initially. Patients with high diastolic WBV had poor survival, and multivariate Cox regression analyses showed high diastolic WBV was an independent risk factor for poor survival with the Child-Pugh B7 and PVTT. High diastolic WBV also predicted poor survival in patients with low alpha-fetoprotein (AFP) and proteins induced by vitamin K antagonist-II (PIVKA-II) levels. In 33 nivolumab-treated patients, high diastolic WBV before the treatment was also tended to be associated with overall and progression-free survival. Our study is the first in which high WBV is associated with the distant metastases and survival in patients with HCC, but future prospective, large cohort studies are necessary to validate the results.
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Affiliation(s)
- Ji Won Han
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Pil Soo Sung
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Won Jang
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jong Young Choi
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea
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32
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Piratvisuth T, Tanwandee T, Thongsawat S, Sukeepaisarnjaroen W, Esteban JI, Bes M, Köhler B, He Y, Swiatek-de Lange M, Morgenstern D, Chan HLY. Multimarker Panels for Detection of Early Stage Hepatocellular Carcinoma: A Prospective, Multicenter, Case-Control Study. Hepatol Commun 2021; 6:679-691. [PMID: 34796691 PMCID: PMC8948551 DOI: 10.1002/hep4.1847] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 08/27/2021] [Accepted: 09/28/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC), the sixth most common cancer worldwide, has an incidence rate equal to mortality. Over 80% of HCC cases occur within a high‐risk population, mainly patients with both cirrhosis and chronic hepatitis B or C. With a 5‐year survival rate ranging from <16% for advanced HCC to >90% for early stage HCC, there is a high medical need for the early detection of HCC. In this study, we systematically evaluated biomarkers mentioned in international guidelines and peer‐reviewed literature for HCC surveillance and diagnosis with the aim of identifying combinations that display high sensitivity and specificity for early stage HCC. Fifty biomarkers were measured in the first sample panel, panel A (n = 110), and subjected to univariate analysis. Of these, 35 biomarkers (38 assays) from panel A and an additional 13 biomarkers from the literature were prioritized for subsequent multivariate evaluation with lasso regression and exhaustive search of two‐ to four‐biomarker combinations (panel B). Panel B included 1,081 samples from patients with HCC (n = 308) or with chronic liver diseases (n = 740). Among all patients, 61.0% had hepatitis B, 32.9% had hepatitis C, and 60.5% had cirrhosis; 40.6% of patients with HCC had early stage cancer. Protein induced by vitamin K absence‐II (PIVKA‐II; also known as des‐gamma‐carboxy prothrombin [DCP]) and alpha‐fetoprotein (AFP) demonstrated the best clinical performance, both individually and in combination, and the addition of a third biomarker (Lens culinaris agglutinin‐reactive fraction of AFP [AFP‐L3], cartilage oligomeric matrix protein [COMP], insulin‐like growth factor‐binding protein 3 [IGFBP3], or matrix metalloproteinase 3 [MMP3]) further increased sensitivity for the detection of both early stage and all‐stage HCC. The addition of age and sex to the three‐biomarker panel resulted in an improved diagnostic performance. Conclusion: The combination of AFP and PIVKA‐II, with either IGFBP3, COMP or MMP3, plus age and sex, demonstrated the best performance for the detection of early‐ and all‐stage HCC. These novel panels performed similar to that of the GALAD score (sex [gender], age, plus serum levels of AFP, AFP‐L3 and DCP [PIVKA‐II]), a promising screening tool developed for HCC detection.
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Affiliation(s)
- Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
| | - Tawesak Tanwandee
- Division of Gastroenterology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Satawat Thongsawat
- Department of Internal Medicine, Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University, Chiang Mai, Thailand
| | | | - Juan Ignacio Esteban
- Liver Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain.,Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas, Insituto de Salud Carlos III, Madrid, Spain
| | - Marta Bes
- Centro de Investigación Biomédica en red de Enfermedades Hepáticas y Digestivas, Insituto de Salud Carlos III, Madrid, Spain.,Transfusion Safety Laboratory, Banc de Sang i Teixits, Barcelona, Spain
| | - Bruno Köhler
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.,Liver Cancer Center Heidelberg, Heidelberg, Germany
| | - Ying He
- Roche Diagnostics GmbH, Penzberg, Germany
| | | | | | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong
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33
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Ahn KS, O'Brien DR, Kim YH, Kim TS, Yamada H, Park JW, Park SJ, Kim SH, Zhang C, Li H, Kang KJ, Roberts LR. Associations of Serum Tumor Biomarkers with Integrated Genomic and Clinical Characteristics of Hepatocellular Carcinoma. Liver Cancer 2021; 10:593-605. [PMID: 34950182 PMCID: PMC8647136 DOI: 10.1159/000516957] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/29/2021] [Indexed: 02/04/2023] Open
Abstract
INTRODUCTION Serum α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-γ-carboxy-pro-thrombin (DCP) are useful biomarkers of hepatocellular carcinoma (HCC). However, associations among molecular characteristics and serum biomarkers are unclear. We analyzed RNA expression and DNA variant data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) to examine their associations with serum biomarker levels and clinical data. METHODS From 371 TCGA-LIHC patients, we selected 91 seen at 3 institutions in Korea and the USA and measured AFP, AFP-L3, and DCP from preoperatively obtained serum. We conducted an integrative clinical and molecular analysis, focusing on biomarkers, and validated the findings with the remaining 280 patients in the TCGA-LIHC cohort. RESULTS Patients were categorized into 4 subgroups: elevated AFP or AFP-L3 alone (↑AFP&L3), elevated DCP alone (↑DCP), elevation of all 3 biomarkers (elevated levels of all 3 biomarkers [↑All]), and reference range values for all biomarkers (RR). CTNNB1 variants were frequently observed in ↑DCP patients (53.8%) and RR patients (38.5%), but ↑DCP patients with a CTNNB1 variant had worse survival than RR patients. TP53 sequence variants were associated with ↑AFP (30.8%) and ↑DCP (30.8%). The Wnt-β-catenin signaling pathway was activated in the ↑AFP&L3, whereas liver-related Wnt signaling was activated in the RR. TGF-β and VEGF signaling were activated in ↑AFP&L3, whereas dysregulated bile acid and fatty acid metabolism were dominant in ↑DCP. We validated these findings by showing similar results between the test cohort and the remainder of the TCGA-LIHC cohort. CONCLUSIONS Serum AFP, AFP-L3, and DCP levels can help predict variants in the genetic profile of HCC, especially for TP53 and CTNNB1. These findings may facilitate development of an evidence-based approach to treatment.
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Affiliation(s)
- Keun Soo Ahn
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Daniel R. O'Brien
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA
| | - Yong Hoon Kim
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Tae-Seok Kim
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Hiroyuki Yamada
- Global Clinical Research Management, FUJIFILM Wako Pure Chemical Corporation, Tokyo, Japan
| | - Joong-Won Park
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Republic of Korea
| | - Sang-Jae Park
- Department of Surgery, National Cancer Center, Goyang, Republic of Korea
| | - Seoung Hoon Kim
- Department of Surgery, National Cancer Center, Goyang, Republic of Korea
| | - Cheng Zhang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
| | - Hu Li
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
| | - Koo Jeong Kang
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea,*Koo Jeong Kang,
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA,**Lewis R. Roberts,
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Su TH, Peng CY, Chang SH, Tseng TC, Liu CJ, Chen CL, Liu CH, Yang HC, Chen PJ, Kao JH. Serum PIVKA-II and alpha-fetoprotein at virological remission predicts hepatocellular carcinoma in chronic hepatitis B related cirrhosis. J Formos Med Assoc 2021; 121:703-711. [PMID: 34452785 DOI: 10.1016/j.jfma.2021.08.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/18/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The risk of hepatocellular carcinoma (HCC) is reduced but not eliminated after nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB). We aimed to investigate the role of serum Prothrombin Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) and alpha-fetoprotein in predicting HCC and mortality in cirrhotic CHB patients at virological remission (VR) following NA therapy. METHODS Patients with CHB-related cirrhosis undergoing NA therapy from two medical centers in Taiwan were retrospectively included. Serum PIVKA-II were quantified by an automated chemiluminescence assay. Multivariable Cox proportional hazards regression models were used to identify predictors for HCC and death. Serial on-treatment PIVKA-II levels after VR were investigated. RESULTS Overall, 293 CHB-related cirrhosis patients were included. At VR, the mean age was 55, and the mean PIVKA-II level was 35 mAU/mL. After a mean follow-up of 78 months, 76 patients developed HCC and 19 died. After adjustment for confounding factors, alpha-fetoprotein >7 ng/mL (hazard ratio [HR]: 2.84, 95% confidence interval [CI]: 1.73-4.67) and PIVKA-II >50 mAU/mL (HR: 2.46, 95%CI: 1.35-4.49) at VR significantly predicted HCC development. In patients with alpha-fetoprotein ≤10 ng/mL or ≤20 ng/mL at VR, PIVKA-II >50 mAU/mL increased 2.45 or 3.16-fold risk of HCC, respectively. PIVKA-II levels after VR increased serially in patients who developed HCC afterwards. CONCLUSIONS In patients with CHB-related cirrhosis, serum alpha-fetoprotein >7 ng/mL and PIVKA-II >50 mAU/mL at the time of antiviral therapy-induced VR is associated with a greater risk of HCC. PIVKA-II is a predictive marker for HCC in patients with low normal alpha-fetoprotein level.
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Affiliation(s)
- Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- School of Medicine, China Medical University, Taichung, Taiwan; Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Shan-Han Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan
| | - Tai-Chung Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Chi-Ling Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chen-Hua Liu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hung-Chih Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
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35
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Lee HA, Lee YR, Lee YS, Jung YK, Kim JH, An H, Yim HJ, Jeen YT, Yeon JE, Byun KS, Seo YS. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein improves diagnostic accuracy for hepatocellular carcinoma. World J Gastroenterol 2021; 27:4687-4696. [PMID: 34366629 PMCID: PMC8326250 DOI: 10.3748/wjg.v27.i28.4687] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/10/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diagnostic accuracy of various tumor markers and their combinations for hepatocellular carcinoma (HCC) was not fully investigated. AIM To evaluate the diagnostic accuracy of alpha-fetoprotein (AFP), the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II) and their combination for HCC diagnosis. METHODS Patients with newly detected liver mass or elevated serum AFP levels were considered eligible. Serum AFP level, AFP-L3 fraction, and PIVKA-II level were measured at the first visit. RESULTS In total, 622 patients were included; 355 patients (57.1%) had chronic liver disease, and 208 (33.4%) had liver cirrhosis. HCC was diagnosed in 160 patients (25.7%). The area under the receiver operating characteristics curves (AUROCs) of the serum AFP, AFP-L3 fraction, AFP-L3, and PIVKA-II levels for the diagnosis of HCC were 0.775, 0.792, 0.814, and 0.834, respectively. A novel diagnostic model was developed by classifying patients in a 1:1 ratio into training and validation sets. Using the binary regression analysis of the training cohort, the AFP, AFP-L3 fraction, and PIVKA-II (ALPs) score was calculated as follows: ALPs score = 3.8 × [serum AFP level (ng/mL) × AFP-L3 fraction (%) × 0.01] + 0.2 × PIVKA-II level (mAU/mL). The AUROC of the ALPs score for diagnosis of HCC was 0.878, significantly higher than that of serum AFP level (P < 0.001), AFP-L3 fraction (P < 0.001), PIVKA-II level (P = 0.036), and AFP-L3 level (P = 0.006). The optimal ALPs score cut-off was 5.3 (sensitivity, 85.0%, specificity 80.1%). The validation cohort showed similar results. CONCLUSION The ALPs score calculated using serum AFP level, AFP-L3 fraction, and PIVKA-II level showed improved accuracy in HCC diagnosis.
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Affiliation(s)
- Han Ah Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Yoo Ra Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Young-Sun Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Hyunggin An
- Department of Biostatistics, Korea University Anam Hospital, Seoul 02841, South Korea
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Yoon Tae Jeen
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Jong Eun Yeon
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Kwan Soo Byun
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
| | - Yeon Seok Seo
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, South Korea
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GALAD Score Detects Early-Stage Hepatocellular Carcinoma in a European Cohort of Chronic Hepatitis B and C Patients. Pharmaceuticals (Basel) 2021; 14:ph14080735. [PMID: 34451832 PMCID: PMC8401792 DOI: 10.3390/ph14080735] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 12/23/2022] Open
Abstract
Despite vaccination programs and direct antiviral treatments, the incidence of virus-related hepatocellular carcinoma (HCC) remains high, while ultrasound-based detection rates for early-stage HCC is continuously low. To address this insufficiency, we set out to characterize whether the GALAD score, which incorporates gender, age, and serum levels of AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy-prothrombin (DCP), can improve early-stage HCC detection in a Caucasian HBV/HCV cohort. In a retrospective German single-center study, 182 patients with HBV, 223 with HCV and 168 with other etiology (OE) of chronic liver disease (CLD) were enrolled. HCC was confirmed in 52 HBV, 84 HCV and 60 OE CLD patients. The diagnostic performance of the single biomarkers in HCC detection was compared to the GALAD model. At initial diagnosis, most patients were at (very) early BCLC 0 (n = 14/7%) or A (n = 56/29%) or intermediate stage BCLC B (n = 93/47%) HCC in all three subgroups. In the BCLC 0/A cohort, GALAD exhibited an AUC of 0.94 discriminating HCC from non-HCC, surpassing AFP (AUC 0.86), AFP-L3 (AUC 0.83) and DCP (AUC 0.83). In the HBV population, GALAD achieved an AUC of 0.96, in HCV an AUC of 0.98 and in OE an AUC of 0.99, clearly superior to the biomarkers alone. Furthermore, in HCV patients GALAD showed a significantly higher specificity (89%) versus AFP (64%) alone. In chronic viral hepatitis, the GALAD model showed superior performance in detection of early-stage HCC, while exhibiting higher specificity in HCV patients compared to AFP alone. We conclude that the GALAD score shows potential for HCC surveillance in Caucasian HBV/HCV patients.
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Circulating lncRNA UCA1 and lncRNA PGM5-AS1 act as potential diagnostic biomarkers for early-stage colorectal cancer. Biosci Rep 2021; 41:229154. [PMID: 34212174 PMCID: PMC8276091 DOI: 10.1042/bsr20211115] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 06/29/2021] [Accepted: 06/29/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common and significant malignant diseases worldwide. In the present study, we evaluated two long non-coding RNAs (lncRNAs) in CRC patients as diagnostic markers for early-stage CRC. METHODS Using Gene Expression Omnibus (GEO) datasets GSE102340, GSE126092, GSE109454 and GSE115856, 14 differentially expressed lncRNAs were identified between cancer and adjacent tissues, among which, the two most differentially expressed were confirmed using quantitative real-time polymerase chain reaction (qRT-PCR) in 200 healthy controls and 188 CRC patients. A receiver operating characteristic (ROC) analysis was employed to evaluate the diagnostic accuracy for CRC. RESULTS From four GEO datasets, three up-regulated and eleven down-regulated lncRNAs were identified in CRC tissues, among which, lncRNA urothelial carcinoma-associated 1 (UCA1) and lncRNA phosphoglucomutase 5-antisense RNA 1 (PGM5-AS1) were the most significantly up- and down-regulated lncRNAs in CRC patient plasma, respectively. The area under the ROC curve was calculated to be 0.766, 0.754 and 0.798 for UCA1, PGM5-AS1 and the combination of these two lncRNAs, respectively. Moreover, the diagnostic potential of these two lncRNAs was even higher for the early stages of CRC. The combination of UCA1 and PGM5-AS1 enhanced the AUC to 0.832, and when the lncRNAs were used with carcinoembryonic antigen (CEA), the AUC was further improved to 0.874. CONCLUSION In the present study, we identified two lncRNAs, UCA1 and PGM5-AS1, in CRC patients' plasma, which have the potential to be used as diagnostic biomarkers of CRC.
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Guo S, Hu C, Zhai X, Sun D. Circular RNA 0006602 in plasma exosomes: a new potential diagnostic biomarker for hepatocellular carcinoma. Am J Transl Res 2021; 13:6001-6015. [PMID: 34306340 PMCID: PMC8290788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 03/02/2021] [Indexed: 06/13/2023]
Abstract
Circular RNAs (circRNAs) in exosomes exhibit stable expression and are not easily degraded in plasma; a characteristic that makes them ideal as novel non-invasive tumor diagnostic markers. In this study, we examined different expression of circRNA in plasma exosomes of primary hepatocellular carcinoma patient and healthy volunteer by full transcriptome sequencing. Five circRNAs with up-regulated expression were selected, and large sample size verified their expression. Among them, it is further confirmed that exo_circ_0006602 is up-regulated in the large sample cohort. In addition, the expression level of exo_circ_0006602 was correlated with HBsAg (P<0.011), HBeAg (P=0.048), liver cirrhosis (P=0.001) and Edmondson-Steiner grade (P<0.001). The receiver operating characteristic (ROC) was used to evaluate the accuracy of exo_circ_0006602 as a diagnostic marker. The AUC value of exo_circ_0006602 was significantly highter than common serum tumor markers AFP and CEA. Exo_circ_0006602 combined with AFP can significantly improve the diagnostic accuracy. Cell function experiments show that exo_circ_0006602 can significantly improve the proliferation and invasion ability of liver cancer cell lines and also promoted the expression of tumor proliferation-related protein Snail. In conclusion, our results suggested that exo_circ_0006602 can be used as a potential non-invasive biomarker for the early diagnosis and screening of liver cancer, the sensitivity and specificity of diagnosis are higher than traditional tumor markers.
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Affiliation(s)
- Sen Guo
- Department of General Surgery, Qilu Hospital of Shandong University Jinan, China
| | - Chunxiao Hu
- Department of General Surgery, Qilu Hospital of Shandong University Jinan, China
| | - Xiangyu Zhai
- Department of General Surgery, Qilu Hospital of Shandong University Jinan, China
| | - Dong Sun
- Department of General Surgery, Qilu Hospital of Shandong University Jinan, China
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She WH, Chan ACY, Ma KW, Dai WC, Chok KSH, Cheung TT, Lo CM. Critical appraisal of TNM versus HKU staging system for postoperative prognostic evaluation of hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:919. [PMID: 34350234 PMCID: PMC8263888 DOI: 10.21037/atm-20-7611] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 03/31/2021] [Indexed: 01/11/2023]
Abstract
Background The 8th edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC 8th) has been launched with modifications in T staging. The University of Hong Kong liver cancer staging system (HKUSS) has been proven to better categorize hepatocellular carcinoma (HCC) into different T stages. This study aimed to compare the two systems’ predictive ability for HCC recurrence after primary surgical resection. Methods Patients who had primary, curative resection for HCC between 1989 and 2017 were reviewed. The Kaplan-Meier plot was used to estimate disease-free survival (DFS), and the log-rank test was used for survival comparison between subgroups. The two systems’ prediction of recurrence was evaluated by the Cox regression model. Results Totally 1,815 patients were included. With AJCC 8th, the 5-year DFS was 58.9% for T1a, 52.3% for T1b, 30% for T2, 16.9% for T3, and 14.4% for T4. No survival difference was demonstrated between T1a and T1b (P=0.668) or between T3 and T4 (P=0.562). With HKUSS, the 5-year DFS was 57.7% for T1, 43.4% for T2, 28.9% for T3, and 15.7% for T4. The T staging in HKUSS showed significant survival differences (T1 vs. T2, T2 vs. T3, and T3 vs. T4; P<0.001). Using receiver operating characteristic curves to show the recurrence status in the two systems, HKUSS had the largest area under curve (AUC) (HKUSS: AUC =0.655, SE 0.014, P<0.001, 95% CI, 0.628–0.681; AJCC 8th: AUC =0.652, SE 0.013, P<0.001, 95% CI, 0.625–0.677). Conclusions HKUSS showed better categorization of HCC. In the context of primary surgical resection, HKUSS may be more appropriate for stratification of patients with HCC with various T stages, and thus the choice of staging system when primary surgical resection is considered for patients of HCC.
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Affiliation(s)
- Wong Hoi She
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Albert C Y Chan
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Department of Surgery, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Ka Wing Ma
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Wing Chiu Dai
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Kenneth S H Chok
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Tan To Cheung
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Department of Surgery, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong, China.,Department of Surgery, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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Maruno M, Imai K, Nakao Y, Kitano Y, Kaida T, Mima K, Hayashi H, Yamashita YI, Mikami Y, Baba H. Multiple hepatic inflammatory pseudotumors with elevated alpha-fetoprotein and alpha-fetoprotein lectin 3 fraction with various PET accumulations: a case report. Surg Case Rep 2021; 7:107. [PMID: 33913027 PMCID: PMC8081814 DOI: 10.1186/s40792-021-01188-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/18/2021] [Indexed: 01/08/2023] Open
Abstract
Background Hepatic inflammatory pseudotumor (IPT) is a rare, benign, tumor-like lesion. Because there are no characteristic laboratory markers or radiological features, hepatic IPT is often misdiagnosed as a malignant neoplasm such as hepatocellular carcinoma (HCC). Case presentation A 68-year-old man with liver dysfunction due to chronic hepatitis C virus infection and alcoholic liver disease presented with hepatic tumors in segments III and VIII. The levels of serum alpha-fetoprotein (AFP) and its Lens culinaris agglutinin-reactive fraction, AFP lectin 3 (AFP-L3), were elevated to 822.8 ng/ml and 75.2%, respectively. The tumor showed contrast enhancement on contrast-enhanced computed tomography and various accumulation on positron emission tomography. Based on these biological and imaging features, HCC was suspected, and we performed laparoscopic partial hepatectomy for these two tumors. Pathological diagnosis revealed that both tumors were hepatic IPTs with no malignant characteristics. After hepatectomy, the serum AFP and AFP-L3 levels decreased to the normal range. Conclusion We report a very rare case of hepatic IPT with elevated serum AFP and AFP-L3, mimicking HCC. Clinicians should include this rare neoplasm in the differential diagnoses of hepatic tumors even when the serum markers for HCC are elevated.
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Affiliation(s)
- Masataka Maruno
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Katsunori Imai
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
| | - Yosuke Nakao
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Yuki Kitano
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Takayoshi Kaida
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Kosuke Mima
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Yo-Ichi Yamashita
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
| | - Yoshiki Mikami
- Department of Diagnostic Pathology, Kumamoto University Hospital, Kumamoto, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan
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Colli A, Nadarevic T, Miletic D, Giljaca V, Fraquelli M, Štimac D, Casazza G. Abdominal ultrasound and alpha-foetoprotein for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease. Cochrane Database Syst Rev 2021; 4:CD013346. [PMID: 33855699 PMCID: PMC8078581 DOI: 10.1002/14651858.cd013346.pub2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) occurs mostly in people with chronic liver disease and ranks sixth in terms of global instances of cancer, and fourth in terms of cancer deaths for men. Despite that abdominal ultrasound (US) is used as an initial test to exclude the presence of focal liver lesions and serum alpha-foetoprotein (AFP) measurement may raise suspicion of HCC occurrence, further testing to confirm diagnosis as well as staging of HCC is required. Current guidelines recommend surveillance programme using US, with or without AFP, to detect HCC in high-risk populations despite the lack of clear benefits on overall survival. Assessing the diagnostic accuracy of US and AFP may clarify whether the absence of benefit in surveillance programmes could be related to under-diagnosis. Therefore, assessment of the accuracy of these two tests for diagnosing HCC in people with chronic liver disease, not included in surveillance programmes, is needed. OBJECTIVES Primary: the diagnostic accuracy of US and AFP, alone or in combination, for the diagnosis of HCC of any size and at any stage in adults with chronic liver disease, either in a surveillance programme or in a clinical setting. Secondary: to assess the diagnostic accuracy of abdominal US and AFP, alone or in combination, for the diagnosis of resectable HCC; to compare the diagnostic accuracy of the individual tests versus the combination of both tests; to investigate sources of heterogeneity in the results. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic-Test-Accuracy Studies Register, Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, until 5 June 2020. We applied no language or document-type restrictions. SELECTION CRITERIA Studies assessing the diagnostic accuracy of US and AFP, independently or in combination, for the diagnosis of HCC in adults with chronic liver disease, with cross-sectional and case-control designs, using one of the acceptable reference standards, such as pathology of the explanted liver, histology of resected or biopsied focal liver lesion, or typical characteristics on computed tomography, or magnetic resonance imaging, all with a six-months follow-up. DATA COLLECTION AND ANALYSIS We independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest-plots, and tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses. MAIN RESULTS We included 373 studies. The index-test was AFP (326 studies, 144,570 participants); US (39 studies, 18,792 participants); and a combination of AFP and US (eight studies, 5454 participants). We judged at high-risk of bias all but one study. Most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time-interval between the index test and the reference standard was rarely defined. Most studies with AFP had a case-control design. We also had major concerns for the applicability due to the characteristics of the participants. As the primary studies with AFP used different cut-offs, we performed a meta-analysis using the hierarchical-summary-receiver-operating-characteristic model, then we carried out two meta-analyses including only studies reporting the most used cut-offs: around 20 ng/mL or 200 ng/mL. AFP cut-off 20 ng/mL: for HCC (147 studies) sensitivity 60% (95% CI 58% to 62%), specificity 84% (95% CI 82% to 86%); for resectable HCC (six studies) sensitivity 65% (95% CI 62% to 68%), specificity 80% (95% CI 59% to 91%). AFP cut-off 200 ng/mL: for HCC (56 studies) sensitivity 36% (95% CI 31% to 41%), specificity 99% (95% CI 98% to 99%); for resectable HCC (two studies) one with sensitivity 4% (95% CI 0% to 19%), specificity 100% (95% CI 96% to 100%), and one with sensitivity 8% (95% CI 3% to 18%), specificity 100% (95% CI 97% to 100%). US: for HCC (39 studies) sensitivity 72% (95% CI 63% to 79%), specificity 94% (95% CI 91% to 96%); for resectable HCC (seven studies) sensitivity 53% (95% CI 38% to 67%), specificity 96% (95% CI 94% to 97%). Combination of AFP (cut-off of 20 ng/mL) and US: for HCC (six studies) sensitivity 96% (95% CI 88% to 98%), specificity 85% (95% CI 73% to 93%); for resectable HCC (two studies) one with sensitivity 89% (95% CI 73% to 97%), specificity of 83% (95% CI 76% to 88%), and one with sensitivity 79% (95% CI 54% to 94%), specificity 87% (95% CI 79% to 94%). The observed heterogeneity in the results remains mostly unexplained, and only in part referable to different cut-offs or settings (surveillance programme compared to clinical series). The sensitivity analyses, excluding studies published as abstracts, or with case-control design, showed no variation in the results. We compared the accuracy obtained from studies with AFP (cut-off around 20 ng/mL) and US: a direct comparison in 11 studies (6674 participants) showed a higher sensitivity of US (81%, 95% CI 66% to 90%) versus AFP (64%, 95% CI 56% to 71%) with similar specificity: US 92% (95% CI 83% to 97%) versus AFP 89% (95% CI 79% to 94%). A direct comparison of six studies (5044 participants) showed a higher sensitivity (96%, 95% CI 88% to 98%) of the combination of AFP and US versus US (76%, 95% CI 56% to 89%) with similar specificity: AFP and US 85% (95% CI 73% to 92%) versus US 93% (95% CI 80% to 98%). AUTHORS' CONCLUSIONS In the clinical pathway for the diagnosis of HCC in adults, AFP and US, singularly or in combination, have the role of triage-tests. We found that using AFP, with 20 ng/mL as a cut-off, about 40% of HCC occurrences would be missed, and with US alone, more than a quarter. The combination of the two tests showed the highest sensitivity and less than 5% of HCC occurrences would be missed with about 15% of false-positive results. The uncertainty resulting from the poor study quality and the heterogeneity of included studies limit our ability to confidently draw conclusions based on our results.
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Affiliation(s)
- Agostino Colli
- Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Tin Nadarevic
- Department of Radiology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Damir Miletic
- Department of Radiology , Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Vanja Giljaca
- Department of Gastroenterology, Heart of England NHS Foundation Trust, Birmingham, UK
| | - Mirella Fraquelli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca´ Granda - Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Davor Štimac
- Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Giovanni Casazza
- Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano, Milan, Italy
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Feng H, Li B, Li Z, Wei Q, Ren L. PIVKA-II serves as a potential biomarker that complements AFP for the diagnosis of hepatocellular carcinoma. BMC Cancer 2021; 21:401. [PMID: 33849479 PMCID: PMC8045263 DOI: 10.1186/s12885-021-08138-3] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 04/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system and has high morbidity and mortality rates. It is essential to search new biomarkers to improve the accuracy of early HCC diagnosis. Therefore, we evaluated the diagnostic value of prothrombin induced by vitamin K deficiency or antagonist- II (PIVKA-II) as a potential biomarker that complements α-fetoprotein (AFP) in HCC by detecting the serum PIVKA-II levels. METHODS Serum PIVKA-II levels were compared in 168 HCC patients, 150 benign liver disease patients and 153 healthy controls to investigate the PIVKA-II potential to be a HCC biomarker. Receiver operating characteristic curve (ROC) analysis was used to evaluate the value of PIVKA-II in the diagnosis of HCC and its complementary role of AFP. The correlation between serum PIVKA-II levels and clinicopathological characteristics was analyzed to study the value of PIVKA-II in assessing HCC progression and prognosis. Finally, the ability of PIVKA-II in assessing the surgical treatment effects of HCC was studied by comparing the pre- and post-operative serum PIVKA-II levels in 89 HCC patients. RESULTS Serum PIVKA-II levels in HCC patients were significantly higher than that in patients with benign liver disease and healthy controls. The PIVKA-II performance in the diagnosing HCC as an individual biomarker was remarkable. The combined detection of PIVKA-II and AFP improved the diagnostic efficiency of HCC. PIVKA-II retained significant diagnosis capabilities for AFP-negative HCC patients. Significant correlations were found between PIVKA-II expression levels and some clinicopathological characteristics, including tumor size, tumor stage, tumor metastasis, differentiation degree and complications. PIVKA-II expression obviously decreased after surgical resection. CONCLUSIONS PIVKA-II is a promising serum biomarker for the HCC diagnosis that can be used as a supplement for AFP. The combined diagnosis of the two markers greatly improved the diagnostic efficiency of HCC. The PIVKA-II levels in HCC patients were widely associated with clinicopathological characteristics representing tumor cell dissemination and/or poor prognosis. PIVKA-II can be used to evaluate the curative effects of HCC resection.
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Affiliation(s)
- Honglei Feng
- Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China
| | - Bole Li
- Department of Pharmacy, Tianjin Medical University Cancer Institute and Hospital, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, China
| | - Ze Li
- Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China
| | - Qian Wei
- Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China
| | - Li Ren
- Department of Laboratory, Tianjin Medical University Cancer Institute and Hospital, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Huanhuxi Road, Hexi District, Tianjin, 300060, China.
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The Diagnostic Value of Serum PIVKA-II Alone or in Combination with AFP in Chinese Hepatocellular Carcinoma Patients. DISEASE MARKERS 2021; 2021:8868370. [PMID: 33628341 PMCID: PMC7884179 DOI: 10.1155/2021/8868370] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 10/13/2020] [Accepted: 01/31/2021] [Indexed: 01/02/2023]
Abstract
Background At present, the diagnostic accuracy of alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) surveillance is insufficient. It remains controversial whether prothrombin induced by vitamin K absence II (PIVKA-II) has a better diagnostic value than AFP for HCC patients. Objective To investigate the diagnostic role of PIVKA-II alone or in combination with AFP in Chinese HCC patients. Methods Serum AFP and PIVKA-II levels were detected and analyzed in 308 HCC afflicted patients and 120 unafflicted controls. The receiver operator curve (ROC) and area under the curve (AUC) were conducted to evaluate the clinical value of AFP and PIVKA-II for diagnosing HCC and early HCC. Results In the whole HCC cohort, the diagnostic values of PIVKA-II were better than that of AFP. The AUC of PIVKA-II and AFP was 0.90 (95% CI 0.87-0.94) and 0.79 (95% CI 0.74-0.84), respectively. “AFP + PIVKA-II” yielded a high sensitivity of 95.1% and a specificity of 83.3%, with the AUC 0.89 (95% CI 0.85-0.93). In the early stage HCC group, the diagnostic accuracy of PIVKA-II was also better than that of AFP. The AUC of PIVKA-II and AFP was 0.83 (95% CI 0.77-0.89) and 0.75 (95% CI 0.68-0.81), respectively. “AFP + PIVKA-II” achieved the sensitivity of 83.3% and specificity of 89.1%, with an AUC of 0.86 (95% CI 0.81-0.91). Moreover, for AFP-negative HCC patients, serum PIVKA-II showed good diagnostic performance, with an AUC of 0.804 (95% CI 0.720-0.887). Besides, elevated PIVKA-II level was a strong independent risk factor for HCC patients with portal vein tumor thrombus (PVTT) (OR = 4.890, P = 0.020). Conclusion PIVKA-II is superior to AFP in HCC screening, and AFP in combination with PIVKA-II significantly improves the diagnostic value for Chinese HCC patients. PIVKA-II could effectively indicate HCC accompanied by PVTT and help to optimize the therapeutic strategy.
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Tarao K, Nozaki A, Komatsu H, Komatsu T, Taguri M, Tanaka K, Chuma M, Numata K, Maeda S. Real impact of tumor marker AFP and PIVKA-II in detecting very small hepatocellular carcinoma (≤ 2 cm, Barcelona stage 0) - assessment with large number of cases. World J Hepatol 2020; 12:1046-1054. [PMID: 33312428 PMCID: PMC7701964 DOI: 10.4254/wjh.v12.i11.1046] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/10/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In hepatocellular carcinoma (HCC), detection and treatment prior to growth beyond 2 cm are relevant as a larger tumor size is more frequently associated with microvascular invasion and/or satellites.
AIM To examine the impact of the tumor marker alpha-fetoprotein (AFP) or PIVKA-II in detecting very small HCC nodules (≤ 2 cm in maximum diameter, Barcelona stage 0) in the large number of very small HCC. The difference in the behavior of these tumor markers in HCC development was also examined.
METHODS A total of 933 patients with single-nodule HCC were examined. They were subdivided into 394 patients with HCC nodules ≤ 2 cm in maximum diameter and 539 patients whose nodules were > 2 cm. The rates of patients whose AFP and PIVKA-II showed normal values were examined.
RESULTS The positive ratio of the marker PIVKA-II was significantly different (P < 0.0001) between patients with nodules ≤ 2 cm in diameter and those with nodules > 2 cm, but there was no significant difference in AFP (P = 0.4254). In the patients whose tumor was ≤ 2 cm, 50.5% showed normal levels in AFP and 68.8% showed normal levels in PIVKA-II. In 36.4% of those patients, both AFP and PIVKA-II showed normal levels. The PIVKA-II-positive ratio was markedly increased with an increase in the tumor size. In contrast, the positivity in AFP was increased gradually and slowly.
CONCLUSION In the surveillance of very small HCC nodules (≤ 2 cm in diameter, Barcelona clinical stage 0) the tumor markers AFP and PIVKA-II are not so useful.
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Affiliation(s)
- Kazuo Tarao
- Department of Gastroenterology, Tarao’s Gastroenterological Clinic, Yokohama 241-0821, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Hirokazu Komatsu
- Department of Gastroenterology, Yokohama Municipal Citizen’s Hospital, Yokohama 221-0855, Japan
| | - Tatsuji Komatsu
- Department of Clinical Research, National Hospital Organization Yokohama Medical Center, Yokohama 245-8575, Japan
| | - Masataka Taguri
- Department of Data Science, Yokohama City University School of Data Science, Yokohama 236-0004, Japan
| | - Katsuaki Tanaka
- Department of Gastroenterology, Hadano Red Cross Hospital, Kanagawa 221-0045, Japan
| | - Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Kazushi Numata
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama 232-0024, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
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45
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Tu M, Wang X, Chen P, Li J, Luo X, He L, Huang W, Hong J, Qu C. RCE1 deficiency enhances invasion via the promotion of epithelial-mesenchymal transition and predicts poor prognosis in hepatocellular carcinoma. Am J Transl Res 2020; 12:7236-7248. [PMID: 33312363 PMCID: PMC7724357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 10/08/2020] [Indexed: 06/12/2023]
Abstract
Ras converting CAAX endopeptidase 1 (RCE1) is an integral membrane protease involved in cell proliferation, differentiation, and carcinogenesis. RCE1 plays opposite roles in different tumor types; however, the actual biological function of RCE1 in hepatocellular carcinoma (HCC) is unknown. Here, we aim to investigate the prognostic value and molecular function of RCE1 in HCC. We performed immunohistochemistry in 20 normal human liver, 216 HCC, and 216 adjacent non-tumorous tissues and analyzed the expression change and clinical value of RCE1. Additionally, in vitro and in vivo studies were performed to investigate the role of RCE1 in regulating HCC proliferation, invasion, and metastasis. We found decreased RCE1 expression in HCC tissues. Moreover, the RCE1 expression level was negatively correlated with pathological parameters characteristic of early recurrence (P < 0.044) and the serum alpha-fetoprotein (AFP) level (P < 0.018). Survival analysis indicated that reduced RCE1 expression was a predictor of poor outcomes in patients with HCC. Functional studies showed that the knockdown of RCE1 promoted proliferation, migration, and invasion of HCC cells, while RCE1 overexpression suppressed these effects. In vivo studies further confirmed that the stable knockdown of RCE1 resulted in more rapid tumor growth and an increased number of lung metastatic nodules. Mechanistically, we found that RCE1 deficiency induced epithelial-mesenchymal transition (EMT) via activation of the P38 signaling pathway. Collectively, these results indicate that RCE1 deficiency enhances invasion via promoting epithelial-mesenchymal transition. The downregulation of RCE1 in HCC tissues predicts an unsatisfactory prognosis for patients with HCC.
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Affiliation(s)
- Mengxian Tu
- Department of Pathophysiology, School of Medicine, Jinan UniversityGuangzhou 510630, Guangdong, China
- Department of Abdominal Surgery, Traditional Chinese Medicine-Integrated Hospital, Southern Medical UniversityGuangzhou 510315, Guangdong, China
| | - Xinyi Wang
- Department of Abdominal Surgery, Traditional Chinese Medicine-Integrated Hospital, Southern Medical UniversityGuangzhou 510315, Guangdong, China
- Guangzhou Medical University Affiliated Cancer HospitalGuangzhou 510315, Guangdong, China
- Department of Oncology, Zhongshan City People’s HospitalZhongshan 528403, Guangdong, China
| | - Peng Chen
- Department of Abdominal Surgery, Traditional Chinese Medicine-Integrated Hospital, Southern Medical UniversityGuangzhou 510315, Guangdong, China
| | - Jinying Li
- Department of Gastroenterology, The First Affiliated Hospital of Jinan UniversityGuangzhou 510630, Guangdong, China
| | - Xiaojun Luo
- Department of Abdominal Surgery, Traditional Chinese Medicine-Integrated Hospital, Southern Medical UniversityGuangzhou 510315, Guangdong, China
| | - Lu He
- Guangzhou Medical University Affiliated Cancer HospitalGuangzhou 510315, Guangdong, China
| | - Wei Huang
- Department of Gastroenterology, The First Affiliated Hospital of Jinan UniversityGuangzhou 510630, Guangdong, China
| | - Jian Hong
- Department of Pathophysiology, School of Medicine, Jinan UniversityGuangzhou 510630, Guangdong, China
- Department of Abdominal Surgery, Traditional Chinese Medicine-Integrated Hospital, Southern Medical UniversityGuangzhou 510315, Guangdong, China
| | - Chen Qu
- Department of Pathophysiology, School of Medicine, Jinan UniversityGuangzhou 510630, Guangdong, China
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46
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Abstract
Hepatocellular carcinoma (HCC) is increasing in prevalence and is the third leading cause of cancer-related death worldwide. Unlike other malignancies, HCC can be diagnosed with dynamic imaging with very high accuracy, and tissue diagnosis is not needed for cancer therapy. There is a unique role of established as well as developing biomarkers in diagnosis, prognosis, and management of HCC. Sequencing HCC tumors has yielded substantial insights into HCC tumor biology and has raised the possibility of precision oncology in which therapy decisions are guided by cancer genetics. However, it is not ready for prime time yet.
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Affiliation(s)
- Vincent L Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Pratima Sharma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
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47
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Valentina P, Zhu J, Lubman DM, Huguet S, Bismut FI, Bolbach G, Clodic G, Matheron L, Ngo Y, Raluca P, Housset C, Rezai K, Poynard T. Input of serum haptoglobin fucosylation profile in the diagnosis of hepatocellular carcinoma in patients with non-cirrhotic liver disease. Clin Res Hepatol Gastroenterol 2020; 44:681-691. [PMID: 31964615 PMCID: PMC7367700 DOI: 10.1016/j.clinre.2019.12.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 11/20/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Haptoglobin bifucosylated tetra-antennary glycan have been identified in patients with early stage hepatocellular carcinoma, but its specificity according to the presence or not of cirrhosis has never been assessed. The aims of this study were to determine if haptoglobin bifucosylated tetra-antennary glycan (1) could be a marker of HCC in patients without cirrhosis; (2) could increase the performance of standard alpha-fetoprotein (AFP) or recent blood tests for HCC detection, i.e., lectin-reactive alpha-fetoprotein (AFP-L3), des-gamma-carboxy prothrombin (DCP) and Liver-Cancer-Risk-test (LCR1-test). METHODS We retrospectively selected patients, 102 with HCC (21 without cirrhosis), matched by stages with 140 controls without HCC (81 without cirrhosis). Haptoglobin fucosylation was assessed by MALDI-TOF. LCR-glycan algorithm was constructed combining components of the LCR-1 test (haptoglobin, gammaglutamyl-transpeptidase, apolipoproteinA1, alpha-2-macroglobulin) with AFP, AFP-L3, DCP and haptoglobin bifucosylated tetra-antennary glycan. RESULTS In 102 patients without cirrhosis (21 HCC and 81 controls), the intention-to-diagnose analyses showed that haptoglobin bifucosylated tetra-antennary glycan alone had a sensitivity of 71% (15/21;95%CI 50-86), significantly better (P=0.02) than standard AFP (43%;9/21;95%CI 24-63), and a specificity of 96% (78/81;95% 90-99). The sensitivity of LCR-glycan, in patients without cirrhosis, was 86% (18/21; 95%CI 63-95) significantly better (P=0.001) than standard AFP (43%; 9/21; 95%CI 24-63), with an AUROC of 0.943 (95%CI 0.806-0.98) compared to 0.811 (95%CI 0.630-0.908) for AFP (P=0.06). CONCLUSION Haptoglobin bifucosylated tetra-antennary glycan is associated with the presence of HCC in patients with chronic liver disease including those without cirrhosis. Its combination with existing HCC biomarkers could improve the performance of standard AFP for HCC detection.
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Affiliation(s)
- Peta Valentina
- BioPredictive, Paris, France,Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Jianhui Zhu
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48019, USA
| | - David M. Lubman
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48019, USA
| | - Samuel Huguet
- Radiopharmacology Department, Institut Curie, Saint Cloud, France
| | - Francoise Imbert Bismut
- Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière (GHPS), Paris, France
| | - Gérard Bolbach
- Sorbonne Université, Institut de Biologie Paris Seine, Plate-forme spectrométrie de masse et protéomique, Paris, France,Sorbonne Université, École normale supérieure, PSL University, CNRS, Laboratoire des Biomolécules (LBM), 75005 Paris, France
| | - Gilles Clodic
- Sorbonne Université, Institut de Biologie Paris Seine, Plate-forme spectrométrie de masse et protéomique, Paris, France
| | - Lucrèce Matheron
- Sorbonne Université, Institut de Biologie Paris Seine, Plate-forme spectrométrie de masse et protéomique, Paris, France
| | - Yen Ngo
- BioPredictive, Paris, France
| | - Pais Raluca
- Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière (GHPS), Paris, France.,Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Chantal Housset
- Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
| | - Keyvan Rezai
- Radiopharmacology Department, Institut Curie, Saint Cloud, France
| | - Thierry Poynard
- Assistance Publique-Hôpitaux de Paris (AP-HP), Groupe Hospitalier Pitié-Salpêtrière (GHPS), Paris, France.,Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France
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48
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Fan J, Chen Y, Zhang D, Yao J, Zhao Z, Jiang Y, Li Y, Guo Y. Evaluation of the diagnostic accuracy of des-gamma-carboxy prothrombin and alpha-fetoprotein alone or in combination for hepatocellular carcinoma: A systematic review and meta-analysis. Surg Oncol 2020; 34:245-255. [PMID: 32891338 DOI: 10.1016/j.suronc.2020.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 04/13/2020] [Accepted: 05/16/2020] [Indexed: 02/07/2023]
Affiliation(s)
- Jia Fan
- Clinical Laboratory of Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, 646000, China
| | - Yu Chen
- Sichuan Luzhou Traditional Chinese Medicine Hospital, Luzhou, 646000, China
| | - Dan Zhang
- Clinical Laboratory of Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, 646000, China
| | - Juan Yao
- Clinical Laboratory of Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, 646000, China
| | - Zijun Zhao
- Clinical Laboratory of Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, 646000, China
| | - Yao Jiang
- Southwest Medical University, Luzhou, 646000, China
| | - Yiqin Li
- Southwest Medical University, Luzhou, 646000, China
| | - Yongcan Guo
- Clinical Laboratory of Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, 646000, China.
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49
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Wang T, Zhang KH. New Blood Biomarkers for the Diagnosis of AFP-Negative Hepatocellular Carcinoma. Front Oncol 2020; 10:1316. [PMID: 32923383 PMCID: PMC7456927 DOI: 10.3389/fonc.2020.01316] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/24/2020] [Indexed: 12/18/2022] Open
Abstract
An early diagnosis of hepatocellular carcinoma (HCC) followed by effective treatment is currently critical for improving the prognosis and reducing the associated economic burden. Alpha-fetoprotein (AFP) is the most widely used biomarker for HCC diagnosis. Based on elevated serum AFP levels as well as typical imaging features, AFP-positive HCC (APHC) can be easily diagnosed, but AFP-negative HCC (ANHC) is not easily detected due to lack of ideal biomarkers and thus mainly reliance on imaging. Imaging for the diagnosis of ANHC is probably insufficient in sensitivity and/or specificity because most ANHC tumors are small and early-stage HCC, and it is involved in sophisticated techniques and high costs. Moreover, ANHC accounts for nearly half of HCC and exhibits a better prognosis compared with APHC. Therefore, the diagnosis of ANHC in clinical practice has been a critical issue for the early treatment and prognosis improvement of HCC. In recent years, tremendous efforts have been made to discover new biomarkers complementary to AFP for HCC diagnosis. In this review, we systematically review and discuss the recent advances of blood biomarkers for HCC diagnosis, including DNA biomarkers, RNA biomarkers, protein biomarkers, and conventional laboratory metrics, focusing on their diagnostic evaluation alone and in combination, in particular on their diagnostic performance for ANHC.
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Affiliation(s)
- Ting Wang
- Department of Gastroenterology, Jiangxi Institute of Gastroenterology & Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Kun-He Zhang
- Department of Gastroenterology, Jiangxi Institute of Gastroenterology & Hepatology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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50
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Loglio A, Iavarone M, Facchetti F, Di Paolo D, Perbellini R, Lunghi G, Ceriotti F, Galli C, Sandri MT, Viganò M, Sangiovanni A, Colombo M, Lampertico P. The combination of PIVKA-II and AFP improves the detection accuracy for HCC in HBV caucasian cirrhotics on long-term oral therapy. Liver Int 2020; 40:1987-1996. [PMID: 32301212 DOI: 10.1111/liv.14475] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 03/09/2020] [Accepted: 04/08/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Protein induced by vitamin K absence or antagonist-II (PIVKA-II) has been suggested as a serum biomarker for hepatocellular carcinoma (HCC) in Asian hepatitis B virus (HBV)-treated subjects but no studies tested it in Caucasian cirrhotics long-term nucleos(t)ide analogues (NUCs)-treated. We assessed the detection accuracy of PIVKA-II alone or in combination with alpha-foetoprotein (AFP) in patients under surveillance. METHODS This cross-sectional, single centre case-control study was conducted in 212 NUC-treated cirrhotics: 64 HCC and 148 HCC-free controls for 84 (60-107) months. PIVKA-II was determined by a CMIA immunoassay (Abbott; limit of quantification: 8.2 mAU/mL). RESULTS Protein induced by vitamin K absence or agonist II (PIVKA-II) and AFP levels were significantly higher in HCC patients [Barcelona Clinic Liver Cancer staging system stage 0/A in 91%, diameter 20 (6-50) mm] compared to controls: 109 (17-12 157) vs 31 (13-82) mAU/mL and 5 (1-1163) vs 2 (1-7) ng/mL (P < .001 for both markers), with a cut-off of 48 mAU/mL and 4.2 ng/mL by AUROC analysis. The PIVKA-II 82 mAU/mL and AFP 7 ng/mL cut-offs showed 100% specificity, with the former more sensitive (54% vs 42%), accurate (86% vs 83%), with higher negative predictive value (80% vs 76%) compared to AFP for HCC detection. PIVKA-II more frequently than AFP levels exceeded the cut-off 6-18 months before HCC diagnosis. Combining PIVKA-II with AFP increased sensitivity, accuracy and negative predictive values to 67%, 90% and 85%, preserving 100% specificity. PIVKA-II was associated with lesions >20 mm or neoplastic thrombosis. CONCLUSIONS Combination of PIVKA-II and AFP increases the detection rate for HCC in NUC-treated HBV Caucasian cirrhotics, a potential new approach for surveillance.
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Affiliation(s)
- Alessandro Loglio
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Massimo Iavarone
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Floriana Facchetti
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Dhanai Di Paolo
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Riccardo Perbellini
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Giovanna Lunghi
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Virology Unit, Milan, Italy
| | - Ferruccio Ceriotti
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Virology Unit, Milan, Italy
| | - Claudio Galli
- Medical & Scientific Affairs, Abbott Diagnostics, Rome, Italy
| | - Maria T Sandri
- European Institute of Oncology, Laboratory Medicine Division, Milan, Italy
| | - Mauro Viganò
- Division of Hepatology, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy
| | - Angelo Sangiovanni
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy
| | - Massimo Colombo
- Center for Translational Hepatology Research, Clinical and Research Center Humanitas Hospital, Rozzano, Italy
| | - Pietro Lampertico
- Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy.,Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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