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Marsh TL, Parikh ND, Roberts LR, Schwartz ME, Nguyen MH, Befeler A, Page-Lester S, Tayob N, Srivastava S, Rinaudo JA, Singal AG, Reddy KR, Marrero JA. A Phase 3 Biomarker Validation of GALAD for the Detection of Hepatocellular Carcinoma in Cirrhosis. Gastroenterology 2025; 168:316-326.e6. [PMID: 39293548 DOI: 10.1053/j.gastro.2024.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 08/12/2024] [Accepted: 09/02/2024] [Indexed: 09/20/2024]
Abstract
BACKGROUND & AIMS Better surveillance tests for hepatocellular carcinoma (HCC) are needed. The GALAD score (gender, age, α-fetoprotein [AFP] L3, AFP, and des-γ carboxyprothrombin) has been shown to have excellent sensitivity and specificity for HCC in phase 2 studies. We performed a phase 3 biomarker validation study to compare GALAD with AFP in detecting HCC. METHODS This is a prospective study of patients with cirrhosis enrolled at 7 centers. Surveillance for HCC was performed every 6 months at each site, and HCC diagnosis was confirmed per American Association for the Study of Liver Diseases guidelines. Blood for biomarker research was obtained at each follow-up visit and stored in a biorepository. Measurements of AFP, AFP-L3, and des-γ carboxyprothrombin) were performed in a FujiFilm laboratory by staff blinded to clinical data. The performance of GALAD in detecting HCC was retrospectively evaluated within 12 months before the clinical diagnosis. All analyses were conducted by an unblinded statistician in the Early Detection Research Network data management and coordinating center. RESULTS A total of 1,558 patients with cirrhosis were enrolled and followed for a median of 2.2 years. A total of 109 patients developed HCC (76 very early or early stage), with an annual incident rate of 2.4%. The areas under the curve for AFP and GALAD within 12 months before HCC were 0.66 and 0.78 (P < .001), respectively. Using a cutoff for GALAD of -1.36, the specificity was 82%, and the sensitivity at 12 months before HCC diagnosis was 62%. For comparison, performance of AFP at 82% specificity showed 41% sensitivity at 12 months before HCC diagnosis (P = .001). CONCLUSIONS GALAD score, compared to AFP, improves the detection of HCC within 12 months before the actual diagnosis.
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Affiliation(s)
- Tracey L Marsh
- Biostatistics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Myron E Schwartz
- Recanati/Miller Transplant Institute, Mount Sinai Medical Center, New York, New York
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology and Department of Epidemiology and Population Health, Stanford University, Palo Alto, California
| | - Alex Befeler
- Division of Gastroenterology, Saint Louis University, St. Louis, Missouri
| | - Stephanie Page-Lester
- Biostatistics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Nabihah Tayob
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts
| | - Sudhir Srivastava
- Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Jo Ann Rinaudo
- Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland
| | - Amit G Singal
- Division of Digestive and Liver Disease, University of Texas Southwestern, Dallas, Texas
| | - K Rajender Reddy
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jorge A Marrero
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania.
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Ramakrishnan K, Sanjeev D, Rehman N, Raju R. A Network Map of Intracellular Alpha-Fetoprotein Signalling in Hepatocellular Carcinoma. J Viral Hepat 2025; 32:e14035. [PMID: 39668590 DOI: 10.1111/jvh.14035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/03/2024] [Accepted: 10/18/2024] [Indexed: 12/14/2024]
Abstract
Alpha fetoprotein (AFP) is a glycoprotein of foetal origin belonging to the albumin protein family. Serum AFP is a long-conceived early-diagnostic biomarker for HCC with its elevated expression in different liver pathologies ranging from hepatitis viral infections to fibrosis, cirrhosis, and HCC. Beyond their utility as biomarkers, in support of its contribution to these clinical outcomes, the function of AFP as an immune suppressor and inducer of malignant transformation in HCC patients is well reported. Multiple reports show that AFP is secreted by hepatocytes, binds to its cognate receptor, AFP-receptor (AFPR), and exerts its actions. However, there is only limited information available in this context. There is an urgent need to gather more insight into the AFP signalling pathway and consider it a classical intracellular signalling pathway, among others. AFP is a highly potent intracellular molecule that has the potential to bind to many interactors like PTEN, Caspase, RAR, and so on. It has been shown that cellular AFP and secreted AFP have different roles in HCC pathophysiology, and a comprehensive map of the AFP signalling pathway is warranted for further theranostic applications.
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Affiliation(s)
| | - Diya Sanjeev
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, India
| | - Niyas Rehman
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, India
| | - Rajesh Raju
- Centre for Integrative Omics Data Science, Yenepoya (Deemed to Be University), Mangalore, India
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Hao W, Zhao D, Meng Y, Yang M, Ma M, Hu J, Liu J, Qin X. Screening of Cancer-Specific Biomarkers for Hepatitis B-Related Hepatocellular Carcinoma Based on a Proteome Microarray. Mol Cell Proteomics 2024; 23:100872. [PMID: 39489219 DOI: 10.1016/j.mcpro.2024.100872] [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: 06/11/2024] [Revised: 10/14/2024] [Accepted: 10/19/2024] [Indexed: 11/05/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is associated with one of the highest mortality rates among cancers, rendering its early diagnosis clinically invaluable. Serum biomarkers, specifically alpha-fetoprotein (AFP), represent the most promising and widely used diagnostic biomarkers for HCC. However, its detection rate is low in the early stages of HCC progression, and distinguishing specific false positives for other liver-related diseases, such as cirrhosis and acute hepatitis, remains challenging. Therefore, this study was conducted to identify biomarkers for hepatitis B (HBV)-related liver diseases by screening differentially expressed autoantibodies against tumor-associated antigens (TAAbs). We designed a large-scale multistage investigation, encompassing initial screening, HCC-focused, and ELISA validation cohorts to identify potential TAAbs in HBV-related liver diseases, spanning from healthy control (HC) individuals to patients with chronic hepatitis B (CHB), hepatitis B-related cirrhosis (HBC), and HCC, using protein microarray technology. The differential biological characteristics of TAAbs were analyzed using bioinformatics analysis. Validation of tumor-specific biomarkers for HCC was performed using ELISA. In the screening cohort, 547 candidate TAAbs were identified in the HCC group compared to those in the HC group. In the HCC-focused cohort, 64, 61, and 65 candidate TAAbs were identified in the CHB, HBC, and HCC groups, respectively, compared to those in the HC group. Thirty-four proteins exhibited continuously elevated expression from HCs to patients with CHB, HBC, and HCC. Among these, nine were identified as cancer-specific proteins. In the validation cohort, UBE2Z, CNOT3, and EID3 were correlated with liver function indicators in patients with hepatitis B-related HCC. Overall, UBE2Z, CNOT3, and EID3 emerged as cancer-specific biomarkers for HBV-related liver disease, providing a scientific basis for clinical application.
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Affiliation(s)
- Wudi Hao
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China; Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Danyang Zhao
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China; Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Yuan Meng
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China; Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Mei Yang
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China; Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Meichen Ma
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China; Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Jingwen Hu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China; Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Jianhua Liu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China; Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China.
| | - Xiaosong Qin
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China; Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China.
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Zhao J, Hu Z, Zheng X, Lin Y, Liu X, Zhang J, Peng J, Gao H. Blood biomarkers of hepatocellular carcinoma: a critical review. Front Cell Dev Biol 2024; 12:1489836. [PMID: 39650722 PMCID: PMC11621223 DOI: 10.3389/fcell.2024.1489836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/13/2024] [Indexed: 12/11/2024] Open
Abstract
Hepatocellular Carcinoma (HCC) is a malignant tumor with high morbidity and mortality worldwide, which represents a serious threat to human life, health and quality of life. Blood-based detection is essential for HCC screening, early diagnosis, prognosis evaluation, and surveillance. Current non-invasive detection strategy including serum alpha-fetoprotein (AFP), ultrasound, computerized tomography, and magnetic resonance imaging. The limited specificity of an AFP and the dependence on operator experience and diagnostic personnel for ultrasound have constrained their utility in early HCC diagnosis. In recent years, with the development of various detection technologies, there has been an increasing focus on exploring blood-based detection markers for HCC. The types of markers include protein markers, DNA mutation, DNA epigenetic modification, mRNA, miRNA, and so on. However, numerous methodological and biological factors limit the clinical sensitivity and generalization performance of these new biomarkers. In this review, we describe the state-of-the-art technologies for cfDNA analysis, and discuss outstanding biological and technical challenges that, if addressed, would substantially improve HCC diagnostics and patient care.
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Affiliation(s)
- Junsheng Zhao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zekai Hu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiaoping Zheng
- Hangzhou Tongchuang Medical Laboratory, Department of pathology, Hangzhou, China
| | - Yajie Lin
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Xiao Liu
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Junjie Zhang
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Jing Peng
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hainv Gao
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
- Key Laboratory of Artificial Organs and Computational Medicine in Zhejiang Province, Shulan (Hangzhou) Hospital Affiliated to Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
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Park I, Lee HB, Kim N, Lee S, Park K, Son MY, Cho HS, Kim DS. Uncovering gene expression signatures and diagnostic - Biomarkers in hepatocellular carcinoma through multinomial logistic regression analysis. J Biotechnol 2024; 395:31-43. [PMID: 39244092 DOI: 10.1016/j.jbiotec.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 08/16/2024] [Accepted: 09/04/2024] [Indexed: 09/09/2024]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, and classifying the developmental stages of HCC can help with early prognosis and treatment. This study aimed to investigate diagnostic and prognostic molecular signatures underlying the progression of HCC, including tumor initiation and growth, and to classify its developmental stages based on gene expression levels. We integrated data from two cancer systems, including 78 patients with Edmondson-Steiner (ES) grade and 417 patients with TNM stage cancer. Functional profiling was performed using identified signatures. Using a multinomial logistic regression model (MLR), we classified controls, early-stage HCC, and advanced-stage HCC. The model was validated in three independent cohorts comprising 45 patients (neoplastic stage), 394 patients (ES grade), and 466 patients (TNM stage). Multivariate Cox regression was employed for HCC prognosis prediction. We identified 35 genes with gradual upregulation or downregulation in both ES grade and TNM stage patients during HCC progression. These genes are involved in cell division, chromosome segregation, and mitotic cytokinesis, promoting tumor cell proliferation through the mitotic cell cycle. The MLR model accurately differentiated controls, early-stage HCC, and advanced-stage HCC across multiple cancer systems, which was further validated in various independent cohorts. Survival analysis revealed a subset of five genes from TNM stage (HR: 3.27, p < 0.0001) and three genes from ES grade (HR: 7.56, p < 0.0001) that showed significant association with HCC prognosis. The identified molecular signature not only initiates tumorigenesis but also promotes HCC development. It has the potential to improve clinical diagnosis, prognosis, and therapeutic interventions for HCC. This study enhances our understanding of HCC progression and provides valuable insights for precision medicine approaches.
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Affiliation(s)
- Ilkyu Park
- Gachon Institute of Genome Medicine and Science, Gachon University Gil Medical Center, 21 Namdong-daero, Namdong-gu, Incheon 21565, Republic of Korea; Department of Digital Bio Technology Innovation, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Hyo-Bin Lee
- Department of Digital Bio Technology Innovation, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Nakyoung Kim
- Department of Digital Bio Technology Innovation, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea
| | - Sugi Lee
- Department of Digital Bio Technology Innovation, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Kunhyang Park
- Department of Core Facility Management Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Mi-Young Son
- Department of Stem Cell Convergence Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Hyun-Soo Cho
- Department of Stem Cell Convergence Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
| | - Dae-Soo Kim
- Department of Digital Bio Technology Innovation, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea; Department of Bioinformatics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea.
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Domínguez-Lazcano DG, Simón-Lara I, Morales-Romero J, Vásquez-Garzón VR, Arroyo-Helguera OE, López-Vazquez J, Campos-Parra AD, Hernández-Nopaltecatl B, Rivera-Hernández XA, Quintana S, García-Román R. Alpha-fetoprotein, glypican-3, and kininogen-1 as biomarkers for the diagnosis of hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2024; 17:383-395. [PMID: 39660335 PMCID: PMC11626288 DOI: 10.62347/qsii4050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 09/23/2024] [Indexed: 12/12/2024]
Abstract
The hepatocarcinoma (HCC) is the most important liver tumor. It represents 90% of liver cancer cases. One of the main problems is the limited prompt cancer diagnosis and the advanced stages where the chances of treatment are limited. The main diagnostic methods for HCC are imaging techniques and liver biopsy. With advances in technology, proteins as significant diagnostic biomarkers have increased. The objective of this review is to describe the role of Alpha-fetoprotein (AFP), Glipican 3 (GPC-3), and Kininogen 1 (KNG-1) as biomarkers for the diagnosis of hepatocellular carcinoma. A systematic search of studies was carried out in the literature and the diagnostic values of these proteins were compared. The results showed that the combined use of biomarkers increases the diagnostic capacity for the detection of hepatocellular carcinoma.
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Affiliation(s)
| | - Ingrid Simón-Lara
- Facultad de Medicina, Región Poza-Rica-Tuxpan, Universidad VeracruzanaXalapa, Veracruz, México
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Singal AG, Parikh ND, Kanwal F, Marrero JA, Deodhar S, Page-Lester S, Lopez C, Feng Z, Tayob N. National Liver Cancer Screening Trial (TRACER) study protocol. Hepatol Commun 2024; 8:e0565. [PMID: 39495136 PMCID: PMC11537583 DOI: 10.1097/hc9.0000000000000565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 09/11/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND Professional guidelines recommend HCC screening in at-risk patients using semi-annual ultrasound with or without alpha-fetoprotein (AFP); however, this strategy has limited effectiveness due to low adherence and sensitivity. Increasing data support the potential role of blood-based biomarker panels, which could improve both aspects. The biomarker panel GALAD, comprised of sex, age, and 3 blood biomarkers (AFP, AFP-L3, and des-carboxy prothrombin des-carboxy prothrombin), has shown high sensitivity and specificity in biomarker phase II (case-control) and phase III (retrospective cohort) validation studies. However, prospective validation in a large phase IV biomarker clinical utility trial is necessary before its adoption in practice. METHODS The National Liver Cancer Screening Trial is an adaptive pragmatic randomized phase IV trial, which began enrollment in January 2024, comparing ultrasound-based versus biomarker-based screening in 5500 patients with chronic hepatitis B infection or cirrhosis from any etiology. Eligible patients are randomly assigned in a 1:1 ratio to semi-annual screening with ultrasound ± alpha-fetoprotein (arm A) or semi-annual screening with GALAD (arm B). Randomization is stratified by enrollment site, liver disease severity (per Child-Pugh class), liver disease etiology (viral, nonviral, and noncirrhotic HBV), and sex. Patients are being recruited from 15 sites (a mix of tertiary care academic referral centers, safety-net health systems, and large community health systems) over a 3-year period, and the primary endpoint, reduction in late-stage HCC, will be assessed at the end of year 5.5. DISCUSSION The results of this trial will inform the best strategy for HCC screening and early-stage detection in patients with chronic liver diseases. If GALAD shows superiority, HCC screening would primarily shift from an ultrasound-based strategy to the adoption of the biomarker panel. TRIAL REGISTRATION NCT06084234. TRIAL STATUS The TRACER Study is actively enrolling.
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Affiliation(s)
- Amit G. Singal
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Neehar D. Parikh
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Fasiha Kanwal
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Jorge A. Marrero
- Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sneha Deodhar
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Stephanie Page-Lester
- Biostatistics Program, Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Camden Lopez
- Biostatistics Program, Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Ziding Feng
- Biostatistics Program, Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Nabihah Tayob
- Department of Data Science, Dana Farber Cancer Institute, Boston, Massachusetts, USA
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Li D, Liu Y, Yang G, He M, Lu L. Recent insights into RNA m5C methylation modification in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2024; 1879:189223. [PMID: 39577751 DOI: 10.1016/j.bbcan.2024.189223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 11/12/2024] [Accepted: 11/14/2024] [Indexed: 11/24/2024]
Abstract
RNA 5-methylcytosine (m5C) methylation involves the addition of a methyl (-CH3) group to the cytosine (C) base within an RNA molecule, forming the m5C modification. m5C plays a role in numerous essential biological processes, including the regulation of RNA stability, nuclear export, and protein translation. Recent studies have highlighted the importance of m5C in the pathogenesis of various diseases, particularly tumors. Emerging evidence indicates that RNA m5C methylation is intricately implicated in the mechanisms underlying hepatocellular carcinoma (HCC). Dysregulation of m5C-associated regulatory factors is common in HCC and shows significant associations with prognosis, treatment response, and clinicopathological features. This review provides an in-depth analysis of the components and functions of m5C regulators, particularly emphasizing their research advancements in the context of HCC.
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Affiliation(s)
- Danyang Li
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong Province 519000, PR China
| | - Yanyan Liu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong Province 519000, PR China
| | - Guang Yang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong Province 519000, PR China
| | - Mingyu He
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong Province 519000, PR China.
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai Clinical Medical College of Jinan University (Zhuhai People's Hospital), Zhuhai, Guangdong Province 519000, PR China; Guangzhou First Pepople's Hospital, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong Province 510006, PR China.
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Kim SJ, Jung CW, Anh NH, Yoon YC, Long NP, Hong SS, Cho EJ, Kwon SW. Metabolic phenotyping combined with transcriptomics metadata fortifies the diagnosis of early-stage Hepatocellular carcinoma. J Adv Res 2024:S2090-1232(24)00391-6. [PMID: 39243943 DOI: 10.1016/j.jare.2024.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 07/31/2024] [Accepted: 09/03/2024] [Indexed: 09/09/2024] Open
Abstract
INTRODUCTION The low sensitivity of alpha-fetoprotein (AFP) renders it unsuitable as a stand-alone marker for early hepatocellular carcinoma (eHCC) surveillance. Therefore, additional blood-based biomarkers with enhanced sensitivities are required. OBJECTIVES In light of the metabolic changes that are distinctive to eHCC development, the current study presents a panel of serum metabolites that may serve as noninvasive diagnostic indicators for patients with eHCC. METHODS Serum samples obtained from normal control (NC), cirrhosis, and eHCC patients were analyzed by four different metabolomic platforms. A meta-analysis of very early-stage HCC transcriptomic datasets retrieved from public sources supports the integrated interpretation with metabolic changes. RESULTS A total of 94 metabolites were significantly correlated with a progressive disease status. Integrated analysis of the significant metabolites and differentially expressed genes from meta-analysis emphasized metabolic pathways including bile acid biosynthesis, phenylalanine and tyrosine metabolism, and butanoate metabolism. The 11 metabolites associated with these pathways were compiled into a metabolite panel for use as diagnostic signatures. With an accuracy of 81.8%, compared with 45.4% for a model trained solely on AFP, the model enhanced its ability to differentiate between the three groups by incorporating a metabolite panel and AFP. Upon examining the trained models using receiver operating characteristic curves, the AFP and metabolite panel combined model exhibited greater area under the curve values in comparisons between NC and eHCC (1.000 versus 0.810) and cirrhosis and eHCC (0.926 versus 0.556). The result was consistent in an independent validation cohort. CONCLUSION This study emphasizes the role of circulating metabolite markers in the diagnosis of eHCC.
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Affiliation(s)
- Sun Jo Kim
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
| | - Cheol Woon Jung
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Nguyen Hoang Anh
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Young Cheol Yoon
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Nguyen Phuoc Long
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea
| | - Soon-Sun Hong
- Department of Biomedical Science, College of Medicine, and Program in Biomedical Sciences and Engineering, Inha University, Incheon 22332, Republic of Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Sung Won Kwon
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea; College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Plant Genomics and Breeding Institute, Seoul National University, Seoul 08826, Republic of Korea.
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10
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Tocci NX, Wehrle CJ, Sun K, Jiao C, Hong H, Gross A, Allkushi E, Uysal M, Linganna MW, Stackhouse K, Hashimoto K, Schlegel A, Walsh RM, Miller C, Kwon DCH, Aucejo F. Circulating tumor DNA in management of primary liver malignancy: A review of the literature and future directions. J Surg Oncol 2024. [PMID: 39155663 DOI: 10.1002/jso.27825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 06/14/2024] [Indexed: 08/20/2024]
Abstract
Primary liver malignancies are a serious and challenging global health concern. The most common primary tumors are hepatocellular carcinoma and cholangiocarcinoma. These diseases portend poor prognosis when presenting with progressive, extensive disease. There is a critical need for improved diagnosis, therapeutic intervention, and monitoring surveillance in liver-related malignancies. Liquid biopsy using ctDNA provides an opportunity for growth within these domains for liver-related malignancy. However, ctDNA is relatively understudied in this field compared with other solid tumor types, possibly due to the complex nature of the pathology. In this review, we aim to discuss ctDNA, the current literature, and future directions of this technology within primary liver malignancies.
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Affiliation(s)
- Noah X Tocci
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Chase J Wehrle
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Keyue Sun
- Lerner Research Institute, Inflammation & Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Chunbao Jiao
- Lerner Research Institute, Inflammation & Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Hanna Hong
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Abby Gross
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Erlind Allkushi
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Melis Uysal
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Maureen Whitsett Linganna
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Katheryn Stackhouse
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Koji Hashimoto
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Andrea Schlegel
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
- Lerner Research Institute, Inflammation & Immunity, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - R Matthew Walsh
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Charles Miller
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - David C H Kwon
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Federico Aucejo
- Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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11
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Qiu C, Fan H, Tao S, Deng Z, Luo H, Liu F. ST8SIA6-AS1, a novel lncRNA star in liver cancer. Front Cell Dev Biol 2024; 12:1435664. [PMID: 39211393 PMCID: PMC11358109 DOI: 10.3389/fcell.2024.1435664] [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: 05/20/2024] [Accepted: 07/26/2024] [Indexed: 09/04/2024] Open
Abstract
Liver cancer is one of the most lethal gastrointestinal malignancies. Emerging evidence has underscored the pivotal role of long non-coding RNAs (lncRNAs) in tumorigenesis, with ST8SIA6-AS1 identified as a novel oncogenic lncRNA contributing to liver cancer progression. ST8SIA6-AS1 is consistently upregulated in hepatic cancer tissues and is strongly associated with unfavorable prognosis. Moreover, it demonstrates high diagnostic efficacy in detecting HCC. ST8SIA6-AS1 is involved in various cellular processes including proliferation, migration, and invasion, primarily through its function as a competing endogenous RNA (ceRNA), thereby facilitating hepatocarcinogenesis and disease advancement. This review provides a detailed examination of the molecular functions and regulatory mechanisms of ST8SIA6-AS1 in hepatocellular carcinoma (HCC) and highlights its potential as a promising biomarker for liver cancer, aiming to propel the development of innovative therapeutic strategies for HCC management.
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Affiliation(s)
- Cheng Qiu
- Department of General Surgery, Pingxiang People’s Hospital, Pingxiang, Jiangxi, China
| | - Haoran Fan
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Siyu Tao
- Second School of Clinical Medicine, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Ziqing Deng
- Department of General Surgery, Nanchang Third Hospital, Nanchang, Jiangxi, China
| | - Hongliang Luo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
| | - Fangteng Liu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China
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12
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Gong L, Wu S, Liu J, Zhang M, Zhuang J, Xu D. Construction of an immunosensor based on Cys/Au@TiO 2 modification for the detection of liver cancer marker PIVKA-II. Talanta 2024; 275:126082. [PMID: 38677167 DOI: 10.1016/j.talanta.2024.126082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 04/02/2024] [Accepted: 04/08/2024] [Indexed: 04/29/2024]
Abstract
An ultrasensitive immunosensor of Cys/Au@TiO2 based on disposable screen-printed electrodes (SPE) for PIVKA-II detection for hepatocellular carcinoma (HCC) diagnosis was developed by utilizing Cystine (Cys) and nanocomposite Au@TiO2. Firstly, HAuCl4 underwent a reduction reaction with NaBH4, then Au nanoparticles were coated onto TiO2 nanoparticles. Followed, Cys/Au@TiO2 was formed through self-assembly of cysteine to allow the monoclonal antibody of abnormal thrombospondin to bound to the amino group on the surface of the composite by covalent bonding. The mechanism is to determine the changes in the current of the sensor caused by the specific binding of the abnormal prothrombin monoclonal antibody adsorbed by the complex with its antigen. The Cys/Au@TiO2 immunosensor was fully characterized by various analytical approaches and it showed a wide linear testing range of 1-10000 pg mL-1 (R2 = 0.991) and the limit of detection down to 0.77 pg ml-1, with highly sensitivity and specificity. The results showed that the developed immunosensor platform can effectively detect trace amounts of PIVKA-II protein and has potent clinical application for HCC diagnosis.
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Affiliation(s)
- Lvhong Gong
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Shengxi Wu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China.
| | - Junjie Liu
- School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China
| | - Mingjun Zhang
- Laboratory Department of Chongqing Jiulongpo District People's Hospital, Chongqing, 400050, China
| | - Jinghao Zhuang
- Department of Physics and Energy, Chongqing University of Technology, Chongqing 400054, China
| | - Doudou Xu
- NMPA Key Laboratory for Quality Monitoring of Narcotic Drugs and Psychotropic Substances, Chongqing Institute for Food and Drug Control, Chongqing, 401121, China.
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13
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Fekry B, Ugartemendia L, Esnaola NF, Goetzl L. Extracellular Vesicles, Circadian Rhythms, and Cancer: A Comprehensive Review with Emphasis on Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:2552. [PMID: 39061191 PMCID: PMC11274441 DOI: 10.3390/cancers16142552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 07/12/2024] [Accepted: 07/14/2024] [Indexed: 07/28/2024] Open
Abstract
This review comprehensively explores the complex interplay between extracellular vesicles (ECVs)/exosomes and circadian rhythms, with a focus on the role of this interaction in hepatocellular carcinoma (HCC). Exosomes are nanovesicles derived from cells that facilitate intercellular communication by transporting bioactive molecules such as proteins, lipids, and RNA/DNA species. ECVs are implicated in a range of diseases, where they play crucial roles in signaling between cells and their surrounding environment. In the setting of cancer, ECVs are known to influence cancer initiation and progression. The scope of this review extends to all cancer types, synthesizing existing knowledge on the various roles of ECVs. A unique aspect of this review is the emphasis on the circadian-controlled release and composition of exosomes, highlighting their potential as biomarkers for early cancer detection and monitoring metastasis. We also discuss how circadian rhythms affect multiple cancer-related pathways, proposing that disruptions in the circadian clock can alter tumor development and treatment response. Additionally, this review delves into the influence of circadian clock components on ECV biogenesis and their impact on reshaping the tumor microenvironment, a key component driving HCC progression. Finally, we address the potential clinical applications of ECVs, particularly their use as diagnostic tools and drug delivery vehicles, while considering the challenges associated with clinical implementation.
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Affiliation(s)
- Baharan Fekry
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.U.); (L.G.)
| | - Lierni Ugartemendia
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.U.); (L.G.)
| | - Nestor F. Esnaola
- Division of Surgical Oncology and Gastrointestinal Surgery, Department of Surgery, Houston Methodist Hospital, Houston, TX 77030, USA;
| | - Laura Goetzl
- McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (L.U.); (L.G.)
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14
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Chinnappan R, Makhzoum T, Arai M, Hajja A, Abul Rub F, Alodhaibi I, Alfuwais M, Elahi MA, Alshehri EA, Ramachandran L, Mani NK, Abrahim S, Mir MS, Al-Kattan K, Mir TA, Yaqinuddin A. Recent Advances in Biosensor Technology for Early-Stage Detection of Hepatocellular Carcinoma-Specific Biomarkers: An Overview. Diagnostics (Basel) 2024; 14:1519. [PMID: 39061656 PMCID: PMC11276200 DOI: 10.3390/diagnostics14141519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 07/06/2024] [Accepted: 07/12/2024] [Indexed: 07/28/2024] Open
Abstract
Hepatocellular carcinoma is currently the most common malignancy of the liver. It typically occurs due to a series of oncogenic mutations that lead to aberrant cell replication. Most commonly, hepatocellular carcinoma (HCC) occurs as a result of pre-occurring liver diseases, such as hepatitis and cirrhosis. Given its aggressive nature and poor prognosis, the early screening and diagnosis of HCC are crucial. However, due to its plethora of underlying risk factors and pathophysiologies, patient presentation often varies in the early stages, with many patients presenting with few, if any, specific symptoms in the early stages. Conventionally, screening and diagnosis are performed through radiological examination, with diagnosis confirmed by biopsy. Imaging modalities tend to be limited by their requirement of large, expensive equipment; time-consuming operation; and a lack of accurate diagnosis, whereas a biopsy's invasive nature makes it unappealing for repetitive use. Recently, biosensors have gained attention for their potential to detect numerous conditions rapidly, cheaply, accurately, and without complex equipment and training. Through their sensing platforms, they aim to detect various biomarkers, such as nucleic acids, proteins, and even whole cells extracted by a liquid biopsy. Numerous biosensors have been developed that may detect HCC in its early stages. We discuss the recent updates in biosensing technology, highlighting its competitive potential compared to conventional methodology and its prospects as a tool for screening and diagnosis.
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Affiliation(s)
- Raja Chinnappan
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
- Tissue/Organ Bioengineering & BioMEMS Laboratory, Organ Transplant Centre of Excellence (TR&I-Dpt), King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia;
| | - Tariq Makhzoum
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Momo Arai
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Amro Hajja
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Farah Abul Rub
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Ibrahim Alodhaibi
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Mohammed Alfuwais
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Muhammad Affan Elahi
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
| | - Eman Abdullah Alshehri
- Tissue/Organ Bioengineering & BioMEMS Laboratory, Organ Transplant Centre of Excellence (TR&I-Dpt), King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia;
| | - Lohit Ramachandran
- Microfluidics, Sensors & Diagnostics (μSenD) Laboratory, Centre for Microfluidics, Biomarkers, Photoceutics and Sensors (μBioPS), Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India; (L.R.); (N.K.M.)
| | - Naresh Kumar Mani
- Microfluidics, Sensors & Diagnostics (μSenD) Laboratory, Centre for Microfluidics, Biomarkers, Photoceutics and Sensors (μBioPS), Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India; (L.R.); (N.K.M.)
| | - Shugufta Abrahim
- Graduate School of Science and Engineering for Education, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan;
| | - Mohammad Shabab Mir
- School of Pharmacy, Desh Bhagat University, Mandi Gobindgarh 147301, Punjab, India;
| | - Khaled Al-Kattan
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
- Lung Health Centre Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Tanveer Ahmad Mir
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
- Tissue/Organ Bioengineering & BioMEMS Laboratory, Organ Transplant Centre of Excellence (TR&I-Dpt), King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia;
| | - Ahmed Yaqinuddin
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; (T.M.); (M.A.); (A.H.); (F.A.R.); (I.A.); (M.A.); (M.A.E.); (K.A.-K.); (T.A.M.)
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15
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Lian S, Lu C, Li F, Yu X, Ai L, Wu B, Gong X, Zhou W, Liang X, Zhan J, Yuan Y, Fang F, Liu Z, Ji M, Zheng Z. Monitoring Hepatocellular Carcinoma Using Tumor Content in Circulating Cell-Free DNA. Clin Cancer Res 2024; 30:2772-2779. [PMID: 38630548 DOI: 10.1158/1078-0432.ccr-23-3449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/19/2024] [Accepted: 04/09/2024] [Indexed: 04/19/2024]
Abstract
PURPOSE The objective of the study was to evaluate the use of tumor content in circulating cell-free DNA (ccfDNA) for monitoring hepatocellular carcinoma (HCC) throughout its natural history. EXPERIMENTAL DESIGN We included 67 patients with hepatitis B virus-related HCC, of whom 17 had paired pre- and posttreatment samples, and 90 controls. Additionally, in a prospective cohort with hepatitis B virus surface antigen-positive participants recruited in 2012 and followed up biannually with blood sample collections until 2019, we included 270 repeated samples before diagnosis from 63 participants who later developed HCC (pre-HCC samples). Shallow whole-genome sequencing and the ichorCNA method were used to analyze genome-wide copy number and tumor content in ccfDNA. RESULTS High tumor content was associated with advanced tumor stage (P < 0.001) and poor survival after HCC diagnosis [HR = 12.35; 95% confidence interval (CI) = 1.413-107.9; P = 0.023]. Tumor content turned negative after surgery (P = 0.027), whereas it remained positive after transarterial chemoembolization treatment (P = 0.578). In non-HCC samples, the mean tumor content (±SD) was 0.011 (±0.007) and had a specificity of 97.8% (95% CI = 92.2%-99.7%). In pre-HCC samples, the tumor content increased from 0.014 at 4 years before diagnosis to 0.026 at 1 year before diagnosis. The sensitivity of tumor content in detecting HCC increased from 22.7% (95% CI = 11.5%-37.8%) within 1 year before diagnosis to 30.4% (95% CI = 13.2%-52.9%) at the Barcelona Clinic Liver Cancer (BCLC) stage 0/A, 81.8% (95% CI = 59.7%-94.8%) at stage B, and 95.5% (95% CI = 77.2%-99.9%) at stage C. CONCLUSIONS The tumor content in ccfDNA is correlated with tumor burden and may help in monitoring HCC 1 yearearlier than clinical diagnosis and in predicting patient prognosis.
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Affiliation(s)
- Shifeng Lian
- Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Sha Tin, Hong Kong SAR, People's Republic of China
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, People's Republic of China
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Chenyu Lu
- Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon, Hong Kong SAR, People's Republic of China
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Research Institute, Shenzhen, People's Republic of China
| | - Fugui Li
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, People's Republic of China
| | - Xia Yu
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, People's Republic of China
| | - Limei Ai
- Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Sha Tin, Hong Kong SAR, People's Republic of China
- Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon, Hong Kong SAR, People's Republic of China
| | - Biaohua Wu
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, People's Republic of China
| | - Xueyi Gong
- Department of General Surgery, Zhongshan City People's Hospital, Zhongshan, People's Republic of China
| | - Wenjing Zhou
- Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon, Hong Kong SAR, People's Republic of China
| | - Xuejun Liang
- Xiaolan Public Health Service Center, Zhongshan, People's Republic of China
| | - Jiyun Zhan
- Xiaolan Public Health Service Center, Zhongshan, People's Republic of China
| | - Yong Yuan
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, People's Republic of China
| | - Fang Fang
- Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Zhiwei Liu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
| | - Mingfang Ji
- Cancer Research Institute of Zhongshan City, Zhongshan City People's Hospital, Zhongshan, People's Republic of China
| | - Zongli Zheng
- Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Sha Tin, Hong Kong SAR, People's Republic of China
- Department of Biomedical Sciences and Tung Biomedical Sciences Centre, City University of Hong Kong, Kowloon, Hong Kong SAR, People's Republic of China
- Department of Precision Diagnostic and Therapeutic Technology, City University of Hong Kong Shenzhen Research Institute, Shenzhen, People's Republic of China
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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16
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Basthi Mohan P, Lochan R, Shetty S. Biomarker in Hepatocellular Carcinoma. Indian J Surg Oncol 2024; 15:261-268. [PMID: 38817995 PMCID: PMC11133295 DOI: 10.1007/s13193-023-01858-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 11/29/2023] [Indexed: 06/01/2024] Open
Abstract
Liver cancer is one of the most prevalent types of cancer and a major contributor to the socioeconomic burden worldwide. The pathogenesis of hepatocellular carcinoma (HCC) is contributed by various etiological factors like virus infection, excessive alcohol consumption, exposure to toxins, or metabolic disorders. Majority of patients are diagnosed with late-stage HCC, which restricts its management to only palliative care. HCC, if diagnosed early, increases the survival and quality of life. Currently available biomarker (alpha-fetoproteins) have several limitations, that impede the early diagnosis and staging of cancer. This warrants the continous search in pursuit of a novel biomarker. Several research works in diverse areas have contributed to the identification of various novel biomarkers that have shown multifaceted application in early disease diagnosis, which further aid in targeted and effective therapy that can prevent cancer progression. This improves the overall health status of the patient along with significant reduction in caretaker's burden. With the aid of novel technologies, several biomarkers have been investigated and validated in mutliple preliminary research works. Therefore in this review, we have outlined various novel biomarkers that showed promising outcomes in their trials and we have highlighted the developing areas that act as game changers in cancer diagnosis and management.
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Affiliation(s)
- Pooja Basthi Mohan
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
| | - Rajiv Lochan
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
- Lead Consultant Surgeon - HPB and Liver transplantation Surgery, Manipal Hospital, Bengaluru, 560017 Karnataka India
| | - Shiran Shetty
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104 Karnataka India
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17
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Mendiratta-Lala M, Fetzer D, Kamaya A, Parikh ND, Singal AG. The Future Role of Abdominal US in Hepatocellular Carcinoma Surveillance. Radiology 2024; 311:e232624. [PMID: 38742973 PMCID: PMC11140528 DOI: 10.1148/radiol.232624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/16/2023] [Accepted: 12/26/2023] [Indexed: 05/16/2024]
Abstract
Abdominal US is currently the best-validated surveillance strategy for hepatocellular carcinoma (HCC) in at-risk patients. It is the only modality shown to have completed all five phases of validation and can achieve high sensitivity and specificity for HCC detection, especially when conducted by expert sonographers in high-volume centers. However, US also has limitations, including operator dependency and varying sensitivity in clinical practice. Further, the sensitivity of US for early-stage HCC detection is lower in patients with obesity or nonviral liver disease, increasingly common populations undergoing surveillance. Imaging-based and blood-based surveillance strategies, including abbreviated MRI and biomarker panels, may overcome some limitations of US-based surveillance. Both strategies have promising test performance in phase II and phase III biomarker studies and are undergoing prospective validation. Considering the variation in HCC risk and test performance between patients, there will likely be a shift away from a one-size-fits-all approach and toward precision screening, in which the "best" test is selected based on individual patient characteristics. In this upcoming era of precision HCC screening among patients with cirrhosis, US will likely continue to have an important, albeit reduced, surveillance role.
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Affiliation(s)
| | | | - Aya Kamaya
- From the Departments of Radiology (M.M.L.) and Internal Medicine
(N.D.P.), University of Michigan, Ann Arbor, Mich; Department of Radiology
(D.F.) and Department of Internal Medicine, Division of Digestive and Liver
Diseases (A.G.S.), University of Texas Southwestern Medical Center, 5959 Harry
Hines Blvd, Ste 420, POB 1, Dallas, TX 75390-8887; and Department of Radiology,
Stanford University School of Medicine, Stanford, Calif (A.K.)
| | - Neehar D. Parikh
- From the Departments of Radiology (M.M.L.) and Internal Medicine
(N.D.P.), University of Michigan, Ann Arbor, Mich; Department of Radiology
(D.F.) and Department of Internal Medicine, Division of Digestive and Liver
Diseases (A.G.S.), University of Texas Southwestern Medical Center, 5959 Harry
Hines Blvd, Ste 420, POB 1, Dallas, TX 75390-8887; and Department of Radiology,
Stanford University School of Medicine, Stanford, Calif (A.K.)
| | - Amit G. Singal
- From the Departments of Radiology (M.M.L.) and Internal Medicine
(N.D.P.), University of Michigan, Ann Arbor, Mich; Department of Radiology
(D.F.) and Department of Internal Medicine, Division of Digestive and Liver
Diseases (A.G.S.), University of Texas Southwestern Medical Center, 5959 Harry
Hines Blvd, Ste 420, POB 1, Dallas, TX 75390-8887; and Department of Radiology,
Stanford University School of Medicine, Stanford, Calif (A.K.)
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18
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Fares S, Wehrle CJ, Hong H, Sun K, Jiao C, Zhang M, Gross A, Allkushi E, Uysal M, Kamath S, Ma WW, Modaresi Esfeh J, Linganna MW, Khalil M, Pita A, Kim J, Walsh RM, Miller C, Hashimoto K, Schlegel A, Kwon DCH, Aucejo F. Emerging and Clinically Accepted Biomarkers for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1453. [PMID: 38672535 PMCID: PMC11047909 DOI: 10.3390/cancers16081453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/03/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and the sixth most diagnosed malignancy worldwide. Serum alpha-fetoprotein (AFP) is the traditional, ubiquitous biomarker for HCC. However, there has been an increasing call for the use of multiple biomarkers to optimize care for these patients. AFP, AFP-L3, and prothrombin induced by vitamin K absence II (DCP) have described clinical utility for HCC, but unfortunately, they also have well established and significant limitations. Circulating tumor DNA (ctDNA), genomic glycosylation, and even totally non-invasive salivary metabolomics and/or micro-RNAS demonstrate great promise for early detection and long-term surveillance, but still require large-scale prospective validation to definitively validate their clinical validity. This review aims to provide an update on clinically available and emerging biomarkers for HCC, focusing on their respective clinical strengths and weaknesses.
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Affiliation(s)
- Sami Fares
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Chase J. Wehrle
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Hanna Hong
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Keyue Sun
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Chunbao Jiao
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Mingyi Zhang
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Abby Gross
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Erlind Allkushi
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Melis Uysal
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Suneel Kamath
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.K.); (W.W.M.)
| | - Wen Wee Ma
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.K.); (W.W.M.)
| | - Jamak Modaresi Esfeh
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (J.M.E.); (M.W.L.)
| | - Maureen Whitsett Linganna
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (J.M.E.); (M.W.L.)
| | - Mazhar Khalil
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Alejandro Pita
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Jaekeun Kim
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - R. Matthew Walsh
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Charles Miller
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Koji Hashimoto
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Andrea Schlegel
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - David Choon Hyuck Kwon
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Federico Aucejo
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
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Sukaram T, Tansawat R, Phathong C, Rerknimitr R, Chaiteerakij R. Volatile organic compounds for diagnosis of early hepatocellular carcinoma in at-risk patients. Clin Chim Acta 2024; 556:117831. [PMID: 38378104 DOI: 10.1016/j.cca.2024.117831] [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: 03/26/2023] [Revised: 02/10/2024] [Accepted: 02/14/2024] [Indexed: 02/22/2024]
Abstract
BACKGROUND Volatile organic compounds (VOCs) have been shown as promising biomarkers for hepatocellular carcinoma (HCC) diagnosis. We aimed to investigate the performance of VOCs for diagnosing early-stage HCC in patients at-risk for HCC. METHODS VOCs were identified in exhaled breath samples collected from 87 early-stage HCC patients, 90 cirrhotic patients, and 72 HBV-infected patients using thermal desorption-gas chromatography/field-asymmetric ion mobility spectrometry. The VOC levels were compared between the three groups. An association between VOCs and HCC was determined using logistic regression analysis. Diagnostic performance of VOCs was estimated using the AUROC and compared to serum alpha-fetoprotein (AFP). RESULTS The levels of acetone monomer, dimethyl sulfide, 1,4-pentadiene, isopropyl alcohol, and acetone dimer were significantly different between the three groups. After adjusting for liver function test and AFP, acetone dimer was significantly associated with HCC. Acetone dimer significantly outperformed AFP with 86.2 % vs. 61.2 % sensitivity, 87.6 % vs. 66.2 % specificity, 86.9 % vs. 63.5 % for accuracy, and AUROC of 0.908 vs. 0.665, p = 0.007, <0.001, <0.001, and 0.001, respectively, for differentiating between HCC and cirrhosis. CONCLUSION Acetone showed a better performance than AFP for diagnosing early HCC in at-risk patients. Further studies to validate the utility of VOCs as an HCC surveillance tool are needed.
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Affiliation(s)
- Thanikan Sukaram
- Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand
| | - Rossarin Tansawat
- Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand; Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Chulalongkorn University, Bangkok, Thailand
| | - Chonlada Phathong
- Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand
| | - Rungsun Rerknimitr
- Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand; Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Chulalongkorn University, Bangkok, Thailand
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross, Bangkok, Thailand; Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Chulalongkorn University, Bangkok, Thailand.
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Johnson PJ, Bhatti E, Toyoda H, He S. Serologic Detection of Hepatocellular Carcinoma: Application of Machine Learning and Implications for Diagnostic Models. JCO Clin Cancer Inform 2024; 8:e2300199. [PMID: 38513163 DOI: 10.1200/cci.23.00199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/11/2023] [Accepted: 02/06/2024] [Indexed: 03/23/2024] Open
Abstract
PURPOSE The gender, age, lens culinaris agglutinin-reactive fraction of alphafetoprotein, alphafetoprotein, des-gamma-carboxyprothrombin (GALAD) score is a biomarker-based statistical model for the serologic diagnosis of hepatocellular carcinoma (HCC) that has been developed and validated using the case-control approach with a view to early detection. Performance has, however, been suboptimal in the first prospective studies which better reflect the real-world situation. In this article, we report the application of machine learning to a large, prospectively accrued, HCC surveillance data set. PATIENTS AND METHODS Models were built on a cohort of 3,473 patients with chronic liver disease within a rigorous surveillance program between 1998 and 2014, during which 459 patients with HCC were detected. Two random forest (RF) models were trained. The first RF model uses the same variables as the original GALAD model (GALAD-RF); the second is based on routinely available clinical and laboratory features (RF-practical). For comparison, we evaluated a logistic regression GALAD model trained on this longitudinal prospective data set (termed GALAD-Ogaki). RESULTS Models were evaluated using a repetitive cross-validation approach with the metrics averaged over 100 independent runs. As judged by area under the receiver operator curve (AUROC) and F1 score, the GALAD RF model significantly outperformed the original GALAD model. The RF-practical model also outperformed the original GALAD model in terms of both AUROC and F1 score, and both models outperformed the individual biomarkers. An online web application that implemented the GALAD-RF and RF-practical models is presented. CONCLUSION RF-based models improve on the diagnostic performance of the original GALAD model in the setting of a standard HCC surveillance program. Further prospective validation studies are warranted using these models and could be expanded to offer prediction of risk of HCC development over defined periods of time.
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Affiliation(s)
- Philip J Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Ehsan Bhatti
- School of Computer Science, University of Birmingham, Birmingham, United Kingdom
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Shan He
- School of Computer Science, University of Birmingham, Birmingham, United Kingdom
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Christou C, Stylianou A, Gkretsi V. Midkine (MDK) in Hepatocellular Carcinoma: More than a Biomarker. Cells 2024; 13:136. [PMID: 38247828 PMCID: PMC10814326 DOI: 10.3390/cells13020136] [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: 12/23/2023] [Revised: 01/02/2024] [Accepted: 01/06/2024] [Indexed: 01/23/2024] Open
Abstract
Midkine (MDK) is a multifunctional secreted protein that can act as a cytokine or growth factor regulating multiple signaling pathways and being implicated in fundamental cellular processes, such as survival, proliferation, and migration. Although its expression in normal adult tissues is barely detectable, MDK serum levels are found to be elevated in several types of cancer, including hepatocellular carcinoma (HCC). In this review, we summarize the findings of recent studies on the role of MDK in HCC diagnosis and progression. Overall, studies show that MDK is a powerful biomarker for HCC early diagnosis, as it can differentiate not only between HCC patients and normal individuals but also between HCC patients and patients with other liver pathologies. It is correlated with high recurrence rates and was shown to be valuable for the diagnosis of early-stage HCC, even in patients negative for α-fetoprotein (AFP), the most commonly used biomarker for HCC diagnosis. A comparison with AFP reveals that MDK is inferior to AFP with regard to specificity but significantly superior with regard to sensitivity, which further indicates the need for using both biomarkers for more effective HCC diagnosis.
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Affiliation(s)
- Christiana Christou
- Cancer Metastasis and Adhesion Laboratory, Basic and Translational Cancer Research Center (BTCRC), European University Cyprus, Nicosia 2404, Cyprus;
- European University Cyprus Research Centre Ltd., Nicosia 2404, Cyprus;
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia 2404, Cyprus
| | - Andreas Stylianou
- European University Cyprus Research Centre Ltd., Nicosia 2404, Cyprus;
- Cancer Mechanobiology and Applied Biophysics Laboratory, Basic and Translational Cancer Research Center (BTCRC), European University Cyprus, Nicosia 2404, Cyprus
| | - Vasiliki Gkretsi
- Cancer Metastasis and Adhesion Laboratory, Basic and Translational Cancer Research Center (BTCRC), European University Cyprus, Nicosia 2404, Cyprus;
- European University Cyprus Research Centre Ltd., Nicosia 2404, Cyprus;
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia 2404, Cyprus
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22
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Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, Jou JH, Kulik LM, Agopian VG, Marrero JA, Mendiratta-Lala M, Brown DB, Rilling WS, Goyal L, Wei AC, Taddei TH. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 2023; 78:1922-1965. [PMID: 37199193 PMCID: PMC10663390 DOI: 10.1097/hep.0000000000000466] [Citation(s) in RCA: 480] [Impact Index Per Article: 240.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 05/01/2023] [Indexed: 05/19/2023]
Affiliation(s)
- Amit G. Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Josep M. Llovet
- Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York, USA
- Translational Research in Hepatic Oncology, Liver Unit, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic, University of Barcelona, Catalonia, Spain
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain
| | - Mark Yarchoan
- Department of Medical Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Neil Mehta
- University of California, San Francisco, San Francisco, California, USA
| | | | - Laura A. Dawson
- Radiation Medicine Program/University Health Network, Department of Radiation Oncology, University of Toronto, Toronto, Canada
| | - Janice H. Jou
- Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, Oregon, USA
| | - Laura M. Kulik
- Northwestern Medical Faculty Foundation, Chicago, Illinois, USA
| | - Vatche G. Agopian
- The Dumont–University of California, Los Angeles, Transplant Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Jorge A. Marrero
- Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Mishal Mendiratta-Lala
- Department of Radiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA
| | - Daniel B. Brown
- Department of Radiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - William S. Rilling
- Division of Interventional Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Lipika Goyal
- Department of Medicine, Stanford School of Medicine, Palo Alto, California, USA
| | - Alice C. Wei
- Memorial Sloan Kettering Cancer Center, New York City, New York, USA
| | - Tamar H. Taddei
- Department of Medicine (Digestive Diseases), Yale School of Medicine, New Haven, CT, USA
- Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
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Singal AG, Kanwal F, Llovet JM. Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat Rev Clin Oncol 2023; 20:864-884. [PMID: 37884736 DOI: 10.1038/s41571-023-00825-3] [Citation(s) in RCA: 182] [Impact Index Per Article: 91.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2023] [Indexed: 10/28/2023]
Abstract
Hepatocellular carcinoma (HCC) mortality rates are increasing globally, and particularly in the Western world. Cirrhosis remains the predominant risk factor for HCC. However, epidemiological shifts in the incidence of HCC from patients with virus-related liver disease to those with non-viral aetiologies, including alcohol-associated and metabolic dysfunction-associated steatotic liver disease, have important implications for prevention, surveillance and treatment. Hepatitis B vaccination and antiviral therapy for hepatitis B and C are effective for primary prevention of virus-related HCCs, but chemoprevention strategies for non-viral liver disease remain an unmet need. Emerging data suggest associations between aspirin, statins, metformin and coffee and reduced HCC incidence, although none has been proved to be causally related. Secondary prevention of HCC via semi-annual surveillance is associated with improvements in early detection and thus reduced mortality; however, current tools, including abdominal ultrasonography, have suboptimal sensitivity for the detection of early stage HCC, particularly in patients with obesity and/or non-viral liver disease. Promising blood-based or imaging-based surveillance strategies are emerging, although these approaches require further validation before adoption in clinical practice. In the interim, efforts should be focused on maximizing use of the existing surveillance tools given their prevalent underuse globally. Remarkable advances have been made in the treatment of HCC, including expanded eligibility for surgical therapies, improved patient selection for locoregional treatments and increased systemic treatment options, including immune-checkpoint inhibitors. In this Review, we discuss trends in the epidemiology of HCC and their implications for screening, prevention and therapy.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology and Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- VA Health Services Research & Development Center for Innovations in Quality, Effectiveness, and Safety (IQuESt), Houston, TX, USA
- Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA
| | - Josep M Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Translational Research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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Piratvisuth T, Hou J, Tanwandee T, Berg T, Vogel A, Trojan J, De Toni EN, Kudo M, Eiblmaier A, Klein HG, Hegel JK, Madin K, Kroeniger K, Sharma A, Chan HL. Development and clinical validation of a novel algorithmic score (GAAD) for detecting HCC in prospective cohort studies. Hepatol Commun 2023; 7:e0317. [PMID: 37938100 PMCID: PMC10635602 DOI: 10.1097/hc9.0000000000000317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/13/2023] [Indexed: 11/09/2023] Open
Abstract
BACKGROUND Alpha-fetoprotein (AFP) and des-gamma carboxyprothrombin (DCP), also known as protein induced by vitamin K absence-II (PIVKA-II [DCP]) are biomarkers for HCC with limited diagnostic value when used in isolation. The novel GAAD algorithm is an in vitro diagnostic combining PIVKA-II (DCP) and AFP measurements, age, and gender (biological sex) to generate a semi-quantitative result. We conducted prospective studies to develop, implement, and clinically validate the GAAD algorithm for differentiating HCC (early and all-stage) and benign chronic liver disease (CLD), across disease stages and etiologies. METHODS Patients aged ≥18 years with HCC or CLD were prospectively enrolled internationally into algorithm development [n = 1084; 309 HCC cases (40.7% early-stage) and 736 controls] and clinical validation studies [n = 877; 366 HCC cases (47.6% early-stage) and 303 controls]. Serum samples were analyzed on a cobas® e 601 analyzer. Performance was assessed using receiver operating characteristic curve analyses to calculate AUC. RESULTS For algorithm development, AUC for differentiation between early-stage HCC and CLD was 90.7%, 84.4%, and 77.2% for GAAD, AFP, and PIVKA-II, respectively. The sensitivity of GAAD for the detection of early-stage HCC was 71.8% with 90.0% specificity. Similar results were shown in the clinical validation study; AUC for differentiation between early-stage HCC and CLD was 91.4% with 70.1% sensitivity and 93.7% specificity. GAAD also showed strong specificity, with a lower rate of false positives regardless of disease stage, etiology, or region. CONCLUSIONS The GAAD algorithm significantly improves early-stage HCC detection for patients with CLD undergoing HCC surveillance. Further phase III and IV studies are warranted to assess the utility of incorporating the algorithm into clinical practice.
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Affiliation(s)
- Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand
| | - Jinlin Hou
- Institute of Hepatology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tawesak Tanwandee
- Division of Gastroenterology and Hepatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Thomas Berg
- Department of Medicine, Leipzig University Medical Center, Leipzig, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Medical University of Hanover, Hannover, Germany
| | - Jörg Trojan
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt, Germany
| | - Enrico N. De Toni
- Department of Medicine II, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology Kindai University, Osaka, Japan
| | - Anja Eiblmaier
- Laboratory Services, Microcoat Biotechnologie GmbH, Bernried, Germany
| | - Hanns-Georg Klein
- Center of Human Genetics and Laboratory Diagnostics, Munich, Germany
| | - Johannes Kolja Hegel
- Studies, Collaborations, and Innovation Management, Labor Berlin Charité Vivantes Services GmbH, Berlin, Germany
| | | | | | - Ashish Sharma
- Clinical Development & Medical Affairs, Roche Diagnostics International AG, Rotkreuz, Switzerland
| | - Henry L.Y. Chan
- Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
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Ugonabo O, Udoh UAS, Rajan PK, Reeves H, Arcand C, Nakafuku Y, Joshi T, Finley R, Pierre SV, Sanabria JR. The Current Status of the Liver Liquid Biopsy in MASH Related HCC: Overview and Future Directions. Biomolecules 2023; 13:1369. [PMID: 37759769 PMCID: PMC10526956 DOI: 10.3390/biom13091369] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/03/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is one of the major risk factors for chronic liver disease and hepatocellular carcinoma (HCC). The incidence of MASH in Western countries continues to rise, driving HCC as the third cause of cancer-related death worldwide. HCC has become a major global health challenge, partly from the obesity epidemic promoting metabolic cellular disturbances but also from the paucity of biomarkers for its early detection. Over 50% of HCC cases are clinically present at a late stage, where curative measures are no longer beneficial. Currently, there is a paucity of both specific and sensitive biological markers for the early-stage detection of HCC. The search for biological markers in the diagnosis of early HCC in high-risk populations is intense. We described the potential role of surrogates for a liver biopsy in the screening and monitoring of patients at risk for nesting HCC.
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Affiliation(s)
- Onyinye Ugonabo
- Department of Medicine, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (O.U.); (T.J.)
| | - Utibe-Abasi Sunday Udoh
- Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25703, USA; (U.-A.S.U.); (P.K.R.); (Y.N.); (S.V.P.)
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Pradeep Kumar Rajan
- Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25703, USA; (U.-A.S.U.); (P.K.R.); (Y.N.); (S.V.P.)
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Heather Reeves
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Christina Arcand
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Yuto Nakafuku
- Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25703, USA; (U.-A.S.U.); (P.K.R.); (Y.N.); (S.V.P.)
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Tejas Joshi
- Department of Medicine, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (O.U.); (T.J.)
| | - Rob Finley
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
| | - Sandrine V. Pierre
- Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25703, USA; (U.-A.S.U.); (P.K.R.); (Y.N.); (S.V.P.)
| | - Juan Ramon Sanabria
- Marshall Institute for Interdisciplinary Research, Marshall University School of Medicine, Huntington, WV 25703, USA; (U.-A.S.U.); (P.K.R.); (Y.N.); (S.V.P.)
- Department of Surgery, Marshall University School of Medicine, Marshall University, Huntington, WV 25701, USA; (H.R.); (C.A.); (R.F.)
- Department of Nutrition and Metabolomic Core Facility, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
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26
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Lominadze Z, Shaik MR, Choi D, Zaffar D, Mishra L, Shetty K. Hepatocellular Carcinoma Genetic Classification. Cancer J 2023; 29:249-258. [PMID: 37796642 PMCID: PMC10686192 DOI: 10.1097/ppo.0000000000000682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/07/2023]
Abstract
ABSTRACT Hepatocellular carcinoma (HCC) represents a significant global burden, with management complicated by its heterogeneity, varying presentation, and relative resistance to therapy. Recent advances in the understanding of the genetic, molecular, and immunological underpinnings of HCC have allowed a detailed classification of these tumors, with resultant implications for diagnosis, prognostication, and selection of appropriate treatments. Through the correlation of genomic features with histopathology and clinical outcomes, we are moving toward a comprehensive and unifying framework to guide our diagnostic and therapeutic approach to HCC.
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Affiliation(s)
- Zurabi Lominadze
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
| | | | - Dabin Choi
- Department of Medicine, University of Maryland Medical Center
| | - Duha Zaffar
- Department of Medicine, University of Maryland Midtown Medical Center
| | - Lopa Mishra
- Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory; Divisions of Gastroenterology and Hepatology, Northwell Health
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, University of Maryland School of Medicine
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27
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Lee K, Hwang JW, Sohn HJ, Suh S, Kim SW. A systematic review of progress on hepatocellular carcinoma research over the past 30 years: a machine-learning-based bibliometric analysis. Front Oncol 2023; 13:1227991. [PMID: 37664017 PMCID: PMC10471147 DOI: 10.3389/fonc.2023.1227991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 07/31/2023] [Indexed: 09/05/2023] Open
Abstract
Introduction Research on hepatocellular carcinoma (HCC) has grown significantly, and researchers cannot access the vast amount of literature. This study aimed to explore the research progress in studying HCC over the past 30 years using a machine learning-based bibliometric analysis and to suggest future research directions. Methods Comprehensive research was conducted between 1991 and 2020 in the public version of the PubMed database using the MeSH term "hepatocellular carcinoma." The complete records of the collected results were downloaded in Extensible Markup Language format, and the metadata of each publication, such as the publication year, the type of research, the corresponding author's country, the title, the abstract, and the MeSH terms, were analyzed. We adopted a latent Dirichlet allocation topic modeling method on the Python platform to analyze the research topics of the scientific publications. Results In the last 30 years, there has been significant and constant growth in the annual publications about HCC (annual percentage growth rate: 7.34%). Overall, 62,856 articles related to HCC from the past 30 years were searched and finally included in this study. Among the diagnosis-related terms, "Liver Cirrhosis" was the most studied. However, in the 2010s, "Biomarkers, Tumor" began to outpace "Liver Cirrhosis." Regarding the treatment-related MeSH terms, "Hepatectomy" was the most studied; however, recent studies related to "Antineoplastic Agents" showed a tendency to supersede hepatectomy. Regarding basic research, the study of "Cell Lines, Tumors,'' appeared after 2000 and has been the most studied among these terms. Conclusion This was the first machine learning-based bibliometric study to analyze more than 60,000 publications about HCC over the past 30 years. Despite significant efforts in analyzing the literature on basic research, its connection with the clinical field is still lacking. Therefore, more efforts are needed to convert and apply basic research results to clinical treatment. Additionally, it was found that microRNAs have potential as diagnostic and therapeutic targets for HCC.
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Affiliation(s)
- Kiseong Lee
- Humanities Research Institute, Chung-Ang University, Seoul, Republic of Korea
| | - Ji Woong Hwang
- Department of Surgery, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Republic of Korea
| | - Hee Ju Sohn
- Department of Surgery, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Republic of Korea
| | - Sanggyun Suh
- Department of Surgery, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Republic of Korea
| | - Sun-Whe Kim
- Department of Surgery, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong, Republic of Korea
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28
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Taru MG, Lupsor-Platon M. Exploring Opportunities to Enhance the Screening and Surveillance of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease (NAFLD) through Risk Stratification Algorithms Incorporating Ultrasound Elastography. Cancers (Basel) 2023; 15:4097. [PMID: 37627125 PMCID: PMC10452922 DOI: 10.3390/cancers15164097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), with its progressive form, non-alcoholic steatohepatitis (NASH), has emerged as a significant public health concern, affecting over 30% of the global population. Hepatocellular carcinoma (HCC), a complication associated with both cirrhotic and non-cirrhotic NAFLD, has shown a significant increase in incidence. A substantial proportion of NAFLD-related HCC occurs in non-cirrhotic livers, highlighting the need for improved risk stratification and surveillance strategies. This comprehensive review explores the potential role of liver ultrasound elastography as a risk assessment tool for HCC development in NAFLD and highlights the importance of effective screening tools for early, cost-effective detection and improved management of NAFLD-related HCC. The integration of non-invasive tools and algorithms into risk stratification strategies could have the capacity to enhance NAFLD-related HCC screening and surveillance effectiveness. Alongside exploring the potential advancement of non-invasive tools and algorithms for effectively stratifying HCC risk in NAFLD, we offer essential perspectives that could enable readers to improve the personalized assessment of NAFLD-related HCC risk through a more methodical screening approach.
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Affiliation(s)
- Madalina-Gabriela Taru
- Hepatology Department, Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400162 Cluj-Napoca, Romania;
- “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Monica Lupsor-Platon
- “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Medical Imaging Department, Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400162 Cluj-Napoca, Romania
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29
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Yıldırım HÇ, Kavgaci G, Chalabiyev E, Dizdar O. Advances in the Early Detection of Hepatobiliary Cancers. Cancers (Basel) 2023; 15:3880. [PMID: 37568696 PMCID: PMC10416925 DOI: 10.3390/cancers15153880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/23/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Hepatocellular cancer (HCC) and biliary tract cancers (BTCs) have poor survival rates and a low likelihood of a cure, especially in advanced-stage disease. Early diagnosis is crucial and can significantly improve survival rates through curative treatment approaches. Current guidelines recommend abdominal ultrasonography (USG) and alpha-fetoprotein (AFP) monitoring for HCC screening in high-risk groups, and abdominal USG, magnetic resonance imaging (MRI), and magnetic resonance cholangiopancreatography (MRCP) monitoring for biliary tract cancer. However, despite this screening strategy, many high-risk individuals still develop advanced-stage HCC and BTC. Blood-based biomarkers are being developed for use in HCC or BTC high-risk groups. Studies on AFP, AFP-L3, des-gamma-carboxy prothrombin, glypican-3 (GPC3), osteopontin (OPN), midkine (MK), neopterin, squamous cell carcinoma antigen (SCCA), Mac-2-binding protein (M2BP), cyclic guanosine monophosphate (cGMP), and interleukin-6 biomarkers for HCC screening have shown promising results when evaluated individually or in combination. In the case of BTCs, the potential applications of circulating tumor DNA, circulating microRNA, and circulating tumor cells in diagnosis are also promising. These biomarkers have shown potential in detecting BTCs in early stages, which can significantly improve patient outcomes. Additionally, these biomarkers hold promise for monitoring disease progression and evaluating response to therapy in BTC patients. However, further research is necessary to fully understand the clinical utility of these biomarkers in the diagnosis and management of HCC and BTCs.
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Affiliation(s)
| | | | | | - Omer Dizdar
- Department of Medical Oncology, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey; (H.Ç.Y.); (G.K.); (E.C.)
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30
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Nair B, Kuriakose A, Baby B, Nath L. Tumor-Specific Growth Factor (TSGF): A Futuristic Tumor Biomarker in Early Diagnosis of Cancer. Adv Pharm Bull 2023; 13:483-488. [PMID: 37646066 PMCID: PMC10460812 DOI: 10.34172/apb.2023.051] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 02/04/2022] [Accepted: 04/29/2022] [Indexed: 09/01/2023] Open
Abstract
Despite the significant improvement in the treatment modalities, cancer is one of the fastest-growing chronic disease conditions all over the world. Genetic and Epigenetic alterations in the normal physiology of the cell are the key factor for tumor development. These changes can trigger the production of abnormal protein expressions through stimulation of different signaling pathways and can deeply affect normal cell growth and proliferation. Any altered protein expression, genetic variation, micro-RNA or post-translational protein modifications that indicate tumorigenesis can act as an early signal termed as biomarker. Cancer, being a multistep process with accumulating genetic and epigenetic alterations, could be detected early with suitable biomarkers. There are several proteins such as AFP, CA-125, PSA, troponin, CEA, osteopontin, CA 19-9 that act as biomarkers which help in early detection, prognosis, and monitoring of disease progression, a hunt for newer biomarkers with higher specificity and sensitivity is still ongoing. Tumor-specific growth factor (TSGF) is one such budding and prevailing tumor biomarker used for the early-stage detection of several types of carcinomas. TSGF is a gene that helps in tumor angiogenesis and gets released during the preliminary stages from cancer cells that ensure the vascular proliferation of the same. In this review, the clinical investigations of TSGF in different kinds of malignancy is discussed in detail and suggests the possibility of using TSGF as a biomarker in early diagnosis of cancer.
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Affiliation(s)
- Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita VishwaVidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
| | - Anisha Kuriakose
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita VishwaVidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
| | | | - Lekshmi.R. Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita VishwaVidyapeetham, AIMS Health Science Campus, Ponekkara P.O., Kochi, Kerala 682041, India
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Biasiolo A, Sandre M, Ferro S, Quarta S, Ruvoletto M, Villano G, Turato C, Guido M, Marin O, Pontisso P. Epitope-Specific Anti-SerpinB3 Antibodies for SerpinB3 Recognition and Biological Activity Inhibition. Biomolecules 2023; 13:biom13050739. [PMID: 37238609 DOI: 10.3390/biom13050739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/13/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
SerpinB3 is a serine protease inhibitor that plays a relevant role in disease progression and cancer by increasing fibrosis, cell proliferation, and invasion, besides conferring resistance to apoptosis. The mechanisms underlying these biological activities are not yet fully understood. The aim of this study was to generate antibodies directed against different SerpinB3 epitopes to better investigate their biological role. Five exposed epitopes were identified using the software DNASTAR Lasergene and the corresponding synthetic peptides were used for NZW rabbit immunization. Anti-P#2 and anti-P#4 antibodies were able to recognize both SerpinB3 and SerpinB4 by ELISA. Anti-P#5 antibody, produced against the reactive site loop of SerpinB3, showed the greatest specific reactivity for human SerpinB3. This antibody was able to recognize SerpinB3 at nuclear level, while anti-P#3 antibody recognized SerpinB3 only at cytoplasmic level, both by immunofluorescence and by immunohistochemistry. The biological activity of each antibody preparation was assessed in HepG2 cells overexpressing SerpinB3 and anti-P#5 antibody reduced proliferation by 12% cell and cell invasion by 75%, while trivial results were obtained with the other antibody preparations. These findings indicate that the reactive site loop of SerpinB3 is essential for the invasiveness features induced by this serpin and it could become a novel druggable target.
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Affiliation(s)
- Alessandra Biasiolo
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Michele Sandre
- Department of Biomedical Sciences, University of Padova, Via Colombo 3, 35131 Padova, Italy
| | - Stefania Ferro
- Department of Biomedical Sciences, University of Padova, Via Colombo 3, 35131 Padova, Italy
| | - Santina Quarta
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Mariagrazia Ruvoletto
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Gianmarco Villano
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Cristian Turato
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy
| | - Maria Guido
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
| | - Oriano Marin
- Department of Biomedical Sciences, University of Padova, Via Colombo 3, 35131 Padova, Italy
| | - Patrizia Pontisso
- Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
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King WW, Richhart R, Culpepper T, Mota M, Banerjee D, Ismael M, Chakraborty J, Ladna M, Khan W, Ruiz N, Wilson J, Altshuler E, Clark V, Cabrera R. Adherence to guideline-directed hepatocellular carcinoma screening: A single-center US experience. World J Hepatol 2023; 15:410-418. [PMID: 37034234 PMCID: PMC10075011 DOI: 10.4254/wjh.v15.i3.410] [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: 11/11/2022] [Revised: 01/16/2023] [Accepted: 02/21/2023] [Indexed: 03/22/2023] Open
Abstract
BACKGROUND The American Association for the Study of Liver Disease recommends screening patients with cirrhosis for hepatocellular carcinoma (HCC) using imaging with or without alpha-fetoprotein every six months. Unfortunately, screening rates remain inadequate.
AIM To assess root causes of screening failure in a subspecialty hepatology clinic.
METHODS The authors identified patients with cirrhosis seen in a subspecialty hepatology clinic and determined whether they underwent appropriate screening, defined as two cross-sectional images between five and seven months apart. The authors characterized the primary driver of screening failure. Finally, other hepatologists were surveyed to determine provider perceptions of screening failure causes.
RESULTS 1034 patients were identified with an average age of 61 years and a mean MELD of 8.1 ± 3.8. Hepatitis C virus was the most common cirrhosis etiology. 489 (47%) underwent appropriate screening. No demographic or clinical differences were detected between those who underwent appropriate screening and those who did not. The most common etiologies of screening failure, in descending order, were: radiology unable to schedule timely imaging, provider did not order imaging, patient canceled follow up appointment, appointments scheduled too far apart, lost to follow up, no-show to radiology appointment, and provider canceled appointment. Hepatologists surveyed believed the most common cause of screening failure was no-show to radiology.
CONCLUSION Rates of screening were poor even in a subspecialty hepatology clinic. Screening failure was mostly due to systemic factors such as radiology availability and time between hepatology appointments rather than individual error.
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Affiliation(s)
- William W King
- Department of Medicine, University of Florida, Gainesville, FL 32610, United States
| | - Raymond Richhart
- Department of Medicine, University of Florida, Gainesville, FL 32610, United States
| | - Tyler Culpepper
- Department of Medicine, University of Florida, Gainesville, FL 32610, United States
| | - Maneola Mota
- Department of Gastroenterology, University of Florida, Gainesville, FL 32610, United States
| | - Debdeep Banerjee
- Department of Medicine, University of Florida, Gainesville, FL 32610, United States
| | - Media Ismael
- Department of Gastroenterology, University of Florida, Gainesville, FL 32610, United States
| | - Joydeep Chakraborty
- Department of Gastroenterology, University of Florida, Gainesville, FL 32610, United States
| | - Michael Ladna
- Department of Hospital Medicine, University of Florida, Gainesville, FL 32610, United States
| | - Walid Khan
- Department of Hospital Medicine, University of Florida, Gainesville, FL 32610, United States
| | - Nicole Ruiz
- Department of Medicine, University of Florida, Gainesville, FL 32610, United States
| | - Jake Wilson
- Department of Medicine, University of Florida, Gainesville, FL 32610, United States
| | - Ellery Altshuler
- Department of Medicine, University of Florida, Gainesville, FL 32610, United States
| | - Virginia Clark
- Department of Gastroenterology, University of Florida, Gainesville, FL 32610, United States
| | - Roniel Cabrera
- Department of Gastroenterology, University of Florida, Gainesville, FL 32610, United States
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Abou-Fadel J, Reid V, Le A, Croft J, Zhang J. Key Members of the CmPn as Biomarkers Distinguish Histological and Immune Subtypes of Hepatic Cancers. Diagnostics (Basel) 2023; 13:diagnostics13061012. [PMID: 36980321 PMCID: PMC10047786 DOI: 10.3390/diagnostics13061012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/23/2023] [Accepted: 03/05/2023] [Indexed: 03/11/2023] Open
Abstract
Liver cancer, comprising hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a leading cause of cancer-related deaths worldwide. The liver is a primary metabolic organ for progesterone (PRG) and PRG exerts its effects through classic nuclear PRG receptors (nPRs) and non-classic membrane PRG receptors (mPRs) or a combination of both. Previous studies have shown that the CCM signaling complex (CSC) couples both nPRs and mPRs to form the CmPn (CSC-mPR-PRG-nPR) signaling network, which is involved in multiple cellular signaling pathways, including tumorigenesis of various cancers. Despite advances in treatment, 5-year survival rates for liver cancer patients remain low, largely due to the chemoresistant nature of HCCs. The lack of sensitive and specific biomarkers for liver cancer diagnosis and prognosis emphasizes the need for identifying new potential biomarkers. We propose the potential use of CmPn members’ expression data as prognostic biomarkers or biomarker signatures for the major types of hepatic cancer, including HCCs and CCAs, as well as rare subtypes such as undifferentiated pleomorphic sarcoma (UPS) and hepatic angiosarcoma (HAS). In this study, we investigated the CmPn network through RNAseq data and immunofluorescence techniques to measure alterations to key cancer pathways during liver tumorigenesis. Our findings reveal significant differential expression of multiple CmPn members, including CCM1, PAQR7, PGRMC1, and nPRs, in both HCCs and CCAs, highlighting the crucial roles of mPRs, nPRs, and CSC signaling during liver tumorigenesis. These key members of the CmPn network may serve as potential biomarkers for the diagnosis and prognosis of liver cancer subtypes, including rare subtypes.
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Affiliation(s)
| | | | | | | | - Jun Zhang
- Correspondence: ; Tel.: +1-(915)-215-4197
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Daher D, Dahan KSE, Singal AG. Non-alcoholic fatty liver disease-related hepatocellular carcinoma. JOURNAL OF LIVER CANCER 2023; 23:127-142. [PMID: 37384032 PMCID: PMC10202236 DOI: 10.17998/jlc.2022.12.30] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 06/30/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), one of the most common causes of liver disease, is an increasingly common cause of hepatocellular carcinoma (HCC). Several demographic, clinical, and genetic factors contribute to HCC risk in NAFLD patients, which may inform risk stratification scores. Proven efficacious approaches to primary prevention approach in patients with non-viral liver disease remain an area of need. Semi-annual surveillance is associated with improved early tumor detection and reduced HCC-related mortality; however, patients with NAFLD have several challenges to effective surveillance, including under-recognition of at-risk patients, low surveillance utilization in clinical practice, and lower sensitivity of current tools for early-stage HCC detection. Treatment decisions are best made in a multidisciplinary fashion and are informed by several factors including tumor burden, liver dysfunction, performance status, and patient preferences. Although patients with NAFLD often have larger tumor burden and increased comorbidities compared to counterparts, they can achieve similar post-treatment survival with careful patient selection. Therefore, surgical therapies continue to provide a curative treatment option for patients diagnosed at an early stage. Although there has been debate about the efficacy of immune checkpoint inhibitors in patients with NAFLD, current data are insufficient to change treatment selection based on liver disease etiology.
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Affiliation(s)
- Darine Daher
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Karim Seif El Dahan
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Amit G. Singal
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
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DelaCourt A, Mehta A. Beyond glyco-proteomics-Understanding the role of genetics in cancer biomarkers. Adv Cancer Res 2023; 157:57-81. [PMID: 36725113 DOI: 10.1016/bs.acr.2022.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The development of robust cancer biomarkers is the most effective way to improve overall survival, as early detection and treatment leads to significantly better clinical outcomes. Many of the cancer biomarkers that have been identified and are clinically utilized are glycoproteins, oftentimes a specific glycoform. Aberrant glycosylation is a common theme in cancer, with dysregulated glycosylation driving tumor initiation and metastasis, and abnormal glycosylation can be detection both on the tissue surface and in serum. However, most cancer types are heterogeneous in regard to tumor genomics, and this heterogeneity extends to cancer glycomics. This limits the sensitivity of standalone glycan-based biomarkers, which has slowed their implementation clinically. However, if targeted biomarker development can take into account genomic tumor information, the development of complementary biomarkers that target unique cancer subgroups can be accomplished. This idea suggests the need for algorithm-based cancer biomarkers, which can utilize multiple biomarkers along with relevant demographic information. This concept has already been established in the detection of hepatocellular carcinoma with the GALAD score, and an algorithm-based approach would likely be effective in improving biomarker sensitivity for additional cancer types. In order to increase cancer diagnostic biomarker sensitivity, there must be more targeted biomarker development that considers tumor genomic, proteomic, metabolomic, and clinical data while identifying tumor biomarkers.
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Affiliation(s)
- Andrew DelaCourt
- Department of Cell & Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States
| | - Anand Mehta
- Department of Cell & Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, United States.
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Cholankeril G, El-Serag HB. Current Challenges and Future Direction in Surveillance for Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease. Semin Liver Dis 2023; 43:89-99. [PMID: 36216350 DOI: 10.1055/a-1957-8540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The burden for hepatocellular carcinoma (HCC) attributed to nonalcoholic fatty liver disease (NAFLD) continues to grow in parallel with rising global trends in obesity. The risk of HCC is elevated among patients with NAFLD-related cirrhosis to a level that justifies surveillance based on cost-effectiveness argument. The quality of current evidence for HCC surveillance in all patients with chronic liver disease is poor, and even lower in those with NAFLD. For a lack of more precise risk-stratification tools, current approaches to defining a target population in noncirrhotic NAFLD are limited to noninvasive tests for liver fibrosis, as a proxy for liver-related morbidity and mortality. Beyond etiology and severity of liver disease, traditional and metabolic risk factors, such as diabetes mellitus, older age, male gender and tobacco smoking, are not enough for HCC risk stratification for surveillance efficacy and effectiveness in NAFLD. There is an association between molecular and genetic factors and HCC risk in NAFLD, and risk models integrating both clinical and genetic factors will be key to personalizing HCC risk. In this review, we discuss concerns regarding defining a target population, surveillance test accuracy, surveillance underuse, and other cost-effective considerations for HCC surveillance in individuals with NAFLD.
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Affiliation(s)
- George Cholankeril
- Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
| | - Hashem B El-Serag
- Department of Internal Medicine, Baylor College of Medicine, Houston, Texas
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Wang M, Singal AG, Parikh N, Kono Y, Marrero J, Mehta A. A Biomarker Panel Based upon AFP, Fucosylated Kininogen and PEG-Precipitated IgG Is Highly Accurate for the Early Detection Hepatocellular Carcinoma in Patients with Cirrhosis in Phase II and Phase III Biomarker Evaluation. Cancers (Basel) 2022; 14:5970. [PMID: 36497452 PMCID: PMC9740205 DOI: 10.3390/cancers14235970] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/07/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022] Open
Abstract
We have previously identified alterations in glycosylation on serum proteins from patients with HCC and developed plate-based assays using lectins to detect the change in glycosylation. However, heterophilic antibodies, which increase with non-malignant liver disease, compromised these assays. To address this, we developed a method of polyethylene glycol (PEG) precipitation that removed the contaminating IgG and IgM but allowed for the lectin detection of the relevant glycoprotein. We found that this PEG-precipitated material itself could differentiate between cirrhosis and HCC. In the analysis of three training cohorts and one validation cohort, consisting of 571 patients, PEG-IgG had AUC values that ranged from 0.713 to 0.810. In the validation cohort, which contained samples from patients at a time of 1-6 months prior to HCC detection or 7+ months prior to detection, the AUC of this marker remained consistent (0.813 and 0.846, respectively). When this marker was incorporated into a biomarker algorithm that also consisted of AFP and fucosylated kininogen, the AUROC increased to 0.816-0.883 in the training cohort and was 0.909 in the external validation cohort. Biomarker performance was also examined though the analysis of partial ROC curves, at false positive values less than 10% (90-ROC), ≤20% (80-ROC) or ≤30% (70-ROC), which highlighted the algorithm's improvement over the individual markers at clinically relevant specificity values.
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Affiliation(s)
- Mengjun Wang
- Basic Science Building Room 310, Department of Cell and Molecular Pharmacology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, University of Texas Southwestern, 5959 Harry Hines Blvd POB I Suite 420B, Dallas, TX 75201, USA
| | - Neehar Parikh
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yuko Kono
- Division of Gastroenterology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
| | - Jorge Marrero
- Division of Gastroenterology, University of Pennsylvania, 3400 Civic Center Boulevard South Pavilion, 4th Floor, Philadelphia, PA 19104, USA
| | - Anand Mehta
- Basic Science Building Room 310, Department of Cell and Molecular Pharmacology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA
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Kanneganti M, Marrero JA, Parikh ND, Kanwal F, Yokoo T, Mendiratta-Lala M, Rich NE, Gopal P, Singal AG. Clinical outcomes of patients with Liver Imaging Reporting and Data System 3 or Liver Imaging Reporting and Data System 4 observations in patients with cirrhosis: A systematic review. Liver Transpl 2022; 28:1865-1875. [PMID: 35980600 PMCID: PMC9669163 DOI: 10.1002/lt.26562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/23/2022] [Accepted: 07/14/2022] [Indexed: 12/13/2022]
Abstract
Patients with indeterminate liver nodules, classified as LR-3 and LR-4 observations per the Liver Imaging Reporting and Data System, are at risk of developing hepatocellular carcinoma (HCC), but risk estimates remain imprecise. We conducted a systematic review of Ovid MEDLINE, EMBASE, and Cochrane databases from inception to December 2021 to identify cohort studies examining HCC incidence among patients with LR-3 or LR-4 observations on computed tomography (CT) or magnetic resonance imaging (MRI). Predictors of HCC were abstracted from each study, when available. Of 13 total studies, nine conducted LR-3 observation-level analyses, with the proportions of incident HCC ranging from 1.2% to 12.5% at 12 months and 4.2% to 44.4% during longer study follow-up. Among three studies with patient-level analyses, 8%-22.2% of patients with LR-3 lesions developed LR-4 observations and 11.1%-24.5% developed HCC. Among nine studies conducting LR-4 observation-level analyses, incident HCC ranged from 30.8% to 44.0% at 12 months and 30.9% to 71.0% during study follow-up; conversely, 6%-42% of observations were downgraded to LR-3 or lower. Patient-level factors associated with HCC included older age, male sex, higher alpha-fetoprotein levels, viral etiology, and prior history of HCC; observation-level factors included maximum diameter, threshold growth, T2 hyperintensity, and visibility on ultrasound. Studies were limited by small sample sizes, inclusion of patients with prior HCC, short follow-up duration, and failure to account for clustering of observations in patients or competing risks of transplantation and death. LR-3 and LR-4 observations have elevated but variable risks of HCC. Higher quality studies are necessary to identify high-risk patients who warrant close CT or MRI-based follow-up.
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Affiliation(s)
- Mounika Kanneganti
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
| | - Jorge A Marrero
- Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA
| | - Neehar D. Parikh
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Fasiha Kanwal
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX
| | - Takeshi Yokoo
- Department of Radiology, UT Southwestern Medical Center, Dallas, TX
| | | | - Nicole E. Rich
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
| | - Purva Gopal
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX
| | - Amit G. Singal
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
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Kramvis A, Chang KM, Dandri M, Farci P, Glebe D, Hu J, Janssen HLA, Lau DTY, Penicaud C, Pollicino T, Testoni B, Van Bömmel F, Andrisani O, Beumont-Mauviel M, Block TM, Chan HLY, Cloherty GA, Delaney WE, Geretti AM, Gehring A, Jackson K, Lenz O, Maini MK, Miller V, Protzer U, Yang JC, Yuen MF, Zoulim F, Revill PA. A roadmap for serum biomarkers for hepatitis B virus: current status and future outlook. Nat Rev Gastroenterol Hepatol 2022; 19:727-745. [PMID: 35859026 PMCID: PMC9298709 DOI: 10.1038/s41575-022-00649-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/16/2022] [Indexed: 12/13/2022]
Abstract
Globally, 296 million people are infected with hepatitis B virus (HBV), and approximately one million people die annually from HBV-related causes, including liver cancer. Although there is a preventative vaccine and antiviral therapies suppressing HBV replication, there is no cure. Intensive efforts are under way to develop curative HBV therapies. Currently, only a few biomarkers are available for monitoring or predicting HBV disease progression and treatment response. As new therapies become available, new biomarkers to monitor viral and host responses are urgently needed. In October 2020, the International Coalition to Eliminate Hepatitis B Virus (ICE-HBV) held a virtual and interactive workshop on HBV biomarkers endorsed by the International HBV Meeting. Various stakeholders from academia, clinical practice and the pharmaceutical industry, with complementary expertise, presented and participated in panel discussions. The clinical utility of both classic and emerging viral and immunological serum biomarkers with respect to the course of infection, disease progression, and response to current and emerging treatments was appraised. The latest advances were discussed, and knowledge gaps in understanding and interpretation of HBV biomarkers were identified. This Roadmap summarizes the strengths, weaknesses, opportunities and challenges of HBV biomarkers.
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Affiliation(s)
- Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, University of the Witwatersrand, Johannesburg, South Africa.
| | - Kyong-Mi Chang
- The Corporal Michael J. Crescenz Veterans Affairs Medical Center and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Centre for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems partner site, Hamburg, Germany
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Dieter Glebe
- National Reference Center for Hepatitis B Viruses and Hepatitis D Viruses, Institute of Medical Virology, Justus Liebig University Giessen, Giessen, Germany
- German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, Giessen, Germany
| | - Jianming Hu
- Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Philadelphia, PA, USA
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University of Toronto, Toronto, Canada
| | - Daryl T Y Lau
- Division of Gastroenterology and Hepatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Capucine Penicaud
- Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Teresa Pollicino
- Laboratory of Molecular Hepatology, Department of Human Pathology, University Hospital "G. Martino" of Messina, Messina, Italy
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
| | - Florian Van Bömmel
- Department of Hepatology, Leipzig University Medical Center, Leipzig, Germany
| | - Ourania Andrisani
- Basic Medical Sciences, Purdue University, West Lafayette, Indiana, USA
| | | | | | - Henry L Y Chan
- Chinese University of Hong Kong, Shatin, Hong Kong
- Union Hospital, Shatin, Hong Kong
| | | | | | - Anna Maria Geretti
- Roche Pharma Research & Early Development, Basel, Switzerland
- Department of Infectious Diseases, Fondazione PTV, Faculty of Medicine, University of Rome Tor Vergata, Rome, Italy
- Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Adam Gehring
- Toronto Centre for Liver Disease, University Health Network, Toronto, Canada
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | | | - Mala K Maini
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Veronica Miller
- Forum for Collaborative Research, University of California Berkeley School of Public Health, Washington DC Campus, Washington, DC, USA
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich, Helmholtz Zentrum München, Munich, Germany
| | | | - Man-Fung Yuen
- Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Fabien Zoulim
- INSERM Unit 1052 - Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon University, Lyon, France
| | - Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
- Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
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Merritt JC, Richbart SD, Moles EG, Cox AJ, Brown KC, Miles SL, Finch PT, Hess JA, Tirona MT, Valentovic MA, Dasgupta P. Anti-cancer activity of sustained release capsaicin formulations. Pharmacol Ther 2022; 238:108177. [PMID: 35351463 PMCID: PMC9510151 DOI: 10.1016/j.pharmthera.2022.108177] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 03/16/2022] [Accepted: 03/22/2022] [Indexed: 11/17/2022]
Abstract
Capsaicin (trans-8-methyl-N-vanillyl-6-noneamide) is a hydrophobic, lipophilic vanilloid phytochemical abundantly found in chili peppers and pepper extracts. Several convergent studies show that capsaicin displays robust cancer activity, suppressing the growth, angiogenesis and metastasis of several human cancers. Despite its potent cancer-suppressing activity, the clinical applications of capsaicin as a viable anti-cancer drug have remained problematic due to its poor bioavailability and aqueous solubility properties. In addition, the administration of capsaicin is associated with adverse side effects like gastrointestinal cramps, stomach pain, nausea and diarrhea and vomiting. All these hurdles may be circumvented by encapsulation of capsaicin in sustained release drug delivery systems. Most of the capsaicin-based the sustained release drugs have been tested for their pain-relieving activity. Only a few of these formulations have been investigated as anti-cancer agents. The present review describes the physicochemical properties, bioavailability, and anti-cancer activity of capsaicin-sustained release agents. The asset of such continuous release capsaicin formulations is that they display better solubility, stability, bioavailability, and growth-suppressive activity than the free drug. The encapsulation of capsaicin in sustained release carriers minimizes the adverse side effects of capsaicin. In summary, these capsaicin-based sustained release drug delivery systems have the potential to function as novel chemotherapies, unique diagnostic imaging probes and innovative chemosensitization agents in human cancers.
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Affiliation(s)
- Justin C Merritt
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Stephen D Richbart
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Emily G Moles
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Ashley J Cox
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Kathleen C Brown
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Sarah L Miles
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Paul T Finch
- Department of Oncology, Edwards Cancer Center, Joan C. Edwards School of Medicine, Marshall University, 1400 Hal Greer Boulevard, Huntington, WV 25755, United States
| | - Joshua A Hess
- Department of Oncology, Edwards Cancer Center, Joan C. Edwards School of Medicine, Marshall University, 1400 Hal Greer Boulevard, Huntington, WV 25755, United States
| | - Maria T Tirona
- Department of Hematology-Oncology, Edwards Cancer Center, Joan C. Edwards School of Medicine, Marshall University, 1400 Hal Greer Boulevard, Huntington, WV 25755, United States
| | - Monica A Valentovic
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Piyali Dasgupta
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States.
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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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Petralia LMC, Santha E, Behrens AJ, Nguyen DL, Ganatra MB, Taron CH, Khatri V, Kalyanasundaram R, van Diepen A, Hokke CH, Foster JM. Alteration of rhesus macaque serum N-glycome during infection with the human parasitic filarial nematode Brugia malayi. Sci Rep 2022; 12:15763. [PMID: 36131114 PMCID: PMC9491660 DOI: 10.1038/s41598-022-19964-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 09/07/2022] [Indexed: 11/09/2022] Open
Abstract
Serum N-glycan profiling studies during the past decades have shown robust associations between N-glycan changes and various biological conditions, including infections, in humans. Similar studies are scarcer for other mammals, despite the tremendous potential of serum N-glycans as biomarkers for infectious diseases in animal models of human disease and in the veterinary context. To expand the knowledge of serum N-glycan profiles in important mammalian model systems, in this study, we combined MALDI-TOF-MS analysis and HILIC-UPLC profiling of released N-glycans together with glycosidase treatments to characterize the glycan structures present in rhesus macaque serum. We used this baseline to monitor changes in serum N-glycans during infection with Brugia malayi, a parasitic nematode of humans responsible for lymphatic filariasis, in a longitudinal cohort of infected rhesus macaques. Alterations of the HILIC-UPLC profile, notably of abundant structures, became evident as early as 5 weeks post-infection. Given its prominent role in the immune response, contribution of immunoglobulin G to serum N-glycans was investigated. Finally, comparison with similar N-glycan profiling performed during infection with the dog heartworm Dirofilaria immitis suggests that many changes observed in rhesus macaque serum N-glycans are specific for lymphatic filariasis.
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Affiliation(s)
- Laudine M C Petralia
- Division of Protein Expression and Modification, New England Biolabs, Ipswich, MA, 01938, USA.
- Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands.
| | - Esrath Santha
- Division of Protein Expression and Modification, New England Biolabs, Ipswich, MA, 01938, USA
| | - Anna-Janina Behrens
- Division of Protein Expression and Modification, New England Biolabs, Ipswich, MA, 01938, USA
| | - D Linh Nguyen
- Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
| | - Mehul B Ganatra
- Division of Protein Expression and Modification, New England Biolabs, Ipswich, MA, 01938, USA
| | - Christopher H Taron
- Division of Protein Expression and Modification, New England Biolabs, Ipswich, MA, 01938, USA
| | - Vishal Khatri
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL, USA
| | - Ramaswamy Kalyanasundaram
- Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL, USA
| | - Angela van Diepen
- Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
| | - Cornelis H Hokke
- Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands
| | - Jeremy M Foster
- Division of Protein Expression and Modification, New England Biolabs, Ipswich, MA, 01938, USA.
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Mechref Y, Peng W, Gautam S, Ahmadi P, Lin Y, Zhu J, Zhang J, Liu S, Singal AG, Parikh ND, Lubman DM. Mass spectrometry based biomarkers for early detection of HCC using a glycoproteomic approach. Adv Cancer Res 2022; 157:23-56. [PMID: 36725111 PMCID: PMC10014290 DOI: 10.1016/bs.acr.2022.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related mortality worldwide and 80%-90% of HCC develops in patients that have underlying cirrhosis. Better methods of surveillance are needed to increase early detection of HCC and the proportion of patients that can be offered curative therapies. Recent work in novel mass spec-based methods for glycomic and glycopeptide analysis for discovery and confirmation of markers for early detection of HCC versus cirrhosis is reviewed in this chapter. Results from recent work in these fields by several groups and the progress made in developing markers of early HCC which can outperform the current serum-based markers are described and discussed. Also, recent developments in isoform analysis of glycans and glycopeptides and in various mass spec fragmentation methods will be described and discussed.
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Affiliation(s)
- Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States.
| | - Wenjing Peng
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Sakshi Gautam
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Parisa Ahmadi
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX, United States
| | - Yu Lin
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - Jianhui Zhu
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - Jie Zhang
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - Suyu Liu
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan Medical Center, Ann Arbor, MI, United States
| | - David M Lubman
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States.
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Comparative Performance of 14 HCC Prediction Models in CHB: A Dynamic Validation at Serial On-Treatment Timepoints. Am J Gastroenterol 2022; 117:1444-1453. [PMID: 35973147 DOI: 10.14309/ajg.0000000000001865] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 05/27/2022] [Indexed: 12/11/2022]
Abstract
INTRODUCTION To assess comparative performance of 14 hepatocellular carcinoma (HCC) prediction models in chronic hepatitis B (CHB) patients using on-treatment values at different timepoints. METHODS Based on a nationwide prospective cohort of 986 treatment-naive CHB patients undergoing entecavir therapy with every 26-week follow-up, 14 HCC risk scores were calculated using on-treatment values at week 26, 52, 78, and 104, respectively. Model performance predicting 3-year HCC was assessed using time-dependent area under the receiver operating characteristic curve (AUC) and calibration index. Model cutoffs were validated through common diagnostic accuracy measures. RESULTS During median 4.7-year follow-up, 56 (7.5%) developed HCC. Discrimination using on-treatment values within first 2 years was generally acceptable for most models (AUCs ranging from 0.68 to 0.81), except for REACH-B, NGM-HCC, and PAGE-B, although AUCs slightly decreased from week 26 to 104. Of these, REAL-B, CAMD, GAG-HCC, AASL-HCC, LSM-HCC, mPAGE-B, and mREACH-BII showed highest discrimination with AUCs ranging from 0.76 to 0.81, 0.72 to 0.76, 0.70 to 0.76, and 0.71 to 0.74 when reassessment at week 26, 52, 78, and 104, respectively. With reassessment within first 2 years, both REAL-B and CAMD calibrated well (Brier score ranging from 0.037 to 0.052). Of 9 models reporting cutoffs, REAL-B, AASL-HCC, and mPAGE-B using on-treatment values could identify 30%-40% of patients as low risk with minimal HCC incidence in the low-risk group (0.40% [REAL-B]-1.56% [mPAGE-B]). DISCUSSION In this undergoing antiviral treatment CHB cohort, most HCC prediction models performed well even using on-treatment values during first 2 years, particularly REAL-B, AASL-HCC, CAMD, and mPAGE-B model.
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Singal AG, Parikh ND. Reply. Hepatology 2022; 76:E40-E41. [PMID: 35302647 PMCID: PMC9288972 DOI: 10.1002/hep.32462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 03/14/2022] [Indexed: 12/08/2022]
Affiliation(s)
- Amit G. Singal
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
| | - Neehar D. Parikh
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI
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Lin Y, Zhu J, Zhang J, Dai J, Liu S, Arroyo A, Rose M, Singal AG, Parikh ND, Lubman DM. Glycopeptides with Sialyl Lewis Antigen in Serum Haptoglobin as Candidate Biomarkers for Nonalcoholic Steatohepatitis Hepatocellular Carcinoma Using a Higher-Energy Collision-Induced Dissociation Parallel Reaction Monitoring-Mass Spectrometry Method. ACS OMEGA 2022; 7:22850-22860. [PMID: 35811936 PMCID: PMC9261276 DOI: 10.1021/acsomega.2c02600] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/13/2022] [Indexed: 06/15/2023]
Abstract
Nonalcoholic steatohepatitis (NASH) is the fastest growing cause of hepatocellular carcinoma (HCC) in the United States. Changes in N-glycosylation on specific glycosites of serum proteins have been investigated as potential markers for the early detection of NASH-related HCC. Herein, we report a glycopeptide with a Sialyl Lewis structure derived from serum haptoglobin (Hp) as a potential marker for NASH related HCCs among 95 patients with NASH, including 46 cirrhosis, 32 early-stage HCC, and 17 late-stage HCC. Hp immuno-isolated from patient serum was analyzed using LC-HCD-PRM-MS/MS followed by data analysis via Skyline software. Two glycopeptides involving site N184 and four glycopeptides involving site N241 were significantly changed in patients with HCC vs NASH cirrhosis (P < 0.05). The two-marker panel using N-glycopeptide N241_A4G4F2S4 showed the best performance for HCC detection when combined with α-fetoprotein (AFP), with an improved estimated area under the curve (AUC) = 0.898 (95% CI: 0.835, 0.951), compared to the AUC of 0.790(95% CI, 0.697 0.872) using AFP alone (P = 0.048). At 90% specificity, the combination of N241_A4G4F2S4 + AFP had an improved sensitivity of 63.3%, compared to the sensitivity of 52.3% using AFP alone. When using three markers, the panel of AFP + N241_A2G2F1S2 + N241_A4G4F2S4 yielded an estimated AUC of 0.928 (95% CI: 0.877, 0.970). Our findings indicated that N241_A4G4F2S4 may play an important role in distinguishing HCC from NASH cirrhosis.
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Affiliation(s)
- Yu Lin
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United States
| | - Jianhui Zhu
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United States
| | - Jie Zhang
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United States
| | - Jianliang Dai
- Department
of Biostatistics, University of Texas MD
Anderson Cancer Center, Houston, Texas 77030, United States
| | - Suyu Liu
- Department
of Biostatistics, University of Texas MD
Anderson Cancer Center, Houston, Texas 77030, United States
| | - Ana Arroyo
- Department
of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Marissa Rose
- Department
of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Amit G. Singal
- Department
of Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Neehar D. Parikh
- Division
of Gastroenterology and Hepatology, University
of Michigan Medical Center, Ann Arbor, Michigan 48109, United States
| | - David M. Lubman
- Department
of Surgery, University of Michigan Medical
Center, Ann Arbor, Michigan 48109, United States
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Parikh ND, Tayob N, Al-Jarrah T, Kramer J, Melcher J, Smith D, Marquardt P, Liu PH, Tang R, Kanwal F, Singal AG. Barriers to Surveillance for Hepatocellular Carcinoma in a Multicenter Cohort. JAMA Netw Open 2022; 5:e2223504. [PMID: 35867057 PMCID: PMC9308050 DOI: 10.1001/jamanetworkopen.2022.23504] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/02/2022] [Indexed: 01/07/2023] Open
Abstract
Importance Hepatocellular carcinoma (HCC) surveillance is underused in clinical practice, which may be owing to patient and clinician barriers. Objective To characterize HCC surveillance barriers and associations with clinical outcomes in a multicenter cohort of patients with cirrhosis. Design, Setting, and Participants This retrospective, multicenter cohort study included 5 medical centers in the United States. Patients with cirrhosis and newly diagnosed HCC treated from 2014 to 2018 were included. Data were analyzed from June 2021 to February 2022. Exposure Surveillance completion in the 36-month period prior to HCC diagnosis. Main Outcomes and Measures Surveillance receipt was classified as semiannual, annual, or no surveillance. Multivariable logistic regression analysis was used to identify factors associated with semiannual surveillance. We conducted multivariable logistic and Cox regression analyses to characterize associations between surveillance completion with curative treatment and overall survival. Results A total 629 eligible patients (median [IQR] age, 63.6 [56.2-71.0] years; 491 [78.1%] men) were assessed, including 7 American Indian or Alaska Native patients (1.1%), 14 Asian patients (2.2), 176 Black patients (28.0%), 86 Hispanic patients (13.1%), and 340 White patients (54.1%). Nearly two-thirds of the cohort had no surveillance prior to HCC diagnosis (mean [range by site] 63.7% [37.9%-80.4%]), with a mean (range by site) of 14.0% (5.3%-33.3%) of patients having received semiannual surveillance and 22.3% (14.3%-28.8%) of patients having received annual surveillance. The most common reasons for no surveillance were lack of surveillance orders or nonadherence (mean [range by site], 82.4% [66.7%-92.4%], although a mean (range by site) of 17.6% (10.2%-22.1%) of patients had unrecognized cirrhosis at HCC presentation. Semiannual surveillance was associated with hepatitis B infection (odds ratio [OR], 3.06 [95% CI, 1.24-7.23]) and inversely associated with Black race (OR, 0.41 [95% CI, 0.20-0.80]) and lack of cirrhosis recognition (OR, 0.14 [95% CI, 0.02-0.46]). Semiannual HCC surveillance was significantly associated with curative treatment receipt (OR, 2.73 [95% CI, 1.60-4.70]) but not overall survival (HR, 0.81 [95% CI, 0.55-1.18]). Conclusions and Relevance In this cohort study of patients with cirrhosis, HCC surveillance was underused in more than 80% of patients and associated with failures across the screening process. Dedicated programs to improve cirrhosis detection and HCC surveillance attainment are needed.
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Affiliation(s)
- Neehar D. Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor
| | - Nabihah Tayob
- Department of Biostatistics, Dana Farber Cancer Center, Boston, Massachusetts
| | - Taim Al-Jarrah
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor
| | - Jennifer Kramer
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas
| | - Jennifer Melcher
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas
| | - Donna Smith
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas
| | - Patrick Marquardt
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
| | - Po-Hong Liu
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
| | - Runlong Tang
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Fasiha Kanwal
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, Texas
- Division of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Amit G. Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
- Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas
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Singal AG, Zhang E, Narasimman M, Rich NE, Waljee AK, Hoshida Y, Yang JD, Reig M, Cabibbo G, Nahon P, Parikh ND, Marrero JA. HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: A meta-analysis. J Hepatol 2022; 77:128-139. [PMID: 35139400 PMCID: PMC9232881 DOI: 10.1016/j.jhep.2022.01.023] [Citation(s) in RCA: 198] [Impact Index Per Article: 66.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS There is controversy regarding the overall value of hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis given the lack of data from randomized-controlled trials. To address this issue, we conducted a systematic review and meta-analysis of cohort studies evaluating the benefits and harms of HCC surveillance in patients with cirrhosis. METHODS We performed a search of the Medline and EMBASE databases and national meeting abstracts from January 2014 through July 2020 for studies reporting early-stage HCC detection, curative treatment receipt, or overall survival, stratified by HCC surveillance status, among patients with cirrhosis. Pooled risk ratios (RRs) and hazard ratios, according to HCC surveillance status, were calculated for each outcome using the DerSimonian and Laird method for random effects models. RESULTS We identified 59 studies including 145,396 patients with HCC, which was detected by surveillance in 41,052 (28.2%) cases. HCC surveillance was associated with improved early-stage detection (RR 1.86, 95% CI 1.73-1.98; I2 = 82%), curative treatment receipt (RR 1.83, 95% CI 1.69-1.97; I2 = 75%), and overall survival (hazard ratio 0.67, 95% CI 0.61-0.72; I2 = 78%) after adjusting for lead-time bias; however, there was notable heterogeneity in all pooled estimates. Four studies examined surveillance-related physical harms due to false positive or indeterminate surveillance results, but no studies examined potential financial or psychological harms. The proportion of patients experiencing surveillance-related physical harms ranged from 8.8% to 27.5% across studies, although most harms were mild in severity. CONCLUSION HCC surveillance is associated with improved early detection, curative treatment receipt, and survival in patients with cirrhosis, although there was heterogeneity in pooled estimates. Available data suggest HCC surveillance is of high value in patients with cirrhosis, although continued rigorous studies evaluating benefits and harms are still needed. LAY SUMMARY There has been ongoing debate about the overall value of hepatocellular carcinoma (HCC) screening in patients with cirrhosis given the lack of data from randomized-controlled trials. In a systematic review of contemporary cohort studies, we found that HCC screening is associated with improved early detection, curative treatment receipt, and survival in patients with cirrhosis, although there were fewer data quantifying potential screening-related harms. Available data suggest HCC screening is of high value in patients with cirrhosis, although continued studies evaluating benefits and harms are still needed.
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Affiliation(s)
- Amit G Singal
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States.
| | - Emily Zhang
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States
| | - Manasa Narasimman
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States
| | - Nicole E Rich
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States
| | - Akbar K Waljee
- Department of Internal Medicine, University of Michigan, Ann Arbor MI, United States
| | - Yujin Hoshida
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai, Los Angeles, CA, United States
| | - Maria Reig
- Barcelona Clinic Liver Cancer (BCLC) Group, Hospital Clinic de Barcelona, CIBEREEHD, Barcelona University, Barcelona, Spain
| | - Giuseppe Cabibbo
- Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Pierre Nahon
- AP-HP, Hôpital Avicenne, Liver Unit, Université Sorbonne Paris Nord, Bobigny, France; Inserm, UMR-1138 Université de Paris, Paris, France
| | - Neehar D Parikh
- Department of Internal Medicine, University of Michigan, Ann Arbor MI, United States
| | - Jorge A Marrero
- Department of Internal Medicine, University of Pennsylvania, Philadelphia PA, United States
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Schoenberger H, Chong N, Fetzer DT, Rich NE, Yokoo T, Khatri G, Olivares J, Parikh ND, Yopp AC, Marrero JA, Singal AG. Dynamic Changes in Ultrasound Quality for Hepatocellular Carcinoma Screening in Patients With Cirrhosis. Clin Gastroenterol Hepatol 2022; 20:1561-1569.e4. [PMID: 34119640 PMCID: PMC8660956 DOI: 10.1016/j.cgh.2021.06.012] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/24/2021] [Accepted: 06/08/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Identifying patients in whom ultrasound may be inadequate to exclude the presence of hepatocellular carcinoma (HCC) can inform interventions to improve screening effectiveness. We aimed to characterize correlates of suboptimal ultrasound quality and changes in ultrasound quality over time in patients with cirrhosis undergoing HCC screening. METHODS We performed a retrospective cohort study of patients with cirrhosis who underwent ultrasound examination at 2 large health systems between July 2016 and July 2019. Exam adequacy was graded by radiologists using the LI-RADS Visualization Score (A, B, C); we evaluated changes in visualization over time among patients with >1 ultrasound exams. We performed multivariable logistic regression to identify characteristics associated with limited ultrasound visualization (scores B or C). RESULTS Of 2053 cirrhosis patients, 1685 (82.1%) had ultrasounds with score A, 262 (12.8%) had score B, and 106 (5.2%) had score C. Limited visualization was associated with alcohol-related or nonalcoholic fatty liver disease cirrhosis and presence of class II-III obesity. Among 1546 patients with >1 ultrasounds, 1129 (73.0%) had the same visualization score on follow-up (1046 score A, 60 score B, 23 score C). However, 255 (19.6%) of 1301 with score A at baseline had limited visualization when repeated (230 score B, 25 score C), and 130 (53.1%) of 245 patients with baseline limited visualization had good visualization when repeated. CONCLUSIONS Nearly 1 in 5 patients with cirrhosis had moderately-severely limited ultrasound visualization for HCC nodules, particularly those with obesity or alcohol-related or nonalcoholic fatty liver disease cirrhosis. Ultrasound quality can change between exams, including improvement in many patients with limited visualization.
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Affiliation(s)
- Haley Schoenberger
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas; Parkland Health & Hospital System, Dallas, Texas
| | - Nicolas Chong
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas; Parkland Health & Hospital System, Dallas, Texas
| | - David T Fetzer
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas
| | - Nicole E Rich
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas; Parkland Health & Hospital System, Dallas, Texas
| | - Takeshi Yokoo
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas
| | - Gaurav Khatri
- Department of Radiology, UT Southwestern Medical Center, Dallas, Texas
| | - Jocelyn Olivares
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Neehar D Parikh
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Adam C Yopp
- Department of Surgery, UT Southwestern Medical Center, Dallas, Texas
| | - Jorge A Marrero
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Amit G Singal
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas; Parkland Health & Hospital System, Dallas, Texas.
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50
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Melendez-Torres J, Singal AG. Early detection of hepatocellular carcinoma: roadmap for improvement. Expert Rev Anticancer Ther 2022; 22:621-632. [PMID: 35514249 PMCID: PMC9845108 DOI: 10.1080/14737140.2022.2074404] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) has a poor prognosis, related, in part, to frequent late-stage diagnosis. Improved implementation of effective HCC surveillance is critical to reduce HCC mortality. AREAS COVERED We performed a targeted literature review to identify intervention targets for improving HCC surveillance effectiveness, including enriched risk stratification tools, improved surveillance tools with higher accuracy for early HCC detection, and increasing surveillance adherence. EXPERT OPINION HCC surveillance has been demonstrated to be efficacious in several cohort studies but has lower surveillance effectiveness in clinical practice. HCC surveillance is currently recommended in all patients with cirrhosis, and improved risk stratification using clinical risk scores, genetic scores, and novel biomarkers are important to move from a 'one-size-fits-all' strategy to one more aligned with values of precision medicine. Current surveillance modalities, ultrasound, and AFP, miss over one-third of HCC at an early stage and are associated with potential surveillance harms, underscoring a need for alternative surveillance strategies with higher accuracy. MRI- and biomarker-based surveillance strategies have promising early data in phase II studies but require validation in phase III cohorts before routine use in practice. Finally, surveillance is underused in clinical practice, highlighting a need for intervention strategies to increase utilization.
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