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Pettas T, Lachanoudi S, Karageorgos FF, Ziogas IA, Fylaktou A, Papalois V, Katsanos G, Antoniadis N, Tsoulfas G. Immunotherapy and liver transplantation for hepatocellular carcinoma: Current and future challenges. World J Transplant 2025; 15:98509. [DOI: 10.5500/wjt.v15.i2.98509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/03/2024] [Accepted: 11/07/2024] [Indexed: 02/21/2025] Open
Abstract
Despite existing curative options like surgical removal, tissue destruction techniques, and liver transplantation for early-stage hepatocellular carcinoma (HCC), the rising incidence and mortality rates of this global health burden necessitate continuous exploration of novel therapeutic strategies. This review critically assesses the dynamic treatment panorama for HCC, focusing specifically on the burgeoning role of immunotherapy in two key contexts: early-stage HCC and downstaging advanced HCC to facilitate liver transplant candidacy. It delves into the unique immunobiology of the liver and HCC, highlighting tumor-mediated immune evasion mechanisms. Analyzing the diverse immunotherapeutic approaches including checkpoint inhibitors, cytokine modulators, vaccines, oncolytic viruses, antigen-targeting antibodies, and adoptive cell therapy, this review acknowledges the limitations of current diagnostic markers alpha-fetoprotein and glypican-3 and emphasizes the need for novel biomarkers for patient selection and treatment monitoring. Exploring the rationale for neoadjuvant and adjuvant immunotherapy in early-stage HCC, current research is actively exploring the safety and effectiveness of diverse immunotherapeutic approaches through ongoing clinical trials. The review further explores the potential benefits and challenges of combining immunotherapy and liver transplant, highlighting the need for careful patient selection, meticulous monitoring, and novel strategies to mitigate post-transplant complications. Finally, this review delves into the latest findings from the clinical research landscape and future directions in HCC management, paving the way for optimizing treatment strategies and improving long-term survival rates for patients with this challenging malignancy.
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Affiliation(s)
- Theodoros Pettas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Sofia Lachanoudi
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Filippos F Karageorgos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Ioannis A Ziogas
- Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Asimina Fylaktou
- Department of Immunology, National Peripheral Histocompatibility Center, Hippokration General Hospital, Thessaloniki 54642, Greece
| | - Vassilios Papalois
- Department of Transplant Surgery, Imperial College Renal and Transplant Centre, London W12 0HS, United Kingdom
| | - Georgios Katsanos
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
| | - Nikolaos Antoniadis
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University School of Medicine, Thessaloniki 54642, Greece
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Center for Research and Innovation in Solid Organ Transplantation, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki 54642, Greece
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Wu ST, Zhu L, Feng XL, Wang HY, Li F. Strategies for discovering novel hepatocellular carcinoma biomarkers. World J Hepatol 2025; 17:101201. [PMID: 40027561 PMCID: PMC11866143 DOI: 10.4254/wjh.v17.i2.101201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/13/2024] [Accepted: 12/23/2024] [Indexed: 02/20/2025] Open
Abstract
Liver cancer, particularly hepatocellular carcinoma (HCC), remains a significant global health challenge due to its high mortality rate and late-stage diagnosis. The discovery of reliable biomarkers is crucial for improving early detection and patient outcomes. This review provides a comprehensive overview of current and emerging biomarkers for HCC, including alpha-fetoprotein, des-gamma-carboxy prothrombin, glypican-3, Golgi protein 73, osteopontin, and microRNAs. Despite advancements, the diagnostic limitations of existing biomarkers underscore the urgent need for novel markers that can detect HCC in its early stages. The review emphasizes the importance of integrating multi-omics approaches, combining genomics, proteomics, and metabolomics, to develop more robust biomarker panels. Such integrative methods have the potential to capture the complex molecular landscape of HCC, offering insights into disease mechanisms and identifying targets for personalized therapies. The significance of large-scale validation studies, collaboration between research institutions and clinical settings, and consideration of regulatory pathways for clinical implementation is also discussed. In conclusion, while substantial progress has been made in biomarker discovery, continued research and innovation are essential to address the remaining challenges. The successful translation of these discoveries into clinical practice will require rigorous validation, standardization of protocols, and cross-disciplinary collaboration. By advancing the development and application of novel biomarkers, we can improve the early detection and management of HCC, ultimately enhancing patient survival and quality of life.
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Affiliation(s)
- Shi-Tao Wu
- Department of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Li Zhu
- Department of General Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Xiao-Ling Feng
- Department of General Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Hao-Yu Wang
- Department of Hepatopancreatobiliary Surgery, Chongqing General Hospital, Chongqing 401147, China
| | - Fang Li
- Department of General Surgery, Chongqing General Hospital, Chongqing 401147, China.
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Zhang H, Pei S, Li J, Zhu J, Li H, Wu G, Weng R, Chen R, Fang Z, Sun J, Chen K. Insights about exosomal circular RNAs as novel biomarkers and therapeutic targets for hepatocellular carcinoma. Front Pharmacol 2024; 15:1466424. [PMID: 39444611 PMCID: PMC11496148 DOI: 10.3389/fphar.2024.1466424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 09/30/2024] [Indexed: 10/25/2024] Open
Abstract
One of the most prevalent pathological types of Primary Liver Cancer (PLC) is the Hepatocellular Carcinoma (HCC) poses a global health issue. The high recurrence and metastasis rate of HCC, coupled with a low 5-year survival rate, result in a bleak prognosis. Exosomes, small extracellular vesicles released by various cells, contain diverse non-coding RNA molecules, including circular RNAs (circRNAs), which play a significant role in intercellular communication and can impact HCC progression. Studies have revealed the potential clinical applications of exosomal circRNAs as biomarkers and therapeutic targets for HCC. These circRNAs can be transferred via exosomes to nearby non-cancerous cells, thereby regulating HCC progression and influencing malignant phenotypes, such as cell proliferation, invasion, metastasis, and drug resistance. This review provides a comprehensive overview of the identified exosomal circRNAs, highlighting their potential as non-invasive biomarkers for HCC, and suggesting new perspectives for HCC diagnosis and treatment. The circRNA from exosomal organelles promotes metastasis and immune scape because of their unique chirality which is different from the Biomolecular Homochirality.
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Affiliation(s)
- Haiyan Zhang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- Zhejiang Chinese Medical University, Shuren College, Hangzhou, China
| | - Shanshan Pei
- School of Pharmacy, Beihua University, Jilin, China
| | - Jiaxuan Li
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jiajie Zhu
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Hongyu Li
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Guangshang Wu
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Ruiqi Weng
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Ruyi Chen
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Zhongbiao Fang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jingbo Sun
- School of Pharmacy, Beihua University, Jilin, China
| | - Keda Chen
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
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Chan YT, Zhang C, Wu J, Lu P, Xu L, Yuan H, Feng Y, Chen ZS, Wang N. Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma. Mol Cancer 2024; 23:189. [PMID: 39242496 PMCID: PMC11378508 DOI: 10.1186/s12943-024-02101-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/23/2024] [Indexed: 09/09/2024] Open
Abstract
Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.
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Affiliation(s)
- Yau-Tuen Chan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Cheng Zhang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Junyu Wu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Pengde Lu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Lin Xu
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Hongchao Yuan
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Yibin Feng
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Zhe-Sheng Chen
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, 8000 Utopia Parkway, Queens, NY, 11439, USA.
| | - Ning Wang
- School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
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Liu L, Li YN, Zhang A, Yin Y, Yue Z, Pei L, Xia CS, Wang D, Jia M, Wang H, Cao LL. Clinical potential of serum prostaglandin A2 as a novel diagnostic biomarker for hepatocellular cancer. Clin Chim Acta 2024; 561:119814. [PMID: 38879063 DOI: 10.1016/j.cca.2024.119814] [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: 03/28/2024] [Revised: 05/18/2024] [Accepted: 06/12/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND Hepatocellular cancer (HCC) is one of the most harmful tumors to human health. Currently, there is still a lack of highly sensitive and specific HCC biomarkers in clinical practice. In this study, we aimed to explore the diagnostic performance of prostaglandin A2 (PGA2) for the early detection of HCC. METHODS Untargeted metabolomic analyses on normal control (NC) and HCC participants in the discovery cohort were performed, and PGA2 was identified to be dysregulated in HCC. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detecting serum PGA2 was established and applied to validate the dysregulation of PGA2 in another independent validation cohort. Receiver operating characteristic (ROC), decision curve analysis (DCA) and some other statistical analyses were performed to evaluate the diagnostic performance of PGA2 for HCC. RESULTS At first, PGA2 was found to be dysregulated in HCC in untargeted metabolomic analyses. Then a precise quantitative LC-MS/MS method for PGA2 has been established and has passed rigorous method validation. Targeted PGA2 analyses confirmed that serum PGA2 was decreased in HCC compared to normal-risk NC and high-risk cirrhosis group. Subsequently, PGA2 was identified as a novel biomarker for the diagnosis of HCC, with an area under the ROC curve (AUC) of 0.911 for differentiating HCC from the combined NC + cirrhosis groups. In addition, PGA2 exhibited high performance for differentiating small-size (AUC = 0.924), early-stage (AUC = 0.917) and AFP (-) HCC (AUC = 0.909) from the control groups. The combination of PGA2 and AFP might be useful in the surveillance of risk population for HCC and early diagnosis of HCC. CONCLUSION This study establishes that PGA2 might be a novel diagnostic biomarker for HCC.
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Affiliation(s)
- Li Liu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China; Department of Clinical Laboratory, Beihua University Affiliated Hospital, Jilin 132011, China
| | - Yi-Ning Li
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China
| | - Aimin Zhang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China
| | - Yue Yin
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China
| | - Zhihong Yue
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China
| | - Lin Pei
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China
| | - Chang-Sheng Xia
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China
| | - Dong Wang
- SCIEX Analytical Instrument Trading Co., Shanghai 200335, China
| | - Mei Jia
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China
| | - Hui Wang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China
| | - Lin-Lin Cao
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing 100044, China.
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Liu J, Yu Y, Zhao H, Guo L, Yang W, Yan Y, Lv J. Latest insights into the epidemiology, characteristics, and therapeutic strategies of chronic hepatitis B patients in indeterminate phase. Eur J Med Res 2024; 29:343. [PMID: 38902822 PMCID: PMC11191257 DOI: 10.1186/s40001-024-01942-0] [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: 05/18/2023] [Accepted: 06/17/2024] [Indexed: 06/22/2024] Open
Abstract
As a hepatotropic virus, hepatitis B virus (HBV) can establish a persistent chronic infection in the liver, termed, chronic hepatitis B (CHB), which causes a series of liver-related complications, including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCC with HBV infection has a significantly increased morbidity and mortality, whereas it could be preventable. The current goal of antiviral therapy for HBV infection is to decrease CHB-related morbidity and mortality, and achieve sustained suppression of virus replication, which is known as a functional or immunological cure. The natural history of chronic HBV infection includes four immune phases: the immune-tolerant phase, immune-active phase, inactive phase, and reactivation phase. However, many CHB patients do not fit into any of these defined phases and are regarded as indeterminate. A large proportion of indeterminate patients are only treated with dynamic monitoring rather than recommended antiviral therapy, mainly due to the lack of definite guidelines. However, many of these patients may gradually have significant liver histopathological changes during disease progression. Recent studies have focused on the prevalence, progression, and carcinogenicity of indeterminate CHB, and more attention has been given to the prevention, detection, and treatment for these patients. Herein, we discuss the latest understanding of the epidemiology, clinical characteristics, and therapeutic strategies of indeterminate CHB, to provide avenues for the management of these patients.
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Affiliation(s)
- Junye Liu
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Heping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Lei Guo
- Department of Spinal Surgery, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Wenjuan Yang
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Yuzhu Yan
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China
| | - Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi'an Jiaotong University, Youyi Dong Road, Xi'an, 710054, China.
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Lyu N, Hassanzadeh-Barforoushi A, Rey Gomez LM, Zhang W, Wang Y. SERS biosensors for liquid biopsy towards cancer diagnosis by detection of various circulating biomarkers: current progress and perspectives. NANO CONVERGENCE 2024; 11:22. [PMID: 38811455 PMCID: PMC11136937 DOI: 10.1186/s40580-024-00428-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/09/2024] [Indexed: 05/31/2024]
Abstract
Liquid biopsy has emerged as a promising non-invasive strategy for cancer diagnosis, enabling the detection of various circulating biomarkers, including circulating tumor cells (CTCs), circulating tumor nucleic acids (ctNAs), circulating tumor-derived small extracellular vesicles (sEVs), and circulating proteins. Surface-enhanced Raman scattering (SERS) biosensors have revolutionized liquid biopsy by offering sensitive and specific detection methodologies for these biomarkers. This review comprehensively examines the application of SERS-based biosensors for identification and analysis of various circulating biomarkers including CTCs, ctNAs, sEVs and proteins in liquid biopsy for cancer diagnosis. The discussion encompasses a diverse range of SERS biosensor platforms, including label-free SERS assay, magnetic bead-based SERS assay, microfluidic device-based SERS system, and paper-based SERS assay, each demonstrating unique capabilities in enhancing the sensitivity and specificity for detection of liquid biopsy cancer biomarkers. This review critically assesses the strengths, limitations, and future directions of SERS biosensors in liquid biopsy for cancer diagnosis.
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Affiliation(s)
- Nana Lyu
- School of Natural Sciences, Macquarie University, Sydney, NSW, 2109, Australia
| | | | - Laura M Rey Gomez
- School of Natural Sciences, Macquarie University, Sydney, NSW, 2109, Australia
| | - Wei Zhang
- School of Natural Sciences, Macquarie University, Sydney, NSW, 2109, Australia
| | - Yuling Wang
- School of Natural Sciences, Macquarie University, Sydney, NSW, 2109, Australia.
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Yu Z, Chen D, Zheng Y, Wang X, Huang S, Lin T, Lin Y, Zhang Y, Huang Y, Ou Q, Huang J. Development and validation of a diagnostic model for AFP-negative hepatocellular carcinoma. J Cancer Res Clin Oncol 2023; 149:11295-11308. [PMID: 37368120 DOI: 10.1007/s00432-023-04997-4] [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: 04/07/2023] [Accepted: 06/15/2023] [Indexed: 06/28/2023]
Abstract
PURPOSE AFP appears to be negative in about 30% of overall hepatocellular carcinoma (HCC). Our study aimed to develop a nomogram model to diagnose AFP-negative HCC (AFPN-HCC). PATIENTS AND METHODS The training set included 294 AFPN-HCC patients, 159 healthy objects, 63 patients with chronic hepatitis B(CHB), and 64 patients with liver cirrhosis (LC). And the validation set enrolled 137 healthy controls objects, 47 CHB patients and 45 patients with LC. LASSO, univariate, and multivariable logistic regression analysis were performed to construct the model and then transformed into a visualized nomogram. The receiver operating characteristic (ROC) curves, the calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were further used for validation. RESULTS Four variables including age, PIVKA-II, platelet (PLT) counts, and prothrombin time (PT) were selected to establish the nomogram. The area under the curve (AUC) of the ROC to distinguish AFPN-HCC patients was 0.937(95% CI 0.892-0.938) in training set and 0.942(95% CI 0.921-0.963) in validation set. We also found that the model had high diagnostic value for small-size HCC (tumor size < 5 cm) (AUC = 0.886) and HBV surface antigen-positive AFPN-HCC (AUC = 0.883). CONCLUSIONS Our model was effective for discrimination of AFPN-HCC from patients with benign liver diseases and healthy controls, and might be helpful for the diagnosis for AFPN-HCC.
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Affiliation(s)
- Zhou Yu
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, Fujian, China
| | - Dongmei Chen
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, Fujian, China
| | - Yansong Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China
| | - Xuedan Wang
- Department of Pathology Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, Fujian Province, China
| | - Shuna Huang
- Department of Clinical Research and Translation Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
| | - Tiansheng Lin
- Department of Hepatobiliary Surgery, Fujian Provincial Hospital, Fuzhou, 350001, Fujian Province, China
| | - Yihan Lin
- Department of Gastroenterology, Fujian Provincial Hospital, Fuzhou, 350001, Fujian Province, China
| | - Yanfang Zhang
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, Fujian, China
| | - Yingna Huang
- Fujian Medical University, Fuzhou, 350005, Fujian Province, China
| | - Qishui Ou
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China.
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, Fujian, China.
| | - Jinlan Huang
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Laboratory Medicine of Immunology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, Fujian, China.
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, Fujian, China.
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Ramadan A, Ghanem HM, Mohamed AA, Elshobaky M, El Agawy W, Gawad EAHA, Eldeeb HH, Ezz Al Arab MR, Kamal MM. GPC3 gene expression and allelic discrimination of FZD7 gene in Egyptian patients with hepatocellular carcinoma. Rep Pract Oncol Radiother 2023; 28:485-495. [PMID: 37795234 PMCID: PMC10547423 DOI: 10.5603/rpor.a2023.0049] [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: 09/22/2022] [Accepted: 07/19/2023] [Indexed: 10/06/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, and especially in Egypt. Early diagnosis of HCC greatly improves the survival and prognosis of patients. Low sensitivity and specificity of alpha-fetoprotein (AFP) has led to the demand for novel biomarkers of HCC. The aim of the present study was to evaluate the validity of frizzled-7 (FZD7) and glypican-3 (GPC3) gene expression as potential biomarkers for HCC early diagnosis, and to investigate the association between FZD7 rs2280509 polymorphism and HCC risk. Materials and methods Quantification of FZD7 and GPC3 gene expression by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay, and genotyping FZD 7 (rs2280509 SNP) gene polymorphism using RT-PCR. Results The current results revealed that FZD7 gene expression had a greater area under the curve (AUC) for identifying HCC than GPC3 gene expression and AFP levels. The combination of the three markers as a panel showed a better diagnostic performance with a greater AUC than any of the single markers alone (p < 0.05). The FZD7 rs2280509 polymorphism (CT) was found to be significantly associated with an increased risk of HCC. The CT genotype and T allele were significantly more prevalent in the HCC group compared to either the cirrhosis (p = 0.03) or control groups (p = 0.0009 and 0.002; respectively). Conclusion FZD7 and GPC3 gene expressions have a complementary role in early HCC detection, with a greater diagnostic sensitivity and accuracy than AFP. In addition, FZD7 rs2280509 polymorphism is significantly associated with an increased risk of HCC in the Egyptian population.
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Affiliation(s)
- Amany Ramadan
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hala M Ghanem
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Amal A Mohamed
- Department of Biochemistry and Molecular Biology, National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Mohamed Elshobaky
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Waleed El Agawy
- Department of Infectious Diseases, Faculty of Medicine, Port Said University, Cairo, Egypt
| | - Eman Al Hussain A Gawad
- Department of Chemical Pathology, National Cancer Institute (NCI), Cairo University, Cairo, Egypt
| | - Hala H Eldeeb
- Clinical and Chemical Pathology Department, El Sahel Teaching Hospital, Cairo, Egypt
| | | | - Maha M Kamal
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
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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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Inoue T, Tanaka Y. Noninvasive assessments of liver disease severity based on biomarkers. COMPREHENSIVE GUIDE TO HEPATITIS ADVANCES 2023:31-60. [DOI: 10.1016/b978-0-323-98368-6.00009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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12
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Guan MC, Ouyang W, Liu SY, Sun LY, Chen WY, Tong XM, Zhu H, Yang T. Alpha-fetoprotein, protein induced by vitamin K absence or antagonist-II, lens culinaris agglutinin-reactive fraction of alpha-fetoprotein alone and in combination for early detection of hepatocellular carcinoma from nonalcoholic fatty liver disease: A multicenter analysis. Hepatobiliary Pancreat Dis Int 2022; 21:559-568. [PMID: 35643910 DOI: 10.1016/j.hbpd.2022.05.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 03/09/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND Current surveillance strategies for hepatocellular carcinoma (HCC) among patients with nonalcoholic fatty liver disease (NAFLD) are insufficient. This study aimed to investigate the diagnostic performance of alpha-fetoprotein (AFP), protein induced by vitamin K absence or antagonist-II (PIVKA-II), lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and their combinations in HCC underlying NAFLD patients. METHODS Serologic AFP, AFP-L3, and PIVKA-II levels in NAFLD patients with and without HCC were measured. By receiver operating characteristic (ROC) analyses, the area under the curve (AUC), sensitivity, and specificity were obtained to evaluate the diagnostic accuracy of each biomarker and their combinations. RESULTS This study was conducted on 139 patients with NAFLD-HCC and 345 NAFLD controls. The elevation of these three biomarkers was observed in patients with NAFLD-HCC compared to those in NAFLD controls (all P < 0.001). When they were analyzed individually, PIVKA-II showed the best performance in diagnosing any-stage HCC with an AUC of 0.869, followed by AFP (0.763; vs. PIVKA-II, P < 0.001) and AFP-L3 (0.689; vs. PIVKA-II, P < 0.001). When they were analyzed in combination, AFP + PIVKA-II yielded the highest AUC (0.906), followed by AFP + PIVKA-II + AFP-L3 (0.904; vs. AFP + PIVKA-II, P = 0.086), PIVKA-II + AFP-L3 (0.881; vs. AFP + PIVKA-II, P < 0.001), and AFP + AFP-L3 (0.759; vs. AFP + PIVKA-II, P < 0.001). Similar findings were obtained in the subgroup with early-stage NAFLD-HCC, as well as the non-cirrhotic subgroup. CONCLUSIONS These data validated the better diagnostic ability of PIVKA-II than AFP or AFP-L3 alone for diagnosing any-stage HCC among patients with NAFLD, and the combination of AFP + PIVKA-II significantly improved the diagnostic accuracy of NAFLD-HCC.
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Affiliation(s)
- Ming-Cheng Guan
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Wei Ouyang
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Si-Yu Liu
- Department of Laboratory, Zhejiang University Lishui Hospital, Lishui 323000, China
| | - Li-Yang Sun
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China
| | - Wei-Yue Chen
- Department of Laboratory, Zhejiang University Lishui Hospital, Lishui 323000, China; The Key Laboratory of Imaging Diagnosis and Minimally Invasive Interventional Research of Zhejiang Province, Department of Interventional Radiology, Zhejiang University Lishui Hospital, Lishui 323000, China
| | - Xiang-Min Tong
- Department of Laboratory, Zhejiang University Lishui Hospital, Lishui 323000, China; Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China; School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310059, China
| | - Hong Zhu
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
| | - Tian Yang
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China; School of Clinical Medicine, Hangzhou Medical College, Hangzhou 310059, China; Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai 200438, China.
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Phan TH, Chi Nguyen VT, Thi Pham TT, Nguyen VC, Ho TD, Quynh Pham TM, Tran TH, Nguyen TD, Khang Le ND, Nguyen TH, Duong ML, Bach HPT, Kim VV, Pham TA, Nguyen BT, Vo Nguyen TN, Nguyen TD, Bieu Phu DT, Huu Phan BH, Nguyen DS, Truong DK, Do TTT, Giang H, Nguyen HN, Phan MD, Tran LS. Circulating DNA methylation profile improves the accuracy of serum biomarkers for the detection of nonmetastatic hepatocellular carcinoma. Future Oncol 2022; 18:4399-4413. [PMID: 36786635 DOI: 10.2217/fon-2022-1218] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
Aim: This study exploited hepatocellular carcinoma (HCC)-specific circulating DNA methylation profiles to improve the accuracy of a current screening assay for HCC patients in high-risk populations. Methods: Differentially methylated regions in cell-free DNA between 58 nonmetastatic HCC and 121 high-risk patients with liver cirrhosis or chronic hepatitis were identified and used to train machine learning classifiers. Results: The model could distinguish HCC from high-risk non-HCC patients in a validation cohort, with an area under the curve of 0.84. Combining these markers with the three serum biomarkers (AFP, lectin-reactive AFP, des-γ-carboxy prothrombin) in a commercial test, μTASWako®, achieved an area under the curve of 0.87 and sensitivity of 68.8% at 95.8% specificity. Conclusion: HCC-specific circulating DNA methylation markers may be added to the available assay to improve the early detection of HCC.
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Affiliation(s)
| | - Van Thien Chi Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | | | - Van-Chu Nguyen
- National Cancer Hospital, Hanoi, Vietnam
- Hanoi Medical University, Hanoi, Vietnam
| | - Tan Dat Ho
- MEDIC Medical Center, Ho Chi Minh City, Vietnam
| | - Thi Mong Quynh Pham
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Thanh-Huong Tran
- National Cancer Hospital, Hanoi, Vietnam
- Hanoi Medical University, Hanoi, Vietnam
| | - Thanh Dat Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Nguyen Duy Khang Le
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Trong-Hieu Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | | | | | - Van-Vu Kim
- National Cancer Hospital, Hanoi, Vietnam
- Hanoi Medical University, Hanoi, Vietnam
| | | | | | | | | | | | | | - Duy-Sinh Nguyen
- Department of Oncology, Faculty of Medicine, Nguyen Tat Thanh University, Ho Chi Minh City, Vietnam
| | | | | | - Hoa Giang
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Hoai-Nghia Nguyen
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Minh-Duy Phan
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
| | - Le Son Tran
- Medical Genetics Institute, Ho Chi Minh City, Vietnam
- Gene Solutions, Ho Chi Minh City, Vietnam
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Phosphorylated Proteins from Serum: A Promising Potential Diagnostic Biomarker of Cancer. Int J Mol Sci 2022; 23:ijms232012359. [PMID: 36293212 PMCID: PMC9604268 DOI: 10.3390/ijms232012359] [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: 09/22/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer is a fatal disease worldwide. Each year ten million people are diagnosed around the world, and more than half of patients eventually die from it in many countries. A majority of cancer remains asymptomatic in the earlier stages, with specific symptoms appearing in the advanced stages when the chances of adequate treatment are low. Cancer screening is generally executed by different imaging techniques like ultrasonography (USG), mammography, CT-scan, and magnetic resonance imaging (MRI). Imaging techniques, however, fail to distinguish between cancerous and non-cancerous cells for early diagnosis. To confirm the imaging result, solid and liquid biopsies are done which have certain limitations such as invasive (in case of solid biopsy) or missed early diagnosis due to extremely low concentrations of circulating tumor DNA (in case of liquid biopsy). Therefore, it is essential to detect certain biomarkers by a noninvasive approach. One approach is a proteomic or glycoproteomic study which mostly identifies proteins and glycoproteins present in tissues and serum. Some of these studies are approved by the Food and Drug Administration (FDA). Another non-expensive and comparatively easier method to detect glycoprotein biomarkers is by ELISA, which uses lectins of diverse specificities. Several of the FDA approved proteins used as cancer biomarkers do not show optimal sensitivities for precise diagnosis of the diseases. In this regard, expression of phosphoproteins is associated with a more specific stage of a particular disease with high sensitivity and specificity. In this review, we discuss the expression of different serum phosphoproteins in various cancers. These phosphoproteins are detected either by phosphoprotein enrichment by immunoprecipitation using phosphospecific antibody and metal oxide affinity chromatography followed by LC-MS/MS or by 2D gel electrophoresis followed by MALDI-ToF/MS analysis. The updated knowledge on phosphorylated proteins in clinical samples from various cancer patients would help to develop these serum phophoproteins as potential diagnostic/prognostic biomarkers of cancer.
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15
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Singal AG, Haaland B, Parikh ND, Ozbay AB, Kirshner C, Chakankar S, Porter K, Chhatwal J, Ayer T. Comparison of a multitarget blood test to ultrasound and alpha-fetoprotein for hepatocellular carcinoma surveillance: Results of a network meta-analysis. Hepatol Commun 2022; 6:2925-2936. [PMID: 35945907 PMCID: PMC9512471 DOI: 10.1002/hep4.2045] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/20/2022] [Accepted: 06/02/2022] [Indexed: 12/21/2022] Open
Abstract
Ultrasound-based surveillance has suboptimal sensitivity for early detection of hepatocellular carcinoma (HCC) in patients with cirrhosis. There are several emerging alternatives, including a novel multitarget HCC blood test (Mt-HBT). We compared performance of mt-HBT against ultrasound with or without alpha-fetoprotein (AFP) for early HCC detection in patients with cirrhosis. Per the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, two reviewers searched PubMed, Cochrane, Embase, and clinicaltrials.gov databases from January 1990 through December 2020 to identify studies reporting sensitivity and/or specificity of ultrasound and AFP for overall and early stage HCC detection in patients with cirrhosis. Mt-HBT diagnostic performance was derived from a clinical validation study. A network meta-analysis model was built for comparative assessment, and pooled estimates of sensitivity at a fixed specificity were estimated based on Bayesian binormal receiver operating characteristic models for each modality. Forty-one studies (comprising 62,517 patients with cirrhosis) met inclusion criteria. Ultrasound-alone sensitivity was 51.6% (95% credible interval [CrI], 43.3%-60.5%) for early stage HCC detection, which increased with the addition of AFP to 74.1% (95% CrI, 62.6%-82.4%); however, this was offset by decreased specificity (87.9% vs. 83.9%, respectively). With specificity fixed at 90%, mt-HBT sensitivity for early stage HCC detection was higher than ultrasound alone (18.2%; 95% CrI, 0.2%-37.7%) and similar to ultrasound with AFP (-3.3%; 95% CrI, -22.3%-17.4%). Pairwise posterior probabilities suggested a preference for mt-HBT over ultrasound alone in 97.4% of cases but only 36.3% of cases versus ultrasound with AFP. Conclusion: A blood-based mt-HBT has higher sensitivity than ultrasound alone for early stage HCC detection but similar sensitivity compared to ultrasound and AFP. Mt-HBT could be a comparable alternative to existing methods for HCC surveillance in patients who are at risk.
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Affiliation(s)
- Amit G. Singal
- Division of Digestive and Liver DiseasesUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Benjamin Haaland
- University of Utah School of Medicine and Huntsman Cancer InstituteSalt Lake CityUtahUSA
| | - Neehar D. Parikh
- Division of Gastroenterology and HepatologyUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | | | | | | | - Kyle Porter
- Exact Sciences CorporationMadisonWisconsinUSA
| | - Jagpreet Chhatwal
- Institute for Technology Assessment, Massachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | - Turgay Ayer
- Georgia Institute of TechnologyAtlantaGeorgiaUSA
- Emory Medical SchoolAtlantaGeorgiaUSA
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16
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Diagnostic Performance of AFP, AFP-L3, or PIVKA-II for Hepatitis C Virus-Associated Hepatocellular Carcinoma: A Multicenter Analysis. J Clin Med 2022; 11:jcm11175075. [PMID: 36079006 PMCID: PMC9456633 DOI: 10.3390/jcm11175075] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/18/2022] [Accepted: 08/26/2022] [Indexed: 11/25/2022] Open
Abstract
Background and Aim: Alpha-fetoprotein (AFP), a lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), is a protein that is induced by vitamin K deficiency or antagonist-II (PIVKA-II) that has been clinically used as a serum biomarker for early detection and diagnosis of hepatocellular carcinoma (HCC). Diagnostic performance of each serum biomarker alone, or their combinations for the detection of hepatitis C virus (HCV)-associated HCC were compared. Methods: Serum AFP, AFP-L3, and PIVKA-II levels were evaluated in patients with HCV-associated HCC, and those with chronic HCV infection without HCC (HCV-controls). The areas under the curve (AUC), sensitivity, and specificity were compared to identify the diagnostic performance of each serum HCC biomarker alone or in combination. Results: Overall, 172 HCV controls and 105 patients with HCV-associated HCC were enrolled. The AFP, AFP-L3, and PIVKA-II levels were significantly increased among patients with HCV-associated HCC when compared with HCV patients without HCC (p < 0.001). When these biomarkers were analyzed individually, PIVKA-II revealed the best predictive performance (AUC: PIVKA-II 0.90 vs. AFP 0.80 vs. AFP-L3 0.69, p < 0.001). In evaluating the combinations of any two biomarkers, the best predictive performance was found in PIVKA-II + AFP (0.93 vs. AFP + AFP-L3 0.78, p = 0.001; and PIVKA-II + AFP-L3 0.89, p < 0.001), which had no difference compared to the predictive performance of the combination of all three serum biomarkers (AFP + AFP-L3 + PIVKA-II 0.93, p = 0.277). Similar results were identified in the subgroups of patients with HCV-induced cirrhosis, and among patients with early-stage HCC defined by BCLC and TNM staging. Conclusions: The addition of the PIVKA-II test to routine AFP test maybe provide a more suitable biomarker approach to detect HCV-induced HCC in patients with HCV infection undergoing HCC surveillance.
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Wang MD, Sun LY, Qian GJ, Li C, Gu LH, Yao LQ, Diao YK, Pawlik TM, Lau WY, Huang DS, Shen F, Yang T. Prothrombin induced by vitamin K Absence-II versus alpha-fetoprotein in detection of both resectable hepatocellular carcinoma and early recurrence after curative liver resection: A retrospective cohort study. Int J Surg 2022; 105:106843. [PMID: 35995351 DOI: 10.1016/j.ijsu.2022.106843] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/26/2022] [Accepted: 08/11/2022] [Indexed: 12/21/2022]
Abstract
BACKGROUND Alpha-fetoprotein (AFP) and prothrombin induced by vitamin K absence-II (PIVKA-II) are two commonly used biomarkers for detection and prognostic prediction of hepatocellular carcinoma (HCC). This study sought to evaluate and compare the use of these two biomarkers to detect HCC, as well as predict postoperative early recurrence (within 2 years after HCC resection). METHODS Data on consecutive patients who underwent curative resection for HCC between 2014 and 2020 was prospectively collected and reviewed. Serum AFP and PIVKA-II levels within one week before surgery or at the time of detection of early recurrence were assessed; preoperative AFP positivity (≥20 ng/ml) and preoperative PIVKA-II positivity (≥40 mAU/ml) were examined relative to recurrence using univariate and multivariate Cox-regression analyses. RESULTS Among 751 patients who underwent curative HCC resection, 589 (78.4%) patients had preoperative PIVKA-II positivity versus 498 (66.3%) patients had preoperative AFP positivity (P < 0.001). With a median follow-up of 41.6 months, 370 (50.1%) patients had an early HCC recurrence; among patients with an early recurrence, the proportion of patients with PIVKA-II positivity versus AFP positivity (76.5% vs. 60.0%, P = 0.002) was higher. On multivariate analysis, preoperative PIVKA-II positivity, but not preoperative AFP positivity was an independent risk factor to predict early recurrence after HCC resection. CONCLUSIONS AFP and PIVKA-II are useful biomarkers to detect resectable HCC and predict early recurrence after HCC resection, with the latter showing higher rates of positivity. Preoperative PIVKA-II positivity was independently associated with early recurrence following HCC resection.
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Affiliation(s)
- Ming-Da Wang
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China; Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Military Medical University, Shanghai, China
| | - Li-Yang Sun
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Guo-Jun Qian
- Department of Ultrasonic Intervention, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chao Li
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Li-Hui Gu
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Lan-Qing Yao
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Yong-Kang Diao
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Timothy M Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, OH, United States
| | - Wan Yee Lau
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China; Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
| | - Dong-Sheng Huang
- Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Feng Shen
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China; Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Military Medical University, Shanghai, China.
| | - Tian Yang
- Department of Hepatic Surgery, Third Affiliated Hospital of Naval Medical University, Shanghai, China; Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Navy Military Medical University, Shanghai, China; Department of General Surgery, Cancer Center, Division of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China.
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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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Hanif H, Ali MJ, Susheela AT, Khan IW, Luna-Cuadros MA, Khan MM, Lau DTY. Update on the applications and limitations of alpha-fetoprotein for hepatocellular carcinoma. World J Gastroenterol 2022; 28:216-229. [PMID: 35110946 PMCID: PMC8776528 DOI: 10.3748/wjg.v28.i2.216] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/26/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Alpha-fetoprotein (AFP) is an oncofetal glycoprotein that has been used as a tumor marker for hepatocellular carcinoma (HCC) in combination with ultrasound and other imaging modalities. Its utility is limited because of both low sensitivity and specificity, and discrepancies among the different methods of measurements. Moreover, its accuracy varies according to patient characteristics and the AFP cut-off values used. Combination of AFP with novel biomarkers such as AFP-L3, Golgi specific membrane protein (GP73) and des-gamma-carboxyprothrombin significantly improved its accuracy in detecting HCC. Increased AFP level could also signify severity of hepatic destruction and subsequent regeneration and is commonly observed in patients with acute and chronic liver conditions and cirrhosis. Hereditary and other non-hepatic disorders can also cause AFP elevation.
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Affiliation(s)
- Hira Hanif
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Mukarram Jamat Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Ammu T Susheela
- Internal Medicine, Loyola MacNeal Hospital, Berwyn, PA 60402, United States
| | - Iman Waheed Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Maria Alejandra Luna-Cuadros
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Muzammil Muhammad Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Daryl Tan-Yeung Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
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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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21
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Frankul L, Frenette C. Hepatocellular Carcinoma: Downstaging to Liver Transplantation as Curative Therapy. J Clin Transl Hepatol 2021; 9:220-226. [PMID: 34007804 PMCID: PMC8111105 DOI: 10.14218/jcth.2020.00037] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 10/04/2020] [Accepted: 03/04/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) ranks among the leading cancer-related causes of morbidity and mortality worldwide. Downstaging of HCC has prevailed as a key method to curative therapy for patients who present with unresectable HCC outside of the listing criteria for liver transplantation (LT). Even though LT paves the way to lifesaving curative therapy for HCC, perpetually severe organ shortage limits its broader application. Debate over the optimal protocol and assessment of response to downstaging treatment has fueled immense research activity and is pushing the boundaries of LT candidate selection criteria. The implicit obligation of refining downstaging protocol is to ensure the maximization of the transplant survival benefit by taking into account the waitlist life expectancy. In the following review, we critically discuss strategies to best optimize downstaging HCC to LT on the basis of existing literature.
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Affiliation(s)
| | - Catherine Frenette
- Correspondence to: Catherine Frenette, Scripps Center for Organ Transplant, Scripps Clinic/Green Hospital, 10666 N. Torrey Pines Rd N200, La Jolla, CA 92037, USA. ORCID: https://orcid.org/0000-0002-2245-8173 Tel: +1-858-554-4310, Fax: +1-858-554-3009, E-mail:
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22
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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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23
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Liu Z, Wu M, Lin D, Li N. Des-gamma-carboxyprothrombin is a favorable biomarker for the early diagnosis of alfa-fetoprotein-negative hepatitis B virus-related hepatocellular carcinoma. J Int Med Res 2020; 48:300060520902575. [PMID: 32054358 PMCID: PMC7111028 DOI: 10.1177/0300060520902575] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Objectives Des-gamma-carboxyprothrombin (DCP) is an important serum biomarker for the clinical screening of hepatocellular carcinoma (HCC). This study aimed to evaluate the value of DCP for the early diagnosis of alpha-fetoprotein (AFP)-negative hepatitis B virus (HBV)-related HCC. Methods We retrospectively enrolled patients with AFP-negative HBV-related HCC and benign liver disease. Serum DCP levels in all participants were measured by chemiluminescent enzyme immunoassay. The value of DCP for the early diagnosis of AFP-negative HBV-related HCC was evaluated by receiver operating characteristic curve (ROC) and area under the curve (AUC) analyses. Results A total of 210 patients, including 87 cases with AFP-negative HBV-related HCC and 123 control cases with chronic HBV infection (CHB) or liver cirrhosis (LC), were included. Serum DCP levels were significantly increased in patients with AFP-negative HBV-related HCC compared with those with CHB or LC. The AUC for DCP for distinguishing between the two groups was 0.731 (95% confidence interval (CI), 0.657 to 0.805) and that for early diagnosis was 0.685 (95%CI, 0.596 to 0.774). Conclusions DCP may be a favorable biomarker to improve the early diagnosis rate of AFP-negative HBV-related HCC.
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Affiliation(s)
- Zhaobo Liu
- Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Min Wu
- Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Dongdong Lin
- Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Ning Li
- Department of General Surgery, Beijing YouAn Hospital, Capital Medical University, Beijing, China
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Aglycosylated antibody-producing mice for aglycosylated antibody-lectin coupled immunoassay for the quantification of tumor markers (ALIQUAT). Commun Biol 2020; 3:636. [PMID: 33128033 PMCID: PMC7599229 DOI: 10.1038/s42003-020-01363-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 10/06/2020] [Indexed: 12/21/2022] Open
Abstract
Targeting aberrant glycoforms has been validated for in vitro cancer diagnostic development, and several assays are currently in routine clinical use. Because N-glycans in Fc region of antibodies show cross-reactivity with various lectins, high-quality aglycosylated antibodies are exceptionally important for immunoassay platform-based quantitative measurements. Previously, aglycosylated antibody acquisition relied on incomplete, uneconomical and onerous enzymatic and chemical methods. Here, we edited four murine immunoglobulin G genes using adenine base-editing and homology-directed recombination (HDR)-mediated gene editing methods to generate aglycosylated antibody-producing mice. Resulting aglycosylated antibodies showed required analytical performances without compromised protein stability. Thus, this aglycosylated monoclonal antibody-lectin coupled immunoassay for the quantification of tumour markers (ALIQUAT) method can provide a robust, versatile and accessible immunoassay platform to quantify specific glycoforms in precision cancer diagnostics. Moreover, the engineered mice can be used as a host to produce various aglycosylated antibodies in a convenient and robust fashion, thereby expanding in vitro diagnostic development opportunities that utilize glycoforms as a disease-specific biomarkers. Lee et al. describe the generation of aglycosylated antibody-producing mice. These aglycosylated antibodies, lacking glycans prevent unwanted interactions with the lectins, and are used as reagents in a tool they developed called ALIQUAT. This aglycosylated antibody and lectin-based immunoassay diagnostic platform can be used to detect disease specific glycan biomarkers.
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25
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Evaluation of the Combined Application of AFP, AFP-L3%, and DCP for Hepatocellular Carcinoma Diagnosis: A Meta-analysis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:5087643. [PMID: 33015170 PMCID: PMC7519464 DOI: 10.1155/2020/5087643] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/25/2020] [Accepted: 09/03/2020] [Indexed: 12/24/2022]
Abstract
The role of α-fetoprotein (AFP) in the surveillance and diagnosis of hepatocellular carcinoma (HCC) has been questioned in recent years due to its low sensitivity and specificity. In addition to AFP, several new serum biomarkers, such as lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-gamma-carboxy prothrombin (DCP), have also been identified as useful HCC serological markers. However, the exact diagnostic value of the combinations of these biomarkers for detecting HCC in patients with liver disease remains unclear. Thus, we performed the current meta-analysis to assess performance of AFP+AFP-L3%+DCP for diagnosing HCC. Studies were systematically searched in PubMed, Embase, the Cochrane Library, CNKI, and WanFang Data databases. After full-text evaluation, 13 studies from 11 articles focusing on the combination of the three serum biomarkers for HCC detection were enrolled. Random-effects models were used due to the presence of heterogeneity. The pooled sensitivity and specificity for AFP+AFP-L3%+DCP were 88% and 79%, respectively. The area under the summary receiver operating characteristic (sROC) curve was 0.91, and the diagnostic odds ratio (DOR) was 28.33 (95% CI 16.78-47.83). Subgroup analysis showed that the pooled sensitivity and specificity of AFP+AFP-L3%+DCP in the diagnosis of HCC versus cirrhosis patients were 0.81 and 0.82, respectively. In conclusion, the combination of AFP, AFP-L3%, and DCP may prove to be useful in the diagnosis and screening of HCC.
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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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27
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Inoue T, Tanaka Y. Novel biomarkers for the management of chronic hepatitis B. Clin Mol Hepatol 2020; 26:261-279. [PMID: 32536045 PMCID: PMC7364351 DOI: 10.3350/cmh.2020.0032] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 04/13/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) cannot be eliminated completely from infected hepatocytes because of the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), it is important to manage CHB to prevent HCC development in high-risk patients with high viral replicative activity or advanced fibrosis. Serum biomarkers are noninvasive and valuable for the management of CHB. Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with hopeful outcomes. Therefore, HBcrAg can predict HCC occurrence or recurrence. Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. Because elevated M2BPGi in CHB is related to liver fibrosis and the prediction of HCC development, monitoring its progression is essential. Because alpha fetoprotein (AFP) has insufficient sensitivity and specificity for early-stage HCC, a combination of AFP plus protein induced by vitamin K absence factor II, or AFP plus Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein might improve the diagnosis of HCC development. Additionally, Dickkopf-1 and circulating immunoglobulin G antibodies are the novel markers to diagnose HCC or assess HCC prognosis. This review provides an overview of novel HBV biomarkers used for the management of intrahepatic viral replicative activity, liver fibrosis, and HCC development.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya, Japan.,Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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28
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Piñero F, Dirchwolf M, Pessôa MG. Biomarkers in Hepatocellular Carcinoma: Diagnosis, Prognosis and Treatment Response Assessment. Cells 2020; 9:E1370. [PMID: 32492896 PMCID: PMC7349517 DOI: 10.3390/cells9061370] [Citation(s) in RCA: 293] [Impact Index Per Article: 58.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/28/2020] [Accepted: 05/28/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the main cancer-related causes of death worldwide. Thus, there is a constant search for improvement in screening, diagnosis, and treatment strategies to improve the prognosis of this malignancy. The identification of useful biomarkers for surveillance and early HCC diagnosis is still deficient, with available serum biomarkers showing low sensitivity and heterogeneous specificity despite different cut-off points, even when assessed longitudinally, or with a combination of serum biomarkers. In contrast, HCC biomarkers used for prognostic (when associated with clinical outcomes) or predictive purposes (when associated with treatment response) may have an increased clinical role in the near future. Furthermore, some serum biomarkers are already implicated as a treatment selection tool, whether to provide access to certain therapies or to assess clinical benefit after treatment. In the present review we will discuss the clinical utility and foreseen future of HCC biomarkers implicated in surveillance, diagnosis, prognosis, and post-treatment assessment.
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Affiliation(s)
- Federico Piñero
- Hepatology and Liver Transplant Unit, Hospital Universitario Austral, School of Medicine, Austral University, B1629AHJ Buenos Aires, Argentina;
- Latin American Liver Research Educational and Awareness Network (LALREAN), B1629AHJ Buenos Aires, Argentina
| | - Melisa Dirchwolf
- Liver Unit, Hospital Privado de Rosario, 2000 Rosario, Santa Fe, Argentina;
| | - Mário G. Pessôa
- Division of Gastroenterology and Hepatology, University of São Paulo School of Medicine, 05403-000 São Paulo, Brazil
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29
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Chen S, Li J, Tan X, Xu Q, Mo Y, Qin H, Zhou L, Ma L, Wei Z. Clinical role of combining alpha-fetoprotein and lens culinaris agglutinin-reactive fraction of alpha-fetoprotein for hepatocellular carcinoma: Evidence from literature and an original study. J Clin Lab Anal 2020; 34:e23262. [PMID: 32167614 PMCID: PMC7370718 DOI: 10.1002/jcla.23262] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 01/18/2020] [Accepted: 01/28/2020] [Indexed: 12/21/2022] Open
Abstract
Background To evaluate the clinical diagnostic efficacy of the combination of alpha‐fetoprotein (AFP) and lens culinaris agglutinin‐reactive fraction of AFP/total AFP (AFP‐L3%) for detecting hepatocellular carcinoma (HCC). Methods A comprehensive and systemic literature search was executed in Web of Science, PubMed, and the Cochrane Library websites. Then, the related articles were reviewed and the quality of included studies was evaluated with the QUADAS tool. Further, serum samples were collected from 49 HCC patients, 52 cirrhosis patients, 47 hepatitis patients, and 48 healthy controls and these samples were tested for AFP and AFP‐L3% levels. Results A total of 16 eligible articles were included in our meta‐analysis. The overall sensitivity (SEN) of AFP + AFP‐L3% was higher than that of AFP or AFP‐L3 alone; the overall specificity (SPE) of AFP + AFP‐L3% was lower than that of AFP or AFP‐L3 alone. In the original study, the related statistics were, respectively, SEN = 0.592 and SPE = 0.918 for AFP; SEN = 0.367 and SPE = 1.000 for AFP‐L3%; and SEN = 0.592 and SPE = 0.918 for the combination. Conclusion The results of meta‐analysis indicate there is a beneficial effect of using the unity of AFP and AFP‐L3% for HCC diagnosing. However, in the original study, just for the results of sensitivity and specificity, there is no significant difference between AFP alone and AFP + AFP‐L3%.
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Affiliation(s)
- Siyuan Chen
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Junhong Li
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiaodan Tan
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Qi Xu
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yuncong Mo
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hongyan Qin
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lili Zhou
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Lingxiu Ma
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhixiao Wei
- Department of Nuclear Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Omran MM, Farid K, Omar MA, Emran TM, El-Taweel FM, Tabll AA. A combination of α-fetoprotein, midkine, thioredoxin and a metabolite for predicting hepatocellular carcinoma. Ann Hepatol 2020; 19:179-185. [PMID: 31648804 DOI: 10.1016/j.aohep.2019.09.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 08/29/2019] [Accepted: 09/03/2019] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND OBJECTIVES The heterogenous nature of hepatocellular carcinoma (HCC) motivated this attempt at developing and validating a model based on combined biomarkers for improving early HCC detection. PATIENTS/MATERIALS AND METHODS This study examined 196 patients for an estimation study (104 patients with HCC, 52 with liver cirrhosis and 40 with liver fibrosis) and 122 patients for the validation study (80 patients with HCC, 42 with liver cirrhosis). All patients were positive for hepatitis C virus. Four markers were measured: Midkine and thioredoxin using ELISA, 1-methyladenosine and 1-methylguanosine using a gas chromatography-mass spectrometry (GC-MS). The results were compared with alpha-fetoprotein (AFP). The performance of the model was estimated in BCLC, CLIP and Okuda staging systems of HCC. RESULTS The model yielded high performance with an area under ROC (AUC) of 0.94 for predicting HCC in patients with liver cirrhosis, compared with AUC of 0.69 for AFP. This model had AUCs of 0.93, 0.94 and 0.94 in patients who had only one single nodule, absent macrovascular invasion and tumor size <2cm, respectively, compared with AUCs of 0.71, 0.6 and 0.59 for AFP. The model produced AUCs of 0.91 for BCLC (0-A), 0.92 for CLIP (0-1) and 0.94 for Okuda (stage I) compared with AUCs of 0.56, 0.58 and 0.64 for AFP. No significant difference was found between AUC in the estimation and the validation groups. CONCLUSION This model may enhance early-stage HCC detection and help to overcome insufficient sensitivity of AFP.
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Affiliation(s)
- Mohamed M Omran
- Chemistry Department, Faculty of Science, Helwan University, Cairo, Egypt.
| | - Khaled Farid
- Tropical Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mona A Omar
- Chemistry Department, Faculty of Science, Damietta University, New Damietta, Egypt
| | - Tarek M Emran
- Clinical Pathology Department, Faculty of Medicine, Al-Azhar University, New Damietta, Egypt
| | - Fathy M El-Taweel
- Chemistry Department, Faculty of Science, Damietta University, New Damietta, Egypt
| | - Ashraf A Tabll
- Microbial Biotechnology Department, National Research Centre, Giza, Egypt
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The threshold of alpha-fetoprotein (AFP) for the diagnosis of hepatocellular carcinoma: A systematic review and meta-analysis. PLoS One 2020; 15:e0228857. [PMID: 32053643 PMCID: PMC7018038 DOI: 10.1371/journal.pone.0228857] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 01/23/2020] [Indexed: 02/08/2023] Open
Abstract
Objective Hepatocellular carcinoma (HCC) has become a pressing health problem facing the world today due to its high morbidity, high mortality, and late discovery. As a diagnostic criteria of HCC, the exact threshold of Alpha-fetoprotein (AFP) is controversial. Therefore, this study was aimed to systematically estimate the performance of AFP in diagnosing HCC and to clarify its optimal threshold. Methods Medline and Embase databases were searched for articles indexed up to November 2019. English language studies were included if both the sensitivity and specificity of AFP in the diagnosis of HCC were provided. The basic information and accuracy data included in the studies were extracted. Combined estimates for sensitivity and specificity were statistically analyzed by random-effects model using MetaDisc 1.4 and Stata 15.0 software at the prespecified threshold of 400 ng/mL, 200 ng/mL, and the range of 20–100 ng/mL. The optimal threshold was evaluated by the area under curve (AUC) of the summary receiver operating characteristic (SROC). Results We retrieved 29,828 articles and included 59 studies and 1 review with a total of 11,731 HCC cases confirmed by histomorphology and 21,972 control cases without HCC. The included studies showed an overall judgment of at risk of bias. Four studies with AFP threshold of 400 ng/mL showed the summary sensitivity and specificity of 0.32 (95%CI 0.31–0.34) and 0.99 (95%CI 0.98–0.99), respectively. Four studies with AFP threshold of 200 ng/mL showed the summary sensitivity and specificity of 0.49 (95%CI 0.47–0.50) and 0.98 (95%CI 0.97–0.99), respectively. Forty-six studies with AFP threshold of 20–100 ng/mL showed the summary sensitivity and specificity of 0.61 (95%CI 0.60–0.62) and 0.86 (95%CI 0.86–0.87), respectively. The AUC of SROC and Q index of 400 ng/mL threshold were 0.9368 and 0.8734, respectively, which were significantly higher than those in 200 ng/mL threshold (0.9311 and 0.8664, respectively) and higher than those in 20–100 ng/mL threshold (0.8330 and 0.7654, respectively). Furthermore, similar result that favored 400 ng/mL were shown in the threshold in terms of AFP combined with ultrasound. Conclusion AFP levels in serum showed good accuracy in HCC diagnosis, and the threshold of AFP with 400 ng/mL was better than that of 200 ng/mL in terms of sensitivity and specificity no matter AFP is used alone or combined with ultrasound.
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Dadfar SMM, Sekula-Neuner S, Trouillet V, Liu HY, Kumar R, Powell AK, Hirtz M. Evaluation of click chemistry microarrays for immunosensing of alpha-fetoprotein (AFP). BEILSTEIN JOURNAL OF NANOTECHNOLOGY 2019; 10:2505-2515. [PMID: 31921529 PMCID: PMC6941445 DOI: 10.3762/bjnano.10.241] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 11/14/2019] [Indexed: 06/10/2023]
Abstract
The level of cancer biomarkers in cells, tissues or body fluids can be used for the prediction of the presence of cancer or can even indicate the stage of the disease. Alpha-fetoprotein (AFP) is the most commonly used biomarker for early screening and diagnosis of hepatocellular carcinoma (HCC). Here, a combination of three techniques (click chemistry, the biotin-streptavidin-biotin sandwich strategy and the use of antigen-antibody interactions) were combined to implement a sensitive fluorescent immunosensor for AFP detection. Three types of functionalized glasses (dibenzocyclooctyne- (DBCO-), thiol- and epoxy-terminated surfaces) were biotinylated by employing the respective adequate click chemistry counterparts (biotin-thiol or biotin-azide for the first class, biotin-maleimide or biotin-DBCO for the second class and biotin-amine or biotin-thiol for the third class). The anti-AFP antibody was immobilized on the surfaces via a biotin-streptavidin-biotin sandwich technique. To evaluate the sensing performance of the differently prepared surfaces, fluorescently labeled AFP was spotted onto them via microchannel cantilever spotting (µCS). Based on the fluorescence measurements, the optimal microarray design was found and its sensitivity was determined.
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Affiliation(s)
- Seyed Mohammad Mahdi Dadfar
- Institute of Nanotechnology (INT), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
- Karlsruhe Nano Micro Facility (KNMF), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
| | - Sylwia Sekula-Neuner
- Institute of Nanotechnology (INT), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
- Karlsruhe Nano Micro Facility (KNMF), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
| | - Vanessa Trouillet
- Karlsruhe Nano Micro Facility (KNMF), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
- Institute for Applied Materials (IAM), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
| | - Hui-Yu Liu
- Institute of Nanotechnology (INT), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
- Karlsruhe Nano Micro Facility (KNMF), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
| | - Ravi Kumar
- Institute of Nanotechnology (INT), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
- Karlsruhe Nano Micro Facility (KNMF), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
| | - Annie K Powell
- Institute of Inorganic Chemistry (AOC), Karlsruhe Institute of Technology (KIT), Engesserstraße 15, 76131 Karlsruhe, Germany
| | - Michael Hirtz
- Institute of Nanotechnology (INT), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
- Karlsruhe Nano Micro Facility (KNMF), Karlsruhe Institute of Technology (KIT), Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany
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Liu XN, Cui DN, Li YF, Liu YH, Liu G, Liu L. Multiple “Omics” data-based biomarker screening for hepatocellular carcinoma diagnosis. World J Gastroenterol 2019; 25:4199-4212. [PMID: 31435173 PMCID: PMC6700689 DOI: 10.3748/wjg.v25.i30.4199] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/28/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
The huge prognostic difference between early and late stage hepatocellular carcinoma (HCC) is a challenging diagnostic problem. Alpha-fetoprotein is the mostly widely used biomarker for HCC used in the clinic, however it’s sensitivity and specificity of is not optimal. The development and application of multiple biotechnologies, including next generation sequencing, multiple “omics” data, that include genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics has been used for HCC diagnostic biomarker screening. Effective biomarkers/panels/models have been identified and validated at different clinical levels. A large proportion of these have a good diagnostic performance for HCC, especially for early HCC. In this article, we reviewed the various HCC biomarkers derived from “omics” data and discussed the advantages and disadvantages for diagnosis HCC.
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Affiliation(s)
- Xiao-Na Liu
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Dan-Ni Cui
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Yu-Fang Li
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Yun-He Liu
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Gang Liu
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
| | - Lei Liu
- Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
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Liu XN, Cui DN, Li YF, Liu YH, Liu G, Liu L. Multiple “Omics” data-based biomarker screening for hepatocellular carcinoma diagnosis. World J Gastroenterol 2019. [DOI: 10.3748/wjg.v25.i29.4199] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Cervena K, Vodicka P, Vymetalkova V. Diagnostic and prognostic impact of cell-free DNA in human cancers: Systematic review. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:100-129. [PMID: 31416571 DOI: 10.1016/j.mrrev.2019.05.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 05/03/2019] [Accepted: 05/07/2019] [Indexed: 02/06/2023]
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Singal AG, Parikh ND, Rich NE, John BV, Pillai A. Hepatocellular Carcinoma Surveillance and Staging. MOLECULAR AND TRANSLATIONAL MEDICINE 2019. [DOI: 10.1007/978-3-030-21540-8_2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Xing H, Zheng YJ, Han J, Zhang H, Li ZL, Lau WY, Shen F, Yang T. Protein induced by vitamin K absence or antagonist-II versus alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: A systematic review with meta-analysis. Hepatobiliary Pancreat Dis Int 2018; 17:487-495. [PMID: 30257796 DOI: 10.1016/j.hbpd.2018.09.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 09/11/2018] [Indexed: 02/05/2023]
Abstract
BACKGROUND As a promising biomarker of hepatocellular carcinoma (HCC), protein induced by vitamin K absence or antagonist-II (PIVKA-II) has been studied extensively. However, its diagnostic capability varies across HCC studies. This study aimed to compare the performance of PIVKA-II with alpha-fetoprotein (AFP) in the diagnosis of HCC. DATA SOURCES A systematic literature search was conducted to identify the studies from MEDLINE, Embase and Cochrane Library Databases, which were published up to December 20, 2017 to compare the diagnostic capability of PIVKA-II and AFP for HCC. The data were pooled using random effects model. Pooled sensitivity and specificity were calculated. Summary receiver operating characteristic curve (ROC) was employed to evaluate the diagnostic accuracy of each marker. RESULTS Thirty-one studies were included. The pooled sensitivity (95% CI) of PIVKA-II and AFP was 0.66 (0.65-0.68) and 0.66 (0.65-0.67), respectively in diagnosis of HCC; and the corresponding pooled specificity (95% CI) was 0.89 (0.88-0.90) and 0.84 (0.83-0.85), respectively. The area under the ROC curve (AUC) of PIVKA-II and AFP was 0.856 (0.817-0.895) and 0.770 (0.728-0.811), respectively. Subgroup analysis showed that PIVKA-II was superior to AFP in terms of the AUC for both small HCC (< 3 cm) [0.863 (0.825-0.901) vs 0.717 (0.658-0.776)] and large HCC (≥ 3 cm) [0.854 (0.811-0.897) vs 0.729 (0.682-0.776)]; for American [0.926 (0.897-0.955) vs 0.698 (0.594-0.662)], European [0.772 (0.743-0.801) vs 0.628 (0.594-0.662)], Asian [0.838 (0.812-0.864) vs 0.785 (0.764-0.806)] and African [0.812 (0.794-0.840) vs 0.721 (0.675-0.767)] HCC patients; and for HBV-related [0.909 (0.866-0.951) vs 0.714 (0.673-0.755)] and mixed-etiology [0.847 (0.821-0.873) vs 0.794 (0.772-0.816)] HCC. CONCLUSION This meta-analysis indicates that PIVKA-II is better than AFP in terms of the accuracy for diagnosing HCC, regardless of tumor size, patient ethnic group, or HCC etiology.
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Affiliation(s)
- Hao Xing
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China
| | - Yi-Jie Zheng
- Medical Scientific Affairs, Abbott Diagnostics, Shanghai 200003, China
| | - Jun Han
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China
| | - Han Zhang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China
| | - Zhen-Li Li
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China
| | - Wan-Yee Lau
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China; Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
| | - Feng Shen
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China
| | - Tian Yang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200438, China.
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Gurakar A, Ma M, Garonzik-Wang J, Kim A, Anders RA, Oshima K, Georgiades C, Gurakar M, Ottmann S, Cameron AM, Philosophe B, Saberi B. Clinicopathological Distinction of Low-AFP-Secreting vs. High-AFP-Secreting Hepatocellular Carcinomas. Ann Hepatol 2018; 17:1052-1066. [PMID: 31208632 DOI: 10.5604/01.3001.0012.7206] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 08/07/2018] [Indexed: 02/04/2023]
Abstract
Ilntroduction and aims. We aimed to investigate the clinical and pathological differences between low-AFP-secreting (AFP < 20 ng/mL) and high-AFP-secreting (AFP ≥ 20 ng/mL) hepatocellular carcinomas in patients who undergo liver transplant (LT). MATERIAL AND METHODS We evaluated 145 patients who underwent deceased donor LT for HCC from January 1, 2005 until August 1, 2015 at the Johns Hopkins Hospital. RESULTS Median pre-LT AFP in the entire cohort was 13 ng/mL (IQR 6-59). Using serum AFP cutoff of 20 ng/mL, 61 (42%) patients had high-AFP-secreting tumors and 84 (58%) had low-AFP-secreting tumors. Patients with high-AFP-secreting tumors had larger lesions (3 cm vs. 2.4 cm, p = 0.024), and were more likely to have microvascular-invasion (36.1% vs. 20.2%, p = 0.02) and poor-differentiation (18% vs. 4.8%, p = 0.01), and tumor recurrence following LT (28% vs. 6%, p < 0.001). The 1-year, 3-year, and 5-year recurrence-free survival for patients in the low-AFP-secreting group compared to the high-AFP-secreting group were 100%, 92%, 92% vs. 81.3%, 71.3%, 68.5% respectively (p = 0.0003). CONCLUSION AFP is a suboptimal predictor of tumor recurrence following liver transplant in HCC patients. However, it can have some value in distinguishing more aggressive forms of HCC (high-AFP-secreting) that are associated with higher tumor recurrence. Novel tumor biomarkers are needed that can enhance predicting tumor recurrence following LT based on tumor biology.
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Affiliation(s)
- Ahmet Gurakar
- Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology-Transplant Hepatology, Baltimore, MD, United States.
| | - Michelle Ma
- Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology-Transplant Hepatology, Baltimore, MD, United States
| | - Jacqueline Garonzik-Wang
- Johns Hopkins University School of Medicine, Division of Transplant Surgery, Baltimore, MD, United States
| | - Amy Kim
- Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology-Transplant Hepatology, Baltimore, MD, United States
| | - Robert A Anders
- Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology-Transplant Hepatology, Baltimore, MD, United States
| | - Kiyoko Oshima
- Johns Hopkins University School of Medicine, Division of Pathology, Baltimore, MD, United States
| | - Christos Georgiades
- Johns Hopkins University School of Medicine, Division of Radiology, Baltimore, MD, United States
| | - Merve Gurakar
- Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, United States
| | - Shane Ottmann
- Johns Hopkins University School of Medicine, Division of Transplant Surgery, Baltimore, MD, United States
| | - Andrew M Cameron
- Johns Hopkins University School of Medicine, Division of Transplant Surgery, Baltimore, MD, United States
| | - Benjamin Philosophe
- Johns Hopkins University School of Medicine, Division of Transplant Surgery, Baltimore, MD, United States
| | - Behnam Saberi
- Johns Hopkins University School of Medicine, Division of Gastroenterology and Hepatology-Transplant Hepatology, Baltimore, MD, United States
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Han C, Gao L, Zhao L, Sheng Q, Zhang C, An Z, Xia T, Ding Y, Wang J, Bai H, Dou X. Immunohistochemistry Detects Increased Expression of Aldo-Keto Reductase Family 1 Member B10 (AKR1B10) in Early-Stage Hepatocellular Carcinoma. Med Sci Monit 2018; 24:7414-7423. [PMID: 30328412 PMCID: PMC6201704 DOI: 10.12659/msm.910738] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) remains difficult to diagnose at an early stage. Aldo-keto reductase family 1 member B10 (AKR1B10) is an oxidoreductase that is upregulated in some chronic liver diseases. The aim of this study was to use immunohistochemistry to evaluate the expression of AKR1B10 in liver tissue from patients with HCC of different stages. Material/Methods Forty-four patients with a tissue diagnosis of HCC (35 males and 9 females) with 37 control samples of liver tissue containing liver cirrhosis were studied using immunohistochemistry for the expression of AKR1B10. Histological examination determined the grade of HCC; the stage of HCC was determined according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Serum alpha-fetoprotein (AFP) levels were measured and compared between the patients with HCC. Results Immunohistochemistry showed increased expression of AKR1B10 in moderately-differentiated HCC compared with well-differentiated HCC, poorly-differentiated HCC, and liver cirrhosis (P<0.05). Sensitivity and specificity of AKR1B10 expression in HCC were high at a cutoff integral optical density (IOD) value of 89.5. A significant increase in AKR1B10 expression was found in early-stage HCC (P<0.05). Serum AFP levels were increased in patients with poorly-differentiated HCC, were increased in intermediate-stage HCC, and were significantly increased in advanced-stage HCC (P<0.05). Conclusions Immunohistochemistry showed that the expression of AKR1B10 was increased in tumor tissue from patients with early-stage HCC. Further studies are needed to determine the role of AKR1B10 in the early detection of HCC.
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Affiliation(s)
- Chao Han
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Lanzhu Gao
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland).,Department of Infectious Diseases, Tongliao Infectious Diseases Hospital, Tongliao, Inner Mongolia, China (mainland)
| | - Lianrong Zhao
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Qiuju Sheng
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Chong Zhang
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Ziying An
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Tingting Xia
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Yang Ding
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Jingyan Wang
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Han Bai
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Xiaoguang Dou
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
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Evaluation of Serum Des-Gamma-Carboxy Prothrombin for the Diagnosis of Hepatitis B Virus-Related Hepatocellular Carcinoma: A Meta-Analysis. DISEASE MARKERS 2018; 2018:8906023. [PMID: 30402170 PMCID: PMC6193331 DOI: 10.1155/2018/8906023] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 08/02/2018] [Accepted: 08/29/2018] [Indexed: 02/08/2023]
Abstract
Aim To explore the diagnostic efficacy of des-gamma-carboxy prothrombin (DCP) in hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC). Methods A retrospective study of 459 cases from June 2016 to March 2018 was undertaken, and records of the DCP levels were extracted. The sensitivity, specificity, and cutoff points were calculated using SPSS 17.0 software. A systematic search in PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials was performed for articles published in English from 1997 to 2017, focusing on serum DCP for HBV-related HCC. Data on sensitivity, specificity, the positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were extracted from five studies by systematic search and one study of our own. The summary receiver operating characteristic (sROC) curve was obtained, and the area under the receiver operating characteristic (AUROC) curve was calculated. Results The pooled sensitivity, specificity, PLR, NLR, and DOR were 0.71 (95% CI: 0.59, 0.80), 0.93 (95% CI: 0.87, 0.96), 9.5 (95% CI: 5.2, 17.5), 0.32 (95% CI: 0.22, 0.46), and 30 (95% CI: 13, 72), respectively. The AUROC curve was 0.91 (95% CI: 0.88, 0.93). Conclusions In the diagnosis of HBV-related hepatocellular carcinoma (HCC), DCP is an ideal marker that should be considered for surveillance purposes.
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Han C, Gao L, Bai H, Dou X. Identification of a role for serum aldo-keto reductase family 1 member B10 in early detection of hepatocellular carcinoma. Oncol Lett 2018; 16:7123-7130. [PMID: 30546447 PMCID: PMC6256343 DOI: 10.3892/ol.2018.9547] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 09/06/2018] [Indexed: 12/11/2022] Open
Abstract
Despite improved screening programs, the vast majority of patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage. A lack of effective diagnosis methods for preclinical HCC has resulted in a low rate of early detection. Aldo-keto reductase family 1 member B10 (AKR1B10) is associated with several cancer types. However, to the best of our knowledge, the diagnostic value of AKR1B10 in early stage HCC is poorly understood. In the current study, the diagnostic performance of serum AKR1B10 in hepatitis B virus/hepatitis C virus (HBV/HCV)-related liver disorders was evaluated and the unique role of AKR1B10 in diagnosing HCC was assessed. Serum AKR1B10 was detected by sandwich ELISA in 84 patients with HBV/HCV-related HCC, 74 patients with liver cirrhosis, 29 patients with chronic hepatitis and 30 healthy controls. Serum AKR1B10 and α-fetoprotein (AFP) levels were analyzed and compared. Elevated levels of serum AKR1B10 were identified in patients with HCC compared with patients with other liver disorders (P<0.05). Compared with advanced and terminal stage HCC, a significant increase in AKR1B10 levels was primarily detected in early and intermediate stage HCC. The sensitivity (81.0%) and specificity (60.9%) for HCC diagnosis with AKR1B10 were high at a cutoff value of 1.51 ng/ml. Conversely, a prominent increase in AFP was observed in advanced and terminal stage HCC. Furthermore, concurrent measurement of serum AKR1B10 and AFP significantly increased sensitivity and negative predictive value for HCC diagnosis. The results presented in the current study strongly indicate AKR1B10 has a unique role as a biomarker for early stage HBV/HCV-related HCC. Compared with AFP alone, a combination of serum AKR1B10 and AFP increased the diagnostic performance in patients with HCC. In summary, the current results identify a unique role of AKR1B10 in HCC diagnosis.
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Affiliation(s)
- Chao Han
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, P.R. China
| | - Lanzhu Gao
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, P.R. China.,Department of Infectious Diseases, Tongliao Infectious Diseases Hospital, Tongliao, Inner Mongolia Autonomous Region 028000, P.R. China
| | - Han Bai
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, P.R. China
| | - Xiaoguang Dou
- Department of Infectious Diseases, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110022, P.R. China
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Canale M, Ulivi P, Foschi FG, Scarpi E, De Matteis S, Donati G, Ercolani G, Scartozzi M, Faloppi L, Passardi A, Tamburini E, Valgiusti M, Marisi G, Frassineti GL, Casadei Gardini A. Clinical and circulating biomarkers of survival and recurrence after radiofrequency ablation in patients with hepatocellular carcinoma. Crit Rev Oncol Hematol 2018; 129:44-53. [PMID: 30097237 DOI: 10.1016/j.critrevonc.2018.06.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 06/08/2018] [Accepted: 06/19/2018] [Indexed: 02/08/2023] Open
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43
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Gupta M, Gabriel H, Miller FH. Role of Imaging in Surveillance and Diagnosis of Hepatocellular Carcinoma. Gastroenterol Clin North Am 2018; 47:585-602. [PMID: 30115439 DOI: 10.1016/j.gtc.2018.04.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
The prognosis for hepatocellular carcinoma (HCC) is dependent on tumor stage at diagnosis, with curative treatment options more available to early-detected HCCs. Professional organizations have produced HCC screening guidelines in at-risk groups, with ultrasound the most commonly used screening tool and increased interest in MRI in specific populations. HCC may be diagnosed by imaging features alone and have been universally incorporated into management guidelines. The radiology community has standardized imaging criteria for HCC with the development of the Liver Imaging Reporting and Data System, which has expanded to incorporate computed tomography, MR, and contrast-enhanced ultrasound for diagnostic purposes.
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Affiliation(s)
- Mohit Gupta
- Department of Radiology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, 676 North Saint Clair Street, Suite 800, Chicago, IL 60611, USA
| | - Helena Gabriel
- Department of Radiology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, 676 North Saint Clair Street, Suite 800, Chicago, IL 60611, USA
| | - Frank H Miller
- Body Imaging Section and Fellowship Program, MRI, Department of Radiology, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, 676 North Saint Clair Street, Suite 800, Chicago, IL 60611, USA.
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44
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Rudnick SR, Russo MW. Liver transplantation beyond or downstaging within the Milan criteria for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2018; 12:265-275. [PMID: 29231769 DOI: 10.1080/17474124.2018.1417035] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Unresectable hepatocellular carcinoma (HCC) is a common indication for liver transplantation (LT). The Milan criteria became standard criteria but expansion beyond the Milan criteria (tumor size and number) have resulted in similar post-transplant outcomes, thus suggesting LT is a viable treatment option for HCC presenting beyond the Milan criteria Areas covered: Expanded criteria and the use of downstaging therapies to meet Milan criteria are reviewed. Surrogates of tumor biology (including biomarkers and response to therapy) are described in detail. The controversy regarding treatment of HCV infection prior to transplant for HCC is addressed. Predictors of post-transplant recurrence and therapeutic options are explored. English-language manuscripts pertaining to LT criteria for HCC, downstaging, and tumor prognosis were reviewed. Effort was made to include manuscripts from throughout the world to ensure the reader a broad international perspective. Expert commentary: Patients can be successfully transplanted with HCC beyond Milan criteria, or patients beyond Milan criteria can be downstaged to within Milan criteria and achieve successful post-liver transplant outcomes. The current reliance on tumor burden (size and number) alone ignores the mounting data supporting the prognostic use of additional surrogates of tumor biology in identifying appropriate candidates.
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Affiliation(s)
- Sean R Rudnick
- a Division of Gastroenterology , Wake Forest University School of Medicine , Winston-Salem , NC , USA
| | - Mark W Russo
- b Division of Hepatology , Carolinas HealthCare System , Charlotte , NC , USA
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45
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Okajima W, Komatsu S, Ichikawa D, Miyamae M, Kawaguchi T, Hirajima S, Ohashi T, Imamura T, Kiuchi J, Arita T, Konishi H, Shiozaki A, Moriumura R, Ikoma H, Okamoto K, Taniguchi H, Itoh Y, Otsuji E. Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function. Oncotarget 2018; 7:53820-53836. [PMID: 27462777 PMCID: PMC5288224 DOI: 10.18632/oncotarget.10781] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 07/09/2016] [Indexed: 12/21/2022] Open
Abstract
Aims This study was designed to identify novel microRNAs (miRNAs) in plasma for detecting and monitoring hepatocellular carcinoma (HCC), independent of hepatic function and background liver diseases with different etiologies. Results (1) Four oncogenic miRNAs (miR-151, 155, 191 and 224) with high expression in HCC tissues were selected as candidates. (2) Quantitative RT-PCR using plasma samples from 107 HCC patients and 75 healthy volunteers revealed a significantly higher level of plasma miR-224 in HCC patients than in healthy volunteers according to a small-scale analysis (P < 0.0001), two independent large-scale cohort analysis (P < 0.0001, AUC 0.908). (3) miR-224 expression was significantly higher in HCC tissues and HCC cell lines than in normal hepatic tissues and fibroblasts, respectively. (P = 0.0011, 0.0150) (4) Plasma miR-224 reflected tumor dynamics; preoperative plasma levels of miR-224 were significantly reduced in postoperative samples (P = 0.0058), and plasma miR-224 levels were significantly correlated with paired miR-224 levels in HCC tissues (P = 0.0005). (5) Furthermore, plasma miR-224 levels significantly discriminated HCC patients from patients with chronic liver disease (P = 0.0008). A high plasma miR-224 level was significantly correlated with larger tumor size (P = 0.0005) and recurrences (P = 0.0027). The plasma miR-224 level could accurately detect small tumors less than 18 mm preoperatively. Methods We performed a systematic review of the NCBI database and selected candidate miRNAs reported as highly expressed in HCC tissue. Conclusions Plasma miR-224 may be a sensitive biomarker for screening HCC and monitoring tumor dynamics.
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Affiliation(s)
- Wataru Okajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Mahito Miyamae
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tsutomu Kawaguchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shoji Hirajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Ryo Moriumura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hiroki Taniguchi
- Department of Surgery, Kyoto Second Red Cross Hospital, Haruobicho, Kamigyo-ku, 602-8026, Kyoto, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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46
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Current Status and Future Prospects of Biomarkers in the Diagnosis of Hepatocellular Carcinoma. Int J Biol Markers 2017; 32:e361-e369. [PMID: 28967065 DOI: 10.5301/ijbm.5000299] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2017] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) has one of the highest death rates of any cancer in the world, and its incidence is increasing worldwide. Early-stage diagnosis of HCC is thus crucial for medical treatment. Detection of tumor biomarkers is one of the main methods for the early diagnosis of HCC. At present, α-fetoprotein (AFP) is the most practical serum biomarker for HCC diagnosis. However, the diagnostic accuracy of HCC with serum AFP exhibits both sensitivity and specificity far below satisfaction, especially with small sizes of HCC. As a result, the discovery of new biomarkers and/or their combination to enhance both the sensitivity and specificity for laboratory diagnosis of HCC is a crucial goal. With the development of new technology and advances in research, a number of new and specific biomarkers of HCC have been discovered. These biomarkers and their applications for the diagnosis, treatment monitoring and prognosis prediction of HCC, are reviewed in this article.
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47
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Okajima W, Komatsu S, Ichikawa D, Miyamae M, Ohashi T, Imamura T, Kiuchi J, Nishibeppu K, Arita T, Konishi H, Shiozaki A, Morimura R, Ikoma H, Okamoto K, Otsuji E. Liquid biopsy in patients with hepatocellular carcinoma: Circulating tumor cells and cell-free nucleic acids. World J Gastroenterol 2017; 23:5650-5668. [PMID: 28883691 PMCID: PMC5569280 DOI: 10.3748/wjg.v23.i31.5650] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 04/14/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), with its high incidence and mortality rate, is one of the most common malignant tumors. Despite recent development of a diagnostic and treatment method, the prognosis of HCC remains poor. Therefore, to provide optimal treatment for each patient with HCC, more precise and effective biomarkers are urgently needed which could facilitate a more detailed individualized decision-making during HCC treatment, including the following; risk assessment, early cancer detection, prediction of treatment or prognostic outcome. In the blood of cancer patients, accumulating evidence about circulating tumor cells and cell-free nucleic acids has suggested their potent clinical utilities as novel biomarker. This concept, so-called "liquid biopsy" is widely known as an alternative approach to cancer tissue biopsy. This method might facilitate a more sensitive diagnosis and better decision-making by obtaining genetic and epigenetic aberrations that are closely associated with cancer initiation and progression. In this article, we review recent developments based on the available literature on both circulating tumor cells and cell-free nucleic acids in cancer patients, especially focusing on Hepatocellular carcinoma.
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Affiliation(s)
- Wataru Okajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Mahito Miyamae
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Ryo Morimura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
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48
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Li GJ, Chen QY, Harrison TJ, Wang XY, Hu LP, Yang QL, Li KW, Fang ZL. Des-γ carboxyprothrombin may not be a good biomarker for hepatocellular carcinoma in those chronically infected with hepatitis B virus with basal core promoter double mutations (T^{1762}, A^{1764}), a prospective study. Cancer Biomark 2017; 18:241-248. [PMID: 28085009 DOI: 10.3233/cbm-160131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The accuracy of des-γ -carboxyprothrombin (DCP) in the detection of hepatocellular carcinoma (HCC) in those infected hepatitis B virus (HBV) from cross-sectional or case-control studies is contradictory. OBJECTIVE To resolve this contradiction using a prospective study. METHODS Three hundred male individuals persistently infected with HBV were recruited from the Chinese cohort and followed up once per year from 2012 to 2015. Each subject was screened for HCC by measurements of serum alpha-fetoprotein (AFP), lectin-bound α -fetoprotein (AFP-L3), DCP concentrations and ultrasonographic examinations. RESULTS Nineteen HCC cases were identified. The area under receiver operating characteristic (AUROC) at first, second and third visit for AFP, AFP-L3 and DCP ranges from 0.710-0.897, 0.566-0.637 and 0.520-0.595, respectively. The rate of elevated DCP is not significantly different between the HCC cases and controls (52.6% vs. 47.4%) (P > 0.05). The incidence of HCC in subjects with elevated DCP is not significantly higher than that of those with normal DCP (9.5% vs. 4.6%) (P > 0.05). The AUROC of combinations of these biomarkers was higher than that of AFP alone at the first visit. However, it was reduced at the second visit. At the third visit, the AUROCs of AFP + DCP and AFP + AFP-L3 + DCP, but not that of AFP + AFP-L3, were higher than that of AFP alone. CONCLUSIONS AFP but DCP or AFP-L3 remains a valuable biomarker for HCC in those chronically infected with HBV. The combination with AFP-L3 and DCP may not increase the accuracy of AFP in differentiating HCC cases from controls, among those infected with HBV.
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Affiliation(s)
- Guo-Jian Li
- Department of Public Health of Guangxi Zhuang Autonomous Region, Nanning, Guangxi 530021, China
| | - Qin-Yan Chen
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | | | - Xue-Yan Wang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | - Li-Ping Hu
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China.,School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Qing-Li Yang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | - Kai-Wen Li
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China.,School of Preclinical Medicine, Guangxi Medical University, Nanning, Guangxi 530021, China
| | - Zhong-Liao Fang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
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49
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Nguyen K, Jimenez M, Moghadam N, Wu C, Farid A, Grotts J, Elashoff D, Choi G, Durazo FA, El-Kabany MM, Han SHB, Saab S. Decrease of Alpha-fetoprotein in Patients with Cirrhosis Treated with Direct-acting Antivirals. J Clin Transl Hepatol 2017; 5:43-49. [PMID: 28507926 PMCID: PMC5411356 DOI: 10.14218/jcth.2016.00057] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 01/26/2017] [Accepted: 02/01/2017] [Indexed: 12/11/2022] Open
Abstract
Background and Aims: The lack of specificity has limited the role of serum alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) screening among patients with cirrhosis related to hepatitis C virus (HCV) infection. We sought to examine whether AFP may decrease after achieving a sustained virological response (SVR) in patients with HCV-related cirrhosis. Methods: We performed a retrospective study of patients with HCV-related cirrhosis who were cured with direct-acting antiviral (DAA) therapy at the University of California, Los Angeles. Laboratory values, including serum AFP, were measured before and after completing the DAA treatment. Results: Fifty-six patients met the inclusion criteria, with median (interquartile range [IQR]) age of 67 (58-69) years and with 51.8% being male. All patients received DAA therapy without interferon. AFP decreased from median (IQR) 7.2 (4.2-13.4) ng/mL before DAAs to 4.2 (2.7-6.3) ng/mL at the end of treatment and 4.2 (2.9-6.8) ng/mL at 12 weeks after treatment (p < 0.001). Model for end-stage liver disease (MELD), fibrosis-4 (FIB4), and aspartate transaminase (AST) to platelet ratio index (APRI) scores at baseline were not significantly associated with AFP reduction. On multivariate analysis, platelet count, AST and total bilirubin at baseline were significantly correlated to AFP reduction (p = 0.04, 0.009 and 0.04, respectively). The higher the baseline AFP, the greater the reduction in AFP. There was no statistically significant correlation between baseline AFP and MELD, FIB4 or APRI scores. Conclusion: There was a significant decrease in AFP in patients with cirrhosis who achieved a SVR with DAAs. Given a reduction in AFP after DAA treatment, AFP should be further studied as a screening modality for HCC in patients with cirrhosis.
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Affiliation(s)
- Kelvin Nguyen
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Melissa Jimenez
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Nima Moghadam
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Crystal Wu
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Alex Farid
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Jonathan Grotts
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
| | - David Elashoff
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Biostatistics, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Gina Choi
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Francisco A. Durazo
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Mohamed M. El-Kabany
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Steven-Huy B. Han
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
| | - Sammy Saab
- Departments of Medicine, the University of California at Los Angeles, Los Angeles, CA, USA
- Departments of Surgery, the University of California at Los Angeles, Los Angeles, CA, USA
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50
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Lou J, Zhang L, Lv S, Zhang C, Jiang S. Biomarkers for Hepatocellular Carcinoma. BIOMARKERS IN CANCER 2017; 9:1-9. [PMID: 28469485 PMCID: PMC5345949 DOI: 10.1177/1179299x16684640] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 11/26/2016] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. The HCC diagnosis is usually achieved by biomarkers, which can also help in prognosis prediction. Furthermore, it might represent certain therapeutic interventions through some combinations of biomarkers. Here, we review on our current understanding of HCC biomarkers.
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Affiliation(s)
- Jiatao Lou
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - LingFei Zhang
- Center for RNA Research, State Key Laboratory of Molecular Biology, Chinese Academy of Sciences (CAS), Shanghai, China.,Department of Anatomy, Histology & Embryology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shaogang Lv
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Chenzi Zhang
- Department of Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Shuai Jiang
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
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