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1
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Chen ZJ, Wang XK, Han CY, He YF, Liang TY, Mo ST, Zhu GZ, Yang CK, Ye XP, Lv ZL, Pang SF, Chen XD, Wang P, Peng T. Diagnostic value of alpha-fetoprotein and prothrombin induced by vitamin K absence-II in serum, bile, and feces in hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:105311. [DOI: 10.4251/wjgo.v17.i5.105311] [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: 01/17/2025] [Revised: 03/06/2025] [Accepted: 03/18/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common pathological type of liver cancer and was the third leading cause of cancer-related deaths worldwide in 2020.
AIM To evaluate the diagnostic potential of key tumor markers in serum, bile, and fecal samples for detecting HCC.
METHODS Blood, bile, and fecal samples were collected from patients (n = 265) with HCC and cholecystitis from Guangxi Medical University’s First Affiliated Hospital. Immunohistochemistry was performed on 69 HCC samples, and 16S ribosomal RNA sequencing was conducted on 166 fecal samples. Tumor marker cut-off values in bile and feces were determined using the Youden index, while serum biomarkers followed hospital standards. Diagnostic performance was evaluated using receiver operating characteristic analysis.
RESULTS The areas under the curve (AUCs) for distinguishing HCC were 0.898, 0.904, and 0.859 for serum alpha-fetoprotein (AFP), prothrombin induced by vitamin K absence-II (PIVKA-II), and bile AFP, respectively. Serum AFP had the highest diagnostic value (80%) for early-stage HCC. Combination analysis found that bile AFP and serum PIVKA-II achieved the highest AUC of 0.965 (P < 0.001), suggesting that bile AFP may serve as a valuable complementary biomarker, particularly in cases where serum AFP is not significantly elevated. Additionally, bile AFP was positively correlated with Actinomyces, which plays a significant role in promoting tumorigenesis; and was negatively correlated with Faecalibacterium, which was associated with robust anticancer immune responses (P < 0.05). These findings suggest the potential role of gut microbiota in modulating AFP levels and HCC progression.
CONCLUSION Bile AFP improved the sensitivity of HCC detection, with the combination of bile AFP and PIVKA-II demonstrating the highest AUC for HCC diagnosis. AFP is associated with poorer clinical outcomes.
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Affiliation(s)
- Zi-Jun Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiang-Kun Wang
- Departments of Hepatobiliary Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Chuang-Ye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yong-Fei He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tian-Yi Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shu-Tian Mo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Cheng-Kun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Xin-Ping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zi-Li Lv
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shi-Fu Pang
- AIage Life Science Corporation Ltd., Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Xiao-Dong Chen
- AIage Life Science Corporation Ltd., Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Peng Wang
- Department of Health Management and Division of Physical Examination, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
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2
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Davis E, Ermi AG, Sarkar D. Astrocyte Elevated Gene-1/Metadherin (AEG-1/MTDH): A Promising Molecular Marker and Therapeutic Target for Hepatocellular Carcinoma. Cancers (Basel) 2025; 17:1375. [PMID: 40282551 PMCID: PMC12025727 DOI: 10.3390/cancers17081375] [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: 03/10/2025] [Revised: 04/16/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. The 5-year survival rate has been estimated to be less than 20% while its incidence rates have more than tripled since the 1980s. Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) has been demonstrated to have an influential role in HCC progression and the development of an aggressive phenotype. AEG-1 has been shown to be upregulated in many cancers, including HCC. Studies have shown that it plays a crucial role in the proliferation, invasion and metastasis, and evasion of apoptosis in HCC. Its relationship with proteins and pathways, such as MYC, SND1, PI3K/AKT, and other signaling pathways demonstrates its pertinent role in oncogenic development and relevance as a biomarker and therapeutic target. Recent studies have shown that AEG-1 is present in tumor tissues, and the anti-AEG-1 antibody is detected in the blood of cancer patients, demonstrating its viability as a diagnostic/prognostic marker. This review paper shines light on recent findings regarding the molecular implications of AEG-1, with emphasis on its role of regulating metabolic dysfunction-associated steatohepatitis (MASH), a key predisposing factor for HCC, new treatment strategies targeting AEG-1, and challenges associated with analyzing this intriguing molecule.
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Affiliation(s)
- Eva Davis
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Ali Gawi Ermi
- Department of Cellular, Molecular and Genetic Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Department of Cellular, Molecular and Genetic Medicine, Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
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3
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Ueda K, Oikawa T, Yamada K, Tsubota A, Saeki C, Katagiri K, Tago N, Matsumoto A, Mikuni H, Ishikawa M, Nishimura T, Sawada R, Haruki K, Furukawa K, Kamioka H, Nakagawa C, Nakano M, Mitsunaga M, Torisu Y, Ikegami T, Yoshida K, Saruta M. Serum PKCδ is a useful biomarker to distinguish hepatocellular carcinoma from other gastrointestinal cancers. Biochem Biophys Res Commun 2025; 751:151431. [PMID: 39908908 DOI: 10.1016/j.bbrc.2025.151431] [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: 07/17/2024] [Revised: 07/19/2024] [Accepted: 01/30/2025] [Indexed: 02/07/2025]
Abstract
Protein kinase C delta (PKCδ) is a leaderless protein generally localized in the cytoplasm and nucleus; however, its extracellular unconventional protein secretion occurs exclusively in hepatocellular carcinoma (HCC) cells (but not in normal and non-cancerous hepatocytes or other gastrointestinal cancer cells) via an autophagy mechanism, despite the lack of a secretory signal. Therefore, PKCδ is detectable in the peripheral blood of HCC patients. Serum PKCδ indicates cancer-related unconventional protein secretion of an inactive form of cytosolic PKCδ and can be a unique biomarker independent of conventional markers. To examine the specificity of serum PKCδ for HCC, its levels and positivity rates were compared between 226 HCC and 108 gastrointestinal cancer patients. Furthermore, we focused on patients with malignant or benign intrahepatic tumors (17 intrahepatic cholangiocarcinoma, 42 liver metastases, and 6 focal nodular hyperplasia). A sandwich enzyme-linked immunosorbent assay was used to measure serum PKCδ levels; the optimal cutoff value was set to 57.7 ng/mL. HCC patients had significantly higher PKCδ levels and positivity rates than gastrointestinal cancer patients (median, 51.1 vs. 34.6 ng/mL; 39.8 % vs. 4.6 %; P < 0.001 for both). Thus, the specificity was 95.4 %. Focusing on intrahepatic tumors, 2 (4.8 %) of 42 gastrointestinal cancer patients with liver metastasis were positive for PKCδ. Notably, all patients with intrahepatic cholangiocarcinoma and focal nodular hyperplasia were negative for PKCδ, irrespective of their intrahepatic tumors being malignant or benign. Serum PKCδ is an extracellularly secreted protein specific for HCC that can be a novel diagnostic biomarker because it distinguishes HCC from other gastrointestinal cancers and intrahepatic non-HCC tumors.
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Affiliation(s)
- Kaoru Ueda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tsunekazu Oikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
| | - Kohji Yamada
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Akihito Tsubota
- Project Research Units, Research Center for Medical Science, The Jikei University School of Medicine, Tokyo, Japan
| | - Chisato Saeki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kuniko Katagiri
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Naoko Tago
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Ayano Matsumoto
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Hayato Mikuni
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Masashi Ishikawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takashi Nishimura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Ryoichi Sawada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Koichiro Haruki
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Kenei Furukawa
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Hiroshi Kamioka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Chika Nakagawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Masanori Nakano
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Makoto Mitsunaga
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Yuichi Torisu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Toru Ikegami
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan
| | - Kiyotsugu Yoshida
- Department of Biochemistry, The Jikei University School of Medicine, Tokyo, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
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4
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Park C, Hwang G, Choi WM, Han JE, Kim C, Lee DY, Heo S, Park RW. Baseline Alpha-Fetoprotein Elevation and the Risk of Hepatocellular Carcinoma in Chronic Hepatitis B: A Multicentre Cohort Study. J Viral Hepat 2025; 32:e70006. [PMID: 39878696 DOI: 10.1111/jvh.70006] [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: 11/12/2024] [Accepted: 01/16/2025] [Indexed: 01/31/2025]
Abstract
Alpha-fetoprotein (AFP) level and its changes in chronic hepatitis B (CHB) may influence the risk of future hepatocellular carcinoma (HCC). This study aims to evaluate the HCC risk in CHB patients with no overt HCC but with elevated AFP level and to explore the prognostic role of longitudinal changes in AFP and liver-related laboratory values. This multicentre cohort study included 10,639 CHB patients without a history of HCC from seven medical facilities in South Korea. Patients with a baseline serum AFP test and no HCC diagnosis on imaging within 3 months were included. Patients were categorised into high-AFP (≥ 10 ng/mL) and normal-AFP (< 10 ng/mL) groups. The primary outcome was the incidence of HCC within 2 years, with secondary outcomes focused on longitudinal changes in AFP and liver-related laboratory values. Propensity score matching (PSM) and Cox proportional hazard models were used to assess HCC risk. After 1:4 PSM, 1278 high-AFP and 3731 normal-AFP patients were analysed. The high-AFP group had a significantly higher 2-year incidence of HCC (HR: 4.29; 95% CI: 3.31-5.57). AFP levels increased in patients who developed HCC in both groups (p < 0.01). Among the high-AFP group, patients who did not develop HCC had elevated baseline alanine aminotransferase levels (p < 0.01), which decreased during follow-up (p < 0.01) unlike those who developed HCC. In conclusion, baseline AFP elevation in CHB patients is associated with an increased risk of developing HCC within 2 years. Longitudinal monitoring of AFP and liver-related laboratory values can help in risk stratification.
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Affiliation(s)
- ChulHyoung Park
- Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Gyubeom Hwang
- Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ji Eun Han
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Chungsoo Kim
- Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut, USA
| | - Dong Yun Lee
- Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Subin Heo
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Rae Woong Park
- Department of Biomedical Informatics, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Sciences, Ajou University Graduate School of Medicine, Suwon, Republic of Korea
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5
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Shin H, Yu SJ. A concise review of updated global guidelines for the management of hepatocellular carcinoma: 2017-2024. JOURNAL OF LIVER CANCER 2025; 25:19-30. [PMID: 39925090 PMCID: PMC12010826 DOI: 10.17998/jlc.2025.02.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 01/30/2025] [Accepted: 02/03/2025] [Indexed: 02/11/2025]
Abstract
Many guidelines for hepatocellular carcinoma (HCC) have been published and are regularly updated worldwide. HCC management involves a broad range of treatment options and requires multidisciplinary care, resulting in significant heterogeneity in management practices across international communities. To support standardized care for HCC, we systematically appraised 13 globally recognized guidelines and expert consensus statements, including five from Asia, four from Europe, and four from the United States. These guidelines share similarities but reveal notable discrepancies in surveillance strategies, treatment allocation, and other recommendations. Geographic differences in tumor biology (e.g., prevalence of viral hepatitis, alcohol-related liver disease, or metabolic dysfunction-associated steatotic liver disease) and disparities in available medical resources (e.g., organ availability, healthcare infrastructure, and treatment accessibility) complicate the creation of universally applicable guidelines. Previously, significant gaps existed between Asian and Western guidelines, particularly regarding treatment strategies. However, these differences have diminished over the years. Presently, variations are often more attributable to publication dates than to regional differences. Nonetheless, Asia-Pacific experts continue to diverge from the Barcelona Clinic Liver Cancer system, particularly with respect to surgical resection and locoregional therapies, which are viewed as overly conservative in Western guidelines. Advancements in systemic therapies have prompted ongoing updates to these guidelines. Given that each set of guidelines reflects distinct regional characteristics, strengths, and limitations, fostering collaboration and mutual complementarity is essential for addressing discrepancies and advancing global HCC care.
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Affiliation(s)
- Hyunjae Shin
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Liver Research Institute, Seoul National University, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Liver Research Institute, Seoul National University, Seoul, Korea
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6
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Zhang B, Ma X, Zhou Y, Zhu B, Yu J, Liu H, Ma Y, Luan Y, Chen M. Diagnostic Value of Circulating microRNAs for Hepatocellular Carcinoma: Results of a Meta-analysis and Validation. Biochem Genet 2025:10.1007/s10528-024-11001-2. [PMID: 39751721 DOI: 10.1007/s10528-024-11001-2] [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: 09/24/2024] [Accepted: 12/09/2024] [Indexed: 01/04/2025]
Abstract
Mounting evidence suggests that circulating microRNAs (miRNAs) hold diagnostic value in various malignancies. To identify circulating miRNAs for the early diagnosis of hepatocellular carcinoma (HCC), we conducted a meta-analysis to evaluate the diagnostic utility of miRNAs in HCC and further validated the results of the meta-analysis. English articles published prior to December 2023 were retrieved from databases including PubMed, Embase, and Web of Science. A random-effects or fixed-effects model was applied depending on the heterogeneity among studies. The pooled sensitivity, specificity, and the area under the summary receiver operating characteristic curve (AUC) were calculated to assess diagnostic accuracy. Additionally, RT-qPCR and receiver operating characteristic (ROC) analyses were employed to further validate the findings. A total of 36 studies were included, involving 3362 patients with HCC and 2150 patients with chronic hepatitis. The pooled sensitivity, specificity, and diagnostic odds ratio were 0.79 (95% CI 0.75-0.82), 0.79 (95% CI 0.73-0.84), and 14 (95% CI 9-22), respectively; the positive and negative likelihood ratios were 4.0 and 0.27, respectively; the area under the curve (AUC) in the summary receiver operating characteristic (ROC) was 0.85 (95% CI 0.82-0.88). Validation indicated a significant upregulation of miR-1246, miR-21, and miR-221 in HCC patients compared to those with chronic hepatitis (P < 0.01), while miR-122 and miR-26a were significantly downregulated (P < 0.01). Moreover, the validation results also demonstrated that serum levels of miR-21, miR-26a, miR-122, miR-221, and miR-1246 exhibit high sensitivity and specificity in the diagnosis of HCC. Circulating miRNAs may be promising biomarkers for HCC diagnosis.
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Affiliation(s)
- Bingqiang Zhang
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - Xiaoyan Ma
- Department of Oncology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266111, Shandong, People's Republic of China
| | - Yang Zhou
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - Boyang Zhu
- School of Clinical and Basic Medical Sciences, Shandong First Medical, University& Shandong Academy of Medical Sciences, Jinan, 250117, Shandong, People's Republic of China
| | - Junmei Yu
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - He Liu
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China
| | - Yongchao Ma
- College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao, 266111, Shandong, People's Republic of China
| | - Yansong Luan
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China.
| | - Mengmeng Chen
- Qingdao Ruiside Medical Laboratory Co., LTD, Qingdao, 266111, Shandong, People's Republic of China.
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7
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Morkunas E, Vaitkeviciute E, Inciuraite R, Kupcinskas J, Link A, Skieceviciene J, Alunni-Fabbroni M, Schütte K, Malfertheiner P, Varkalaite G, Ricke J. miRNome Profiling Analysis Reveals Novel Hepatocellular Carcinoma Diagnostic, Prognostic and Treatment-Related Candidate Biomarkers: Post hoc Analysis of SORAMIC Trial. Dig Dis 2024; 42:336-348. [PMID: 38657585 DOI: 10.1159/000538757] [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: 10/13/2023] [Accepted: 03/26/2024] [Indexed: 04/26/2024]
Abstract
INTRODUCTION Early diagnosis of hepatocellular carcinoma (HCC) as well as evaluation of prognosis and prediction of treatment efficacy remains challenging due to the missing specific non-invasive biomarkers. The aim of this study was to identify disease-specific microRNA (miRNA) patterns for diagnosis, prediction of prognosis, and treatment response in patients with HCC. METHODS The study population included 42 HCC patients from SORAMIC clinical trial: 22 patients received sorafenib monotherapy, 20 patients underwent 90Y radioembolization in combination with sorafenib. 20 individuals were included in the control group. HCC patients underwent collection of plasma samples before and 7-9 weeks after the beginning of the treatment. Isolation of circulating miRNAs, preparation of small RNA sequencing libraries and next-generation sequencing were performed. Association analysis for novel diagnostic, prognostic, and treatment-related candidate biomarkers was performed. RESULTS A total of 42 differentially expressed (16 up-regulated and 26 down-regulated) miRNAs were identified comparing baseline and control group plasma samples. hsa-miR-215-5p and hsa-miR-192-5p were down-regulated, while hsa-miR-483-5p and hsa-miR-23b-3p were up-regulated comparing baseline and 7-9 weeks post-sorafenib monotherapy samples. hsa-miR-215-5p was the sole down-regulated miRNA in the same combination therapy comparison. hsa-miR-183-5p, hsa-miR-28-3p, and hsa-miR-1246 were found to be significantly up-regulated comparing non-responders versus responders to sorafenib. High hsa-miR-215-5p expression was significantly associated with worse HCC patients' prognosis. CONCLUSIONS Systematic miRNA profiling of highly characterized samples from SORAMIC study revealed a subset of potential miRNA biomarkers for HCC diagnosis and prognosis of sorafenib-treated patients' survival.
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Affiliation(s)
- Egidijus Morkunas
- Institute for Digestive Research and Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Evelina Vaitkeviciute
- Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Ruta Inciuraite
- Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Juozas Kupcinskas
- Institute for Digestive Research and Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Jurgita Skieceviciene
- Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | | | - Kerstin Schütte
- Department of Internal Medicine and Gastroenterology, Niels-Stensen-Kliniken Marienhospital, Osnabrück, Germany
- Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Peter Malfertheiner
- Department of Internal Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Greta Varkalaite
- Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
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8
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Lumkul L, Jantaree P, Jaisamak K, Wongkummool W, Lapisatepun W, Orrapin S, Udomruk S, Lo Piccolo L, Chaiyawat P. Combinatorial Gene Expression Profiling of Serum HULC, HOTAIR, and UCA1 lncRNAs to Differentiate Hepatocellular Carcinoma from Liver Diseases: A Systematic Review and Meta-Analysis. Int J Mol Sci 2024; 25:1258. [PMID: 38279264 PMCID: PMC10816616 DOI: 10.3390/ijms25021258] [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: 12/27/2023] [Revised: 01/11/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) presents a significant global health challenge due to limited early detection methods, primarily relying on conventional approaches like imaging and alpha-fetoprotein (AFP). Although non-coding RNAs (ncRNAs) show promise as potential biomarkers in HCC, their true utility remains uncertain. We conducted a comprehensive review of 76 articles, analyzing 88 circulating lncRNAs in 6426 HCC patients. However, the lack of a standardized workflow protocol has hampered holistic comparisons across the literature. Consequently, we herein confined our meta-analysis to only a subset of these lncRNAs. The combined analysis of serum highly upregulated in liver cancer (HULC) gene expression with homeobox transcript antisense intergenic RNA (HOTAIR) and urothelial carcinoma-associated 1 (UCA1) demonstrated markedly enhanced sensitivity and specificity in diagnostic capability compared to traditional biomarkers or other ncRNAs. These findings could have substantial implications for the early diagnosis and tailored treatment of HCC.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Liver Neoplasms/diagnosis
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- RNA, Long Noncoding/metabolism
- Genes, Homeobox
- RNA, Antisense
- Carcinoma, Transitional Cell/genetics
- Gene Expression Regulation, Neoplastic
- Urinary Bladder Neoplasms/genetics
- RNA, Untranslated
- Biomarkers
- Gene Expression Profiling
- Biomarkers, Tumor/genetics
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Affiliation(s)
- Lalita Lumkul
- Center of Multidisciplinary Technology for Advanced Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (L.L.); (P.J.); (K.J.); (W.W.); (S.O.); (S.U.)
- Center for Clinical Epidemiology and Clinical Statistics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Phatcharida Jantaree
- Center of Multidisciplinary Technology for Advanced Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (L.L.); (P.J.); (K.J.); (W.W.); (S.O.); (S.U.)
| | - Kritsada Jaisamak
- Center of Multidisciplinary Technology for Advanced Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (L.L.); (P.J.); (K.J.); (W.W.); (S.O.); (S.U.)
| | - Wasinee Wongkummool
- Center of Multidisciplinary Technology for Advanced Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (L.L.); (P.J.); (K.J.); (W.W.); (S.O.); (S.U.)
| | - Worakitti Lapisatepun
- Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand;
| | - Santhasiri Orrapin
- Center of Multidisciplinary Technology for Advanced Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (L.L.); (P.J.); (K.J.); (W.W.); (S.O.); (S.U.)
| | - Sasimol Udomruk
- Center of Multidisciplinary Technology for Advanced Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (L.L.); (P.J.); (K.J.); (W.W.); (S.O.); (S.U.)
| | - Luca Lo Piccolo
- Center of Multidisciplinary Technology for Advanced Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (L.L.); (P.J.); (K.J.); (W.W.); (S.O.); (S.U.)
| | - Parunya Chaiyawat
- Center of Multidisciplinary Technology for Advanced Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; (L.L.); (P.J.); (K.J.); (W.W.); (S.O.); (S.U.)
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9
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Yazdanpanah O, Lee FC, Houshyar R, Nourbakhsh M, Mar N. A case report of challenges in distinguishing gastroesophageal junction hepatoid adenocarcinoma from testicular germ cell tumor: Insights for improved diagnosis with gene expression profiling. SAGE Open Med Case Rep 2024; 12:2050313X231223469. [PMID: 38187811 PMCID: PMC10768574 DOI: 10.1177/2050313x231223469] [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: 08/16/2023] [Accepted: 12/11/2023] [Indexed: 01/09/2024] Open
Abstract
Gastroesophageal junction hepatoid adenocarcinoma is a rare form of gastroesophageal cancer. We present a case of a 38-year-old man with no significant medical history who was diagnosed with gastroesophageal junction hepatoid adenocarcinoma but initially misdiagnosed with a testicular germ cell tumor, given the elevated alpha-feto protein and poorly differentiated pathology. We will elaborate on the importance of gene expression profiling in modern oncology to better define the tumor of origin in patients with cancer of unknown primary origin, how it helped us to diagnose gastroesophageal junction hepatoid adenocarcinoma and how it can help identify potential additional therapeutic targets in some cases. Due to the rarity of this subtype of gastroesophageal junction cancer there is a lack of standard therapeutic options, and we will discuss the most commonly used treatment regimens. The patient underwent three lines of antineoplastic therapy and unfortunately passed after 51 weeks of follow-up.
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Affiliation(s)
- Omid Yazdanpanah
- Division of Hematology and Oncology, UC Irvine Medical Center, Orange, CA, USA
| | - Fa-Chyi Lee
- Division of Hematology and Oncology, UC Irvine Medical Center, Orange, CA, USA
| | - Roozbeh Houshyar
- Department of Radiology, UC Irvine Medical Center, Orange, CA, USA
| | - Mahra Nourbakhsh
- Department of Pathology, UC Irvine Medical Center, Orange, CA, USA
| | - Nataliya Mar
- Division of Hematology and Oncology, UC Irvine Medical Center, Orange, CA, USA
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10
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Koh JH, Wang M, Suzuki H, Muthiah M, Ng CH, Huang DQ. NAFLD and NAFLD-related HCC in Asia: Burden and Surveillance. J Clin Exp Hepatol 2024; 14:101213. [PMID: 38076360 PMCID: PMC10701133 DOI: 10.1016/j.jceh.2023.06.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 06/30/2023] [Indexed: 06/21/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is rapidly emerging as a leading etiology of chronic liver disease (CLD) in Asia. The increasing incidence of NAFLD is projected to drive a surge in NAFLD-related hepatocellular carcinoma (HCC). A notable characteristic of NAFLD-HCC is its capacity for development in individuals without cirrhosis in more than a third of patients. Most practice guidelines recommend biannual ultrasound screening for patients with cirrhosis. In cases of severe limitations to ultrasound visualisation, cross-sectional abdominal imaging may be warranted. Improved strategies for HCC risk stratification are required for people with NAFLD but without cirrhosis. In this Review, we discuss the evolving trends of NAFLD and HCC in Asia, and implications for surveillance.
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Affiliation(s)
- Jia H. Koh
- Department of Medicine, National University Hospital, Singapore, Singapore
| | - Meng Wang
- Department of Medicine, National University Hospital, Singapore, Singapore
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Cheng H. Ng
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Daniel Q. Huang
- NAFLD Research Center, University of California at San Diego, USA
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11
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Zhang Y, Wang JW, Su X, Li JE, Wei XF, Yang JR, Gao S, Fan YC, Wang K. F-box protein 43 promoter methylation as a novel biomarker for hepatitis B virus-associated hepatocellular carcinoma. Front Microbiol 2023; 14:1267844. [PMID: 38029156 PMCID: PMC10652413 DOI: 10.3389/fmicb.2023.1267844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) has a high prevalence and poor prognosis worldwide. Therefore, it is urgent to find effective and timely diagnostic markers. The objective of this study was to evaluate the diagnostic value of F-box protein 43 promoter methylation in peripheral blood mononuclear cells (PBMCs) for HCC. METHOD A total of 247 participants were included in this study, comprising individuals with 123 hepatitis B virus-associated HCC, 79 chronic hepatitis B, and 45 healthy controls. F-box protein 43 methylation and mRNA levels in PBMCs were detected by MethyLight and quantitative real-time PCR. RESULT F-box protein 43 promoter methylation levels were significantly lower in HCC PBMCs than the chronic hepatitis B (P < 0.001) and healthy control PBMCs (P < 0.001). Relative mRNA expression levels of F-box protein 43 in HCC PBMCs were significantly higher than those in chronic hepatitis B (P < 0.001) and healthy control PBMCs (P < 0.001). Receiver operating characteristic analysis of F-box protein 43 promoter methylation levels yielded an area under curve (AUC) of 0.793 with 76.42% sensitivity and 68.35% specificity when differentiating HCC from chronic hepatitis. These values for the F-box protein 43 promoter methylation level were superior to those of the alpha-fetoprotein serum (AFP) level (AUC: 0.780, sensitivity: 47.97%, and specificity: 96.20%), with increments in values for the combination of F-box protein 43 promoter methylation AFP levels (AUC: 0.888, sensitivity: 76.42%, and specificity: 86.08%). CONCLUSION Hypomethylation of the F-box protein 43 promoter in PBMCs is a promising biochemical marker for HBV-associated HCC.
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Affiliation(s)
- Ying Zhang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Jing-Wei Wang
- Department of Hepatology, Qilu Hospital (Qingdao) of Shandong University, Qingdao, China
| | - Xing Su
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Jin-E Li
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Xue-Fei Wei
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Jie-Ru Yang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Shuai Gao
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Hepatology Institute of Shandong University, Shandong University, Jinan, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Hepatology Institute of Shandong University, Shandong University, Jinan, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Department of Hepatology, Qilu Hospital (Qingdao) of Shandong University, Qingdao, China
- Hepatology Institute of Shandong University, Shandong University, Jinan, China
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12
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Téllez L, Payancé A, Tjwa E, Del Cerro MJ, Idorn L, Ovroutski S, De Bruyne R, Verkade HJ, De Rita F, de Lange C, Angelini A, Paradis V, Rautou PE, García-Pagán JC. EASL-ERN position paper on liver involvement in patients with Fontan-type circulation. J Hepatol 2023; 79:1270-1301. [PMID: 37863545 DOI: 10.1016/j.jhep.2023.07.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 07/06/2023] [Indexed: 10/22/2023]
Abstract
Fontan-type surgery is the final step in the sequential palliative surgical treatment of infants born with a univentricular heart. The resulting long-term haemodynamic changes promote liver damage, leading to Fontan-associated liver disease (FALD), in virtually all patients with Fontan circulation. Owing to the lack of a uniform definition of FALD and the competitive risk of other complications developed by Fontan patients, the impact of FALD on the prognosis of these patients is currently debatable. However, based on the increasing number of adult Fontan patients and recent research interest, the European Association for The Study of the Liver and the European Reference Network on Rare Liver Diseases thought a position paper timely. The aims of the current paper are: (1) to provide a clear definition and description of FALD, including clinical, analytical, radiological, haemodynamic, and histological features; (2) to facilitate guidance for staging the liver disease; and (3) to provide evidence- and experience-based recommendations for the management of different clinical scenarios.
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Affiliation(s)
- Luis Téllez
- Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), University of Alcalá, Madrid, Spain
| | - Audrey Payancé
- DHU Unity, Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Hôpital Beaujon, AP-HP, Clichy, France; Université Denis Diderot-Paris 7, Sorbonne Paris Cité, Paris, France
| | - Eric Tjwa
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - María Jesús Del Cerro
- Pediatric Cardiology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá, Madrid, Spain
| | - Lars Idorn
- Department of Pediatrics, Section of Pediatric Cardiology, Rigshospitalet, Copenhagen, Denmark
| | - Stanislav Ovroutski
- Department of Congenital Heart Disease/Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany
| | - Ruth De Bruyne
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Belgium
| | - Henkjan J Verkade
- Department of Pediatrics, Beatrix Children's Hospital/University Medical Center Groningen, The Netherlands
| | - Fabrizio De Rita
- Adult Congenital and Paediatric Heart Unit, Freeman Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Charlotte de Lange
- Department of Pediatric Radiology, Queen Silvia Childrens' Hospital, Sahlgrenska University Hospital, Behandlingsvagen 7, 41650 Göteborg, Sweden
| | - Annalisa Angelini
- Pathology of Cardiac Transplantation and Regenerative Medicine Unit, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padua, Padua, Italy
| | - Valérie Paradis
- Centre de recherche sur l'inflammation, INSERM1149, Université Paris Cité, Paris, France; Pathology Department, Beaujon Hospital, APHP.Nord, Clichy, France
| | - Pierre Emmanuel Rautou
- AP-HP, Service d'Hépatologie, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, Clichy, France; Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, France
| | - Juan Carlos García-Pagán
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Departament de Medicina i Ciències de la Salut, University of Barcelona, Barcelona, Spain; CIBEREHD (Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas), Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Spain.
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13
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Farag FSAA, Anwar HM, Aboushousha T, Mohammed HS, Ismail LDM. Ameliorative Effects of Thunbergia erecta L. Leaves Against the Initiation of Hepatocarcinogenesis Induced by Diethylnitrosamine in the Rat Model. Appl Biochem Biotechnol 2023; 195:5881-5902. [PMID: 36708488 PMCID: PMC10511368 DOI: 10.1007/s12010-022-04292-x] [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] [Accepted: 12/16/2022] [Indexed: 01/29/2023]
Abstract
Thunbergia erecta L. contains cytotoxic and liver-protective compounds. Thunbergia erecta L. leaves were macerated in 70% aqueous ethanol, then fractionated with ethyl acetate (9.3 g) and butanol (12.7 g), and attenuated Den-induced liver cancer in a Wistar rat experimental model. Ethyl acetate and butanol fractions were chromatographed using column chromatography and solid-phase extraction (SPE); Vicenin-II (1), kaempferol (2), biochanin A, sissotrin 7-O-β-glucopyranoside (3), gentianose (4), acacetin 7-O-β-glucopyranoside (5), apigenin 7-O-β-glucopyranoside (6), and rosmarinic acid (7) were extracted, and their structures were determined using NMR spectroscopy and ESI-mass spectrometry. Sixty rats were divided into six groups (ten each): control group, Den group, doxorubicin/Den-treated group, butanol fraction/Den-treated group, and isolated acacetin 7-O-β-glucopyranoside/Den-treated group. The liver enzymes and proinflammatory biomarkers were used to estimate the liver function. In addition, liver tissues were collected for analysis of oxidative stress markers, gene expression, and histopathology. There is a significant increase in the levels of liver enzymes, AFP, and TNF-ἁ. This was conveyed by a significant increase of IL-1 and caspase-3, elevation of MDA and reduction of GSH, and suppression of Bcl2 and elevation of Bax expression. All parameters in butanol, ethyl acetate fractions, and isolated acacetin 7-O-β-glucopyranoside (major constituents) of T. erecta L. were significantly improved to values close to those of the control group.
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Affiliation(s)
- Fatma Sayed Abdel-Aal Farag
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, 11651, Egypt.
| | - Hend Mohamed Anwar
- Department of Biochemistry, National Organization for Drug Control & Research, Cairo, Egypt
| | - Tarek Aboushousha
- Department of Pathology, Theodor Bilharz Research Institute, Kornaish El-Nile, Warrak El-Hadar, P.O. 30 Imbaba, Giza, 12411, Egypt
| | - Hala Sh Mohammed
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, 11651, Egypt
| | - Lotfi Diab Mousa Ismail
- Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11651, Egypt
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14
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Yu J, Park R, Kim R. Promising Novel Biomarkers for Hepatocellular Carcinoma: Diagnostic and Prognostic Insights. J Hepatocell Carcinoma 2023; 10:1105-1127. [PMID: 37483311 PMCID: PMC10362916 DOI: 10.2147/jhc.s341195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 07/07/2023] [Indexed: 07/25/2023] Open
Abstract
The systemic therapy landscape for hepatocellular carcinoma is rapidly evolving, as the recent approvals of checkpoint inhibitor-based regimens such as atezolizumab-bevacizumab and durvalumab-tremelimumab in advanced disease have led to an expanding therapeutic armamentarium. The development of biomarkers, however, has not kept up with the approvals of new agents. Nevertheless, biomarker research for hepatocellular carcinoma has recently been growing at a rapid pace. The most active areas of research are biomarkers for early detection and screening, accurate prognostication, and detection of minimal residual disease following curative intent therapies, and, perhaps most importantly, predictive markers to guide selection and sequencing of the individual agents, including tyrosine kinase inhibitors and immunotherapy. In this review, we briefly summarize the recent developments in systemic therapeutics for hepatocellular carcinoma, introduce the key completed and ongoing prospective and retrospective studies evaluating diagnostic, prognostic, and predictive biomarkers with high clinical relevance, highlight several potentially important areas of future research, and share our insights for each biomarker.
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Affiliation(s)
- James Yu
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Robin Park
- Division of Hematology and Medical Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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15
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Tiyuri A, Baghermanesh SS, Davatgaran-Taghipour Y, Eslami SS, Shaygan N, Parsaie H, Barati M, Jafari D. Diagnostic accuracy of serum derived exosomes for hepatocellular carcinoma: a systematic review and meta-analysis. Expert Rev Mol Diagn 2023; 23:971-983. [PMID: 37715364 DOI: 10.1080/14737159.2023.2260306] [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: 02/10/2023] [Revised: 08/26/2023] [Accepted: 09/01/2023] [Indexed: 09/17/2023]
Abstract
INTRODUCTION Early and non-invasive detection of hepatocellular carcinoma (HCC), which is usually asymptomatic, can improve overall survival outcomes. The objective of this systematic review and meta-analysis was to evaluate the diagnostic accuracy of serum-derived exosomes for diagnosing HCC. METHODS PubMed, Web of Science, and Scopus databases were searched for relevant studies up to April 2023. The quality of included studies was assessed using the QUADAS-2 checklist, and data were extracted. Statistical analysis was performed on 18 studies from 3,993 records, and a diagnostic meta-analysis was conducted. Biomarkers were categorized into four groups based on their type (exosomal miRNAs, exosomal RNAs, alpha-fetoprotein (AFP), and exosomal RNAs+AFP panel), and a meta-analysis was conducted for each category separately. RESULTS The highest pooled sensitivity was 0.86 for exosomal miRNAs, and exosomal RNAs+AFP had the highest pooled specificity; (0.89). Furthermore, exosomal RNAs+AFP had the highest pooled positive likelihood ratio; (7.55), the highest pooled diagnostic odds ratio (35.96) and the highest pooled area under the curve (0.93). Exosomal miRNAs had the lowest pooled negative likelihood ratio; (0.17). CONCLUSIONS The diagnostic accuracy of exosomal biomarkers is superior to that of AFP, and combining the two in a panel yields the better results.
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Affiliation(s)
- Amir Tiyuri
- Department of Epidemiology and Biostatistics, School of Health, Birjand University of Medical Sciences, Birjand, Iran
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Shayeste Sadat Baghermanesh
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Yasamin Davatgaran-Taghipour
- Department of Medical Nanotechnology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyed Sadegh Eslami
- Institut National de la Recherche Scientifique (INRS), Centre Armand-Frappier Santé Biotechnologie, Laval, Canada
| | - Nasibeh Shaygan
- Department of Plant Breeding and Biotechnology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Houman Parsaie
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Mahmood Barati
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Davod Jafari
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
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16
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Ivashkin VT, Chulanov VP, Mamonova NA, Maevskaya MV, Zharkova MS, Tikhonov IN, Bogomolov PO, Volchkova EV, Dmitriev AS, Znojko OO, Klimova EA, Kozlov KV, Kravchenko IE, Malinnikova EY, Maslennikov RV, Mikhailov MI, Novak KE, Nikitin IG, Syutkin VE, Esaulenko EV, Sheptulin AA, Shirokova EN, Yushchuk ND. Clinical Practice Guidelines of the Russian Society for the Study of the Liver, the Russian Gastroenterological Association, the National Scientific Society of Infectious Disease Specialists for the Diagnosis and Treatment of Chronic Hepatitis C. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2023; 33:84-124. [DOI: 10.22416/1382-4376-2023-33-1-84-124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/26/2024]
Abstract
Аim:diagnosis and treatment algorithms in the clinical recommendations intended for general practitioners, gastroenterologists, infectious disease specialists, hepatologists on the of chronic hepatitis C are presented.Summary.Chronic viral hepatitis C is a socially significant infection, the incidence of which in the Russian Federation remains significantly high. Over the past 10 years, great progress has been made in the treatment of hepatitis C — direct acting antiviral drugs have appeared. The spectrum of their effectiveness allows to achieve a sustained virological response in more than 90 % of cases, even in groups that were not previously considered even as candidates for therapy or were difficult to treat — patients receiving renal replacement therapy, after liver transplantation (or other organs), at the stage of decompensated liver cirrhosis, HIV co-infected, etc. Interferons are excluded from the recommendations due to their low effectiveness and a wide range of adverse events. The indications for the treatment have been expanded, namely, the fact of confirmation of viral replication. The terms of dispensary observation of patients without cirrhosis of the liver have been reduced (up to 12 weeks after the end of therapy). Also, these recommendations present approaches to active screening of hepatitis in risk groups, preventive and rehabilitation measures after the end of treatment.Conclusion.Great success has been achieved in the treatment of chronic hepatitis C. In most cases, eradication of viral HCV infection is a real task even in patients at the stage of cirrhosis of the liver, with impaired renal function, HIV co-infection, after solid organs transplantation.
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Affiliation(s)
- V. T. Ivashkin
- Sechenov First Moscow State Medical University (Sechenov University)
| | - V. P. Chulanov
- Center for Epidemiologically Significant Infectious Diseases, National Medical Research Center for Phthisiopulmonology and Infectious Diseases
| | - N. A. Mamonova
- Center for Epidemiologically Significant Infectious Diseases, National Medical Research Center for Phthisiopulmonology and Infectious Diseases
| | - M. V. Maevskaya
- Sechenov First Moscow State Medical University (Sechenov University)
| | - M. S. Zharkova
- Sechenov First Moscow State Medical University (Sechenov University)
| | - I. N. Tikhonov
- Sechenov First Moscow State Medical University (Sechenov University)
| | - P. O. Bogomolov
- M.F. Vladimirsky Moscow Regional Research Clinical Institute
| | - E. V. Volchkova
- Sechenov First Moscow State Medical University (Sechenov University)
| | - A. S. Dmitriev
- Sechenov First Moscow State Medical University (Sechenov University)
| | - O. O. Znojko
- Moscow State University of Medicine and Dentistry
| | | | | | | | - E. Yu. Malinnikova
- Department of Virology, Russian Medical Academy of Continuing Professional Education
| | - R. V. Maslennikov
- Sechenov First Moscow State Medical University (Sechenov University)
| | - M. I. Mikhailov
- North-Western State Medical University named after I.I. Mechnikov
| | | | | | - V. E. Syutkin
- Sklifosovsky Clinical and Research Institute for Emergency Medicine; Russian State Research Center — Burnazyan Federal Medical Biophysical Center
| | | | - A. A. Sheptulin
- Sechenov First Moscow State Medical University (Sechenov University)
| | - E. N. Shirokova
- Sechenov First Moscow State Medical University (Sechenov University)
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17
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Pommergaard HC. Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma. APMIS 2023; 131 Suppl 146:1-39. [PMID: 37186326 DOI: 10.1111/apm.13309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
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18
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Zhang Q, Ye M, Lin C, Hu M, Wang Y, Lou Y, Kong Q, Zhang J, Li J, Zhang Y, Yang T, Sun X, Yao W, Hua Y, Huang H, Xu M, Wang X, Yu X, Tao W, Liu R, Gao Y, Wang T, Wang J, Wei X, Wu J, Yu Z, Zhang C, Yu C, Bai X, Liang T. Mass cytometry-based peripheral blood analysis as a novel tool for early detection of solid tumours: a multicentre study. Gut 2023; 72:996-1006. [PMID: 36113977 PMCID: PMC10086490 DOI: 10.1136/gutjnl-2022-327496] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 09/08/2022] [Indexed: 12/08/2022]
Abstract
OBJECTIVE Early detection of a tumour remains an unmet medical need, and approaches with high sensitivity and specificity are urgently required. Mass cytometry time-of-flight (CyTOF) is a powerful technique to profile immune cells and could be applied to tumour detection. We attempted to establish diagnostic models for hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). DESIGN We performed CyTOF analysis for 2348 participants from 15 centres, including 1131 participants with hepatic diseases, 584 participants with pancreatic diseases and 633 healthy volunteers. Diagnostic models were constructed through random forest algorithm and validated in subgroups. RESULTS We determined the disturbance of systemic immunity caused by HCC and PDAC, and calculated a peripheral blood immune score (PBIScore) based on the constructed model. The PBIScore exhibited good performance in detecting HCC and PDAC, with both sensitivity and specificity being around 80% in the validation cohorts. We further established an integrated PBIScore (iPBIScore) by combining PBIScore and alpha-fetoprotein or carbohydrate antigen 19-9. The iPBIScore for HCC had an area under the curve (AUC) of 0.99, 0.97 and 0.96 in training, internal validation and external validation cohorts, respectively. Similarly, the iPBIScore for PDAC showed an AUC of 0.99, 0.98 and 0.97 in the training, internal validation and external validation cohorts, respectively. In early-stage and tumour-marker-negative patients, our iPBIScore-based models also showed an AUC of 0.95-0.96 and 0.81-0.92, respectively. CONCLUSION Our study proved that the alterations of peripheral immune cell subsets could assist tumour detection, and provide a ready-to-use detection model for HCC and PDAC.
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Affiliation(s)
- Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
- Alibaba Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou, China
| | - Mao Ye
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Cheng Lin
- Zhejiang Puluoting Health Technology Co Ltd, Hangzhou, China
| | - Manyi Hu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yangyang Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Lou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Quanming Kong
- Zhejiang Puluoting Health Technology Co Ltd, Hangzhou, China
| | - Jungang Zhang
- Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Junjian Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou University School of Medicine, Wenzhou, China
| | - Yuhua Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, China
| | - Tianxing Yang
- Department of Medical Oncology, Sanmen People's Hospital, Taizhou, China
| | - Xu Sun
- Department of General Surgery, Huzhou Central Hospital, Zhejiang University School of Medicine, Huzhou, China
| | - Weiyun Yao
- Department of Surgery, Changxing People's Hospital, Huzhou, China
| | - Yongfei Hua
- Department of General Surgery, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo, China
| | - Haifeng Huang
- Department of General Surgery, Shengzhou People's Hospital, Shengzhou, China
| | - Minghui Xu
- Department of General Surgery, Haining People's Hospital, Haining, China
| | - Xiaoguang Wang
- Department of General Surgery, Jiaxing Second People's Hospital, Jiaxing, China
| | - Xin Yu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Weifeng Tao
- Department of General Surgery, Shangyu People's Hospital of Shaoxing, Shangyu, China
| | - Runtian Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yuming Gao
- Department of General Surgery, Jixi County People's Hospital, Jixi, China
| | - Tian Wang
- Zhejiang Puluoting Health Technology Co Ltd, Hangzhou, China
| | - Jianing Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaobao Wei
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiangchao Wu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengping Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Wenzhou University School of Medicine, Wenzhou, China
| | - Chengwu Zhang
- Department of Hepatobiliary and Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, China
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
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19
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Villalba-López F, Sáenz-Mateos LF, Sánchez-Lorencio MI, De La Orden-García V, Alconchel-Gago F, Cascales-Campos PA, García-Bernardo C, Noguera-Velasco JA, Baroja-Mazo A, Ramírez-Romero P. Usefulness of PIVKA-II for monitoring after liver transplantation in patients with hepatocellular carcinoma. Sci Rep 2023; 13:5621. [PMID: 37024609 PMCID: PMC10079651 DOI: 10.1038/s41598-023-32879-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 04/04/2023] [Indexed: 04/08/2023] Open
Abstract
The high morbidity and mortality of hepatocellular carcinoma (HCC) has encouraged the search for new biomarkers to be used alongside alpha-foetoprotein (AFP) and imaging tests. The aim of this study was to evaluate the clinical contribution of protein induced by vitamin K absence or antagonist-II (PIVKA-II) for HCC monitoring after liver transplantation (LT) and compare it with AFP, a routinely used tumour marker. A total of 46 HCC patients (Milan criteria) were enrolled in this study. Serum levels of PIVKA-II and AFP were measured before and after transplantation. Clinical features were determined for all the patients that were included. Significant correlations were found between PIVKA-II expression levels and some clinicopathological features, such as tumour size and number of pre-transplant transarterial chemoembolizations (TACEs). Serum levels of PIVKA-II and AFP decreased significantly after LT and increased in patients with tumour recurrence. Serum PIVKA-II levels may play an important role in predicting disease severity. Furthermore, monitoring PIVKA-II levels in HCC transplant recipients reflects the tumor early recurrence after transplantation and could be used, complementing AFP and imaging tests, as a novel biomarker of this pathology.
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Affiliation(s)
| | | | | | | | - Felipe Alconchel-Gago
- Liver Transplant Unit, University Hospital Virgen de la Arrixaca, 30120, Murcia, Spain
| | | | | | | | | | - Pablo Ramírez-Romero
- Liver Transplant Unit, University Hospital Virgen de la Arrixaca, 30120, Murcia, Spain
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20
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Short Half-Life of Des-γ-Carboxy Prothrombin Is a Superior Factor for Early Prediction of Outcomes of Hepatocellular Carcinoma Treated with Radiofrequency Ablation. Diagnostics (Basel) 2023; 13:diagnostics13040696. [PMID: 36832184 PMCID: PMC9955975 DOI: 10.3390/diagnostics13040696] [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: 01/02/2023] [Revised: 02/06/2023] [Accepted: 02/08/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND The role of des-γ-carboxy prothrombin (DCP) in patients undergoing radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) needs to be clarified. MATERIALS AND METHODS 174 HCC patients that underwent RFA were enrolled. We calculated the HLs of DCP from the available values before and on first day after ablation and assessed the correlation between HLs of DCP and RFA efficacy. RESULTS Of 174 patients, 63 with pre-ablation DCP concentrations of ≥80 mAU/mL were analyzed. The ROC analysis showed the optimal cut-off value of HLs of DCP for predicting RFA response was 47.5 h. Therefore, we defined short HLs of DCP < 48 h as a predictor of favorable treatment response. Of 43 patients with a complete radiological response, 34 (79.1%) had short HLs of DCP. In 36 patients with short HLs of DCP, 34 (94.4%) had a complete radiologic response. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 79.1%, 90.0%, 82.5%, 94.4%, and 66.7%. During the 12-month follow-up, patients who had short HLs of DCP had a better disease-free survival rate than patients with long HLs of DCP (p < 0.001). CONCLUSIONS Short HLs of DCP < 48 h calculated on the first day post-RFA are a useful predictor for treatment response and recurrence-free survival after RFA.
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21
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Leal C, Strogoff-de-Matos J, Theodoro C, Teixeira R, Perez R, Guaraná T, de Tarso Pinto P, Guimarães T, Artimos S. Incidence and Risk Factors of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C Treated with Direct-Acting Antivirals. Viruses 2023; 15:221. [PMID: 36680260 PMCID: PMC9863874 DOI: 10.3390/v15010221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Conflicting data regarding the incidence of hepatocellular carcinoma (HCC) after cure of HCV infection with direct-acting antivirals (DAAs) remains. We investigated the incidence and risk factors to HCC after treatment with DAAs followed up for five years. METHODS A total of 1075 HCV patients ≥ 18 years were treated with DAAs from 2015 to 2019 and followed until 2022. Ultrasonography was performed before DAAs and each 6 months thereafter. RESULTS Of the total, 51/1075 (4.7%) developed HCC in the median of 40 (IQR 25-58) months: 26/51 (51%) male, median age 60 (IQR 54-66) years, alpha-fetoprotein (AFP) 12.2 (IQR 6.1-18.8) ng/mL, 47/51 (92.1%) cirrhotic 78.7%, 8/51 (15.7%) without sustained virological response (SVR). Seventeen percent had non-characterized nodules before DAAs. Cumulative HCC incidence was 5.9% in 5 years. Overall incidence was 1.46/100 patient-years (PY) (95% CI = 1.09-1.91), being 2.31/100 PY (95% CI = 1.70-3.06), 0.45/100 PY (95% CI = 0.09-1.32) and 0.20/100 PY (95% CI 0.01-1.01) in METAVIR F4, F3 and F2, respectively, and the main risks to HCC were non-characterized nodule, cirrhosis, high AFP values and non-SVR. CONCLUSION HCV cure reduced risk for HCC, but it still occurred particularly in cirrhotic patients. Some risk factors can be identified to predict early HCC diagnosis.
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Affiliation(s)
- Cassia Leal
- Gastroenterology and Hepatology Unit, Internal Medicine Department, Hospital Federal dos Servidores do Estado, Rio de Janeiro 20221-161, Brazil
- Gastroenterology and Hepatology Unit, Antônio Pedro Universitary Hospital, Fluminense Federal University, Rio de Janeiro 24033-900, Brazil
| | - Jorge Strogoff-de-Matos
- Departamento de Medicina Clínica, Faculdade de Medicina, Universidade Federal Fluminense, Rio de Janeiro 24033-900, Brazil
| | - Carmem Theodoro
- Gastroenterology and Hepatology Unit, Internal Medicine Department, Hospital Federal dos Servidores do Estado, Rio de Janeiro 20221-161, Brazil
- Gastroenterology and Hepatology Unit, Antônio Pedro Universitary Hospital, Fluminense Federal University, Rio de Janeiro 24033-900, Brazil
| | - Rosangela Teixeira
- Departamento de Clínica Médica, Faculdade de Medicina, Instituto Alfa de Gastroenterologia Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Brazil
- Hospital Felício Rocho, Belo Horizonte 30110-934, Brazil
| | - Renata Perez
- Hepatology Division, D’Or Institute for Research and Education (IDOR), Rio de Janeiro 22281-100, Brazil
- Hepatology Division, Federal University of Rio de Janeiro, Rio de Janeiro 21941913, Brazil
| | - Thais Guaraná
- Gastroenterology and Hepatology Unit, Antônio Pedro Universitary Hospital, Fluminense Federal University, Rio de Janeiro 24033-900, Brazil
| | - Paulo de Tarso Pinto
- Gastroenterology and Hepatology Unit, Internal Medicine Department, Hospital Federal dos Servidores do Estado, Rio de Janeiro 20221-161, Brazil
| | - Tatiana Guimarães
- Departamento Materno Infantil, Faculdade de Medicina, Universidade Federal Fluminense, Rio de Janeiro 24033-900, Brazil
| | - Solange Artimos
- Departamento de Medicina Clínica, Faculdade de Medicina, Universidade Federal Fluminense, Rio de Janeiro 24033-900, Brazil
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22
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Heo HJ, Park Y, Lee JH, Kim Y, Kim EK, Kim GH, Yu Y, Park SY, Seo HB, Pak K, Goh TS, Park S, Oh SO, Kwon W, Kim YH. Clinical big-data-based design of GLUT2-targeted carbon nanodots for accurate diagnosis of hepatocellular carcinoma. NANOSCALE 2022; 14:17053-17064. [PMID: 36367284 DOI: 10.1039/d2nr04238j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Despite advances in diagnostic and therapeutic methods, the prognosis of patients with hepatocellular carcinoma (HCC) remains poor due to the delay in diagnosis. Herein, we aimed to discover a highly sensitive and specific biomarker for HCC based on genomic big data analysis and create an HCC-targeted imaging probe using carbon nanodots (CNDs) as contrast agents. In genomic analysis, we selected glucose transporter 2 (GLUT2) as a potential imaging target for HCC. We confirmed the target suitability by immunohisto-chemistry tests of 339 patient samples, where 81.1% of the patients exhibited underexpression of GLUT2, i.e., higher GLUT2 intensity in non-tumor tissues than in tumor tissues. To visualize GLUT2, we conjugated CNDs with glucosamine (GLN) as a targeting ligand to yield glucosamine-labeled CNDs (GLN-CNDs). A series of in vitro and in vivo experiments were conducted on GLUT2-modified HepG2 cells to confirm the specificity of the GLN-CNDs. Since the GLUT2 expression is higher in hepatocytes than in HCC cells, the GLUT2-targeted contrast agent is highly attached to normal cells. However, it is possible to produce images in the same form as the images obtained with a cancer cell-targeted contrast agent by inverting color scaling. Our results indicate that GLUT2 is a promising target for HCC and that GLN-CNDs may potentially be used as targeted imaging probes for diagnosing HCC.
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Affiliation(s)
- Hye Jin Heo
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
| | - Yoonsang Park
- Institute of Advanced Materials and Systems, Sookmyung Women's University, Seoul 04310, Republic of Korea.
- Nano Convergence Technology Research Center, Korea Electronics Technology Institute (KETI), Seongnam 13509, Republic of Korea
| | - Jung Hee Lee
- Department of Pathology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
| | - Yujin Kim
- Department of Chemical and Biological Engineering, Sookmyung Women's University, Seoul 04310, Republic of Korea
| | - Eun Kyoung Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
| | - Ga Hyun Kim
- Interdisciplinary Program of Genomic Data Science, Pusan National University, Yangsan 50612, Republic of Korea
| | - Yeuni Yu
- Biomedical Research Institute, Pusan National University Hospital, Yangsan 50612, Republic of Korea.
| | - So Youn Park
- Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan 50612, Republic of Korea
| | - Hie Bum Seo
- Department of Radiology, School of Medicine, Pusan National University, Pusan National University Hospital, Yangsan 50612, Republic of Korea
| | - Kyoungjune Pak
- Biomedical Research Institute, Pusan National University Hospital, Yangsan 50612, Republic of Korea.
- Department of Nuclear Medicine, Pusan National University Hospital, Yangsan 50612, Republic of Korea
| | - Tae Sik Goh
- Biomedical Research Institute, Pusan National University Hospital, Yangsan 50612, Republic of Korea.
- Department of Orthopaedic Surgery, Pusan National University Hospital, Yangsan 50612, Republic of Korea
| | - Sehyeon Park
- Department of Chemical and Biological Engineering, Sookmyung Women's University, Seoul 04310, Republic of Korea
| | - Sae-Ock Oh
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
| | - Woosung Kwon
- Institute of Advanced Materials and Systems, Sookmyung Women's University, Seoul 04310, Republic of Korea.
- Department of Chemical and Biological Engineering, Sookmyung Women's University, Seoul 04310, Republic of Korea
| | - Yun Hak Kim
- Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea.
- Biomedical Research Institute, Pusan National University Hospital, Yangsan 50612, Republic of Korea.
- Department of Biomedical Informatics, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
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23
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Khan A, Zhang X. Function of the Long Noncoding RNAs in Hepatocellular Carcinoma: Classification, Molecular Mechanisms, and Significant Therapeutic Potentials. Bioengineering (Basel) 2022; 9:406. [PMID: 36004931 PMCID: PMC9405066 DOI: 10.3390/bioengineering9080406] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common and serious type of primary liver cancer. HCC patients have a high death rate and poor prognosis due to the lack of clear signs and inadequate treatment interventions. However, the molecular pathways that underpin HCC pathogenesis remain unclear. Long non-coding RNAs (lncRNAs), a new type of RNAs, have been found to play important roles in HCC. LncRNAs have the ability to influence gene expression and protein activity. Dysregulation of lncRNAs has been linked to a growing number of liver disorders, including HCC. As a result, improved understanding of lncRNAs could lead to new insights into HCC etiology, as well as new approaches for the early detection and treatment of HCC. The latest results with respect to the role of lncRNAs in controlling multiple pathways of HCC were summarized in this study. The processes by which lncRNAs influence HCC advancement by interacting with chromatin, RNAs, and proteins at the epigenetic, transcriptional, and post-transcriptional levels were examined. This critical review also highlights recent breakthroughs in lncRNA signaling pathways in HCC progression, shedding light on the potential applications of lncRNAs for HCC diagnosis and therapy.
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Affiliation(s)
| | - Xiaobo Zhang
- College of Life Sciences, Zhejiang University, Hangzhou 310058, China
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24
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Qian X, Liu Y, Wu F, Zhang S, Gong J, Nan Y, Hu B, Chen J, Zhao J, Chen X, Pan W, Dang S, Lu F. The Performance of Serum Alpha-Fetoprotein for Detecting Early-Stage Hepatocellular Carcinoma Is Influenced by Antiviral Therapy and Serum Aspartate Aminotransferase: A Study in a Large Cohort of Hepatitis B Virus-Infected Patients. Viruses 2022; 14:1669. [PMID: 36016291 PMCID: PMC9416230 DOI: 10.3390/v14081669] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 06/25/2022] [Accepted: 07/14/2022] [Indexed: 11/17/2022] Open
Abstract
Background and aims: Factors associated with abnormally elevated alpha-fetoprotein (AFP) in hepatitis B virus (HBV)-infected patients remain to be studied. We aimed to identify factors associated with elevated serum AFP in patients with non-hepatocellular carcinoma (HCC) and early-stage HCC and their influences on the performance of AFP for detecting early-stage HCC. Methods: This multicenter, retrospective study was conducted in 4401 patients with chronic HBV infection, including 3680 patients with non-HCC and 721 patients with early-stage HCC. Factors associated with elevated AFP were analyzed. Diagnostic performance of AFP for early-stage HCC were compared among groups through area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Results: When analyzed by multivariate logistic regression, antiviral therapy was negatively associated with elevated AFP, while hepatitis B e antigen (HBeAg) and aspartate aminotransferase (AST) > 1× upper limit of normal (ULN) were positively associated with elevated AFP both in patients with non-HCC and early-stage HCC (all p < 0.05). The AUCs of AFP for detecting early-stage HCC in patients with antiviral therapy, HBV DNA (−), alanine aminotransferase (ALT) ≤ 1× ULN, and AST ≤ 1× ULN were significantly higher compared to those in non-antiviral therapy, HBV DNA (+), ALT > 1× ULN, and AST > 1× ULN groups, respectively. When categorizing patients into AST ≤ 1× ULN and > 1× ULN, AFP achieved the highest AUCs in patients with AST ≤ 1× ULN regardless of antiviral treatment (AUCs = 0.813 and 0.806, respectively). Furthermore, there were considerable differences in the cut-off values of AFP in detecting early-stage HCC in different subgroups when applying similar sensitivity and specificity. Conclusions: Antiviral therapy and serum AST might be used to help judge and select the specific cut-off values of serum AFP for HCC surveillance in different at-risk populations.
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Affiliation(s)
- Xiangjun Qian
- Department of Microbiology, Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; (X.Q.); (Y.L.); (X.C.)
- Department of Pancreatic Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
| | - Yanna Liu
- Department of Microbiology, Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; (X.Q.); (Y.L.); (X.C.)
| | - Fengping Wu
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China;
| | - Siyu Zhang
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China; (S.Z.); (Y.N.)
| | - Jiao Gong
- Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; (J.G.); (B.H.)
| | - Yuemin Nan
- Department of Traditional and Western Medical Hepatology, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China; (S.Z.); (Y.N.)
| | - Bo Hu
- Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; (J.G.); (B.H.)
| | - Junhui Chen
- Intervention and Cell Therapy Center, Peking University Shenzhen Hospital, Shenzhen 518035, China;
| | - Jingmin Zhao
- Department of Pathology and Hepatology, The 5th Medical Centre, Chinese PLA General Hospital, Beijing 100039, China;
| | - Xiangmei Chen
- Department of Microbiology, Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; (X.Q.); (Y.L.); (X.C.)
| | - Weidong Pan
- Department of Pancreatic Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
| | - Shuangsuo Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China;
| | - Fengmin Lu
- Department of Microbiology, Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; (X.Q.); (Y.L.); (X.C.)
- Precision Medicine Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
- Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University Hepatology Institute, Peking University People’s Hospital, Beijing 100044, China
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25
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Ali AH, Yaqub AH, Faraj IA. Tumor biomarkers CEA, CA19.9, CA15.3 and AFP levels in the serum of patients with COVID-19. UKRAINIAN BIOCHEMICAL JOURNAL 2022. [DOI: 10.15407/ubj94.02.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Early diagnosis is very important to reduce morbidity and mortality in COVID-19 infected patients. The aim of this study was to detect of tumor antigens CEA, CA19.9, CA15.3, and AFP and to compare their levels in the serum of 69 COVID-19 patients and 69 healthy individuals who did not have COVID-19. The levels of CEA, CA19.9, CA15.3, and AFP in the serum were measured using ELISA. The levels of the tumor biomarkers in the serum of COVID-19 patients were found to be 7.74 ± 4.65 ng/ml for CEA, 29.33 ± 16.35 U/ml for CA19.9, 23.24 ± 13.48 U/ml for CA15.3 and 7.46 ± 5.57 ng/ml for AFP, while in the serum of healthy control patients 9.73 ± 43.58 ng/ml for CEA, 20.66 ± 11.1 for CA19.9, 19.64 ± 10.99 U/ml for CA15.3, and 3.83 ± 9.20 ng/ml for AFP, indicating no differences in the levels of the studied tumor biomarkers in the two experimental groups. It is concluded that tumor biomarkers CEA, CA19.9, CA15.3, and AFP cannot be used as effective screening tools for patients with COVID-19.
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26
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Zaidi S, Amdur R, Xiang X, Yu H, Wong LL, Rao S, He AR, Amin K, Zaheer D, Narayan RK, Satapathy SK, Latham PS, Shetty K, Guha C, Gough NR, Mishra L. Using quantitative immunohistochemistry in patients at high risk for hepatocellular cancer. Genes Cancer 2022; 13:9-20. [PMID: 35677836 PMCID: PMC9170384 DOI: 10.18632/genesandcancer.220] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 05/20/2022] [Indexed: 11/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a major cause of cancer death worldwide. Early detection is key to effective treatment. Yet, early diagnosis is challenging, especially in patients with cirrhosis, who are at high risk of developing HCC. Dysfunction or loss of function of the transforming growth factor β (TGF-β) pathway is associated with HCC. Here, using quantitative immunohistochemistry analysis of samples from a multi-institutional repository, we evaluated if differences in TGF-β receptor abundance were present in tissue from patients with only cirrhosis compared with those with HCC in the context of cirrhosis. We determined that TGFBR2, not TGFBR1, was significantly reduced in HCC tissue compared with cirrhotic tissue. We developed an artificial intelligence (AI)-based process that correctly identified cirrhotic and HCC tissue and confirmed the significant reduction in TGFBR2 in HCC tissue compared with cirrhotic tissue. Thus, we propose that a reduction in TGFBR2 abundance represents a useful biomarker for detecting HCC in the context of cirrhosis and that incorporating this biomarker into an AI-based automated imaging pipeline could reduce variability in diagnosing HCC from biopsy tissue.
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Affiliation(s)
- Sobia Zaidi
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY 11030, USA
| | - Richard Amdur
- Department of Surgery, The George Washington University, Washington, DC 20037, USA
| | - Xiyan Xiang
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY 11030, USA
| | - Herbert Yu
- Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Linda L. Wong
- Department of Surgery, University of Hawaii, Honolulu, HI 96813, USA
| | - Shuyun Rao
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY 11030, USA
| | - Aiwu R. He
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
| | - Karan Amin
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY 11030, USA
| | - Daewa Zaheer
- Department of Surgery, The George Washington University, Washington, DC 20037, USA
| | - Raj K. Narayan
- Department of Neurosurgery, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11030, USA
| | - Sanjaya K. Satapathy
- Sandra Atlas Bass Center for Liver Diseases and Transplantation, Department of Medicine, North Shore University Hospital/Northwell Health, NY 11030, USA
| | - Patricia S. Latham
- Department of Pathology, The George Washington University, Washington, DC 20037, USA
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, University of Maryland, Baltimore, MD 21201, USA
| | - Chandan Guha
- Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Nancy R. Gough
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY 11030, USA
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, NY 11030, USA
- Department of Surgery, The George Washington University, Washington, DC 20037, USA
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Reappraisal of the roles of alpha-fetoprotein in hepatocellular carcinoma surveillance using large-scale nationwide database and hospital-based information. J Formos Med Assoc 2022; 121:2085-2092. [PMID: 35450743 DOI: 10.1016/j.jfma.2022.04.001] [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: 08/29/2021] [Revised: 03/22/2022] [Accepted: 04/05/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND/PURPOSE Controversies over the use of alpha-fetoprotein (AFP) for detection of hepatocellular carcinoma (HCC) existed from guidelines. Using large-scale database and hospital-based information, we aimed to reappraise the role of AFP in HCC surveillance, including proportion of AFP elevation by stage of HCC, additional benefit of AFP in combination of ultrasonography (US) in the detection of early HCC, and survival in early HCC with high AFP levels. METHODS This retrospective study enrolled 43,437 patients from database of the Taiwan Cancer Registry (TCR) and 4250 patients from Kaohsiung Chang Gung Memorial Hospital (KCGMH) between January 2011 and December 2017. RESULTS The HCC cases in KCGMH accounted for 9.8% of the total cases in the TCR. Among both nationwide database and hospital-based information, the proportion of early HCC patients with an AFP level of ≥20 ng/mL was approximately 40%. In KCGMH, the proportion of patients with an AFP level of ≥20 ng/mL and a virus-related (hepatitis B and C) etiology was around 41.7%; furthermore, among patients with early HCC, those with an AFP level of ≥20 ng/mL had 4.7 years of median survival and 48.3% of the 5-year overall survival rate. By hospital electronic medical records review of early HCC cohort in KCGMH, approximately 10.9% of patients with AFP levels ≥20 ng/mL had US-undetectable early HCC. CONCLUSION This study suggested that AFP in combination with US would add an additional benefit as being a prompted role for detection of early HCC in patients with US-undetectable HCC.
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Stefanini B, Tonnini M, Serio I, Renzulli M, Tovoli F. Surveillance for hepatocellular carcinoma: current status and future perspectives for improvement. Expert Rev Anticancer Ther 2022; 22:371-381. [PMID: 35263211 DOI: 10.1080/14737140.2022.2052276] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 03/08/2022] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is a globally relevant medical problem. Fortunately, risk factors for this tumor have been identified, and surveillance protocols developed. Patients with liver cirrhosis have the highest risk of developing HCC and have historically been included in surveillance programs. Special categories have also emerged in recent years, especially patients with eradicated HCV infection or nonalcoholic fatty liver disease. Novel serum biomarkers and magnetic resonance imaging protocols are currently being proposed to refine existing surveillance protocols. AREAS COVERED We discuss the rationale of surveillance programs for HCC and report the most recent recommendations from international guidelines about this topic. Gray areas, such as nonalcoholic fatty liver disease and the role of intrahepatic cholangiocellular carcinoma, are also discussed. EXPERT OPINION Surveillance is recognized as a tool to favor early diagnosis of HCC, access to curative treatment, and increase survival, even if the supporting evidence is mainly based on observational studies. As new randomized clinical trials are difficult to propose, future challenges will include optimizing implementation in the primary care setting and a more personalized approach, balancing the opportunities and risks of overdiagnosis of novel techniques and biomarkers.
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Affiliation(s)
- Bernardo Stefanini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Matteo Tonnini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Ilaria Serio
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Matteo Renzulli
- Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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El-shaarawy F, Abo ElAzm MM, Mohamed RH, Radwan MI, Abo-Elmatty DM, Mehanna ET. Relation of the methylation state of RUNX3 and p16 gene promoters with hepatocellular carcinoma in Egyptian patients. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2022. [DOI: 10.1186/s43042-022-00256-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy of adults. RUNX3 and p16 are tumor suppressor genes that may be inactivated by hypermethylation which is a key epigenetic mechanism that contributes to the initiation and progression of various types of human carcinomas including HCC. The aim of this study was to assess the association of hypermethylation of RUNX3 and p16 gene promoters with the incidence of HCC in Egyptian patients. The study included 120 subjects: 30 HCC patients, 30 patients with hepatitis C virus (HCV) without cirrhosis, 30 cirrhotic patients, and 30 healthy volunteers. Methylation-specific polymerase chain reaction (PCR) was done for detection of hypermethylated p16 and RUNX3. Serum levels of liver enzymes and albumin were detected spectrophotometrically and alpha fetoprotein (AFP) was measured in serum by ELISA.
Results
Methylation of RUNX3 and p16 was detected in 25/30 (83.3%) and 26/30 (86.7%) of HCC patients, respectively. The methylation state of both RUNX3 and p16 genes was significantly higher in HCC patients compared to the control subjects (P = 0.016, OR = 4.38) and (P = 0.014, OR = 4.97), respectively. The methylation of both promoters was associated with higher AFP levels in the serum of all patients.
Conclusions
Hypermethylation of RUNX3 and p16 is significantly associated with the development of HCC and may be implicated in its pathogenesis.
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30
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Hanif H, Ali MJ, Susheela AT, Khan IW, Luna-Cuadros MA, Khan MM, Lau DTY. Update on the applications and limitations of alpha-fetoprotein for hepatocellular carcinoma. World J Gastroenterol 2022; 28:216-229. [PMID: 35110946 PMCID: PMC8776528 DOI: 10.3748/wjg.v28.i2.216] [Citation(s) in RCA: 125] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/26/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
Alpha-fetoprotein (AFP) is an oncofetal glycoprotein that has been used as a tumor marker for hepatocellular carcinoma (HCC) in combination with ultrasound and other imaging modalities. Its utility is limited because of both low sensitivity and specificity, and discrepancies among the different methods of measurements. Moreover, its accuracy varies according to patient characteristics and the AFP cut-off values used. Combination of AFP with novel biomarkers such as AFP-L3, Golgi specific membrane protein (GP73) and des-gamma-carboxyprothrombin significantly improved its accuracy in detecting HCC. Increased AFP level could also signify severity of hepatic destruction and subsequent regeneration and is commonly observed in patients with acute and chronic liver conditions and cirrhosis. Hereditary and other non-hepatic disorders can also cause AFP elevation.
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Affiliation(s)
- Hira Hanif
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Mukarram Jamat Ali
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Ammu T Susheela
- Internal Medicine, Loyola MacNeal Hospital, Berwyn, PA 60402, United States
| | - Iman Waheed Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Maria Alejandra Luna-Cuadros
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Muzammil Muhammad Khan
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
| | - Daryl Tan-Yeung Lau
- Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States
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31
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Hu X, Chen R, Wei Q, Xu X. The Landscape Of Alpha Fetoprotein In Hepatocellular Carcinoma: Where Are We? Int J Biol Sci 2022; 18:536-551. [PMID: 35002508 PMCID: PMC8741863 DOI: 10.7150/ijbs.64537] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 10/15/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has been acknowledged as a leading cause of death among cirrhosis patients. Difficulties in early diagnosis and heterogeneity are obstacles to effective treatment, especially for advanced HCC. Liver transplantation (LT) is considered the best therapy for HCC. Although many biomarkers are being proposed, alpha-fetoprotein (AFP), which was identified over 60 years ago, remains the most utilized. Recently, much hope has been placed in the immunogenicity of AFP to develop novel therapies, such as AFP vaccines and AFP-specific adoptive T-cell transfer (ACT). This review summarizes the performance of AFP as a biomarker for HCC diagnosis and prognosis, as well as its correlation with molecular classes. In addition, the role of AFP in LT is also described. Finally, we highlight the mechanism and application prospects of two immune therapies (AFP vaccine and ACT) for HCC. In general, our review points out the prevalence of AFP in HCC, accompanied by some controversies and novel directions for future research.
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Affiliation(s)
- Xin Hu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Zhejiang University Cancer Center, Hangzhou, 310058, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Ronggao Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.,Zhejiang University Cancer Center, Hangzhou, 310058, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China
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Centonze L, De Carlis R, Vella I, Carbonaro L, Incarbone N, Palmieri L, Sgrazzutti C, Ficarelli A, Valsecchi MG, Dello Iacono U, Lauterio A, Bernasconi D, Vanzulli A, De Carlis L. From LI-RADS Classification to HCC Pathology: A Retrospective Single-Institution Analysis of Clinico-Pathological Features Affecting Oncological Outcomes after Curative Surgery. Diagnostics (Basel) 2022; 12:160. [PMID: 35054327 PMCID: PMC8775107 DOI: 10.3390/diagnostics12010160] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/08/2022] [Accepted: 01/09/2022] [Indexed: 02/08/2023] Open
Abstract
Background: The latest Liver Imaging Reporting and Data System (LI-RADS) classification by the American College of Radiology has been recently endorsed in the American Association for the Study of Liver Disease (AASLD) guidelines for Hepatocellular carcinoma (HCC) management. Although the LI-RADS protocol has been developed as a diagnostic algorithm, there is some evidence concerning a possible correlation between different LI-RADS classes and specific pathological features of HCC. We aimed to investigate such radiological/pathological correlation and the possible prognostic implication of LI-RADS on a retrospective cohort of HCC patients undergoing surgical resection. Methods: We performed a retrospective analysis of the pathological characteristics of resected HCC, exploring their distribution among different LI-RADS classes and analyzing the risk factors for recurrence-free, overall and cancer-specific survival Results: LI-RADS-5 (LR-5) nodules showed a higher prevalence of microvascular invasion (MVI), satellitosis and capsule infiltration, as well as higher median values of alpha-fetoprotein (αFP) compared to LI-RADS-3/4 (LR-3/4) nodules. MVI, αFP, satellitosis and margin-positive (R1) resection resulted as independent risk factors for recurrence-free survival, while LI-RADS class did not exert any significant impact. Focusing on overall survival, we identified patient age, Eastern Cooperative Oncology Group performance status (ECOG-PS), Model for End Stage Liver Disease (MELD) score, αFP, MVI, satellitosis and R1 resection as independent risk factors for survival, without any impact of LI-RADS classification. Last, MELD score, log10αFP, satellitosis and R1 resection resulted as independent risk factors for cancer-specific survival, while LI-RADS class did not exert any significant impact. Conclusions: Our results suggest an association of LR-5 class with unfavorable pathological characteristics of resected HCC; tumor histology and underlying patient characteristics such as age, ECOG-PS and liver disease severity exert a significant impact on postoperative oncological outcomes.
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Affiliation(s)
- Leonardo Centonze
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (R.D.C.); (I.V.); (N.I.); (L.P.); (A.F.); (A.L.); (L.D.C.)
| | - Riccardo De Carlis
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (R.D.C.); (I.V.); (N.I.); (L.P.); (A.F.); (A.L.); (L.D.C.)
| | - Ivan Vella
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (R.D.C.); (I.V.); (N.I.); (L.P.); (A.F.); (A.L.); (L.D.C.)
| | - Luca Carbonaro
- Department of Diagnostic and Interventional Radiology, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (L.C.); (C.S.); (U.D.I.); (A.V.)
| | - Niccolò Incarbone
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (R.D.C.); (I.V.); (N.I.); (L.P.); (A.F.); (A.L.); (L.D.C.)
| | - Livia Palmieri
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (R.D.C.); (I.V.); (N.I.); (L.P.); (A.F.); (A.L.); (L.D.C.)
| | - Cristiano Sgrazzutti
- Department of Diagnostic and Interventional Radiology, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (L.C.); (C.S.); (U.D.I.); (A.V.)
| | - Alberto Ficarelli
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (R.D.C.); (I.V.); (N.I.); (L.P.); (A.F.); (A.L.); (L.D.C.)
| | - Maria Grazia Valsecchi
- Bicocca Bioinformatics Biostatistics and Bioimaging Centre—B4, School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.G.V.); (D.B.)
| | - Umberto Dello Iacono
- Department of Diagnostic and Interventional Radiology, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (L.C.); (C.S.); (U.D.I.); (A.V.)
| | - Andrea Lauterio
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (R.D.C.); (I.V.); (N.I.); (L.P.); (A.F.); (A.L.); (L.D.C.)
| | - Davide Bernasconi
- Bicocca Bioinformatics Biostatistics and Bioimaging Centre—B4, School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy; (M.G.V.); (D.B.)
| | - Angelo Vanzulli
- Department of Diagnostic and Interventional Radiology, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (L.C.); (C.S.); (U.D.I.); (A.V.)
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20161 Milan, Italy; (R.D.C.); (I.V.); (N.I.); (L.P.); (A.F.); (A.L.); (L.D.C.)
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy
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Isfordink CJ, Maan R, de Man RA, van Erpecum KJ, van der Meer AJ. Should we continue surveillance for hepatocellular carcinoma and gastroesophageal varices in patients with cirrhosis and cured HCV infection? Eur J Intern Med 2021; 94:6-14. [PMID: 34563447 DOI: 10.1016/j.ejim.2021.08.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/02/2021] [Accepted: 08/27/2021] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) and variceal bleeding are among the most common causes of liver-related mortality in patients with hepatitis C virus (HCV)-induced cirrhosis. Current guidelines recommend HCC and gastroesophageal varices (GEV) surveillance in patients with HCV infection and cirrhosis. However, since the recent introduction of direct-acting antivirals, most patients with cirrhosis are now cured of their chronic HCV infection. As virological cure is considered to substantially reduce the risk of cirrhosis-related complications, this review discusses the current literature concerning the surveillance of HCC and GEV in patients with HCV-induced cirrhosis with a focus on the setting following sustained virological response.
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Affiliation(s)
- Cas J Isfordink
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands; Division of Infectious Diseases, Amsterdam Infection & Immunity Institute Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Raoel Maan
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Robert A de Man
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Karel J van Erpecum
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
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Abstract
Liver cancer is the fourth leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for approximately 80% of all liver cancers. The serum concentration of alpha-fetoprotein (AFP) is the only validated biomarker for HCC diagnosis. MicroRNAs (miRNAs) are small non-coding RNAs of 21–30 nucleotides playing a critical role in human carcinogenesis, with types of miRNAs with oncogenic (oncomiRs) or tumor suppressor features. The altered expression of miRNAs in HCC is associated with many pathological processes, such as cancer initiation, tumor growth, apoptosis escape, promotion of migration and invasion. Moreover, circulating miRNAs have been increasingly investigated as non-invasive biomarkers for HCC diagnosis. MiRNAs’ expression patterns are altered in HCC and several single miRNAs or miRNAs panels have been found significantly up or downregulated in HCC with respect to healthy controls or non-oncological patients (cirrhotic or with viral hepatitis). However, any of the investigated miRNAs or miRNAs panels has entered clinical practice so far. This has mostly to do with lack of protocols standardization, small sample size and discrepancies in the measurement techniques. This review summarizes the major findings regarding the diagnostic role of miRNAs in HCC and their possible use together with standard biomarkers in order to obtain an early diagnosis and easier differential diagnosis from non-cancerous liver disease.
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35
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Lee J, Lim YS, Lee JH, Gwak GY, Do M, Yeo I, Shin D, Han D, Park T, Kim Y. Inclusive Quantification Assay of Serum Des-γ-Carboxyprothrombin Proteoforms for Hepatocellular Carcinoma Surveillance by Targeted Mass Spectrometry. Hepatol Commun 2021; 5:1767-1783. [PMID: 34558815 PMCID: PMC8485883 DOI: 10.1002/hep4.1752] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/25/2021] [Accepted: 05/05/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignant cancer with one of the highest mortality rates. Des-γ-carboxyprothrombin (DCP) is an HCC serologic surveillance marker that can complement the low sensitivity of alpha-fetoprotein (AFP). DCP exists in the blood as a mixture of proteoforms from an impaired carboxylation process at glutamic acid (Glu) residues within the N-terminal domain. The heterogeneity of DCP may affect the accuracy of measurements because DCP levels are commonly determined using an immunoassay that relies on antibody reactivity to an epitope in the DCP molecule. In this study, we aimed to improve the DCP measurement assay by applying a mass spectrometry (MS)-based approach for a more inclusive quantification of various DCP proteoforms. We developed a multiple-reaction monitoring-MS (MRM-MS) assay to quantify multiple noncarboxylated peptides included in the various des-carboxylation states of DCP. We performed the MRM-MS assay in 300 patients and constructed a robust diagnostic model that simultaneously monitored three noncarboxylated peptides. The MS-based quantitative assay for DCP had reliable surveillance power, which was evident from the area under the receiver operating characteristic curve (AUROC) values of 0.874 and 0.844 for the training and test sets, respectively. It was equivalent to conventional antibody-based quantification, which had AUROC values at the optimal cutoff (40 mAU/mL) of 0.743 and 0.704 for the training and test sets, respectively. The surveillance performance of the MS-based DCP assay was validated using an independent validation set consisting of 318 patients from an external cohort, resulting in an AUROC value of 0.793. Conclusion: Due to cost effectiveness and high reproducibility, the quantitative DCP assay using the MRM-MS method is superior to antibody-based quantification and has equivalent performance.
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Affiliation(s)
- Jihyeon Lee
- Department of Biomedical SciencesSeoul National University College of MedicineSeoulKorea
| | - Young-Suk Lim
- Department of GastroenterologyAsan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research InstituteSeoul National University College of MedicineSeoulKorea
| | - Geum-Youn Gwak
- Department of MedicineSamsung Medical CenterSungkyunkwan University School of MedicineSeoulKorea
| | - Misol Do
- Department of Biomedical EngineeringSeoul National University College of EngineeringSeoulKorea
| | - Injoon Yeo
- Department of Biomedical EngineeringSeoul National University College of EngineeringSeoulKorea
| | - Dongyoon Shin
- Department of Biomedical SciencesSeoul National University College of MedicineSeoulKorea
| | - Dohyun Han
- Biomedical Research InstituteSeoul National University HospitalSeoulKorea
| | - Taesung Park
- Department of StatisticsSeoul National UniversitySeoulKorea
| | - Youngsoo Kim
- Department of Biomedical SciencesSeoul National University College of MedicineSeoulKorea.,Department of Biomedical EngineeringSeoul National University College of EngineeringSeoulKorea
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Kyei-Barffour I, Kwarkoh RKB, Acheampong DO, Brah AS, Akwetey SA, Aboagye B. Alkaloidal extract from Carica papaya seeds ameliorates CCl 4-induced hepatocellular carcinoma in rats. Heliyon 2021; 7:e07849. [PMID: 34471716 PMCID: PMC8387916 DOI: 10.1016/j.heliyon.2021.e07849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/22/2021] [Accepted: 08/18/2021] [Indexed: 01/06/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the third cause of cancer-related mortality globally. However, available treatments are expensive and are associated with adverse effects or poor treatment outcomes in advanced disease. Meanwhile, plants like Carica papaya have demonstrated various biological activities that further studies may lead to the identification of newer and safer treatment options for HCC. Aim To evaluate the anticancer activity of an alkaloidal extract derived from Carica papaya seeds using rodent models of HCC. Experimental procedure Carica Papaya fruits were collected and authenticated. The seeds were isolated and air-dried. Alkaloidal extract was prepared from a 70% ethanol soxhlet crude extract and referred to as Carica papaya alkaloidal extract (CPAE). HCC was induced in 68 out of 84 healthy male Sprague Dawley rats by intraperitoneal injection of carbon tetrachloride (CCl4) for 16 weeks. These rats were put into five groups of 10; Carica papaya alkaloidal extract [(CPAE) (50, 100, and 200 mg/kg), Lenvatinib (4 mg/kg)], 1% dimethyl sulphoxide (DMSO), and 2 untreated groups (control and model). A prophylaxis study was performed with 10 rats by co-administration of CPAE (200 mg/kg) and CCl4 six hours apart for 16 weeks. Rats were sacrificed after a twelve-week treatment program under anesthesia for histological, hematological, and biochemical analyses. Results and conclusion CPAE (100 and 200 mg/kg) significantly restored weight loss (48.44 and 51.75% respectively), reduced tumor multiplicity, and dose-dependently reversed liver histomorphological changes induced by CCl4 compared to the model group. The CPAE (100 and 200 mg/kg) further reduced bleeding time, improved prothrombin time and restored platelet count (p < 0.01) compared to the model. The CPAE (200 mg/kg) again significantly (p < 0.0001) reduced serum alpha-fetoprotein levels compared to the model group and prevented the establishment of HCC in rats when concerrently administered with CCl4 in 16 weeks prophylactic study.
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Affiliation(s)
- Isaac Kyei-Barffour
- Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Ghana
| | - Roselind Kyei Baah Kwarkoh
- Department of Physician Assistant Studies, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Ghana
| | - Desmond Omane Acheampong
- Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Ghana
| | - Augustine Suurinobah Brah
- Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Ghana
| | - Samuel Addo Akwetey
- Department of Biomedical Sciences, School of Allied Health Sciences, College of Health and Allied Sciences, University of Cape Coast, Ghana
| | - Benjamin Aboagye
- Department of Forensic Sciences, School of Biological Sciences, College of Agricultural and Natural Sciences, University of Cape Coast, Ghana
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Shyu S, Ali SZ. Significance of hepatocyte atypia in liver fine needle aspiration. Diagn Cytopathol 2021; 50:186-195. [PMID: 34459153 DOI: 10.1002/dc.24851] [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: 06/16/2021] [Revised: 08/04/2021] [Accepted: 08/05/2021] [Indexed: 11/06/2022]
Abstract
Fine needle aspiration (FNA) of the liver is frequently the diagnostic procedure of choice for sampling hepatic lesions. One of the main diagnostic challenges in the interpretation of liver FNA is distinguishing dysplastic lesions and well-differentiated hepatocellular carcinoma (WD-HCC) from benign processes, as they share significant cytomorphologic overlap. Furthermore, the diagnosis of HCC often requires evaluation of stroma for invasion, which may not be present on cytology and small needle biopsy specimens. A reporting system for liver cytopathology has yet to be instituted. Without standardized and well-defined criteria for hepatocyte atypia, we recommend limiting the use of atypia in evaluation of liver FNA specimens to describe a diagnosis of exclusion, in which all known benign and neoplastic processes have been ruled out. The cytologic findings on the FNA of a liver nodule may be best reported as atypical hepatocytes in the absence of a core needle biopsy or cell block sufficient to render a definitive diagnosis of HCC.
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Affiliation(s)
- Susan Shyu
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Syed Z Ali
- Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA
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Barbosa WF, Andrade VG, Braz AMM, Winckler FC, Barbosa LR, Golim MDA, Silveira LVDA, Simões RP, Silva GF. Cirrhosis regression after SVR with indirect methods of fibrosis analysis: How far is it real? Clin Exp Med 2021; 22:269-275. [PMID: 34347205 DOI: 10.1007/s10238-021-00749-1] [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: 05/17/2021] [Accepted: 07/22/2021] [Indexed: 12/01/2022]
Abstract
Hepatitis C virus has infected over 71 million people worldwide, and it is the main cause of cirrhosis in the western world. Currently, the treatment involves direct-acting antiviral agents (DAAs) and its main goal is to achieve sustained virologic response (SVR). The aim of this study was to evaluate the impact of SVR using DAAs in the improvement of liver fibrosis using scores evaluation by indirect method, liver function, and inflammation indirect biomarkers. Patients with cirrhosis with SVR after treatment (n = 104) were evaluated using liver function scores, indirect fibrosis methods, alpha-fetoprotein, and ferritin at t-base and t-SVR. Statistically significant positive results in all parameters were observed: 54 patients were classified as 5 in the CP score in t-base, and 77 in t-SVR; a significant decrease was observed in MELD score, alpha-fetoprotein, ferritin, APRI, FIB-4 and liver stiffness in liver elastography. We did not observe difference in the liver function scores between regressors and non-regressors of liver stiffness, as well as in indirect inflammation biomarkers. The measurements of fibrosis using the indirect methods have significantly decreased in patients with cirrhosis treated who achieved SVR associated with decreased indirect inflammation biomarkers and improved liver function scores.
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Affiliation(s)
- Walnei Fernandes Barbosa
- Department of Clinical Medicine, Botucatu Medical School, São Paulo State University (UNESP), Av. Prof. Mário Rubens Guimarães Montenegro, s/n - UNESP, Botucatu, São Paulo, Brazil
| | - Vanessa Gutierrez Andrade
- Department of Clinical Medicine, Botucatu Medical School, São Paulo State University (UNESP), Av. Prof. Mário Rubens Guimarães Montenegro, s/n - UNESP, Botucatu, São Paulo, Brazil
| | - Aline Márcia Marques Braz
- Department of Clinical Medicine, Botucatu Medical School, São Paulo State University (UNESP), Av. Prof. Mário Rubens Guimarães Montenegro, s/n - UNESP, Botucatu, São Paulo, Brazil
| | - Fernanda Cristina Winckler
- Department of Clinical Medicine, Botucatu Medical School, São Paulo State University (UNESP), Av. Prof. Mário Rubens Guimarães Montenegro, s/n - UNESP, Botucatu, São Paulo, Brazil
| | - Livia Roma Barbosa
- Undergraduate Course in Medicine, Taubaté Medical School - UNITAU, Taubaté, São Paulo, Brazil
| | - Márjorie de Assis Golim
- Graduate Program in Research and Development (Medical Biotechnology), Botucatu Medical School, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Liciana Vaz de Arruda Silveira
- Department of Bioestatistics, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Rafael Plana Simões
- Graduate Program in Research and Development (Medical Biotechnology), Botucatu Medical School, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.,Department of Biotechnology and Bioprocess Engineering, Faculty of Agronomic Sciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil
| | - Giovanni Faria Silva
- Department of Clinical Medicine, Botucatu Medical School, São Paulo State University (UNESP), Av. Prof. Mário Rubens Guimarães Montenegro, s/n - UNESP, Botucatu, São Paulo, Brazil. .,Graduate Program in Research and Development (Medical Biotechnology), Botucatu Medical School, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.
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GALAD Score Detects Early-Stage Hepatocellular Carcinoma in a European Cohort of Chronic Hepatitis B and C Patients. Pharmaceuticals (Basel) 2021; 14:ph14080735. [PMID: 34451832 PMCID: PMC8401792 DOI: 10.3390/ph14080735] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 12/23/2022] Open
Abstract
Despite vaccination programs and direct antiviral treatments, the incidence of virus-related hepatocellular carcinoma (HCC) remains high, while ultrasound-based detection rates for early-stage HCC is continuously low. To address this insufficiency, we set out to characterize whether the GALAD score, which incorporates gender, age, and serum levels of AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy-prothrombin (DCP), can improve early-stage HCC detection in a Caucasian HBV/HCV cohort. In a retrospective German single-center study, 182 patients with HBV, 223 with HCV and 168 with other etiology (OE) of chronic liver disease (CLD) were enrolled. HCC was confirmed in 52 HBV, 84 HCV and 60 OE CLD patients. The diagnostic performance of the single biomarkers in HCC detection was compared to the GALAD model. At initial diagnosis, most patients were at (very) early BCLC 0 (n = 14/7%) or A (n = 56/29%) or intermediate stage BCLC B (n = 93/47%) HCC in all three subgroups. In the BCLC 0/A cohort, GALAD exhibited an AUC of 0.94 discriminating HCC from non-HCC, surpassing AFP (AUC 0.86), AFP-L3 (AUC 0.83) and DCP (AUC 0.83). In the HBV population, GALAD achieved an AUC of 0.96, in HCV an AUC of 0.98 and in OE an AUC of 0.99, clearly superior to the biomarkers alone. Furthermore, in HCV patients GALAD showed a significantly higher specificity (89%) versus AFP (64%) alone. In chronic viral hepatitis, the GALAD model showed superior performance in detection of early-stage HCC, while exhibiting higher specificity in HCV patients compared to AFP alone. We conclude that the GALAD score shows potential for HCC surveillance in Caucasian HBV/HCV patients.
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Isac T, Isac S, Ioanitescu S, Mihaly E, Tanasescu MD, Balan DG, Tulin A, Iliescu L. Dynamics of serum α-fetoprotein in viral hepatitis C without hepatocellular carcinoma. Exp Ther Med 2021; 22:749. [PMID: 34035846 PMCID: PMC8135122 DOI: 10.3892/etm.2021.10181] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 02/22/2021] [Indexed: 01/04/2023] Open
Abstract
Viral hepatitis C represents a significant liver pathology worldwide, with a detrimental impact on national health systems. The present study aimed to correlate the levels of serum α-fetoprotein (AFP) with prognostic tools such as Fibroscan®, the presence of mixed cryoglobulinemia, and various demographic and standard biochemical markers, in patients with chronic hepatitis C, unrelated to hepatocellular carcinoma (HCC). A clinical study was designed considering three study groups: Hepatitis C virus (HCV) group including 35 patients with chronic hepatitis C and detectible viral load; sustained viral response (SVR) group including 20 HCV patients without detectable virus load 12 weeks after therapy cessation; a control group represented by 37 healthy volunteers. It was observed that serum AFP was moderately increased in the HCV and SVR groups and was positively correlated with aspartate transaminase (AST), alkaline phosphatase (AP), and γ-glutamyl transferase (GGT). The incidence of mixed cryoglobulinemia was increased in the HCV group, and the degree of fibrosis assessed by Fibroscan® was increased in both the HCV and SVR groups. In conclusion, the data revealed that a moderate increase in AFP levels could be present in patients with HCV even in the absence of HCC, unrelated to viral load or therapy response and that there was a linear positive correlation between serum levels of AFP and the degree of hepatic cytolysis and cholestasis. Additionally, mixed cryoglobulinemia was present in HCV patients with patent viral load, decreasing in those with SVR after therapy cessation unrelated to any renal impairment, while the degree of fibrosis was increased in HCV-infected patients, with no reversibility 12 weeks after successful therapy.
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Affiliation(s)
- Teodora Isac
- Department of Internal Medicine II, Faculty of Medicine, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Sebastian Isac
- Department of Physiology and Neuroscience, Faculty of Medicine, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Simona Ioanitescu
- Department of Internal Medicine II, Faculty of Medicine, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Enyedi Mihaly
- Department of Anatomy, Faculty of Medicine, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Maria-Daniela Tanasescu
- Department of Medical Semiology, Discipline of Internal Medicine I and Nephrology, Faculty of Medicine, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Daniela Gabriela Balan
- Discipline of Physiology, Faculty of Dental Medicine, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Adrian Tulin
- Department of Anatomy, Faculty of Medicine, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania.,Department of General Surgery, 'Prof. Dr. Agrippa Ionescu' Clinical Emergency Hospital, 011356 Bucharest, Romania
| | - Laura Iliescu
- Department of Internal Medicine II, Faculty of Medicine, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Reig M, Forner A, Ávila MA, Ayuso C, Mínguez B, Varela M, Bilbao I, Bilbao JI, Burrel M, Bustamante J, Ferrer J, Gómez MÁ, Llovet JM, De la Mata M, Matilla A, Pardo F, Pastrana MA, Rodríguez-Perálvarez M, Tabernero J, Urbano J, Vera R, Sangro B, Bruix J. Diagnosis and treatment of hepatocellular carcinoma. Update of the consensus document of the AEEH, AEC, SEOM, SERAM, SERVEI, and SETH. Med Clin (Barc) 2021; 156:463.e1-463.e30. [PMID: 33461840 DOI: 10.1016/j.medcli.2020.09.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/12/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm and one of the most common causes of death in patients with cirrhosis of the liver. In parallel, with recognition of the clinical relevance of this cancer, major new developments have recently appeared in its diagnosis, prognostic assessment and in particular, in its treatment. Therefore, the Spanish Association for the Study of the Liver (AEEH) has driven the need to update the clinical practice guidelines, once again inviting all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document: Spanish Society for Liver Transplantation (SETH), Spanish Society of Diagnostic Radiology (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Association of Surgeons (AEC) and Spanish Society of Medical Oncology (SEOM). The clinical practice guidelines published in 2016 and accepted as National Health System Clinical Practice Guidelines were taken as the reference documents, incorporating the most important recent advances. The scientific evidence and the strength of the recommendation is based on the GRADE system.
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Affiliation(s)
- María Reig
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Alejandro Forner
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Matías A Ávila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Programa de Hepatología, Centro de Investigación Médica Aplicada, Universidad de Navarra-IDISNA, Pamplona, España
| | - Carmen Ayuso
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Beatriz Mínguez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Hepatología, Hospital Universitario Vall d́Hebron, Grupo de Investigación en Enfermedades Hepáticas (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universidad Autónoma de Barcelona. Barcelona, España
| | - María Varela
- Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias. Oviedo, España
| | - Itxarone Bilbao
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Cirugía Hepatobiliopancreática y Trasplantes Digestivos, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona. Barcelona, España
| | - José Ignacio Bilbao
- Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, España
| | - Marta Burrel
- Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Javier Bustamante
- Servicio de Gastroenterología y Hepatología, Sección de Hepatología y Trasplante, Hospital Universitario de Cruces, Baracaldo, España
| | - Joana Ferrer
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Cirugía Hepatobiliopancreática, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Miguel Ángel Gómez
- Unidad de Cirugía Hepatobiliopancreática y Trasplantes, Hospital Universitario Virgen del Rocío, Sevilla, España
| | - Josep María Llovet
- Grupo de Investigación Traslacional en Oncología Hepática, Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Manuel De la Mata
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Ana Matilla
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Sección de Hepatología, Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - Fernando Pardo
- Servicio de Cirugía Hepatobiliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, España
| | - Miguel A Pastrana
- Servicio de Radiodiagnóstico, Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, Madrid, España
| | - Manuel Rodríguez-Perálvarez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Josep Tabernero
- Servicio de Oncología Médica, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, España
| | - José Urbano
- Unidad de Radiología Vascular e Intervencionista, Servicio de Radiodiagnóstico, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, España
| | - Ruth Vera
- Servicio de Oncología Médica, Complejo hospitalario de Navarra, Navarrabiomed-IDISNA, Pamplona, España
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad de Hepatología y Área de Oncología HBP, Clínica Universidad de Navarra-IDISNA, Pamplona, España.
| | - Jordi Bruix
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
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Aishanjiang K, Wei XD, Fu Y, Lin X, Ma Y, Le J, Han Q, Wang X, Kong X, Gu J, Wu H. Circular RNAs and Hepatocellular Carcinoma: New Epigenetic Players With Diagnostic and Prognostic Roles. Front Oncol 2021; 11:653717. [PMID: 33959506 PMCID: PMC8093866 DOI: 10.3389/fonc.2021.653717] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/22/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Due to the lack of potent diagnosis and prognosis biomarkers and effective therapeutic targets, the overall prognosis of survival is poor in HCC patients. Circular RNAs (circRNAs) are a class of novel endogenous non-coding RNAs with covalently closed loop structures and implicated in diverse physiological processes and pathological diseases. Recent studies have demonstrated the involvement of circRNAs in HCC diagnosis, prognosis, development, and drug resistance, suggesting that circRNAs may be a class of novel targets for improving HCC diagnosis, prognosis, and treatments. In fact, some artificial circRNAs have been engineered and showed their therapeutic potential in treating HCV infection and gastric cancer. In this review, we introduce the potential of circRNAs as biomarkers for HCC diagnosis and prognosis, as therapeutic targets for HCC treatments and discuss the challenges in circRNA research and chances of circRNA application.
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Affiliation(s)
- Kedeerya Aishanjiang
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Department of Collaborative Innovation Center for Biomedicine, Shanghai, China.,Department of Transplantation, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xin-Dong Wei
- Department of General Surgery, The 81st Hospital Affiliated to Nanjing University of Traditional Chinese Medicine, Nanjing, China
| | - Yi Fu
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Department of Collaborative Innovation Center for Biomedicine, Shanghai, China
| | - Xinjie Lin
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Department of Collaborative Innovation Center for Biomedicine, Shanghai, China
| | - Yujie Ma
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Department of Collaborative Innovation Center for Biomedicine, Shanghai, China
| | - Jiamei Le
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Department of Collaborative Innovation Center for Biomedicine, Shanghai, China
| | - Qiuqin Han
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Department of Collaborative Innovation Center for Biomedicine, Shanghai, China
| | - Xuan Wang
- Department of General Surgery, The 81st Hospital Affiliated to Nanjing University of Traditional Chinese Medicine, Nanjing, China
| | - Xiaoni Kong
- Institute of Clinical Immunology, Department of Liver Diseases, Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jinyang Gu
- Department of Transplantation, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hailong Wu
- Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Department of Collaborative Innovation Center for Biomedicine, Shanghai, China.,Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China.,Collaborative Innovation Center for Biomedicine, Shanghai University of Medicine & Health Sciences, Shanghai, China
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Colli A, Nadarevic T, Miletic D, Giljaca V, Fraquelli M, Štimac D, Casazza G. Abdominal ultrasound and alpha-foetoprotein for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease. Cochrane Database Syst Rev 2021; 4:CD013346. [PMID: 33855699 PMCID: PMC8078581 DOI: 10.1002/14651858.cd013346.pub2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) occurs mostly in people with chronic liver disease and ranks sixth in terms of global instances of cancer, and fourth in terms of cancer deaths for men. Despite that abdominal ultrasound (US) is used as an initial test to exclude the presence of focal liver lesions and serum alpha-foetoprotein (AFP) measurement may raise suspicion of HCC occurrence, further testing to confirm diagnosis as well as staging of HCC is required. Current guidelines recommend surveillance programme using US, with or without AFP, to detect HCC in high-risk populations despite the lack of clear benefits on overall survival. Assessing the diagnostic accuracy of US and AFP may clarify whether the absence of benefit in surveillance programmes could be related to under-diagnosis. Therefore, assessment of the accuracy of these two tests for diagnosing HCC in people with chronic liver disease, not included in surveillance programmes, is needed. OBJECTIVES Primary: the diagnostic accuracy of US and AFP, alone or in combination, for the diagnosis of HCC of any size and at any stage in adults with chronic liver disease, either in a surveillance programme or in a clinical setting. Secondary: to assess the diagnostic accuracy of abdominal US and AFP, alone or in combination, for the diagnosis of resectable HCC; to compare the diagnostic accuracy of the individual tests versus the combination of both tests; to investigate sources of heterogeneity in the results. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic-Test-Accuracy Studies Register, Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, until 5 June 2020. We applied no language or document-type restrictions. SELECTION CRITERIA Studies assessing the diagnostic accuracy of US and AFP, independently or in combination, for the diagnosis of HCC in adults with chronic liver disease, with cross-sectional and case-control designs, using one of the acceptable reference standards, such as pathology of the explanted liver, histology of resected or biopsied focal liver lesion, or typical characteristics on computed tomography, or magnetic resonance imaging, all with a six-months follow-up. DATA COLLECTION AND ANALYSIS We independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest-plots, and tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses. MAIN RESULTS We included 373 studies. The index-test was AFP (326 studies, 144,570 participants); US (39 studies, 18,792 participants); and a combination of AFP and US (eight studies, 5454 participants). We judged at high-risk of bias all but one study. Most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time-interval between the index test and the reference standard was rarely defined. Most studies with AFP had a case-control design. We also had major concerns for the applicability due to the characteristics of the participants. As the primary studies with AFP used different cut-offs, we performed a meta-analysis using the hierarchical-summary-receiver-operating-characteristic model, then we carried out two meta-analyses including only studies reporting the most used cut-offs: around 20 ng/mL or 200 ng/mL. AFP cut-off 20 ng/mL: for HCC (147 studies) sensitivity 60% (95% CI 58% to 62%), specificity 84% (95% CI 82% to 86%); for resectable HCC (six studies) sensitivity 65% (95% CI 62% to 68%), specificity 80% (95% CI 59% to 91%). AFP cut-off 200 ng/mL: for HCC (56 studies) sensitivity 36% (95% CI 31% to 41%), specificity 99% (95% CI 98% to 99%); for resectable HCC (two studies) one with sensitivity 4% (95% CI 0% to 19%), specificity 100% (95% CI 96% to 100%), and one with sensitivity 8% (95% CI 3% to 18%), specificity 100% (95% CI 97% to 100%). US: for HCC (39 studies) sensitivity 72% (95% CI 63% to 79%), specificity 94% (95% CI 91% to 96%); for resectable HCC (seven studies) sensitivity 53% (95% CI 38% to 67%), specificity 96% (95% CI 94% to 97%). Combination of AFP (cut-off of 20 ng/mL) and US: for HCC (six studies) sensitivity 96% (95% CI 88% to 98%), specificity 85% (95% CI 73% to 93%); for resectable HCC (two studies) one with sensitivity 89% (95% CI 73% to 97%), specificity of 83% (95% CI 76% to 88%), and one with sensitivity 79% (95% CI 54% to 94%), specificity 87% (95% CI 79% to 94%). The observed heterogeneity in the results remains mostly unexplained, and only in part referable to different cut-offs or settings (surveillance programme compared to clinical series). The sensitivity analyses, excluding studies published as abstracts, or with case-control design, showed no variation in the results. We compared the accuracy obtained from studies with AFP (cut-off around 20 ng/mL) and US: a direct comparison in 11 studies (6674 participants) showed a higher sensitivity of US (81%, 95% CI 66% to 90%) versus AFP (64%, 95% CI 56% to 71%) with similar specificity: US 92% (95% CI 83% to 97%) versus AFP 89% (95% CI 79% to 94%). A direct comparison of six studies (5044 participants) showed a higher sensitivity (96%, 95% CI 88% to 98%) of the combination of AFP and US versus US (76%, 95% CI 56% to 89%) with similar specificity: AFP and US 85% (95% CI 73% to 92%) versus US 93% (95% CI 80% to 98%). AUTHORS' CONCLUSIONS In the clinical pathway for the diagnosis of HCC in adults, AFP and US, singularly or in combination, have the role of triage-tests. We found that using AFP, with 20 ng/mL as a cut-off, about 40% of HCC occurrences would be missed, and with US alone, more than a quarter. The combination of the two tests showed the highest sensitivity and less than 5% of HCC occurrences would be missed with about 15% of false-positive results. The uncertainty resulting from the poor study quality and the heterogeneity of included studies limit our ability to confidently draw conclusions based on our results.
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Affiliation(s)
- Agostino Colli
- Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Tin Nadarevic
- Department of Radiology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Damir Miletic
- Department of Radiology , Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Vanja Giljaca
- Department of Gastroenterology, Heart of England NHS Foundation Trust, Birmingham, UK
| | - Mirella Fraquelli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca´ Granda - Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Davor Štimac
- Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Giovanni Casazza
- Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano, Milan, Italy
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Su F, Weiss NS, Beste LA, Moon AM, Jin GY, Green P, Berry K, Ioannou GN. Screening is associated with a lower risk of hepatocellular carcinoma-related mortality in patients with chronic hepatitis B. J Hepatol 2021; 74:850-859. [PMID: 33245934 PMCID: PMC8045451 DOI: 10.1016/j.jhep.2020.11.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 11/06/2020] [Accepted: 11/16/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Patients with chronic hepatitis B (CHB) infection routinely undergo screening for hepatocellular carcinoma (HCC), but the efficacy of screening remains unclear. We aimed to evaluate the impact of screening with ultrasound and/or serum alpha-fetoprotein (AFP) on HCC-related mortality in patients with CHB. METHODS We performed a matched case-control study of patients with CHB receiving care through the Veterans Affairs (VA) health administration. Cases were patients who died of HCC between 01/01/2004 and 12/31/2017, while controls were patients with CHB who did not die of HCC. Cases were matched to controls by CHB diagnosis date, age, sex, race/ethnicity, cirrhosis, antiviral therapy exposure, hepatitis B e antigen status, and viral load. We identified screening ultrasound and AFPs obtained in the 4 years preceding HCC diagnosis in cases and the equivalent index date in controls. Using conditional logistic regression, we compared cases and controls with respect to receipt of screening. A lower likelihood of screening in cases corresponds to an association between screening and reduced risk of HCC-related mortality. RESULTS We identified 169 cases, matched to 169 controls. Fewer cases than controls underwent screening with either screening modality (33.7% vs. 58.6%) or both modalities (19.5% vs. 34.4%). In multivariable conditional logistic regression, screening with either modality was associated with a lower risk of HCC-related mortality (adjusted odds ratio [aOR] 0.21, 95% CI 0.09-0.50), as was screening with both modalities (aOR of 0.13; 95% CI 0.04-0.43). CONCLUSIONS HCC screening was associated with a substantial reduction in HCC-related mortality in VA patients with CHB. LAY SUMMARY Patients with hepatitis B infection have a high risk of developing liver cancer. It is therefore recommended that they undergo frequent screening for liver cancer, but whether this leads to a lower risk of dying from liver cancer is not clear. In this study, we show that liver cancer screening is associated with a reduction in the mortality from liver cancer in patients with hepatitis B infection.
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Affiliation(s)
- Feng Su
- Divisions of Gastroenterology, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle WA.,Department of Epidemiology, University of Washington, Seattle WA, and the Fred Hutchinson Cancer Research Center, Seattle WA
| | - Noel S. Weiss
- Department of Epidemiology, University of Washington, Seattle WA, and the Fred Hutchinson Cancer Research Center, Seattle WA
| | - Lauren A. Beste
- Division of General Internal Medicine, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle WA
| | - Andrew M. Moon
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Ga-Young Jin
- Health Services Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle WA
| | - Pamela Green
- Health Services Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle WA
| | - Kristin Berry
- Health Services Research and Development, Veterans Affairs Puget Sound Healthcare System, Seattle WA
| | - George N. Ioannou
- Divisions of Gastroenterology, Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle WA
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Centonze L, Di Sandro S, Lauterio A, De Carlis R, Frassoni S, Rampoldi A, Tuscano B, Bagnardi V, Vanzulli A, De Carlis L. Surgical Resection vs. Percutaneous Ablation for Single Hepatocellular Carcinoma: Exploring the Impact of Li-RADS Classification on Oncological Outcomes. Cancers (Basel) 2021; 13:1671. [PMID: 33916311 PMCID: PMC8038048 DOI: 10.3390/cancers13071671] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/25/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Background: Single hepatocellular carcinoma (HCC) benefits from surgical resection (SR) or US-guided percutaneous ablation (PA), although the best approach is still debated. We evaluated the impact of Li-RADS classification on the oncological outcomes of SR vs. PA as single HCC first-line treatment. Methods: We retrospectively and blindly classified treatment-naïve single HCC that underwent SR or PA between 2010 and 2016 according to Li-RADS protocol. Overall survival (OS), recurrence free survival (RFS) and local recurrence after SR and PA were compared for each Li-RADS subclass before and after propensity-score matching (PS-M). Results: Considering the general population, SR showed better 5-year OS (68.3% vs. 52.2%; p = 0.049) and RFS (42.5% vs. 29.8%; p = 0.002), with lower incidence of local recurrence (8.2% vs. 44.4%; p < 0.001), despite a significantly higher frequency of clinically-relevant complications (12.8% vs. 1.9%; p = 0.002) and a higher Comprehensive Complication Index (12.1 vs. 2.2; p < 0.001). Focusing on different Li-RADS subclasses, we highlighted better 5-year OS (67.1% vs. 46.2%; p = 0.035), RFS (45.0% vs. 27.0% RFS; p < 0.001) and lower incidence of local recurrence (9.7% vs. 48.6%; p < 0.001) after SR for Li-RADS-5 HCCs, while these outcomes did not differ for Li-RADS-3/4 subclasses; such results were confirmed after PS-M. Conclusions: Our analysis suggests a potential prognostic role of Li-RADS classification, supporting SR over PA especially for Li-RADS-5 single HCC.
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Affiliation(s)
- Leonardo Centonze
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20162 Milan, Italy; (S.D.S.); (A.L.); (R.D.C.); (L.D.C.)
| | - Stefano Di Sandro
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20162 Milan, Italy; (S.D.S.); (A.L.); (R.D.C.); (L.D.C.)
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Andrea Lauterio
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20162 Milan, Italy; (S.D.S.); (A.L.); (R.D.C.); (L.D.C.)
| | - Riccardo De Carlis
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20162 Milan, Italy; (S.D.S.); (A.L.); (R.D.C.); (L.D.C.)
| | - Samuele Frassoni
- Department of Statistics and Quantitative Methods, University of Milan-Bicocca, 20126 Milan, Italy; (S.F.); (V.B.)
| | - Antonio Rampoldi
- Department of Diagnostic and Interventional Radiology, Niguarda Ca’ Granda Hospital, 20162 Milan, Italy; (A.R.); (B.T.); (A.V.)
| | - Bruno Tuscano
- Department of Diagnostic and Interventional Radiology, Niguarda Ca’ Granda Hospital, 20162 Milan, Italy; (A.R.); (B.T.); (A.V.)
| | - Vincenzo Bagnardi
- Department of Statistics and Quantitative Methods, University of Milan-Bicocca, 20126 Milan, Italy; (S.F.); (V.B.)
| | - Angelo Vanzulli
- Department of Diagnostic and Interventional Radiology, Niguarda Ca’ Granda Hospital, 20162 Milan, Italy; (A.R.); (B.T.); (A.V.)
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, Niguarda Ca’ Granda Hospital, 20162 Milan, Italy; (S.D.S.); (A.L.); (R.D.C.); (L.D.C.)
- School of Medicine and Surgery, University of Milan-Bicocca, 20126 Milan, Italy
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Sakr MA, Mohamed KAH, Hussein AM, Fouad MH, Allam AS, Safwat E. Diagnostic and prognostic value of serum soluble CD163 in cirrhotic patients with hepatitis C virus-related hepatocellular carcinoma before and after locoregional therapy. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00090-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Abstract
Background
Tumor-associated macrophages (TAMs), inflammatory cells in tumor microenvironment, are crucial for the tumor occurrence and progression which in turn increase the expression of soluble CD163 (sCD163). Nevertheless, not much has been established regarding sCD163 and its connection to HCC diagnosis and prognosis. This study was conducted to evaluate the diagnostic and prognostic role of sCD163 in patients with HCC on top of HCV-related liver cirrhosis. Forty adult patients with HCV-related liver cirrhosis and HCC (HCC group) were randomly selected and subjected to locoregional therapies, either transarterial chemoembolization (TACE) or radiofrequency ablation (RFA). Four patients were excluded because of portal vein invasion. Another group of 20 patients with liver cirrhosis only served as controls (LC group). Routine laboratory studies and abdominal ultrasound were done for all. Alpha-fetoprotein (AFP) and sCD163 were measured twice, at baseline and 1-month post-intervention, using a commercially available enzyme-linked immunosorbent assay kit.
Results
At baseline, sCD163 showed an insignificant higher value in HCC group (p > 0.05). The best cutoff value for sCD163 and AFP was 6.2 mg/L and 195 ng/mL, respectively. AFP had a larger area under the curve (0.88 vs. 0.767). An overall significant decline was seen in sCD163 after treatment (6.5±1.5 to 3.1±2.5 mg/L; p < 0.001), while AFP showed an insignificant decrease (p > 0.05). Also, sCD163 decreased significantly in the eradicated cases (6.1±1.4 mg/L before intervention vs. 2.3±1.4 mg/L after intervention, p < 0.01), while there was a significant increase in the recurrent cases (8.4±0.4 mg/L before intervention vs. 10.3±1.6 after intervention; p < 0.05). Moreover, sCD163 showed a significant difference in its pre-intervention and post-intervention values between recurrent and eradicated HCC cases (p < 0.01).
Conclusions
It is concluded that sCD163 has a minor role as a diagnostic marker for HCC, yet it could be used as a good prognostic marker in predicting the tumor response to locoregional therapies.
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Change in γ-glutamyl transpeptidase activity as a useful tool in identifying a group of patients with elevated risk of hepatocellular carcinoma development after DAA treatment of chronic hepatitis C. Clin Exp Hepatol 2021; 7:93-100. [PMID: 34027121 PMCID: PMC8122098 DOI: 10.5114/ceh.2021.104466] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 12/16/2020] [Indexed: 12/30/2022] Open
Abstract
Aim of the study Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) incidence will be diminishing due to use of direct acting antiviral agents (DAA), but there is still constant risk for HCC development. Elevated serum g-glutamyl transpeptidase (GGT) activity is associated with increased risk of liver cancer. In our study we tried to determine whether change in GGT activity may be useful in identifying patients with elevated risk of HCC development after DAA treatment. Material and methods The study population consisted of 111 patients with chronic hepatitis C (CHC) treated with DAA. Laboratory tests [alanine aminotransferase (ALT), GGT, a-fetoprotein (AFP)] and liver stiffness measurement (using FibroScan) were performed at the beginning and at the end of therapy. Results Pre-treatment ALT activity, GGT activity and AFP concentration in patients with CHC were directly associated with the stage of liver fibrosis. Elimination of HCV after DAA treatment caused significant reduction in serum GGT activity and was not associated with pre-treatment liver fibrosis. AFP concentration was significantly lower after treatment. It was observed regardless of pre-treatment AFP concentration, but the largest reduction was demonstrated in the group of patients with advanced fibrosis. In multivariate analysis there was no significant difference in GGT activity after treatment only in patients with pre-treatment normal AFP concentration and advanced liver fibrosis. Conclusions Patients who after achieving a sustained virological response (SVR) did not lower both AFP concentration and GGT activity may have higher risk of HCC development. Special monitoring may be required in patients with advanced liver fibrosis and normal AFP concentration before treatment.
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Wu D, Pan Y, Zheng X. Identification of hub genes-based predictive model in hepatocellular carcinoma by robust rank aggregation and regression analysis. J Cancer 2021; 12:1884-1893. [PMID: 33753986 PMCID: PMC7974519 DOI: 10.7150/jca.52089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 12/27/2020] [Indexed: 12/24/2022] Open
Abstract
Background: Though various hub genes for HCC have been identified in decades, the limited sample size, inconsistent bioinformatic analysis methods and lacking evaluation in validation cohorts would make the results less reliable, novel biomarkers and risk model for HCC prognosis are still urgently desired. Methods: The Robust Rank Aggression method was applied to integrate 12 HCC microarray datasets to screen for robustly and stably differentially expressed candidates. The Least Absolute Shrinkage and Selection Operator regression and multivariate Cox regression analysis were performed to construct a six hub genes-based prognostic model, which was further verified in matched tumor and non-tumor hepatic samples and two independent validation cohorts. Results: Six hub genes for HCC were identified including CD163, EHHADH, KIAA0101, SLC16A2, SPP1 and THBS4. The risk score according to hub genes-based prognostic model could be an independent predictive factor for HCC. Quantitative real-time polymerase chain reaction results showed significant difference in expression level between tumor and non-tumor hepatic tissues. Prognostic value of risk model has been verified in TCGA-HCC and GSE76240 datasets. Biological function analysis revealed these hub genes were closely associated with tumorigenesis processes. Conclusion: A novel six hub genes predictive risk model for HCC has been established based on multiple datasets analyses, providing novel features for the prediction of HCC patients' outcome.
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Affiliation(s)
- Di Wu
- Department of General Surgery, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Yun Pan
- Department of Emergency, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
| | - Xueyong Zheng
- Department of General Surgery, Sir Run-Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China
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Qian X, Liu S, Long H, Zhang S, Yan X, Yao M, Zhou J, Gong J, Wang J, Wen X, Zhou T, Zhai X, Xu Q, Zhang T, Chen X, Hu G, Wang J, Gao Z, Nan Y, Chen J, Hu B, Zhao J, Lu F. Reappraisal of the diagnostic value of alpha-fetoprotein for surveillance of HBV-related hepatocellular carcinoma in the era of antiviral therapy. J Viral Hepat 2021; 28:20-29. [PMID: 32852885 PMCID: PMC7756791 DOI: 10.1111/jvh.13388] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 07/03/2020] [Accepted: 07/30/2020] [Indexed: 12/15/2022]
Abstract
This study was designed to explore if antiviral treatment influences the performance of serum alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) among the high-risk chronic HBV-infected patients. A total of 5936 patients who had evidence of chronic HBV infection were enrolled from four independent centres in this retrospective study, including 1721 chronic hepatitis B (CHB), 2286 liver cirrhosis (LC), 798 HCC within Milan criteria and 1131 HCC beyond Milan criteria patients. Stratified by whether they received treatment or not, the patients were further divided into antiviral and non-antiviral groups. Then, the performance of AFP for discriminating HCC was evaluated. Patients receiving antivirals had significantly lower median levels of AFP compared with the non-antiviral patients (P < .001), and there were significantly less patients with abnormal AFP levels in antiviral groups (P < .001). Antiviral therapy improved the AUROCs of AFP for discriminating HCC within Milan criteria. When setting the cut-off values at 20 ng/mL and 100 ng/mL as surveillance and confirmatory tests respectively for HCC among patients receiving antiviral treatment, AFP exhibited a significantly higher sensitivity than those of 200 ng/mL and 400 ng/mL, which are currently recommended by some guidelines, without compromising specificity. Further analysis in antiviral patients revealed that serum AFP had better performance for discriminating HCC within Milan criteria in ALT ≤ 1ULN patients than that in ALT > 1ULN patients. In conclusion, in the era of antiviral therapy, serum AFP's surveillance performance was substantially improved for HCC within Milan criteria among the high-risk population of CHB and LC patients.
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Affiliation(s)
- Xiangjun Qian
- Department of Microbiology & Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Shuhong Liu
- Department of Pathology and HepatologyThe 5th Medical CentreChinese PLA General HospitalBeijingChina
| | - Huiling Long
- Department of Infectious DiseasesThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Siyu Zhang
- Department of Traditional and Western Medical HepatologyThe Third Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Xiaotong Yan
- Department of Epidemiology and BiostatisticsCollege of Public HealthZhengzhou UniversityZhengzhouChina
| | - Mingjie Yao
- Department of Microbiology & Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Jiyuan Zhou
- Intervention and Cell Therapy CenterPeking University Shenzhen HospitalShenzhenChina
| | - Jiao Gong
- Department of Laboratory MedicineThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Jianwen Wang
- Department of Microbiology & Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Xiajie Wen
- Department of Microbiology & Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Tao Zhou
- Intervention and Cell Therapy CenterPeking University Shenzhen HospitalShenzhenChina
| | - Xiangwei Zhai
- Department of Epidemiology and BiostatisticsCollege of Public HealthZhengzhou UniversityZhengzhouChina
| | - Qiang Xu
- Department of Microbiology & Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Ting Zhang
- Department of Microbiology & Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Xiangmei Chen
- Department of Microbiology & Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Guoxin Hu
- Department of Infectious DiseasesPeking University Shenzhen HospitalShenzhenChina
| | - Jie Wang
- Department of Microbiology & Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina
| | - Zhiliang Gao
- Department of Infectious DiseasesThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Yuemin Nan
- Department of Traditional and Western Medical HepatologyThe Third Hospital of Hebei Medical UniversityShijiazhuangChina
| | - Junhui Chen
- Intervention and Cell Therapy CenterPeking University Shenzhen HospitalShenzhenChina
| | - Bo Hu
- Department of Laboratory MedicineThird Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouChina
| | - Jingmin Zhao
- Department of Pathology and HepatologyThe 5th Medical CentreChinese PLA General HospitalBeijingChina
| | - Fengmin Lu
- Department of Microbiology & Infectious Disease CenterSchool of Basic Medical SciencesPeking University Health Science CenterBeijingChina,Department of Epidemiology and BiostatisticsCollege of Public HealthZhengzhou UniversityZhengzhouChina
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Influence of Alanine Transaminase Levels on Alpha-Fetoprotein for Predicting Hepatocellular Carcinoma in Patients with Hepatitis B Infection. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2043715. [PMID: 33490235 PMCID: PMC7787738 DOI: 10.1155/2020/2043715] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 11/24/2020] [Accepted: 11/30/2020] [Indexed: 01/22/2023]
Abstract
Purpose To investigate the influence of alanine transaminase (ALT) on the accuracy of alpha-fetoprotein (AFP) for detecting hepatocellular carcinoma (HCC). Methods This retrospective study recruited 799 patients with HCC, cirrhosis, and chronic hepatitis due to hepatitis B infection and healthy adults between July 2017 and January 2019. Comparisons of the area under the receiver operating characteristic curves (AUCs) for detecting HCC in different ALT levels were calculated. Results Serum ALT and gamma-glutamyl transferase levels were significantly associated with elevated AFP in patients without HCC. The AUC of AFP was higher in patients with ALT ≤ 2 upper limit of normal (ULN) than in patients with ALT > 2 ULN (0.806 vs. 0.611, P < 0.001). Nevertheless, there were no significant differences in the AUCs of AFP/(ALT × aspartate aminotransferase (AST)) in patients with ALT ≤ 2 ULN and with ALT > 2 ULN (0.745 vs. 0.769, P = 0.68). AFP/(ALT × AST) was better than AFP in patients with ALT > 2 ULN for detecting HCC (P < 0.001). Conclusions Higher ALT levels might impair the accuracy of AFP for diagnosing HCC. AFP tests showed better accuracy in patients with ALT ≤ 2 ULN whereas the AFP/(ALT × AST) ratio was recommended in patients with elevated ALT levels.
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