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Jeng LB, Chan WL, Teng CF. Prognostic Significance of Serum Albumin Level and Albumin-Based Mono- and Combination Biomarkers in Patients with Hepatocellular Carcinoma. Cancers (Basel) 2023; 15:cancers15041005. [PMID: 36831351 PMCID: PMC9953807 DOI: 10.3390/cancers15041005] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 01/31/2023] [Accepted: 02/03/2023] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. Although many surgical and nonsurgical therapeutic options have been established for treating HCC, the overall prognosis for HCC patients receiving different treatment modalities remains inadequate, which causes HCC to remain among the most life-threatening human cancers worldwide. Therefore, it is vitally important and urgently needed to develop valuable and independent prognostic biomarkers for the early prediction of poor prognosis in HCC patients, allowing more time for more timely and appropriate treatment to improve the survival of patients. As the most abundant protein in plasma, human serum albumin (ALB) is predominantly expressed by the liver and exhibits a wide variety of essential biological functions. It has been well recognized that serum ALB level is a significant independent biomarker for a broad spectrum of human diseases including cancer. Moreover, ALB has been commonly used as a potent biomaterial and therapeutic agent in clinical settings for the treatment of various human diseases. This review provides a comprehensive summary of the evidence from the up-to-date published literature to underscore the prognostic significance of serum ALB level and various ALB-based mono- and combination biomarkers in the prediction of the prognosis of HCC patients after treatment with different surgical, locoregional, and systemic therapies.
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Affiliation(s)
- Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan
- Department of Surgery, China Medical University Hospital, Taichung 404, Taiwan
- Cell Therapy Center, China Medical University Hospital, Taichung 404, Taiwan
| | - Wen-Ling Chan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung 413, Taiwan
- Epigenome Research Center, China Medical University Hospital, Taichung 404, Taiwan
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- Program for Cancer Biology and Drug Development, China Medical University, Taichung 404, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung 404, Taiwan
- Correspondence: ; Tel.: +886-4-2205-2121; Fax: +886-4-2202-9083
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Youssef SS, Elfiky A, Nabeel MM, Shousha HI, Elbaz T, Omran D, Marie MS, Elzahry MA, Abul-Fotouh A, Hashem A, Guda MF, Abdelaziz AO. Assessment of circulating levels of microRNA-326, microRNA-424, and microRNA-511 as biomarkers for hepatocellular carcinoma in Egyptians. World J Hepatol 2022; 14:1562-1575. [PMID: 36157872 PMCID: PMC9453463 DOI: 10.4254/wjh.v14.i8.1562] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 01/14/2022] [Accepted: 07/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the fifth most common cancer. Differential expression of microRNAs (miRNAs)-326, miRNA-424, and miRNA-511 has been associated with the diagnosis and prognosis of HCC in different populations. However, limited information is available regarding their expression in Egyptian HCC patients. AIM To assess the role of circulating miRNAs-326, miRNA-424, and miRNA-511 in Egyptian HCC patients. METHODS This prospective observational study included 70 HCC patients and 25 healthy controls. The circulating levels of these three miRNAs were evaluated by real-time PCR. Receiver operating characteristic curve analysis was used to test the diagnostic accuracy of microRNA expression levels. RESULTS All miRNAs were differentially expressed in HCC patients; miRNAs326 and miRNA-424 were upregulated, while miRNA-511 was downregulated. Both miRNA-326 and miRNA-424 showed sensitivity and specificity of 97%, 71.4%, and 52%, 60%, respectively, to differentiate HCC from controls. Moreover, miRNA-326 was associated with survival and could differentiate between Child grades (A vs B); miRNA-424 significantly differentiated early vs intermediate stages of HCC; while miRNA-511 was significantly correlated with response to modified Response Evaluation Criteria in Solid Tumors (mRECIST). CONCLUSION We conclude that miRNA-326, miRNA-424, and miRNA-511 have diagnostic and prognostic roles in Egyptian patients with hepatitis C virus-related HCC and should be considered for better disease management.
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Affiliation(s)
- Samar Samir Youssef
- Department of Microbial Biotechnology, National Research Centre, Cairo 1211, Egypt.
| | - Asmaa Elfiky
- Department of Environmental and Occupational Medicine, National Research Centre, Cairo 1211, Egypt
| | - Mohamed M Nabeel
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo 11562 Egypt
| | - Hend Ibrahim Shousha
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo 11562 Egypt
| | - Tamer Elbaz
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo 11562 Egypt
| | - Dalia Omran
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo 1256, Egypt
| | - Mohammad Saeed Marie
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo 11562 Egypt
| | - Mohammad A Elzahry
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo 1256, Egypt
| | - Amr Abul-Fotouh
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo 1256, Egypt
| | - Ahmed Hashem
- Department of Endemic Medicine, Faculty of Medicine, Cairo University, Cairo 1256, Egypt
| | | | - Ashraf O Abdelaziz
- Department of Endemic Medicine and Hepatogastroenterology, Faculty of Medicine, Cairo University, Cairo 11562 Egypt
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Li L, Li X, Li W, Ding X, Zhang Y, Chen J, Li W. Prognostic models for outcome prediction in patients with advanced hepatocellular carcinoma treated by systemic therapy: a systematic review and critical appraisal. BMC Cancer 2022; 22:750. [PMID: 35810271 PMCID: PMC9270753 DOI: 10.1186/s12885-022-09841-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/29/2022] [Indexed: 11/22/2022] Open
Abstract
Objective To describe and analyze the predictive models of the prognosis of patients with hepatocellular carcinoma (HCC) undergoing systemic treatment. Design Systematic review. Data sources PubMed and Embase until December 2020 and manually searched references from eligible articles. Eligibility criteria for study selection The development, validation, or updating of prognostic models of patients with HCC after systemic treatment. Results The systematic search yielded 42 eligible articles: 28 articles described the development of 28 prognostic models of patients with HCC treated with systemic therapy, and 14 articles described the external validation of 32 existing prognostic models of patients with HCC undergoing systemic treatment. Among the 28 prognostic models, six were developed based on genes, of which five were expressed in full equations; the other 22 prognostic models were developed based on common clinical factors. Of the 28 prognostic models, 11 were validated both internally and externally, nine were validated only internally, two were validated only externally, and the remaining six models did not undergo any type of validation. Among the 28 prognostic models, the most common systemic treatment was sorafenib (n = 19); the most prevalent endpoint was overall survival (n = 28); and the most commonly used predictors were alpha-fetoprotein (n = 15), bilirubin (n = 8), albumin (n = 8), Child–Pugh score (n = 8), extrahepatic metastasis (n = 7), and tumor size (n = 7). Further, among 32 externally validated prognostic models, 12 were externally validated > 3 times. Conclusions This study describes and analyzes the prognostic models developed and validated for patients with HCC who have undergone systemic treatment. The results show that there are some methodological flaws in the model development process, and that external validation is rarely performed. Future research should focus on validating and updating existing models, and evaluating the effects of these models in clinical practice. Systematic review registration PROSPERO CRD42020200187. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09841-5.
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Affiliation(s)
- Li Li
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Xiaomi Li
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Wendong Li
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Xiaoyan Ding
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Yongchao Zhang
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China
| | - Jinglong Chen
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China.
| | - Wei Li
- Department of Cancer Center, Beijing Ditan Hospital, Capital Medical University, 100015, Beijing, China.
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Marasco G, Poggioli F, Colecchia A, Cabibbo G, Pelizzaro F, Giannini EG, Marinelli S, Rapaccini GL, Caturelli E, Di Marco M, Biasini E, Marra F, Morisco F, Foschi FG, Zoli M, Gasbarrini A, Svegliati Baroni G, Masotto A, Sacco R, Raimondo G, Azzaroli F, Mega A, Vidili G, Brunetto MR, Nardone G, Alemanni LV, Dajti E, Ravaioli F, Festi D, Trevisani F, on behalf of the Italian Liver Cancer (ITA.LI.CA.) Group. A Nomogram-Based Prognostic Model for Advanced Hepatocellular Carcinoma Patients Treated with Sorafenib: A Multicenter Study. Cancers (Basel) 2021; 13:2677. [PMID: 34072309 PMCID: PMC8199276 DOI: 10.3390/cancers13112677] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/17/2021] [Accepted: 05/26/2021] [Indexed: 12/14/2022] Open
Abstract
Among scores and staging systems used for HCC, none showed a good prognostic ability in patients with advanced HCC treated with Sorafenib. We aimed to evaluate predictive factors of overall survival (OS) and drug response in HCC patients undergoing Sorafenib included in the Italian Liver Cancer (ITA.LI.CA.) multicenter cohort. Patients in the ITA.LI.CA database treated with Sorafenib and updated on 30 June 2019 were included. Demographic and clinical data before starting Sorafenib treatment were considered. For the evaluation of predictive factors for OS, a time-dependent Cox proportional hazard model was used. A total of 1107 patients were included in our analysis. The mean age was 64.3 years and 81.7% were male. Most patients were staged as BCLC B (205, 18.9%) or C (706, 65.1%). The median time of Sorafenib administration was 4 months (interquartile range (IQR) 2-12), and the median OS was 10 months (IQR: 4-20). A total of 263 patients (33.8%) out of 780 with available evaluation experienced objective tumoral response to Sorafenib. The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (hazard ratio (HR) 1.284), maximum tumoral diameter (HR 1.100), plasma total bilirubin (HR 1.119), aspartate amino transferase assessed as multiple of the upper normal value (HR 1.032), alpha-fetoprotein ≥200 ng/mL (HR 1.342), hemoglobin (HR 0.903) and platelet count (HR 1.002) were associated with OS at multivariate Cox regression analysis. Drug response was predicted by maximum tumoral diameter and platelet count. A novel prognostic nomogram for patients undergoing Sorafenib is hereby proposed. The novelty introduced is the comprehensive patient's assessment using common markers of patient's general status, liver damage and function and HCC biology. Further studies are required to test its accuracy and provide external validation.
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Affiliation(s)
- Giovanni Marasco
- Division of Internal Medicine and Digestive Pathophysiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
| | - Francesco Poggioli
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
| | - Antonio Colecchia
- Gastroenterology Unit, Borgo Trento University Hospital Verona, 37126 Verona, Italy;
| | - Giuseppe Cabibbo
- Gastroenterology & Hepatology Unit, Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, University of Palermo, 90133 Palermo, Italy;
| | - Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35124 Padua, Italy;
| | - Edoardo Giovanni Giannini
- Gastroenterology Unit, Department of Internal Medicine, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy;
| | - Sara Marinelli
- Division of Internal Medicine, Hepatobiliary and Immunoallergologic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Gian Ludovico Rapaccini
- Division of Internal Medicine and Gastroenterology, Complesso Integrato Columbus, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | | | | | - Elisabetta Biasini
- Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, 43126 Parma, Italy;
| | - Fabio Marra
- Internal Medicine and Hepatology Unit, Department of Experimental and Clinical Medicine, University of Firenze, 50139 Florence, Italy;
| | - Filomena Morisco
- Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Napoli “Federico II”, 80138 Napoli, Italy;
| | | | - Marco Zoli
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
- Division of Internal Medicine, Neurovascular and Hepatometabolic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Antonio Gasbarrini
- Division of Internal Medicine and Gastroenterology, Policlinico Gemelli, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
| | | | - Alberto Masotto
- Gastroenterology Unit, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, 37024 Verona, Italy;
| | - Rodolfo Sacco
- Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, 71100 Foggia, Italy;
| | - Giovanni Raimondo
- Division of Clinical and Molecular Hepatology, University of Messina, 98124 Messina, Italy;
| | - Francesco Azzaroli
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
- Division of Gastroenterology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Andrea Mega
- Division of Gastroenterology, Bolzano Regional Hospital, 39100 Bolzano, Italy;
| | - Gianpaolo Vidili
- U.O.C. Clinica Medica, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Azienda Ospedaliero-Universitaria di Sassari, 07100 Sassari, Italy;
| | - Maurizia Rossana Brunetto
- Hepatology and Liver Physiopathology Laboratory and Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, 56124 Pisa, Italy;
| | - Gerardo Nardone
- Hepato-Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80138 Naples, Italy;
| | - Luigina Vanessa Alemanni
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
- Division of Gastroenterology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Elton Dajti
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
- Division of Gastroenterology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Federico Ravaioli
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
| | - Davide Festi
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
| | - Franco Trevisani
- Department of Medical and Surgical Science, University of Bologna, 40138 Bologna, Italy; (F.P.); (M.Z.); (F.A.); (L.V.A.); (E.D.); (F.R.); (D.F.); (F.T.)
- Division of Semeiotics, Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
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Hu Z, Xie F, Hu A, Xu M, Liu Y, Zhang J, Xiao J, Song Y, Zhong J, Chen B. Silencing glioma-associated oncogene homolog 1 suppresses the migration and invasion of hepatocellular carcinoma in vitro. Oncol Lett 2020; 20:228. [PMID: 32968450 PMCID: PMC7500057 DOI: 10.3892/ol.2020.12091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 08/20/2020] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-associated death worldwide. Glioma-associated oncogene homolog 1 (Gli1) is a key component and functions as a reliable marker of Hedgehog signaling pathway activation. Previous studies have demonstrated that Gli1 serves important roles in the progression of various types of cancer, including HCC. However, its effect on HCC invasion and metastasis and the underlying mechanism remain to be elucidated. Small interference RNA was employed to silence the Gli1 gene in liver cancer cells. Reverse transcription-quantitative PCR and western blot analysis were performed to evaluate the mRNA and protein expression of Gli1, respectively. A series of assays, including Cell Counting Kit-8, adhesion, wound healing and Matrigel invasion were performed to investigate cell viability, adhesive, migratory and invasive capabilities of liver cancer cells, respectively. In addition, immunofluorescence staining was performed to determine the cellular localization of focal adhesion kinase (FAK), phosphorylated (p-)FAK and p-AKT. The mRNA and protein expression of Gli1 in liver cancer cells (HepG2 and SK-Hep1) were markedly decreased in a dose-dependent manner following Gli1-knockdown. Gli1 silencing significantly inhibited the adhesion, migration and invasion of SK-Hep1 cells. Additionally, knockdown of Gli1 markedly suppressed the expression of metalloproteinase (MMP)-2 and MMP-9. Furthermore, downregulation of Gli1 blocked the FAK/AKT signaling pathway. Gli1 serves significant roles in the migration and invasion of HCC cells through activation of the FAK/AKT signaling pathway and subsequent upregulation of MMP-2 and MMP-9 expression. Thus, Gli1 may be a potential protein target for the regulation of HCC migration and invasion.
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Affiliation(s)
- Zeming Hu
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Fangfang Xie
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Ang Hu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Mengjing Xu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Yuwen Liu
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Jiankang Zhang
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Jianbo Xiao
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Yunlei Song
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Jianing Zhong
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
| | - Bin Chen
- Department of General Surgery, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China
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Chi Q, Geng X, Xu K, Wang C, Zhao H. Potential targets and molecular mechanism of miR-331-3p in hepatocellular carcinoma identified by weighted gene coexpression network analysis. Biosci Rep 2020; 40:BSR20200124. [PMID: 32537629 PMCID: PMC7317601 DOI: 10.1042/bsr20200124] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 03/27/2020] [Accepted: 04/01/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumor. miR-331-3p has been reported relevant to the progression of HCC, but the molecular mechanism of its regulation is still unclear. In the study, we comprehensively studied the role of miR-331-3p in HCC through weighted gene coexpression network analysis (WGCNA) based on The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Oncomine. WGCNA was applied to build gene co-expression networks to examine the correlation between gene sets and clinical characteristics, and to identify potential biomarkers. Five hundred one target genes of miR-331-3p were obtained by overlapping differentially expressed genes (DEGs) from the TCGA database and target genes predicted by miRWalk. The critical turquoise module and its eight key genes were screened by WGCNA. Enrichment analysis was implemented based on the genes in the turquoise module. Moreover, 48 genes with a high degree of connectivity were obtained by protein-protein interaction (PPI) analysis of the genes in the turquoise module. From overlapping genes analyzed by WGCNA and PPI, two hub genes were obtained, namely coatomer protein complex subunit zeta 1 (COPZ1) and elongation factor Tu GTP binding domain containing 2 (EFTUD2). In addition, the expression of both hub genes was also significantly higher in tumor tissues compared with normal tissues, as confirmed by analysis based on TCGA and Oncomine. Both hub genes were correlated with poor prognosis based on TCGA data. Receiver operating characteristic (ROC) curve validated that both hub genes exhibited excellent diagnostic efficiency for normal and tumor tissues.
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Affiliation(s)
- Qingjia Chi
- Department of Mechanics and Engineering Structure, Wuhan University of Technology, Wuhan 430070, China
| | - Xinge Geng
- Department of Mechanics and Engineering Structure, Wuhan University of Technology, Wuhan 430070, China
| | - Kang Xu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chunli Wang
- ‘111’ Project Laboratory of Biomechanics and Tissue Repair, Bioengineering College, Chongqing University, Chongqing 400044, China
| | - Han Zhao
- Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan 430056, China
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Berhane S, Fox R, García-Fiñana M, Cucchetti A, Johnson P. Using prognostic and predictive clinical features to make personalised survival prediction in advanced hepatocellular carcinoma patients undergoing sorafenib treatment. Br J Cancer 2019; 121:117-124. [PMID: 31182766 PMCID: PMC6738086 DOI: 10.1038/s41416-019-0488-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/01/2019] [Accepted: 05/10/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Sorafenib is the current standard of care for patients with advanced hepatocellular carcinoma (aHCC) and has been shown to improve survival by about 3 months compared to placebo. However, survival varies widely from under three months to over two years. The aim of this study was to build a statistical model that allows personalised survival prediction following sorafenib treatment. METHODS We had access to 1130 patients undergoing sorafenib treatment for aHCC as part of the control arm for two phase III randomised clinical trials (RCTs). A multivariable model was built that predicts survival based on baseline clinical features. The statistical approach permits both group-level risk stratification and individual-level survival prediction at any given time point. The model was calibrated, and its discrimination assessed through Harrell's c-index and Royston-Sauerbrei's R2D. RESULTS The variables influencing overall survival were vascular invasion, age, ECOG score, AFP, albumin, creatinine, AST, extra-hepatic spread and aetiology. The model-predicted survival very similar to that observed. The Harrell's c-indices for training and validation sets were 0.72 and 0.70, respectively indicating good prediction. CONCLUSIONS Our model ('PROSASH') predicts patient survival using baseline clinical features. However, it will require further validation in a routine clinical practice setting.
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Affiliation(s)
- Sarah Berhane
- Department of Biostatistics, University of Liverpool, Liverpool, UK
| | - Richard Fox
- Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, University of Birmingham, Birmingham, UK
| | | | - Alessandro Cucchetti
- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Philip Johnson
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
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McNamara MG, Slagter AE, Nuttall C, Frizziero M, Pihlak R, Lamarca A, Tariq N, Valle JW, Hubner RA, Knox JJ, Amir E. Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur J Cancer 2018; 105:1-9. [PMID: 30384012 DOI: 10.1016/j.ejca.2018.09.031] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 09/09/2018] [Accepted: 09/26/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND Sorafenib has demonstrated survival benefit in first-line treatment of advanced hepatocellular carcinoma (HCC); utility of sorafenib in patients with advanced HCC and Child-Pugh B (CP-B) liver function remains a subject of debate. METHODS A systematic review identified studies using first-line sorafenib in patients with advanced HCC and CP-A/B liver function. Meta-regression analysis comprising linear regression was conducted to explore the association between the baseline factors and overall survival (OS). Differences between efficacy/safety and tolerability parameters were explored using meta-analysis. RESULTS Thirty studies (12 Asian) comprising 8678 patients (August 2002 - September 2012) were included (four randomised controlled trials, 26 cohort studies). Median age was 61 years and 83% were men. Hepatitis B/C status was positive in 35%/22%, respectively. The CP status was available for 8577 patients (99%); CP-A, 79% and CP-B, 19%. Median OS on sorafenib for entire cohort was 7.2 months; 8.8 months in CP-A and 4.6 months in CP-B. Multivariable meta-regression analysis showed significant negative association between OS and proportion of patients with the Eastern Cooperative Oncology Group performance status 2 (P = 0.04) and CP-B liver function (P = 0.001). Among four studies reporting multivariable comparison of the CP status, CP-B was associated with significantly worse OS (P < 0.001). There were no differences in the response rate to sorafenib between patients with CP-A (4.6%) and CP-B (4.2%) liver function. Safety and tolerability were similar; 35% of patients with CP-A/B liver function developed grade III/IV adverse events (P = 0.7). Meta-regression analysis showed similar rates of treatment discontinuation without progression (P = 0.31) and treatment-related death (P = 0.94) in patients with CP-B liver function. CONCLUSION CP-B liver function (versus CP-A) is associated with worse OS (but the similar response rate, safety and tolerability of first-line sorafenib, is unlikely to be clinically meaningful).
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Affiliation(s)
- Mairéad Geraldine McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK.
| | - Astrid E Slagter
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Amsterdam, the Netherlands
| | - Christina Nuttall
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Melissa Frizziero
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Rille Pihlak
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK
| | - Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Noor Tariq
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK; University of Manchester, Division of Cancer Sciences, Manchester, M20 4BX, UK
| | - Richard A Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
| | - Jennifer J Knox
- Department of Medical Oncology, Princess Margaret Cancer Centre/University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada
| | - Eitan Amir
- Department of Medical Oncology, Princess Margaret Cancer Centre/University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada
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9
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MYC associated zinc finger protein promotes the invasion and metastasis of hepatocellular carcinoma by inducing epithelial mesenchymal transition. Oncotarget 2018; 7:86420-86432. [PMID: 27861158 PMCID: PMC5349923 DOI: 10.18632/oncotarget.13416] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 11/09/2016] [Indexed: 01/10/2023] Open
Abstract
MYC associated zinc finger protein (MAZ) plays a key role in regulation of gene expression and tumor development. Studies have shown that deregulated expression of MAZ is closely related to the progression of tumors such as glioblastoma, breast cancer, prostate cancer and liposarcoma. However, the role of MAZ in hepatocellular carcinoma (HCC) has not been fully elucidated. Here, we found that expression of MAZ was increased in HCC and correlated to the distant metastasis of HCC. Moreover, we found that MAZ had a relationship with zinc finger E-box binding homeobox 1 and 2 (ZEB1 and ZEB2), two important mesenchymal markers in epithelial-mesenchymal transition (EMT) that were over-expressed in HCC. After knocking-down MAZ expression in HCC cell lines using RNA interruption, HCC cell proliferation, tumorigenesis, invasion and migration were significantly inhibited. In addition, we found that expression of other EMT markers was also changed besides ZEB1 and ZEB2 by decreasing MAZ expression, both detected in vivo and in vitro assays. Therefore, we conclude that MAZ can promote the invasion and metastasis of HCC by inducing EMT.
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10
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Yen C, Sharma R, Rimassa L, Arizumi T, Bettinger D, Choo HY, Pressiani T, Burlone ME, Pirisi M, Giordano L, Abdulrahman A, Kudo M, Thimme R, Park JW, Pinato DJ. Treatment Stage Migration Maximizes Survival Outcomes in Patients with Hepatocellular Carcinoma Treated with Sorafenib: An Observational Study. Liver Cancer 2017; 6:313-324. [PMID: 29234635 PMCID: PMC5704701 DOI: 10.1159/000480441] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Level I evidence supports the use of sorafenib in patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma, where heterogeneity in efficacy exists due to varying clinicopathologic features of the disease. AIM We evaluated whether prior treatment with curative or locoregional therapies influences sorafenib-specific survival. METHODS From a prospective data set of 785 consecutive patients from international specialist centres, 264 patients (34%) were treatment naïve (TN) and 521 (66%) were pre-treated (PT), most frequently with transarterial chemoembolization (n = 413; 79%). The primary endpoint was overall survival (OS) from sorafenib initiation with prognostic factors tested on uni- and multivariate analyses. RESULTS Median OS for the entire cohort was 9 months; the median sorafenib duration was 2.8 months, with discontinuation being secondary to progression (n = 454; 58%) or toxicity (n = 149; 19%). PT patients had significantly longer OS than TN patients (10.5 vs. 6.6 months; p < 0.001). Compared to TN patients, PT patients had a better Child-Pugh (CP) class (CP A: 57 vs. 47%; p < 0.001) and a lower BCLC stage (BCLC A-B, 40 vs. 30%; p = 0.007). PT status preserved an independent prognostic role (p = 0.002) following adjustment for BCLC stage, α-fetoprotein, CP class, aetiology, and post-sorafenib treatment status. PT patients were more likely to receive further anticancer treatment after sorafenib (31 vs. 9%; p < 0.001). CONCLUSION Patients receiving sorafenib after having failed curative or locoregional therapies survive longer and are more likely to receive further treatment after sorafenib. This suggests an incremental benefit to OS from sequential exposure to multiple lines of therapy, justifying treatment stage migration in eligible patients.
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Affiliation(s)
- Clarence Yen
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Rohini Sharma
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Lorenza Rimassa
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Milan, Italy
| | - Tadaaki Arizumi
- Department of Gastroenterology and Hepatology, Kindai University School of Medicine, Osakasayama, Japan
| | - Dominik Bettinger
- Department of Medicine II, University Medical Center, Freiburg, Germany,Berta Ottenstein Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Huay Yee Choo
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Tiziana Pressiani
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Milan, Italy
| | - Michela E. Burlone
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale “A. Avogadro,” Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università degli Studi del Piemonte Orientale “A. Avogadro,” Novara, Italy
| | - Laura Giordano
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Milan, Italy
| | - Anisa Abdulrahman
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University School of Medicine, Osakasayama, Japan
| | - Robert Thimme
- Department of Medicine II, University Medical Center, Freiburg, Germany,Berta Ottenstein Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Joong Won Park
- Center for Liver Cancer, National Cancer Center Hospital, Goyang, South Korea
| | - David James Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, UK,*Dr. David James Pinato, MD, MRes, MRCP (UK), PhD, NIHR Academic Clinical Lecturer in Medical Oncology, Imperial College London Hammersmith Campus, Du Cane Road, London W12 0HS (UK), E-Mail
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11
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Involvement of PI3K/Akt pathway in the inhibition of hepatocarcinoma cell invasion and metastasis induced by SASH1 through downregulating Shh-Gli1 signaling. Int J Biochem Cell Biol 2017; 89:95-100. [DOI: 10.1016/j.biocel.2017.06.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 05/18/2017] [Accepted: 06/05/2017] [Indexed: 12/12/2022]
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12
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Nakanishi H, Kurosaki M, Tsuchiya K, Yasui Y, Higuchi M, Yoshida T, Komiyama Y, Takaura K, Hayashi T, Kuwabara K, Nakakuki N, Takada H, Ueda M, Tamaki N, Suzuki S, Itakura J, Takahashi Y, Izumi N. Novel Pretreatment Scoring Incorporating C-reactive Protein to Predict Overall Survival in Advanced Hepatocellular Carcinoma with Sorafenib Treatment. Liver Cancer 2016; 5:257-268. [PMID: 27781198 PMCID: PMC5075810 DOI: 10.1159/000449337] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVES This study aimed to build a prediction score of prognosis for patients with advanced hepatocellular carcinoma (HCC) after sorafenib treatment. METHODS A total of 165 patients with advanced HCC who were treated with sorafenib were analyzed. Readily available baseline factors were used to establish a scoring system for the prediction of survival. RESULTS The median survival time (MST) was 14.2 months. The independent prognostic factors were C-reactive protein (CRP) <1.0 mg/dL [hazard ratio (HR) =0.51], albumin >3.5 g/dL (HR =0.55), alpha-fetoprotein <200 ng/mL (HR =0.45), and a lack of major vascular invasion (HR =0.39). Each of these factors had a score of 1, and after classifying the patients into five groups, the total scores ranged from 0 to 4. Higher scores were linked to significantly longer survival (p<0.0001). Twenty-nine patients (17.6%) with a score of 4 had a MST as long as 36.5 months, whereas MST was as short as 2.4 and 3.7 months for seven (4.2%) and 22 (13.3%) patients with scores of 0 and 1, respectively. CONCLUSIONS A novel prognostic scoring system, which includes the CRP level, has the ability to stratify the prognosis of patients with advanced stage HCC after treatment with sorafenib.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Namiki Izumi
- *Namiki Izumi, MD, PhD, Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo (Japan), Tel. +81 422 32 3111, E-Mail
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13
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Xia F, Wu LL, Lau WY, Huan HB, Wen XD, Ma KS, Li XW, Bie P. Adjuvant sorafenib after heptectomy for Barcelona Clinic Liver Cancer-stage C hepatocellular carcinoma patients. World J Gastroenterol 2016; 22:5384-5392. [PMID: 27340354 PMCID: PMC4910659 DOI: 10.3748/wjg.v22.i23.5384] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 03/31/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy and safety of adjuvant sorafenib after curative resection for patients with Barcelona Clinic Liver Cancer (BCLC)-stage C hepatocellular carcinoma (HCC).
METHODS: Thirty-four HCC patients, classified as BCLC-stage C, received adjuvant sorafenib for high-risk of tumor recurrence after curative hepatectomy at a tertiary care university hospital. The study group was compared with a case-matched control group of 68 patients who received curative hepatectomy for HCC during the study period in a 1:2 ratio.
RESULTS: The tumor recurrence rate was markedly lower in the sorafenib group (15/34, 44.1%) than in the control group (51/68, 75%, P = 0.002). The median disease-free survival was 12 mo in the study group and 10 mo in the control group. Tumor number more than 3, macrovascular invasion, hilar lymph nodes metastasis, and treatment with sorafenib were significant factors of disease-free survival by univariate analysis. Tumor number more than 3 and treatment with sorafenib were significant risk factors of disease-free survival by multivariate analysis in the Cox proportional hazards model. The disease-free survival and cumulative overall survival in the study group were significantly better than in the control group (P = 0.034 and 0.016, respectively).
CONCLUSION: Our study verifies the potential benefit and safety of adjuvant sorafenib for both decreasing HCC recurrence and extending disease-free and overall survival rates for patients with BCLC-stage C HCC after curative resection.
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14
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Prognosis of advanced hepatocellular carcinoma: a new stratification of Barcelona Clinic Liver Cancer stage C: results from a French multicenter study. Eur J Gastroenterol Hepatol 2016; 28:433-40. [PMID: 26695429 DOI: 10.1097/meg.0000000000000558] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Advanced hepatocellular carcinoma (HCC) includes a wide spectrum of tumors and patients' prognosis after treatment is highly variable. Moreover, therapeutic options based on the Barcelona Clinic Liver Cancer (BCLC) staging system algorithm are restricted to one systemic therapy. AIM OF THE STUDY To refine the stratification among BCLC C HCC patients by establishing a new simple prognostic score. PATIENTS AND METHODS A regression model based on a BCLC stage C population and validated with an external cohort of BCLC C HCC patients defined the score. It was therefore validated among three external cohorts of BCLC C HCC patients treated with sorafenib. RESULTS Five variables had independent prognostic values: the number of nodules, the infiltrating nature of the HCC, α-fetoprotein serum level, Child-Pugh score, and Eastern Cooperative Oncology Group Performance Status grade. They were integrated into a new score named NIACE ranging from 0 to 7, well correlated with survival. With the use of one threshold value, this score enables defining of two populations with different survivals among BCLC C patients and specifically among those treated with sorafenib. CONCLUSION The NIACE score defines different prognostic subgroups after palliative treatment of HCC. It could be an additional tool for BCLC C HCC before inclusion in clinical trials or for the management of patients. These results must be validated in a prospective study.
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15
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Tang B, Qi G, Tang F, Yuan S, Wang Z, Liang X, Li B, Yu S, Liu J, Huang Q, Wei Y, Zhai R, Lei B, Yu H, Jiao X, He S. JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells. Oncotarget 2016; 6:12723-39. [PMID: 25909289 PMCID: PMC4494969 DOI: 10.18632/oncotarget.3713] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 03/10/2015] [Indexed: 01/02/2023] Open
Abstract
JARID1B is a member of the family of JmjC domain-containing proteins that removes methyl residues from methylated lysine 4 on histone H3 lysine 4 (H3K4). JARID1B has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unknown. Here we show that JARID1B is elevated in HCC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of JARID1B was associated with decreased overall survival of HCC patients. Overexpression of JARID1B in HCC cells increased proliferation, epithelial-mesenchymal transition, migration and invasion in vitro, and enhanced tumorigenic and metastatic capacities in vivo. In contrast, silencing JARID1B in aggressive and invasive HCC cells inhibited these processes. Mechanistically, we found JARID1B exerts its function through modulation of H3K4me3 at the PTEN gene promoter, which was associated with inactive PTEN transcription. PTEN overexpression blocked JARID1B-driven proliferation, EMT, and metastasis. Our results, for the first time, portray a pivotal role of JARID1B in stimulating metastatic behaviors of HCC cells. Targeting JARID1B may thus be a useful strategy to impede HCC cell invasion and metastasis.
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Affiliation(s)
- Bo Tang
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Guangying Qi
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China.,Department of Pathology and Physiopathology, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Fang Tang
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Shengguang Yuan
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Zhenran Wang
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Xingsi Liang
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Bo Li
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Shuiping Yu
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Jie Liu
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Qi Huang
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Yangchao Wei
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Run Zhai
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Biao Lei
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
| | - Hongping Yu
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical College, Guilin, Guangxi, People's Republic of China
| | - Xingyuan Jiao
- Department of General Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Songqing He
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, People's Republic of China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, People's Republic of China
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16
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CT imaging findings in patients with advanced hepatocellular carcinoma treated with sorafenib: Alternative response criteria (Choi, European Association for the Study of the Liver, and modified Response Evaluation Criteria in Solid Tumor (mRECIST)) versus RECIST 1.1. Eur J Radiol 2016; 85:103-112. [DOI: 10.1016/j.ejrad.2015.10.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 10/30/2015] [Indexed: 01/15/2023]
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17
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Ho YJ, Lin YM, Huang YC, Yeh KT, Lin LI, Lu JW. Tissue microarray-based study of hepatocellular carcinoma validating SPIB as potential clinical prognostic marker. Acta Histochem 2016; 118:38-45. [PMID: 26610895 DOI: 10.1016/j.acthis.2015.11.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 11/07/2015] [Accepted: 11/09/2015] [Indexed: 01/11/2023]
Abstract
Currently, the prognostic significance of SPIB protein overexpression in human hepatocellular carcinoma (HCC) is unclear. The aim of the present study was to investigate the level of SPIB expression in human HCC in order to determine possible correlations between SPIB expression and clinicopathological findings. The expression of SPIB proteins was detected using immunohistochemical staining in commercial multiple-tissue microarrays as a means of examining expression profiles in patients. Using online biomarker validation tool SurvExpress, we focused on the correlation between SPIB overexpression and survival as well as relapse-free survival (RFS). Results show that SPIB protein expression levels were significantly higher in colon, liver, and stomach tumors than in non-tumor tissues (p<0.05). SPIB overexpression in patients with HCC was also significantly higher than that of the normal samples (p<0.001). Among patients with liver disease, SPIB protein expression levels differ significantly according to the stage of liver disease, specifically between stages I, II, and III of HCC (p<0.05). SPIB expression was also shown to be significantly correlated with age (p=0.046) and histological grade (p=0.027). Furthermore, the SurvExpress analysis suggested that high SPIB and KI-67 mRNA expression were significantly associated with the poor survival of patients with HCC (p<0.05). Our results indicate that cross-talk in the expression of SPIB and KI-67 may be associated with poor prognosis and may potentially serve as a clinical prognostic indicator of HCC. This is the first time that such an association has been reported.
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Affiliation(s)
- Yi-Jung Ho
- Institute of Preventive Medicine, National Defense Medical Center, Taipei, Taiwan.
| | - Yueh-Min Lin
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan; Department of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
| | - Yen-Chi Huang
- Department of Styling & Cosmetology, Hsin Sheng Junior College of Medical Care and Management, Taoyuan, Taiwan.
| | - Kun-Tu Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan; School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
| | - Liang-In Lin
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
| | - Jeng-Wei Lu
- Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan.
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18
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Alencar RSSM, Kikuchi L, Tani CM, Chagas AL, Camargo CC, Pfiffer TEF, Hoff PMG, Carrilho FJ. Better Management of Adverse Events Favors Sorafenib Treatment of HCC Patients and Impact on Survival. ACTA ACUST UNITED AC 2016. [DOI: 10.4236/jct.2016.74029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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19
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Takeda H, Nishikawa H, Osaki Y, Tsuchiya K, Joko K, Ogawa C, Taniguchi H, Orito E, Uchida Y, Izumi N. Proposal of Japan Red Cross score for sorafenib therapy in hepatocellular carcinoma. Hepatol Res 2015; 45:E130-40. [PMID: 25581351 DOI: 10.1111/hepr.12480] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Revised: 12/22/2014] [Accepted: 01/04/2015] [Indexed: 12/22/2022]
Abstract
AIM There have been no established predictors of the outcome on sorafenib therapy for hepatocellular carcinoma (HCC) patients. We aimed to establish a new prognostic model suitable for sorafenib in HCC. METHODS Among 465 HCC patients treated with sorafenib in 14 hospitals, we formed a training cohort with 270 patients at seven hospitals located in West Japan and a validation cohort with 167 patients at seven hospitals located in East Japan. In the training cohort, we examined the relationship between overall survival (OS) and pretreatment clinical factors, and structured a new prognostic model. We verified this model in the validation cohort and compared with four existing staging models. RESULTS Multivariate analysis demonstrated distant metastases, portal invasion, intrahepatic tumor burden of more than 50%, serum α-fetoprotein of 150 ng/dL or more, des-γ-carboxyprothrombin of 1200 mAU/mL or more, albumin of 3.5 g/dL or less and total bilirubin of more than 1.0 mg/dL were significant independent adverse prognostic factors. We calculated a Japan Red Cross (JRC) score with these factors and classified three groups: low-, intermediate- or high-risk. Their median OS were well stratified (18.0, 8.8 and 3.7 months, respectively, P < 0.001) in the training cohort. In the validation cohort, OS were also statistically stratified (23.9, 10.3 and 2.9 months, P < 0.001). C-statistics of the JRC score was 0.755, the highest in the five models, indicating its novel predictability. CONCLUSION Our proposed JRC score well predicts the prognosis of sorafenib therapy, and would be useful to plan individualized strategies for unresectable HCC.
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Affiliation(s)
- Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan.,Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Yukio Osaki
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Kouji Joko
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Chikara Ogawa
- Department of Gastroenterology and Hepatology, Takamatsu Red Cross Hospital, Takamatsu, Japan
| | - Hiroyoshi Taniguchi
- Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan
| | - Etsuro Orito
- Department of Gastroenterology and Hepatology, Nagoya Daini Red Cross Hospital, Nagoya, Japan
| | - Yasushi Uchida
- Department of Gastroenterology, Matsue Red Cross Hospital, Matsue, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
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Bouattour M, Payancé A, Wassermann J. Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging. World J Hepatol 2015; 7:2245-2263. [PMID: 26380650 PMCID: PMC4568486 DOI: 10.4254/wjh.v7.i20.2245] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 05/16/2015] [Accepted: 08/30/2015] [Indexed: 02/06/2023] Open
Abstract
Many years after therapeutic wilderness, sorafenib finally showed a clinical benefit in patients with advanced hepatocellular carcinoma. After the primary general enthusiasm worldwide, some disappointments emerged particularly since no new treatment could exceed or at least match sorafenib in this setting. Without these new drugs, research focused on optimizing care of patients treated with sorafenib. One challenging research approach deals with identifying prognostic and predictive biomarkers of sorafenib in this population. The task still seems difficult; however appropriate investigations could resolve this dilemma, as observed for some malignancies where other drugs were used.
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Affiliation(s)
- Mohamed Bouattour
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Audrey Payancé
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Johanna Wassermann
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
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Qi X, Ng KTP, Lian QZ, Liu XB, Li CX, Geng W, Ling CC, Ma YY, Yeung WH, Tu WW, Fan ST, Lo CM, Man K. Clinical significance and therapeutic value of glutathione peroxidase 3 (GPx3) in hepatocellular carcinoma. Oncotarget 2015; 5:11103-20. [PMID: 25333265 PMCID: PMC4294380 DOI: 10.18632/oncotarget.2549] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 09/30/2014] [Indexed: 12/22/2022] Open
Abstract
AIMS We aimed to investigate the clinical significance of GPx3 in hepatocellular carcinoma (HCC) and to characterize its tumor suppressive role. METHODS HCC patients (113) who underwent hepatectomy were recruited to examine the clinical relevance of GPx3. The tumor suppressive role of GPx3 was studied by administration of recombinant GPx3 (rGPx3) or over-expression of GPx3 in HCC cells in vitro and in vivo. The therapeutic value of GPx3 for HCC was further investigated using human induced pluripotent stem cell derived mesenchymal stem cells (hiPSC-MSCs) as its delivery vehicle. RESULTS Down-regulation of GPx3 significantly correlated with advanced tumor stage (P = 0.024), venous infiltration (P = 0.043) and poor overall survival (P = 0.007) after hepatectomy. Lower plasma GPx3 in HCC patients was significantly associated with larger tumor size (P = 0.011), more tumor nodules (P = 0.032) and higher recurrence (P = 0.016). Over-expression of GPx3 or administration of rGPx3 significantly inhibited proliferation and invasiveness of HCC cells in vitro and in vivo. Tumor suppressive activity of GPx3 was mediated through Erk-NFκB-SIP1 pathway. GPx3 could be delivered by hiPSC-MSCs into the tumor and exhibited tumor suppressive activity in vivo. CONCLUSIONS GPx3 is a tumor suppressor gene in HCC and may possess prognostic and therapeutic value for HCC patients.
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Affiliation(s)
- Xiang Qi
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Kevin Tak Pan Ng
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Qi Zhou Lian
- Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Xiao Bing Liu
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Chang Xian Li
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Wei Geng
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Chang Chun Ling
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Yuen Yuen Ma
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Wai Ho Yeung
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Wen Wei Tu
- Department of Paediatrics & Adolescent Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Sheung Tat Fan
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Chung Mau Lo
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Kwan Man
- Department of Surgery, Centre for Cancer Research, The University of Hong Kong, Pokfulam, Hong Kong, China
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ITPKA expression is a novel prognostic factor in hepatocellular carcinoma. Diagn Pathol 2015; 10:136. [PMID: 26249031 PMCID: PMC4528344 DOI: 10.1186/s13000-015-0374-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Accepted: 07/29/2015] [Indexed: 12/15/2022] Open
Abstract
Background Inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) has recently been found to be implicated in the tumor progression of various cancers. However, the expression and the prognostic value of ITPKA in hepatocellular carcinoma (HCC) remains unexplored. The aim of this study is to investigate the clinical significance of ITPKA expression in HCC. Methods We determined the expression level of ITPKA in 135 cases of HCC tissues and the matched adjacent nontumorous tissues by quantitative real-time RT-PCR. The correlation between ITPKA expression and prognosis of HCC patients was further evaluated by univariate and multivariate analysis. Multivariate analysis of the prognostic factors was performed with Cox proportional hazards model. Results Up-regulation of ITPKA occurred in 48.9 % of primary HCCs compared with their nontumor counterparts (P < 0.001). In addition, high expression of ITPKA was significantly associated with vascular invasion (P = 0.001) and TNM stage (P = 0.005). Kaplan–Meier analysis showed that the 5-year overall survival (OS) and relapse-free survival (RFS) rate in the group with high expression of ITPKA is poorer than that in low expression group (32.2 and 26.8 % versus 59.2 and 57.7 %). Univariate and multivariate analyses revealed that ITPKA was an independent prognostic factor for OS and RFS. Moreover, Stratified analysis revealed that its prognostic significance still existed within the subgroup of patients with early clinical stage (TNM stage I) or normal serum AFP level (≤25 μg/L). Conclusion Our data indicated that ITPKA expression was significantly up-regulated in HCC and could serve as a potential novel prognostic biomarker for HCC patients after surgery.
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Lee IC, Chen YT, Chao Y, Huo TI, Li CP, Su CW, Lin HC, Lee FY, Huang YH. Determinants of survival after sorafenib failure in patients with BCLC-C hepatocellular carcinoma in real-world practice. Medicine (Baltimore) 2015; 94:e688. [PMID: 25860213 PMCID: PMC4554055 DOI: 10.1097/md.0000000000000688] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Sorafenib may improve progression-free survival (PFS) and overall survival (OS) of advanced hepatocellular carcinoma (HCC). However, the survival benefit is short lived and survivals after progressive disease (PD) have not been well characterized. This study aimed to evaluate the survival predictors of OS and postprogression survival (PPS) in advanced HCC patients receiving sorafenib treatment. Consecutive 149 HCC patients receiving sorafenib under National Health Insurance were retrospectively enrolled. All patients fulfilled the reimbursement criteria: Barcelona Clinic Liver Cancer stage C HCC with macroscopic vascular invasion or extrahepatic metastasis (Mets), and Child-Pugh class A. Radiologic assessment was performed at a 2-month interval using modified Response Evaluation Criteria in Solid Tumors. Patients who maintained Eastern Cooperative Oncology Group ≤2 and Child-Pugh class A at PD were assumed to be candidates for second-line treatment. During the median follow-up period of 7.5 months (range, 1.1-18.5), PD developed in 120 (80.5%) patients and 96 (64.4%) deaths occurred. The median PFS, OS, and PPS were 2.5, 8.0, and 4.6 months, respectively. In general, patients with Mets only had better OS and PPS than those with portal vein invasion. Independent predictors of OS include baseline performance status (hazard ratio [HR] = 1.956), tumor size (HR = 1.597), alpha-fetoprotein (HR = 1.869), discontinuation of sorafenib due to liver function deterioration (LD) (HR = 6.142), or concurrent PD and LD (HR = 2.661) and PD within 4 months (HR = 5.164). Independent predictors of PPS include deteriorated performance status (HR = 7.680), deteriorated liver functions (HR = 5.603), bilirubin (HR = 2.114), early PD (HR = 6.109), and new extrahepatic lesion (HR = 1.804). In 46 candidates for second-line trials, development of new extrahepatic lesion independently predicts poorer PPS (HR = 3.669). In conclusion performance status, liver functions, early disease progression, and progression pattern are important determinants of survival after sorafenib failure. These factors should be considered in clinical practice and second-line trial designs for patients with sorafenib failure.
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Affiliation(s)
- I-Cheng Lee
- From the Division of Gastroenterology (I-CL, T-IH, C-PL, C-WS, H-CL, F-YL, Y-HH), Department of Medicine, Taipei Veterans General Hospital; Institute of Clinical Medicine (I-CL, Y-HH), National Yang-Ming University School of Medicine; Department of Nursing (Y-TC), Taipei Veterans General Hospital; Cancer Center (YC), Taipei Veterans General Hospital; and Institute of Pharmacology (T-IH), National Yang-Ming University School of Medicine, Taipei, Taiwan
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24
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Di Costanzo GG, de Stefano G, Tortora R, Farella N, Addario L, Lampasi F, Lanza AG, Cordone G, Imparato M, Caporaso N. Sorafenib off-target effects predict outcomes in patients treated for hepatocellular carcinoma. Future Oncol 2015; 11:943-51. [DOI: 10.2217/fon.14.291] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Yao H, Liu X, Chen S, Xia W, Chen X. Decreased expression of serum miR-424 correlates with poor prognosis of patients with hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:14830-5. [PMID: 26823812 PMCID: PMC4713598 DOI: pmid/26823812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 10/26/2015] [Indexed: 02/05/2023]
Abstract
BACKGROUND MicroRNAs (miRNAs) play important roles in many important cellular processes and deregulation of miRNAs is linked to many human diseases including cancer. Although miR-424 has been demonstrated to inhibit progression of hepatocellular carcinoma (HCC), its expression level in serum samples and the potential clinical values remain unknown. MATERIALS AND METHODS The expression level of miR-424 in the serum clinical samples from HCC patients and healthy volunteers were determined by qRT-PCR. Then the association of serum miR-424 expression level with various important clinicopathological parameters and survival rates was evaluated. Multivariate Cox regression analysis was used to identify the independent risk factors for HCC. RESULTS The expression level of serum miR-424 was significantly decreased in patients with HCC compared with the healthy volunteers (P<0.01). Reduced expression of serum miR-424 was associated with serum AFP (P=0.048), vein invasion (P=0.006) and TNM stage (P=0.003). In addition, survival analysis showed that HCC patients with lower serum miR-424 expression suffered poorer overall survival (P=0.018) and disease free survival (P=0.008). Moreover, serum miR-424 was demonstrated to be an independent risk factor for HCC. CONCLUSIONS Our findings provide the compelling evidence that the decreased expression of serum miR-424 may serve as a novel biomarker to predict the unfavorable prognosis of HCC patients.
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Affiliation(s)
- Huaiqi Yao
- Department of Ultrasound, The First Affiliated Hospital of Shantou University Medical CollegeShantou 515041, Guangdong Province, China
| | - Xuanzhi Liu
- Department of Ultrasound, The First Affiliated Hospital of Shantou University Medical CollegeShantou 515041, Guangdong Province, China
| | - Suzuan Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical CollegeShantou 515041, Guangdong Province, China
| | - Wei Xia
- Department of Intervention, The First Affiliated Hospital of Shantou University Medical CollegeShantou 515041, Guangdong Province, China
| | - Xiaojun Chen
- Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical CollegeShantou 515041, Guangdong Province, China
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Okuyama H, Ikeda M, Kuwahara A, Takahashi H, Ohno I, Shimizu S, Mitsunaga S, Senda S, Okusaka T. Prognostic factors in patients with hepatocellular carcinoma refractory or intolerant to sorafenib. Oncology 2014; 88:241-6. [PMID: 25503567 DOI: 10.1159/000369351] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Accepted: 10/22/2014] [Indexed: 12/29/2022]
Abstract
OBJECTIVE The aim of this study was to identify the prognostic factors in patients with advanced hepatocellular carcinoma (HCC) who are refractory or intolerant to sorafenib and to exclude unsuitable candidates from subsequent therapy. METHODS The study cohort consisted of 111 patients who had discontinued sorafenib therapy. Uni- and multivariate analyses were conducted to identify the prognostic factors for survival after discontinuation of sorafenib therapy. RESULTS The median age of the patients was 70 years, and 96 of them (86%) were male. The Eastern Cooperative Oncology Group performance status was 0-1 in 94 patients (85%). Forty patients (36%) were classified as Child-Pugh class A and 57 (51%) as Child-Pugh class B. The median survival time after discontinuation of sorafenib therapy was 146 days. Hepatitis C viral antibody negativity, presence of ascites, absence of a history of previous treatment excluding sorafenib, elevated serum total bilirubin level, and elevated serum α-fetoprotein level were identified as the independent unfavorable prognostic factors by multivariate analysis. The median survival time of the patients with 4 or 5 unfavorable prognostic factors was 59 days. CONCLUSIONS We should judge the indication of any subsequent therapy carefully in patients with 4 or 5 of the aforementioned factors.
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Affiliation(s)
- Hiroyuki Okuyama
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Pre-treatment neutrophil-to-lymphocyte ratio affects survival in patients with advanced hepatocellular carcinoma treated with sorafenib. Med Oncol 2014; 31:264. [PMID: 25273866 DOI: 10.1007/s12032-014-0264-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 09/20/2014] [Indexed: 12/17/2022]
Abstract
Sorafenib is the first systemic therapy to demonstrate survival benefit in advanced hepatocellular carcinoma (HCC) in randomized controlled trials with rigorous patient selection. Neutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with poor survival in various solid tumors. Our aim is to evaluate the prognostic role of NLR in HCC patients treated with sorafenib. A total of 105 advanced HCC patients treated with sorafenib were retrospectively reviewed, and relevant data from the clinical records were collected. Univariate and multivariate analysis were carried out to identify factors associated with survival. The median age of the cohort was 59.7 years, and 84.8 % were Child-Pugh class A, and 86.7 % had ECOG performance status 0 or 1. Median duration of sorafenib treatment was 100 days. Median overall survival (OS) of the entire cohort was 8.03 months. Median OS was 5.23 months (95 % CI 2.96-7.50 months) and 10.05 months (95 % IC 2.52-18.47 months) for patients with NLR > 3.5 and NLR ≤ 3.5, respectively (p = 0.002). Alpha-fetoprotein >1,030 ng/mL and serum albumin ≤3.8 g/dL were also associated with worse prognosis (p = 0.006 and p = 0.042, respectively). The subgroup of patients with high alpha-fetoprotein, low albumin and NLR > 3.5 had median OS of 1.7 months, whereas the subgroup with none of these parameters had median OS of 16.5 months (p < 0.001). NLR affects survival in advanced HCC patients treated with sorafenib. Selecting HCC patients based on the laboratorial features may improve the therapeutic effectiveness of sorafenib.
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Gyöngyösi B, Végh É, Járay B, Székely E, Fassan M, Bodoky G, Schaff Z, Kiss A. Pretreatment MicroRNA Level and Outcome in Sorafenib-treated Hepatocellular Carcinoma. J Histochem Cytochem 2014; 62:547-555. [PMID: 24804874 DOI: 10.1369/0022155414537277] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Accepted: 04/22/2014] [Indexed: 02/07/2023] Open
Abstract
Sorafenib represents the first effective targeted therapy for advanced stage hepatocellular carcinoma (HCC); however, adequate patient stratification regarding sorafenib-responsiveness is still missing. Our aim was to analyse the association between the pretreatment microRNA profile of HCC and patient survival under sorafenib treatment. Total RNA was extracted from diagnostic fine-needle aspiration biopsy (FNAB) cytological smears of 20 advanced stage HCC patients collected between June 2008 and July 2012. All patients underwent sorafenib administration after FNA. Clinicopathological and survival data were recorded. Fourteen frequently deregulated miRNAs in HCC (miR-17-5p, miR-18a, miR-21, miR-34a, miR-122, miR-195, miR-210, miR-214, miR-221, miR-222, miR-223, miR-224, miR-140, miR-328) were tested by qRT-PCR. NormFinder software was used to select proper miR (mir-140) as a reference. Satisfactory amount of total RNA was obtained from all the considered samples (mean 10.8 ± 9.3 µg, range 0.2-32.2 µg). Among the analysed miRNAs, high miR-214 expression was associated with smaller tumor size (p=0.019), whereas high miR-17-5p expression correlated with better Eastern Cooperative Oncology Group performance status (p=0.003). The survival analysis revealed that high miR-224 expression was associated with increased progression-free and overall survival (PFS p=0.029; OS p=0.012). Pretreatment microRNA profiling, especially miR-224 expression, might serve as an ancillary tool for the better assessment of expected survival rates for patients under sorafenib treatment.
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Affiliation(s)
- Benedek Gyöngyösi
- Second Department of Pathology, Semmelweis University, Budapest, Hungary (BG, BJ, ES, ZS, AK)MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary (ZS)Department of Oncology, United Saint Stephen and Saint Laslo Hospital and Outpatient Clinics, Budapest, Hungary (ÉV, GB)ARC-NET Research Centre, Department of Pathology and Diagnostic, Policlinico GB Rossi, University of Verona, Verona, Italy (MF)
| | - Éva Végh
- Second Department of Pathology, Semmelweis University, Budapest, Hungary (BG, BJ, ES, ZS, AK)MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary (ZS)Department of Oncology, United Saint Stephen and Saint Laslo Hospital and Outpatient Clinics, Budapest, Hungary (ÉV, GB)ARC-NET Research Centre, Department of Pathology and Diagnostic, Policlinico GB Rossi, University of Verona, Verona, Italy (MF)
| | - Balázs Járay
- Second Department of Pathology, Semmelweis University, Budapest, Hungary (BG, BJ, ES, ZS, AK)MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary (ZS)Department of Oncology, United Saint Stephen and Saint Laslo Hospital and Outpatient Clinics, Budapest, Hungary (ÉV, GB)ARC-NET Research Centre, Department of Pathology and Diagnostic, Policlinico GB Rossi, University of Verona, Verona, Italy (MF)
| | - Eszter Székely
- Second Department of Pathology, Semmelweis University, Budapest, Hungary (BG, BJ, ES, ZS, AK)MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary (ZS)Department of Oncology, United Saint Stephen and Saint Laslo Hospital and Outpatient Clinics, Budapest, Hungary (ÉV, GB)ARC-NET Research Centre, Department of Pathology and Diagnostic, Policlinico GB Rossi, University of Verona, Verona, Italy (MF)
| | - Matteo Fassan
- Second Department of Pathology, Semmelweis University, Budapest, Hungary (BG, BJ, ES, ZS, AK)MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary (ZS)Department of Oncology, United Saint Stephen and Saint Laslo Hospital and Outpatient Clinics, Budapest, Hungary (ÉV, GB)ARC-NET Research Centre, Department of Pathology and Diagnostic, Policlinico GB Rossi, University of Verona, Verona, Italy (MF)
| | - György Bodoky
- Second Department of Pathology, Semmelweis University, Budapest, Hungary (BG, BJ, ES, ZS, AK)MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary (ZS)Department of Oncology, United Saint Stephen and Saint Laslo Hospital and Outpatient Clinics, Budapest, Hungary (ÉV, GB)ARC-NET Research Centre, Department of Pathology and Diagnostic, Policlinico GB Rossi, University of Verona, Verona, Italy (MF)
| | - Zsuzsa Schaff
- Second Department of Pathology, Semmelweis University, Budapest, Hungary (BG, BJ, ES, ZS, AK)MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary (ZS)Department of Oncology, United Saint Stephen and Saint Laslo Hospital and Outpatient Clinics, Budapest, Hungary (ÉV, GB)ARC-NET Research Centre, Department of Pathology and Diagnostic, Policlinico GB Rossi, University of Verona, Verona, Italy (MF)
| | - András Kiss
- Second Department of Pathology, Semmelweis University, Budapest, Hungary (BG, BJ, ES, ZS, AK)MTA-SE Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary (ZS)Department of Oncology, United Saint Stephen and Saint Laslo Hospital and Outpatient Clinics, Budapest, Hungary (ÉV, GB)ARC-NET Research Centre, Department of Pathology and Diagnostic, Policlinico GB Rossi, University of Verona, Verona, Italy (MF)
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Takeda H, Nishikawa H, Iguchi E, Ohara Y, Sakamoto A, Saito S, Nishijima N, Nasu A, Komekado H, Kita R, Kimura T, Osaki Y. Effect of treatment with branched-chain amino acids during sorafenib therapy for unresectable hepatocellular carcinoma. Hepatol Res 2014; 44:302-12. [PMID: 23607614 DOI: 10.1111/hepr.12125] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 02/17/2013] [Accepted: 03/27/2013] [Indexed: 02/08/2023]
Abstract
AIM To examine the effect of branched-chain amino acid (BCAA) therapy for patients with unresectable hepatocellular carcinoma (HCC) treated with sorafenib. METHODS Seventy-eight subjects with unresectable HCC with a serum level of albumin of 3.5 g/dL or less treated with sorafenib were evaluated. They were classified into two groups: those receiving BCAA granules (n = 34; BCAA group) or a regular diet (n = 44; control group). We compared overall survival and administration period of sorafenib, and analyzed absolute changes in serum levels of albumin during sorafenib therapy in 41 patients who continued sorafenib therapy for 1 month or more with a follow up of more than 3 months. RESULTS Median survival time (MST) in BCAA and control groups was 350 and 143 days (P = 0.007), respectively. Median administration period of sorafenib in the two groups was 59 and 41 days (P = 0.018). In the 41 patients described above, at 1 month, there was no significant change in the serum level of albumin between the two groups, but at 3 months, the difference in the absolute change in the serum level of albumin in the two groups reached significance (P = 0.023). In these subgroup analyses, the administration period of sorafenib as well as the MST in the BCAA group were significantly longer than those in the control group (P = 0.020 and = 0.004). CONCLUSION BCAA treatment during sorafenib therapy in HCC patients is useful for maintaining hepatic functional reserve, which may help to avoid early discontinuance of sorafenib therapy and improve survival.
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Affiliation(s)
- Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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Nishikawa H, Osaki Y. Clinical significance of therapy using branched-chain amino acid granules in patients with liver cirrhosis and hepatocellular carcinoma. Hepatol Res 2014; 44:149-58. [PMID: 23819582 DOI: 10.1111/hepr.12194] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Revised: 06/24/2013] [Accepted: 06/25/2013] [Indexed: 02/07/2023]
Abstract
The liver is the major organ for the metabolism of protein, fat and carbohydrate. A nutritional approach is required in the treatment of cirrhosis, which is frequently complicated with protein-energy malnutrition. Several advanced treatment approaches for hepatocellular carcinoma (HCC) have been established in the past decade. HCC is often complicated by cirrhosis, so treatment of the underlying liver diseases is also necessary to improve the prognosis. Branched-chain amino acid (BCAA) granules were developed originally for the treatment of hypoalbuminemia associated with decompensated cirrhosis. However, subsequent studies found various other pharmacological actions of this agent. We review the clinical significance of therapy using BCAA granules in patients receiving different treatment approaches for cirrhosis and HCC based on the published work as well as our own data.
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Affiliation(s)
- Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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Lee S, Kim BK, Kim SU, Park SY, Kim JK, Lee HW, Park JY, Kim DY, Ahn SH, Tak WY, Kweon YO, Lee JI, Lee KS, Kim HJ, Han KH. Clinical outcomes and prognostic factors of patients with advanced hepatocellular carcinoma treated with sorafenib as first-line therapy: a Korean multicenter study. J Gastroenterol Hepatol 2014; 29:1463-1469. [PMID: 25273508 DOI: 10.1111/jgh.12542] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/22/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Sorafenib is recommended as a standard treatment for advanced hepatocellular carcinoma (HCC). The efficacy and safety of sorafenib as a first-line therapy in Korean patients with advanced HCC were investigated. METHODS From 2007 to 2012, 86 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) treated with sorafenib as a first-line therapy were enrolled from five tertiary hospitals. Predictors of overall survival (OS) and progression-free survival (PFS) were analyzed. RESULTS The median age was 59.5 years, and 71 (82.6%) were males; 57 (66.3%) patients were in Child-Pugh class A. The median OS and PFS were 5.0 (range 4.0-5.9) and 3.2 (range 2.6-3.7) months, respectively. Regarding OS, Child-Pugh class A (6.0 vs 2.8 months), tumor diameter < 5 cm (6.0 vs 4.3 months), baseline α-fetoprotein < 200 ng/mL (5.8 vs 4.1 months), and the advent of hand-foot-skin reaction of ≥ grade 2 (5.9 vs 4.0 months) were independent favorable predictors (all P < 0.05). Similarly, regarding PFS, Child-Pugh class A (4.3 vs 2.1 months), tumor diameter < 5 cm (3.9 vs 2.8 months), baseline α-fetoprotein < 200 ng/mL (5.6 vs 2.8 months), and the advent of hand-foot-skin reaction of ≥ grade 2 (4.5 vs 2.6 months) were independent favorable predictors (all P < 0.05). All toxicities during sorafenib treatment were manageable. CONCLUSIONS Because the efficacy of sorafenib seems marginal in Korean patients with treatment-naïve HCC, how to select candidates with favorable outcomes should be further investigated.
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Affiliation(s)
- Sangheun Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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Kim HY, Park JW, Joo J, Kim H, Woo SM, Lee WJ, Kim CM. Worse outcome of sorafenib therapy associated with ascites and Child-Pugh score in advanced hepatocellular carcinoma. J Gastroenterol Hepatol 2013; 28:1756-61. [PMID: 23800278 DOI: 10.1111/jgh.12310] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/14/2013] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND AIM The outcomes of sorafenib therapy in patients with advanced hepatocellular carcinoma (HCC) and impaired liver function remain unresolved. Although Child-Pugh (CP) classification is widely used for patient categorization, heterogeneity within a given CP class makes outcomes less predictable. The aim was to investigate the prognostic significance of CP score elements on the outcome of sorafenib in patients with advanced HCC and impaired liver function. METHODS Of 1385 consecutive patients with advanced HCC in our center between January 2007 and December 2010, we reviewed the medical records of 325 patients who received sorafenib monotherapy. RESULTS Median duration of sorafenib was 2.0 months (range 0.4-24.2) and median follow-up was 4.9 months (range 0.5-43.4). Disease control rates were significantly higher in CP class A (CPA) than in CP class B (CPB) patients. Median overall survival (OS) was 5.8 months. Subgroups with different CP scores showed significantly different OS (months): CPA5, 8.4; CPA6, 5.1; CPB7, 3.5; CPB8-9, 2.6 (P < 0.001). The presence of ascites was a significant prognostic factor in CPB7 patients (hazard ratio 2.262; P = 0.016). OS of CPB7 patients without ascites was similar to that of CPA6 patients (4.6 months) and was significantly longer than that of CPB7 patients with ascites (2.5 months; P = 0.027). OS of CPB7 patients with ascites was similar to that of CPB8-9 patients. CONCLUSIONS CP score was more important than CP class in predicting the outcome of sorafenib therapy in patients with advanced HCC. Among the CP score components, presence of ascites was a significant prognostic factor, especially in CPB7 patients.
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Affiliation(s)
- Hwi Young Kim
- Center for Liver Cancer, National Cancer Center Hospital, Goyang, Korea
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Nishikawa H, Kimura T, Kita R, Osaki Y. Treatment for hepatocellular carcinoma in elderly patients: a literature review. J Cancer 2013; 4:635-43. [PMID: 24155775 PMCID: PMC3805991 DOI: 10.7150/jca.7279] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 09/07/2013] [Indexed: 02/06/2023] Open
Abstract
An aging society means that the number of elderly patients with cancer is predicted to rise in the future. Hepatocellular carcinoma (HCC) usually develops in patients with hepatitis B virus infection, hepatitis C virus infection, or alcoholic liver disease. The risk of developing HCC is also known to be age-dependent and elderly patients sometimes present with HCC. The increased longevity of the population thus means that more elderly HCC patients are to be expected in the coming years. In general, many elderly patients are not receiving optimal therapy for malignancies, because it is often withheld from them because of perceived minimal survival advantage and the fear of potential toxicity. Comprehensive data with regard to treatment of elderly patients with HCC are currently limited. Furthermore, current guidelines for the management of HCC do not satisfy strategies according to age. Thus, there is urgent need for investigation of safety and clinical outcomes in elderly patients who receive therapy for HCC. In this review, we primarily refer to current knowledge of clinical characteristics and outcome in elderly patients with HCC who underwent different treatment approaches (i.e., surgical resection, liver transplantation, locoregional therapies, and molecular-targeting therapy).
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Affiliation(s)
- Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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Prognostic impact of pERK in advanced hepatocellular carcinoma patients treated with sorafenib. Eur J Surg Oncol 2013; 39:974-80. [PMID: 23845703 DOI: 10.1016/j.ejso.2013.06.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Revised: 05/01/2013] [Accepted: 06/17/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Sorafenib represents the standard of care targeted therapy for patients with advanced hepatocellular carcinoma (HCC). However, biomolecules that predict a patient's response to sorafenib treatment for HCC remain largely unknown. Thus, this study was designed to investigate whether phosphorylated ERK (pERK) and members of the sorafenib target or PI3K/Akt/mTOR signaling pathway predict the efficacy of sorafenib in advanced HCC patients. METHODOLOGY From December 2008 to October 2011, pathological specimens from 54 advanced HCC patients received sorafenib treatment were obtained. Clinicopathological variables, treatment response, survival and time to progression (TTP) were recorded. Immunophenotypical analysis was carried out using antibodies against pERK, phosphorylated S6K (pS6K), VEGFR2 and PTEN. RESULTS The median overall survival (OS) and TTP were 14.2 and 3.4 months, respectively, and the disease control rate (DCR) was 59.3%. Better Eastern Cooperative Oncology Group Performance Status (ECOG PS) (95% CI: 3.27-4.93 m vs. 1.15-2.85 m, p = 0.01), Child-Pugh class A score (95% CI: 3.47-4.53 vs. 1.14-2.06 m, p < 0.01), and higher pERK (3.34-6.66 m vs. 1.33-2.67 m, p = 0.03) and VEGFR2 (3.49-6.52 m vs. 2.15-2.73 m, p = 0.04) immunohistochemical staining score were associated with increased TTP by univariate analysis. The ECOG PS (p = 0.022), Child-Pugh class (p = 0.045) and pERK staining score (p = 0.012) were found to be associated with TTP using multivariate analysis. CONCLUSION Sorafenib treatment outcome is favorable in advanced HCC patients who received tumor resection and who have a good ECOG PS and Child-Pugh class A liver function. The pERK immunohistological staining score, ECOG PS and Child-Pugh class may be helpful in determining patients most likely to benefit from sorafenib therapy.
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Cho JY, Paik YH, Lim HY, Kim YG, Lim HK, Min YW, Gwak GY, Choi MS, Lee JH, Koh KC, Paik SW, Yoo BC. Clinical parameters predictive of outcomes in sorafenib-treated patients with advanced hepatocellular carcinoma. Liver Int 2013; 33:950-7. [PMID: 23601249 DOI: 10.1111/liv.12168] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 02/28/2013] [Indexed: 12/19/2022]
Abstract
BACKGROUND Sorafenib is an orally active multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma (HCC). However, clinical parameters that may predict the treatment outcomes in sorafenib-treated advanced HCC patients remains unknown. METHODS A total of 99 advanced (BCLC C) HCC patients treated with sorafenib as an initial treatment modality from January 2007 to December 2011 were retrospectively reviewed. Overall survival was the primary endpoint for the analysis. Various clinical parameters including tumour stage and adverse effects to sorafenib were analysed. Univariate and multivariate analysis were carried out to identify clinical parameters predictive of the effect of sorafenib. RESULTS There were 86 males and 13 females included in this study, with a median age of 53 years. The median overall survival was 91 days. Sixty-nine patients had Child-Pugh class A cirrhosis and 30 patients had Child-Pugh class B cirrhosis. Hepatitis B virus was the predominant cause of HCC (75.8%). Noted adverse effects were hand-foot syndrome, diarrhoea, fatigue, abdominal pain, nausea and stomatitis. The presence of hand-foot syndrome and diarrhoea and the absence of portal vein thrombosis and lymph node metastasis predicted a better overall survival in the multivariate analysis. Excluding the absence of lymph node metastasis, the same parameters were associated with a longer radiological time to progression. CONCLUSION Advanced HCC patients treated with sorafenib who experienced hand-foot syndrome and diarrhoea showed better overall survival than patients without these side effects. These side effects may be used as clinical parameters predictive of sorafenib response in patients with HCC.
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Affiliation(s)
- Ju-Yeon Cho
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Wörns MA, Koch S, Niederle IM, Marquardt JU, Nguyen-Tat M, Gamstätter T, Schuchmann M, Schulze-Bergkamen H, Galle PR, Weinmann A. The impact of patient and tumour baseline characteristics on the overall survival of patients with advanced hepatocellular carcinoma treated with sorafenib. Dig Liver Dis 2013. [PMID: 23182599 DOI: 10.1016/j.dld.2012.10.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Impact of patient and tumour baseline characteristics on the overall survival is not well characterized in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. AIMS/METHODS Univariate/multivariate analyses were conducted to identify retrospectively the impact of baseline characteristics on the survival of 110 patients with advanced HCC treated with sorafenib. RESULTS Median survival of the whole cohort was 6.7 months, median survival in Child-Pugh A, B, C patients was 10.5, 6.1 and 3.0 months and median survival of patients with Barcelona Clinic Liver Cancer (BCLC) stage C/D was 6.8/2.6 months. Presence of ascites, presence of macrovascular invasion and BCLC stage D (mainly determined by Child-Pugh C status and Eastern Cooperative Oncology Group Performance Status>2) remained independent prognostic factors for the survival on multivariate analysis. Particularly, the presence of macrovascular invasion significantly influenced survival both in patients with liver cirrhosis Child-Pugh A and Child-Pugh B. CONCLUSION Well maintained liver function and performance status are prerequisites for sorafenib treatment in patients with advanced HCC. Our findings do not support routine clinical use of sorafenib in Child-Pugh B patients. Evaluation of ascites and particularly macrovascular invasion might help to identify patients more likely to benefit from sorafenib treatment.
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Affiliation(s)
- Marcus A Wörns
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
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Chu JS, Ge FJ, Zhang B, Wang Y, Silvestris N, Liu LJ, Zhao CH, Lin L, Brunetti AE, Fu YL, Wang J, Paradiso A, Xu JM. Expression and prognostic value of VEGFR-2, PDGFR-β, and c-Met in advanced hepatocellular carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2013; 32:16. [PMID: 23552472 PMCID: PMC3623756 DOI: 10.1186/1756-9966-32-16] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 02/28/2013] [Indexed: 02/09/2023]
Abstract
BACKGROUND We explore the clinical and prognostic significance of expression of vascular endothelial growth factor receptor (VEGFR)-2, platelet-derived growth factor receptor (PDGFR)-β, and c-Met in patients with hepatocellular carcinoma (HCC). METHODS The expression of VEGFR-2, PDGFR-β, and c-Met were determined by immunohistochemical examination of the tissues of 93 HCC patients. The relationships of these markers with clinicopathological factors and prognosis were then analyzed. RESULTS High expression of VEGFR-2, PDGFR-β, and c-Met was found in 86%, 19.4%, and 80.6% of patients, respectively. Expression of VEGFR-2 correlated with gender (P = 0.044), hepatitis B surface antigen positivity (P = 0.024), degree of tumor differentiation (P = 0.023), and hepatic cirrhosis (P = 0.026). Expression of PDGFR-β correlated with alpha-fetoprotein level (P = 0.029), tumor size (P = 0.033), and hepatic cirrhosis (P = 0.023). No significant correlations were identified between expression of c-Met and clinicopathological factors. Expression of PDGFR-β correlated with overall survival (P = 0.046) and expression of c-Met correlated with progression-free survival (P = 0.01). CONCLUSIONS We found that in patients with HCC, high expression of VEGFR-2 correlates with chronic hepatitis B virus infection and hepatic cirrhosis. High expression of PDGFR-β is a predictor of poor prognosis. High expression of C-Met may predict therapeutic effectiveness of sorafenib in HCC patients.
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Affiliation(s)
- Jie Sheng Chu
- The Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, Beijing 100071, People's Republic of China
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Shao YY, Hsu CH, Cheng AL. Predictive biomarkers of antiangiogenic therapy for advanced hepatocellular carcinoma: where are we? Liver Cancer 2013; 2:93-107. [PMID: 24159601 PMCID: PMC3740718 DOI: 10.1159/000343845] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Antiangiogenic therapy, especially treatment with sorafenib, is the primary treatment for patients with advanced hepatocellular carcinoma (HCC). However, the efficacy of such therapy is modest, with low objective response rates and limited prolongation of survival times. Several researchers have investigated predictive biomarkers to help identify patients who can benefit most from antiangiogenic therapy. The largest study on this topic to date was based on the pivotal phase III study of sorafenib (the SHARP study) and did not find any plasma markers that could predict the efficacy of sorafenib. Other studies based on single-arm phase II clinical trials found some potential predictive markers, such as early alpha-fetoprotein response, the serum insulin-like growth factor-1 level at baseline, and the volume transfer constants of dynamic contrast-enhanced magnetic resonance imaging. These findings require validation by further studies. Identifying predictive biomarkers of antiangiogenic therapy for HCC remains challenging and warrants further investigations.
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Affiliation(s)
- Yu-Yun Shao
- Departments of Oncology, National Taiwan University Hospital, Taiwan, ROC,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taiwan, ROC
| | - Chih-Hung Hsu
- Departments of Oncology, National Taiwan University Hospital, Taiwan, ROC,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taiwan, ROC
| | - Ann-Lii Cheng
- Departments of Oncology, National Taiwan University Hospital, Taiwan, ROC,Internal Medicine, National Taiwan University Hospital, Taiwan, ROC,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taiwan, ROC,*Departments of Oncology and Internal Medicine, National Taiwan University Hospital,7 Chung-Shan South Road, Taipei, Taiwan 10002 (ROC), Tel. +886 2 23123456 ext. 67251, E-mail
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Takeda H, Nishikawa H, Iguchi E, Ohara Y, Sakamoto A, Hatamaru K, Henmi S, Saito S, Nasu A, Komekado H, Kita R, Kimura T, Osaki Y. Impact of pretreatment serum cholinesterase level in unresectable advanced hepatocellular carcinoma patients treated with sorafenib. Mol Clin Oncol 2012; 1:241-248. [PMID: 24649154 DOI: 10.3892/mco.2012.48] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 11/16/2012] [Indexed: 12/18/2022] Open
Abstract
The value of serum cholinesterase (ChE) level as a predictive marker in sorafenib therapy for advanced hepatocellular carcinoma (HCC) has not yet been investigated. The present retrospective study therefore analyzed the impact of the serum ChE level in 93 patients with advanced HCC treated with sorafenib. Patients were categorized into two groups: group A with pretreatment serum ChE ≥140 IU/l (n=46) and group B with pretreatment serum ChE <140 IU/l (n=47). The correlation between clinicopathological findings, including serum ChE level, and overall survival (OS) and liver damage during sorafenib therapy was investigated. The median OS of the patients was 275 days, while OS was markedly higher in group A compared to group B (P=0.002). In 70 Child-Pugh A patients, serum ChE level was a significant prognostic predictor in multivariate analysis [P=0.019, hazard ratio (HR) =2.612; 95% confidence interval (CI), 1.174-5.810]. During sorafenib treatment, 22 patients developed liver dysfunction of grade 3 or higher. Only two group A patients (4.3%) developed liver dysfunction, compared to 20 group B patients (42.6%) (P<0.001). Multivariate analysis demonstrated that the pretreatment serum ChE level was the strongest predictor of liver damage (P=0.002, HR=0.061, 95% CI: 0.010-0.373), indicating serum ChE <140 IU/l to be the only independent predictor associated with severe liver function damage during sorafenib treatment in 70 patients with grade A Child-Pugh (P= 0.016; HR= 0.122; 95% CI, 0.022-0.676). In conclusion, lower serum ChE level is a significant predictor of poor prognosis and severe liver damage in HCC patients treated with sorafenib. Advanced HCC patients with lower serum ChE levels, including those with a Child-Pugh A pretreatment liver function score, should be given sorafenib therapy with caution.
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Affiliation(s)
- Haruhiko Takeda
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Eriko Iguchi
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Yoshiaki Ohara
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Azusa Sakamoto
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Keiichi Hatamaru
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Shinichiro Henmi
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Sumio Saito
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Akihiro Nasu
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Hideyuki Komekado
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Ryuichi Kita
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Toru Kimura
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
| | - Yukio Osaki
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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Haney CR, Fan X, Markiewicz E, Mustafi D, Karczmar GS, Stadler WM. Monitoring anti-angiogenic therapy in colorectal cancer murine model using dynamic contrast-enhanced MRI: comparing pixel-by-pixel with region of interest analysis. Technol Cancer Res Treat 2012; 12:71-8. [PMID: 22905809 DOI: 10.7785/tcrt.2012.500255] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Sorafenib is a multi-kinase inhibitor that blocks cell proliferation and angiogenesis. It is currently approved for advanced hepatocellular and renal cell carcinomas in humans, where its major mechanism of action is thought to be through inhibition of vascular endothelial growth factor and platelet-derived growth factor receptors. The purpose of this study was to determine whether pixel-by-pixel analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is better able to capture the heterogeneous response of Sorafenib in a murine model of colorectal tumor xenografts (as compared with region of interest analysis). MRI was performed on a 9.4 T pre-clinical scanner on the initial treatment day. Then either vehicle or drug were gavaged daily (3 days) up to the final image. Four days later, the mice were again imaged. The two-compartment model and reference tissue method of DCE-MRI were used to analyze the data. The results demonstrated that the contrast agent distribution rate constant (K(trans)) were significantly reduced (p < 0.005) at day-4 of Sorafenib treatment. In addition, the K(trans) of nearby muscle was also reduced after Sorafenib treatment. The pixel-by-pixel analysis (compared to region of interest analysis) was better able to capture the heterogeneity of the tumor and the decrease in K(trans) four days after treatment. For both methods, the volume of the extravascular extracellular space did not change significantly after treatment. These results confirm that parameters such as K(trans), could provide a non-invasive biomarker to assess the response to anti-angiogenic therapies such as Sorafenib, but that the heterogeneity of response across a tumor requires a more detailed analysis than has typically been undertaken.
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Affiliation(s)
- C R Haney
- Department of Radiology, The University of Chicago, Chicago, IL 60637, USA.
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Raoul JL, Bruix J, Greten TF, Sherman M, Mazzaferro V, Hilgard P, Scherubl H, Scheulen ME, Germanidis G, Dominguez S, Ricci S, Nadel A, Moscovici M, Voliotis D, Llovet JM. Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses. J Hepatol 2012; 56:1080-1088. [PMID: 22245896 DOI: 10.1016/j.jhep.2011.12.009] [Citation(s) in RCA: 96] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Revised: 12/06/2011] [Accepted: 12/12/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Hepatic markers are utilized in many classification systems of patients with hepatocellular carcinoma and, by measuring organ damage and tumor stage, can influence treatment. Moreover, elevated serum concentrations of aminotransferases and alpha-fetoprotein are indicators of poor prognosis in patients with hepatocellular carcinoma. We examined the effects of sorafenib on hepatic markers by performing exploratory subset analyses of the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial in patients categorized by baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, and bilirubin; and by evaluating the effects of sorafenib on bilirubin concentrations during treatment. METHODS Patients (n=602) were grouped by baseline concentrations of alanine aminotransferase/aspartate aminotransferase (not significantly elevated, mildly elevated, or moderately elevated), alpha-fetoprotein (normal or elevated), and bilirubin (normal or elevated). Bilirubin was measured at baseline and on day 1 of each cycle. RESULTS Patients with elevated baseline concentrations of alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin had shorter overall survival (OS) than those with normal baseline concentrations, irrespective of treatment group. No notable differences in safety profiles were observed between patients with normal vs. elevated alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin. Median changes from baseline in bilirubin concentration at the last cycle of treatment were +0.17 and +0.19 mg/dl in the sorafenib and placebo groups, respectively. CONCLUSIONS These subset analyses suggest that sorafenib is safe and effective for hepatocellular carcinoma, irrespective of baseline alanine aminotransferase/aspartate aminotransferase, alpha-fetoprotein, or bilirubin concentration and that hepatic function remains stable over the course of sorafenib therapy.
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Affiliation(s)
- Jean-Luc Raoul
- Institut Paoli-Calmettes, Marseille, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U991, Rennes, France.
| | - Jordi Bruix
- Barcelona Clínic Liver Cancer (BCLC) Group, Liver Unit, CIBERehd, Institut d'Investigacions Biomèdiques, August Pi i Sunyer (IDIBAPS), Hospital Clínic Barcelona, Barcelona, Spain
| | - Tim F Greten
- Medizinische Hochschule Hannover, Abteilung fur Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany
| | | | - Vincenzo Mazzaferro
- National Cancer Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation, Milan, Italy
| | | | - Hans Scherubl
- Medizinische Klinik "Charite", Campus Benjamin Franklin, Berlin, Germany
| | - Max E Scheulen
- Innere Klinik (Tumorforschung), West German Cancer Center, Universitätsklinikum Essen, Essen, Germany
| | - Georgios Germanidis
- AHEPA University Hospital, First Department of Medicine, Thessaloniki, Greece
| | - Sophie Dominguez
- Centre Oscar Lambret, Departement de Cancerologie Digestive et Urologique, Lille, France
| | | | - Andrea Nadel
- Bayer HealthCare Pharmaceuticals, Montville, NJ, USA
| | | | | | - Josep M Llovet
- Barcelona Clínic Liver Cancer (BCLC) Group, Liver Unit, CIBERehd, Institut d'Investigacions Biomèdiques, August Pi i Sunyer (IDIBAPS), Hospital Clínic Barcelona, Barcelona, Spain; Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY, USA; Institució Catalana de Recerca I Estudis Avançats, Catalonia, Spain
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42
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Affiliation(s)
- G Han
- Department of Liver Disease and Digestive Interventional Radiology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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