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Krupa K, Fudalej M, Cencelewicz-Lesikow A, Badowska-Kozakiewicz A, Czerw A, Deptała A. Current Treatment Methods in Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:4059. [PMID: 39682245 DOI: 10.3390/cancers16234059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 11/28/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent malignant tumour worldwide. Depending on the stage of the tumour and liver function, a variety of treatment options are indicated. Traditional radiotherapy and chemotherapy are ineffective against HCC; however, the U.S. Food and Drug Administration (FDA) has approved radiofrequency ablation (RFA), surgical resection, and transarterial chemoembolization (TACE) for advanced HCC. On the other hand, liver transplantation is recommended in the early stages of the disease. Tyrosine kinase inhibitors (TKIs) like lenvatinib and sorafenib, immunotherapy and anti-angiogenesis therapy, including pembrolizumab, bevacizumab, tremelimumab, durvalumab, camrelizumab, and atezolizumab, are other treatment options for advanced HCC. Moreover, to maximize outcomes for patients with HCC, the combination of immune checkpoint inhibitors (ICIs) along with targeted therapies or local ablative therapy is being investigated. This review elaborates on the current status of HCC treatment, outlining the most recent clinical study results and novel approaches.
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Affiliation(s)
- Kamila Krupa
- Students' Scientific Organization of Cancer Cell Biology, Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Marta Fudalej
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
- Department of Oncology, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | - Anna Cencelewicz-Lesikow
- Department of Oncology, National Medical Institute of the Ministry of the Interior and Administration, 02-507 Warsaw, Poland
| | | | - Aleksandra Czerw
- Department of Health Economics and Medical Law, Medical University of Warsaw, 01-445 Warsaw, Poland
- Department of Economic and System Analyses, National Institute of Public Health NIH-National Research Institute, 00-791 Warsaw, Poland
| | - Andrzej Deptała
- Department of Oncological Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
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Diao YK, Sun L, Wang MD, Han J, Zeng YY, Yao LQ, Sun XD, Li C, Shao GZ, Gu LH, Wu H, Xu JH, Lin KY, Fan ZQ, Lau WY, Pawlik TM, Shen F, Lv GY, Yang T. Development and validation of nomograms to predict survival and recurrence after hepatectomy for intermediate/advanced (BCLC stage B/C) hepatocellular carcinoma. Surgery 2024; 176:137-147. [PMID: 38734502 DOI: 10.1016/j.surg.2024.03.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/13/2024] [Accepted: 03/18/2024] [Indexed: 05/13/2024]
Abstract
BACKGROUND Despite the Barcelona Clinic Liver Cancer system discouraging hepatectomy for intermediate/advanced hepatocellular carcinoma, the procedure is still performed worldwide, particularly in Asia. This study aimed to develop and validate nomograms for predicting survival and recurrence for these patients. METHODS We analyzed patients who underwent curative-intent hepatectomy for intermediate/advanced hepatocellular carcinoma between 2010 and 2020 across 3 Chinese hospitals. The Eastern Hepatobiliary Surgery Hospital cohort was used as the training cohort for the nomogram construction, and the Jilin First Hospital and Fujian Mengchao Hepatobiliary Hospital cohorts served as the external validation cohorts. Independent preoperative predictors for survival and recurrence were identified through univariable and multivariable Cox regression analyses. Predictive accuracy was measured using the concordance index and calibration curves. The predictive performance between nomograms and conventional hepatocellular carcinoma staging systems was compared. RESULTS A total of 1,328 patients met the inclusion criteria. The nomograms for predicting survival and recurrence were developed using 10 and 6 independent variables, respectively. Nomograms' concordance indices in the training cohort were 0.777 (95% confidence interval 0.759-0.800) and 0.719 (95% confidence interval 0.697-0.742) for survival and recurrence, outperforming 4 conventional staging systems (P < .001). Nomograms accurately stratified risk into low, intermediate, and high subgroups. These results were validated well by 2 external validation cohorts. CONCLUSION We developed and validated nomograms predicting survival and recurrence for patients with intermediate/advanced hepatocellular carcinoma, contradicting Barcelona Clinic Liver Cancer surgical guidelines. These nomograms may facilitate clinicians to formulate personalized surgical decisions, estimate long-term prognosis, and strategize neoadjuvant/adjuvant anti-recurrence therapy.
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Affiliation(s)
- Yong-Kang Diao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China; Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Lu Sun
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Jun Han
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China; Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Lan-Qing Yao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China; Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Xiao-Dong Sun
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Guang-Zhao Shao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Li-Hui Gu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Han Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Jia-Hao Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Kong-Ying Lin
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Zhong-Qi Fan
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Wan Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China; Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
| | - Timothy M Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, OH
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Guo-Yue Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Tian Yang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China; Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai, China; Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center of Chinese PLA General Hospital, Beijing, China.
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Xu X, Wang MD, Xu JH, Fan ZQ, Diao YK, Chen Z, Jia HD, Liu FB, Zeng YY, Wang XM, Wu H, Qiu W, Li C, Pawlik TM, Lau WY, Shen F, Lv GY, Yang T. Adjuvant immunotherapy improves recurrence-free and overall survival following surgical resection for intermediate/advanced hepatocellular carcinoma a multicenter propensity matching analysis. Front Immunol 2024; 14:1322233. [PMID: 38268916 PMCID: PMC10806403 DOI: 10.3389/fimmu.2023.1322233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/14/2023] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND & AIMS The effectiveness of adjuvant immunotherapy to diminish recurrence and improve long-term prognosis following curative-intent surgical resection for hepatocellular carcinoma (HCC) is of increased interest, especially among individuals at high risk of recurrence. The objective of the current study was to investigate the impact of adjuvant immunotherapy on long-term recurrence and survival after curative resection among patients with intermediate/advanced HCC. METHODS Using a prospectively-collected multicenter database, patients who underwent curative-intent resection for Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC were identified. Propensity score matching (PSM) analysis was used to compare recurrence-free survival (RFS) and overall survival (OS) between patients treated with and without adjuvant immune checkpoint inhibitors (ICIs). Multivariate Cox-regression analysis further identified independent factors of RFS and OS. RESULTS Among the 627 enrolled patients, 109 patients (23.3%) received adjuvant immunotherapy. Most ICI-related adverse reactions were grading I-II. PSM analysis created 99 matched pairs of patients with comparable baseline characteristics between patients treated with and without adjuvant immunotherapy. In the PSM cohort, the median RFS (29.6 vs. 19.3 months, P=0.031) and OS (35.1 vs. 27.8 months, P=0.036) were better among patients who received adjuvant immunotherapy versus patients who did not. After adjustment for other confounding factors on multivariable analyzes, adjuvant immunotherapy remained independently associated with favorable RFS (HR: 0.630; 95% CI: 0.435-0.914; P=0.015) and OS (HR: 0.601; 95% CI: 0.401-0.898; P=0.013). Subgroup analyzes identified potentially prognostic benefits of adjuvant immunotherapy among patients with intermediate-stage and advanced-stage HCC. CONCLUSION This real-world observational study demonstrated that adjuvant immunotherapy was associated with improved RFS and OS following curative-intent resection of intermediate/advanced HCC. Future randomized controlled trials are warranted to establish definitive evidence for this specific population at high risks of recurrence.
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Affiliation(s)
- Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
- Department of Gastrointestinal Surgery, Wuhan Fourth Hospital, Wuhan, Hubei, China
| | - Ming-Da Wang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Jia-Hao Xu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Zhong-Qi Fan
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Yong-Kang Diao
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Zhong Chen
- Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Hang-Dong Jia
- Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, Zhejiang, China
| | - Fu-Bao Liu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yong-Yi Zeng
- Department of Hepatobiliary Surgery, Mengchao Hepatobiliary Hospital, Fujian Medical University, Fuzhou, Fujian, China
| | - Xian-Ming Wang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China
| | - Han Wu
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Wei Qiu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Chao Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Timothy M. Pawlik
- Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, OH, United States
| | - Wan Yee Lau
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
- Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China
| | - Feng Shen
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
| | - Guo-Yue Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Tian Yang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, China
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Xu J, Shan Y, Zhang C, Hong Z, Qiu Y. Effect of Chinese Medicines combined with transarterial chemoembolization on primary hepatic carcinoma: A systematic review and meta-analysis. Medicine (Baltimore) 2023; 102:e34165. [PMID: 37390274 PMCID: PMC10313245 DOI: 10.1097/md.0000000000034165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/09/2023] [Indexed: 07/02/2023] Open
Abstract
BACKGROUND To systematically evaluate the survival rate and postoperative adverse reactions of patients with hepatocellular carcinoma treated with traditional Chinese medicine combined with TACE by meta-analysis. METHODS Four major literature databases (Cochrane Library, Embase, PubMed, and Web of Science) were retrieved to collect published English articles since 2009. After determining the random effect model or fixed utility model based on a heterogeneity test, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS This meta-analysis included 8 prospective studies published between 2009 and 2019. Due to moderate heterogeneity (P < .05, I2 = 54.8%), Therefore, the random effect model is used to analyze the data, so as to explore the relationship between CMs combined with TACE treatment and survival rate and postoperative adverse reactions. All the comprehensive test results show that there is a statistical significance between CMs combined with TACE treatment and survival rate. (OR = 1.88, 95% CI 1.34-2.64, P = .03). Then subgroup analysis and sensitivity analysis were carried out. The results indicated that the overall results ranged from 1.12(95% CI = 1.03-1.11) to 1.21(95% CI = 1.22-1.33). CONCLUSIONS The 1-year survival rate of patients treated with traditional Chinese medicine TACE is a protective factor, and the quality score included in the study affects the evaluation of the effective dose. At the same time, traditional Chinese medicine combined with TACE has nothing to do with the reduction of postoperative complications.
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Affiliation(s)
- Jianyuan Xu
- Department of Infectious Diseases, Nanjing Medical University, Nanjing, Jiangsu Province, China
- The Wuxi Fifth Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China
| | - Yue Shan
- The Wuxi Fifth Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China
| | - Chenxia Zhang
- The Wuxi Fifth Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China
| | - Zehua Hong
- Department of Infectious Diseases, Nanjing Medical University, Nanjing, Jiangsu Province, China
- The Wuxi Fifth Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China
| | - Yuanwang Qiu
- Department of Infectious Diseases, Nanjing Medical University, Nanjing, Jiangsu Province, China
- The Wuxi Fifth Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu Province, China
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Han S, Ye T, Mao Y, Hu B, Wang C. Cuproptosis-Related Genes CDK1 and COA6 Involved in the Prognosis Prediction of Liver Hepatocellular Carcinoma. DISEASE MARKERS 2023; 2023:5552798. [PMID: 37215201 PMCID: PMC10195163 DOI: 10.1155/2023/5552798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/07/2023] [Accepted: 03/29/2023] [Indexed: 05/24/2023]
Abstract
Background Liver hepatocellular carcinoma (LIHC) is the most frequently seen type of primary liver cancer. Cuproptosis is a novel form of cell death highly associated with mitochondrial metabolism. However, the clinical impact and pertinent mechanism of cuproptosis genes in LIHC remain largely unknown. Methods From public databases, we systematically assessed common genes from LIHC differentially expressed genes (DEGs) and cuproptosis-related genes using bioinformatics analysis. These common genes were then analyzed by enrichment analysis, mutation analysis, risk score model, and others to find candidate hub genes related to LIHC and cuproptosis. Next, hub genes were determined by expression, clinical factors, immunoassay, and prognostic nomogram. Results Based on 129 cuproptosis-related genes and 3492 LIHC DEGs, we totally identified 21 downregulated and 18 upregulated common genes, and they were enriched in pathways, such as zinc ion homeostasis and oxidative phosphorylation. In the mutation analysis, missense mutation was the most common type in LIHC patients, and the common gene F5 had the highest mutation frequency. After LASSO-Cox regression analysis and prognostic analysis, CDK1, ABCB6, LCAT, and COA6 were identified as prognostic signature genes. Among them, ABCB6 and LCAT were lowly expressed in tumors, and CDK1 and COA6 were highly expressed in tumors. In addition, ABCB6 and LCAT were negatively correlated with 6 kinds of immune cells, while CDK1 and COA6 were positively correlated with them. CDK1 and COA6 were identified as hub genes related to LIHC by Cox regression analysis and prognostic nomogram. Conclusion CDK1 and COA6 are two oncogenes in LIHC, which are involved in the molecular mechanism of cuproptosis and LIHC. Besides, CDK1 and COA6 can positively regulate the expressions of immune cells in LIHC. In clinical practice, they can be used as immunotherapeutic targets and prognostic predictors in LIHC, which sheds new light on the scientific fields of cuproptosis and LIHC.
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Affiliation(s)
- Sanfeng Han
- Central Laboratory, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University, China
| | - Tao Ye
- Department of Oncology, Minhang Hospital, Fudan University, China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, China
| | - Yuqin Mao
- Center for Traditional Chinese Medicine and Gut Microbiota, Minhang Hospital, Fudan University, 201199 Shanghai, China
| | - Bo Hu
- Department of Oncology, Minhang Hospital, Fudan University, China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, China
| | - Chen Wang
- Department of Oncology, Minhang Hospital, Fudan University, China
- Key Laboratory of Whole-Period Monitoring and Precise Intervention of Digestive Cancer (SMHC), Minhang Hospital & AHS, Fudan University, China
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Abdel Ghafar MT, Morad MA, El-Zamarany EA, Ziada D, Soliman H, Abd-Elsalam S, Salama M. Autologous dendritic cells pulsed with lysate from an allogeneic hepatic cancer cell line as a treatment for patients with advanced hepatocellular carcinoma: A pilot study. Int Immunopharmacol 2020; 82:106375. [PMID: 32169808 DOI: 10.1016/j.intimp.2020.106375] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 02/14/2020] [Accepted: 03/03/2020] [Indexed: 02/08/2023]
Abstract
OBJECTIVES This is a randomized trial adopted to evaluate the safety and efficacy of immunization with specific anti-hepatocellular carcinoma dendritic cells (DCs) in Egyptian patients with advanced hepatocellular carcinoma (HCC) as a treatment or adjuvant therapy in comparison with the traditional therapy. METHODS This study was conducted on 20 HCC patients who were assigned to four groups according to BCLC staging; group I: HCC patients (stage B) received trans-arterial chemoembolization (TACE) and DCs as an adjuvant therapy; group II: HCC patients (stage B) received TACE only; group III: advanced HCC patients (stage D) received DCs vaccine; group IV: advanced HCC patients (stage D) received supportive treatment. DCs were generated from peripheral blood monocytes and pulsed with a lysate of an allogeneic hepatic cancer cell line (HepG2). Toxicity and immunological response were reported as primary outcomes whereas clinical biochemical and radiological responses were reported as secondary outcomes. RESULTS Our study detected that patients who received DCs vaccine (group III) showed mild decrease in Child-Pugh score as well as AFP and PIVKA II levels and developed 20% partial response [PR] 40% stable disease [SD] and 40% progressive disease [PD] compared to the patients of group IV on supportive treatment who developed 100% PD. Although group I patients developed PR (60%) SD (20%) and PD (20%) no significant difference was detected in the clinical biochemical or radiological response between group I and group II patients. DCs vaccine had minimal adverse effects with no autoimmunity and elicited a better immunological response such as increased CD8 cells percentage and number as well as decreased TGFβ levels in the vaccinated patients. CONCLUSION DCs vaccine is safe as it is not associated with significant toxicity. However due to the small number of included patients the efficacy and immune response of using DCs vaccine in the treatment of advanced HCC patients need to be justified by testing of a large cohort.
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Affiliation(s)
| | - Morad Ahmed Morad
- Clinical Pathology Department Faculty of Medicine, Tanta University, Egypt
| | - Enas A El-Zamarany
- Clinical Pathology Department Faculty of Medicine, Tanta University, Egypt
| | - Dina Ziada
- Tropical Medicine Department Faculty of Medicine, Tanta University, Egypt
| | - Hanan Soliman
- Tropical Medicine Department Faculty of Medicine, Tanta University, Egypt
| | | | - Marwa Salama
- Tropical Medicine Department Faculty of Medicine, Tanta University, Egypt
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Dong G, Lin XH, Liu HH, Gao DM, Cui JF, Ren ZG, Chen RX. Intermittent hypoxia alleviates increased VEGF and pro-angiogenic potential in liver cancer cells. Oncol Lett 2019; 18:1831-1839. [PMID: 31423251 PMCID: PMC6607353 DOI: 10.3892/ol.2019.10486] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 04/25/2019] [Indexed: 12/22/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) is an important angiogenic factor. The VEGF rebound induced by hypoxia following transarterial embolization/chemoembolization for primary liver cancer is associated with treatment failure and poor survival rates in patients. The present study investigated the ability of intermittent hypoxia to alleviate the acute hypoxia-induced increase of VEGF and decrease the pro-angiogenic potential of liver cancer cells. The liver cancer cells were exposed to normoxia, or acute or intermittent hypoxia, and the expression of VEGF was determined using reverse transcription-quantitative polymerase chain reaction analysis and western blotting. The pro-angiogenic effects of acute or intermittent hypoxia-exposed liver cancer cells on endothelial cells were assessed in vitro and in vivo. The expression of VEGF in the liver cancer cells exposed to intermittent hypoxia was significantly lower than that in cells exposed to acute hypoxia. Compared with conditioned medium (CM) from acute hypoxia-exposed liver cancer cells, the CM from intermittent hypoxia-exposed liver cancer cells showed markedly less promotion of proliferation and tube formation in endothelial cells. Activation of the reactive oxygen species (ROS)/NF-κB/hypoxia-inducible factor-1α/VEGF signaling pathway was increased in the liver cancer cells exposed to acute hypoxia. Exposure to ROS scavenger N-acetyl-cysteine or NF-κB inhibitor PDTC inhibited the activation of the above pathway and the expression of VEGF induced by acute hypoxia. The in vivo pro-angiogenic effects of intermittent hypoxia-exposed liver cancer cells on endothelial cells were significantly reduced compared with those of acute hypoxia-exposed liver cancer cells. Intermittent hypoxia may alleviate the acute hypoxia-induced increase of VEGF and decrease the pro-angiogenic potential of liver cancer cells, suggesting a novel treatment strategy.
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Affiliation(s)
- Gang Dong
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
| | - Xia-Hui Lin
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
| | - Hua-Hua Liu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
| | - Dong-Mei Gao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
| | - Jie-Feng Cui
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
| | - Zheng-Gang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
| | - Rong-Xin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China
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Stokes E, Shuang T, Zhang Y, Pei Y, Fu M, Guo B, Parissenti A, Wu L, Wang R, Yang G. Efflux inhibition by H2S confers sensitivity to doxorubicin-induced cell death in liver cancer cells. Life Sci 2018; 213:116-125. [DOI: 10.1016/j.lfs.2018.10.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 10/09/2018] [Accepted: 10/17/2018] [Indexed: 02/07/2023]
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Paik KY. Appropriate surgical therapy for patients with hepatocellular carcinoma beyond Milan criteria. Hepatobiliary Surg Nutr 2017; 6:327-328. [PMID: 29152479 DOI: 10.21037/hbsn.2017.05.06] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Kwang Yeol Paik
- Department of Surgery, Yeouido St. Mary's Hospital, the Catholic University of Korea College of Medicine, Seoul, Korea
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10
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Zhao Z, Huang R, Cai H, Liu B, Zeng Y, Kuang A. Targeting of pertechnetate imaging of HepG2 hepatocellular carcinoma through the transduction of the survivin promoter controls the sodium iodide symporter. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:11037-11043. [PMID: 31966449 PMCID: PMC6965826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 10/30/2017] [Indexed: 06/10/2023]
Abstract
Currently, the intratumoral (i.t.) injection of adenovirus-mediated cancer gene therapy has been reported in numerous investigations. However, the intravenous (i.v.) injection of adenovirus is more suited for disseminated tumors and distant metastatic lesions. The survivin promoter, which has tumor-selective capability, was used to construct an adenoviral vector, and its feasibility to carry the sodium iodide symporter (NIS) gene for potential tumor-targeting transfection into carcinoma was evaluated in this study. An in vitro cellular assay using HepG2 hepatocellular carcinoma (HCC) cells exhibited iodide uptake after infection with Ad-Sur-NIS, and the uptake reached a maximum level at 30 min. The effective half-life of 125I efflux from Ad-Sur-NIS infected HepG2 cells was 16.67 ± 1.08 min. Moreover, in vivo transfection of Ad-Sur-NIS via i.v. injection induced more effective transfection and, accordingly, induced higher uptake of pertechnetate in HCC xenograft tumors than did the non-specific transfection of Ad-CMV-NIS (i.v.) (P<0.05), indicating possible selective NIS gene-transfecting image strategies by the survivin promoter.
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Affiliation(s)
- Zhen Zhao
- Department of Nuclear Medicine, West China Hospital of Sichuan University Chengdu, Sichuan Province, China
| | - Rui Huang
- Department of Nuclear Medicine, West China Hospital of Sichuan University Chengdu, Sichuan Province, China
| | - Huawei Cai
- Department of Nuclear Medicine, West China Hospital of Sichuan University Chengdu, Sichuan Province, China
| | - Bin Liu
- Department of Nuclear Medicine, West China Hospital of Sichuan University Chengdu, Sichuan Province, China
| | - Yu Zeng
- Department of Nuclear Medicine, West China Hospital of Sichuan University Chengdu, Sichuan Province, China
| | - Anren Kuang
- Department of Nuclear Medicine, West China Hospital of Sichuan University Chengdu, Sichuan Province, China
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Kim H, Yu SJ, Yeo I, Cho YY, Lee DH, Cho Y, Cho EJ, Lee JH, Kim YJ, Lee S, Jun J, Park T, Yoon JH, Kim Y. Prediction of Response to Sorafenib in Hepatocellular Carcinoma: A Putative Marker Panel by Multiple Reaction Monitoring-Mass Spectrometry (MRM-MS). Mol Cell Proteomics 2017; 16:1312-1323. [PMID: 28550167 DOI: 10.1074/mcp.m116.066704] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 05/10/2017] [Indexed: 12/11/2022] Open
Abstract
Sorafenib is the only standard treatment for unresectable hepatocellular carcinoma (HCC), but it provides modest survival benefits over placebo, necessitating predictive biomarkers of the response to sorafenib. Serum samples were obtained from 115 consecutive patients with HCC before sorafenib treatment and analyzed by multiple reaction monitoring-mass spectrometry (MRM-MS) and ELISA to quantify candidate biomarkers. We verified a triple-marker panel to be predictive of the response to sorafenib by MRM-MS, comprising CD5 antigen-like (CD5L), immunoglobulin J (IGJ), and galectin-3-binding protein (LGALS3BP), in HCC patients. This panel was a significant predictor (AUROC > 0.950) of the response to sorafenib treatment, having the best cut-off value (0.4) by multivariate analysis. In the training set, patients who exceeded this cut-off value had significantly better overall survival (median, 21.4 months) than those with lower values (median, 8.6 months; p = 0.001). Further, a value that was lower than this cutoff was an independent predictor of poor overall survival [hazard ratio (HR), 2.728; 95% confidence interval (CI), 1.312-5.672; p = 0.007] and remained an independent predictive factor of rapid progression (HR, 2.631; 95% CI, 1.448-4.780; p = 0.002). When applied to the independent validation set, levels of the cut-off value for triple-marker panel maintained their prognostic value for poor clinical outcomes. On the contrast, the triple-marker panel was not a prognostic factor for patients who were treated with transarterial chemoembolization (TACE). The discriminatory signature of a triple-marker panel provides new insights into targeted proteomic biomarkers for individualized sorafenib therapy.
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Affiliation(s)
- Hyunsoo Kim
- From the ‡Department of Biomedical Engineering.,§Institute of Medical and Biological Engineering, Medical Research Center, and
| | - Su Jong Yu
- ¶Department of Internal Medicine and Liver Research Institute, Yongon-Dong, Seoul 110-799 Korea
| | - Injun Yeo
- From the ‡Department of Biomedical Engineering
| | - Young Youn Cho
- ¶Department of Internal Medicine and Liver Research Institute, Yongon-Dong, Seoul 110-799 Korea
| | - Dong Hyeon Lee
- ¶Department of Internal Medicine and Liver Research Institute, Yongon-Dong, Seoul 110-799 Korea
| | - Yuri Cho
- ¶Department of Internal Medicine and Liver Research Institute, Yongon-Dong, Seoul 110-799 Korea
| | - Eun Ju Cho
- ¶Department of Internal Medicine and Liver Research Institute, Yongon-Dong, Seoul 110-799 Korea
| | - Jeong-Hoon Lee
- ¶Department of Internal Medicine and Liver Research Institute, Yongon-Dong, Seoul 110-799 Korea
| | - Yoon Jun Kim
- ¶Department of Internal Medicine and Liver Research Institute, Yongon-Dong, Seoul 110-799 Korea
| | | | - Jongsoo Jun
- **Department of Statistics, Seoul National University, Daehak-dong, Seoul 151-742 Korea
| | - Taesung Park
- ‖Interdisciplinary program in Bioinformatics and.,**Department of Statistics, Seoul National University, Daehak-dong, Seoul 151-742 Korea
| | - Jung-Hwan Yoon
- ¶Department of Internal Medicine and Liver Research Institute, Yongon-Dong, Seoul 110-799 Korea;
| | - Youngsoo Kim
- From the ‡Department of Biomedical Engineering; .,§Institute of Medical and Biological Engineering, Medical Research Center, and
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12
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Sugino Y, Yamakado K, Yamanaka T, Fujimori M, Nakatsuka A, Takaki H, Takei Y, Sakuma H, Isaji S. Role of curative treatment in patients with intermediate-stage hepatocellular carcinoma. Jpn J Radiol 2017; 35:254-261. [PMID: 28357723 DOI: 10.1007/s11604-017-0628-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 02/19/2017] [Indexed: 12/15/2022]
Abstract
PURPOSE To retrospectively evaluate the role of curative treatment in patients with intermediate-stage hepatocellular carcinomas (HCCs), and to identify the subgroup having benefit from curative treatment. METHODS From April 2000 to December 2014, 100 patients with intermediate-stage HCCs underwent either curative treatment (hepatectomy: n = 23, radiofrequency ablation (RFA); n = 29, both: n = 4) or transarterial chemoembolization (TACE): n = 44) as initial treatments for HCCs. Overall survival, influence of treatment allocation on prognosis, and factors affecting treatment allocation were evaluated. RESULTS The 5-year survival rate was 59.2% [95% confidence interval (CI) 51.6-66.8%] in the curative group, and 25.1% (95% CI 11.5-38.7%) in the TACE group. Treatment allocation was the only significant prognostic factor (p = 0.014, hazard ratio: 0.382, 95% CI 0.177-0.821). The curative group consisted of more patients with Child-Pugh A (p = 0.0016) than the TACE group, a tumor number of 3 or fewer (p < 0.0001), a unilobar tumor location (p = 0.02), within 4 of 7 cm criterion (p = 0.001), and within up-to-7 criterion (p = 0.04). Child-Pugh A, within the 4 of 7 cm criterion, and a unilobar tumor location were significantly linked with treatment allocation in multivariate analysis. CONCLUSIONS Curative treatment can prolong survival in selected patients with intermediate-stage HCCs.
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Affiliation(s)
- Yuichi Sugino
- Department of Radiology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
| | - Koichiro Yamakado
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Takashi Yamanaka
- Department of Radiology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Masashi Fujimori
- Department of Radiology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Atsuhiro Nakatsuka
- Department of Radiology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Haruyuki Takaki
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Mie University School of Medicine, Tsu, Mie, Japan
| | - Hajime Sakuma
- Department of Radiology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Shuji Isaji
- Department of Hepato-Biliary-Pancreas Transplant Surgery, Mie University School of Medicine, Tsu, Mie, Japan
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13
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Kolly P, Reeves H, Sangro B, Knöpfli M, Candinas D, Dufour JF. Assessment of the Hong Kong Liver Cancer Staging System in Europe. Liver Int 2016; 36:911-7. [PMID: 26677809 DOI: 10.1111/liv.13045] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Accepted: 11/30/2015] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS European and American guidelines have endorsed the Barcelona Clinic Liver Cancer (BCLC) staging system. The aim of this study was to assess the performance of the recently developed Hong Kong Liver Cancer (HKLC) classification as a staging system for hepatocellular carcinoma (HCC) in Europe. METHODS We used a pooled set of 1693 HCC patients combining three prospective European cohorts. Discrimination ability between the nine substages and five stages of the HKLC classification system was assessed. To evaluate the predictive power of the HKLC and BCLC staging systems on overall survival, Nagelkerke pseudo R2, Bayesian Information Criterion and Harrell's concordance index were calculated. The number of patients who would benefit from a curative therapy was assessed for both staging systems. RESULTS The HKLC classification in nine substages shows suboptimal discrimination between the staging groups. The classification in five stages shows better discrimination between groups. However, the BCLC classification performs better than the HKLC classification in the ability to predict overall survival (OS). The HKLC treatment algorithm tags significantly more patients to curative therapy than the BCLC. CONCLUSIONS The BCLC staging system performs better for European patients than the HKLC staging system in predicting OS. Twice more patients are eligible for a curative therapy with the HKLC algorithm; whether this translates in survival benefit remains to be investigated.
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Affiliation(s)
- Philippe Kolly
- Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland.,University Clinic for Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland
| | - Helen Reeves
- The Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.,The Liver Unit, Freeman Hospital, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, UK
| | - Bruno Sangro
- Liver Unit, Clínica Universidad de Navarra and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Pamplona, España
| | - Marina Knöpfli
- University Clinic for Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland
| | - Daniel Candinas
- University Clinic for Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland
| | - Jean-François Dufour
- Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland.,University Clinic for Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland
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14
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Yi PS, Zhang M, Zhao JT, Xu MQ. Liver resection for intermediate hepatocellular carcinoma. World J Hepatol 2016; 8:607-615. [PMID: 27190577 PMCID: PMC4867418 DOI: 10.4254/wjh.v8.i14.607] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 03/14/2016] [Accepted: 04/21/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. The Barcelona Clinic Liver Cancer (BCLC) staging system is regarded as the gold standard staging system for HCC, classifying HCC as early, intermediate, or advanced. For intermediate HCC, trans-catheter arterial chemoembolization (TACE) is recommended as the optimal strategy by the BCLC guideline. This review investigates whether liver resection is better than TACE for intermediate HCC. Based on published studies, we compare the survival benefits and complications of liver resection and TACE for intermediate HCC. We also compare the survival benefits of liver resection in early and intermediate HCC. We find that liver resection can achieve better or at least comparable survival outcomes compared with TACE for intermediate HCC; however, we do not observe a significant difference between liver resection and TACE in terms of safety and morbidity. We conclude that liver resection may improve the short- and long-term survival of carefully selected intermediate HCC patients, and the procedure may be safely performed in the management of intermediate HCC.
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Affiliation(s)
- Peng-Sheng Yi
- Peng-Sheng Yi, Ming Zhang, Ming-Qing Xu, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ming Zhang
- Peng-Sheng Yi, Ming Zhang, Ming-Qing Xu, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ji-Tong Zhao
- Peng-Sheng Yi, Ming Zhang, Ming-Qing Xu, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ming-Qing Xu
- Peng-Sheng Yi, Ming Zhang, Ming-Qing Xu, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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15
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Garancini M, Pinotti E, Nespoli S, Romano F, Gianotti L, Giardini V. Hepatic resection beyond barcelona clinic liver cancer indication: When and how. World J Hepatol 2016; 8:513-519. [PMID: 27099652 PMCID: PMC4832093 DOI: 10.4254/wjh.v8.i11.513] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 02/18/2016] [Accepted: 03/24/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the main common primary tumour of the liver and it is usually associated with cirrhosis. The barcelona clinic liver cancer (BCLC) classification has been approved as guidance for HCC treatment algorithms by the European Association for the Study of Liver and the American Association for the Study of Liver Disease. According to this algorithm, hepatic resection should be performed only in patients with small single tumours of 2-3 cm without signs of portal hypertension (PHT) or hyperbilirubinemia. BCLC classification has been criticised and many studies have shown that multiple tumors and large tumors, as wide as those with macrovascular infiltration and PHT, could benefit from liver resection. Consequently, treatment guidelines should be revised and patients with intermediate/advanced stage HCC, when technically resectable, should receive the opportunity to be treated with radical surgical treatment. Nevertheless, the surgical treatment of HCC on cirrhosis is complex: The goal to be oncologically radical has always to be balanced with the necessity to minimize organ damage. The aim of this review was to analyze when and how liver resection could be indicated beyond BCLC indication. In particular, the role of multidisciplinary approach to assure a proper indication, of the intraoperative ultrasound for intra-operative restaging and resection guidance and of laparoscopy to minimize surgical trauma have been enhanced.
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Affiliation(s)
- Mattia Garancini
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
| | - Enrico Pinotti
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
| | - Stefano Nespoli
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
| | - Fabrizio Romano
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
| | - Luca Gianotti
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
| | - Vittorio Giardini
- Mattia Garancini, Enrico Pinotti, Stefano Nespoli, Fabrizio Romano, Luca Gianotti, Vittorio Giardini, Department of Surgery, Hepatobiliopancreatic Unit, San Gerardo Hospital, University of Milano Bicocca, 20900 Monza, Italy
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16
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Colombo GL, Cammà C, Attili AF, Ganga R, Gaeta GB, Brancaccio G, Franzini JM, Volpe M, Turchetti G. Patterns of treatment and costs of intermediate and advanced hepatocellular carcinoma management in four Italian centers. Ther Clin Risk Manag 2015; 11:1603-12. [PMID: 26527877 PMCID: PMC4621183 DOI: 10.2147/tcrm.s88208] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a severe health condition associated with high hospitalizations and mortality rates, which also imposes a relevant economic burden. PURPOSE The aim of the present survey is to investigate treatment strategies and related costs for HCC in the intermediate and advanced stages of the disease. PATIENTS AND METHODS The survey was conducted in four Italian centers through structured interviews with physicians. Information regarding the stage of disease, treatments performed, and related health care resource consumption was included in the questionnaire. Direct health care cost per patient associated with the most relevant treatments such as sorafenib, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE) was evaluated. RESULTS Between 2013 and 2014, 285 patients with HCC were treated in the four participating centers; of these, 80 were in intermediate stage HCC (Barcelona Clinic Liver Cancer Classification [BCLC] B), and 57 were in the advanced stage of the disease (BCLC C). In intermediate stage HCC, the most frequent first-line treatment was TACE (63%) followed by sorafenib (15%), radiofrequency ablation (14%), and TARE (1.3%). In the advanced stage of HCC, the most frequently used first-line therapy was sorafenib (56%), followed by best supportive care (21%), TACE (18%), and TARE (3.5%). The total costs of treatment per patient amounted to €12,214.54 with sorafenib, €13,418.49 with TACE, and €26,106.08 with TARE. Both in the intermediate and in the advanced stage of the disease, variability in treatment patterns among centers was observed. CONCLUSION The present analysis raises for the first time the awareness of the overall costs incurred by the Italian National Healthcare System for different treatments used in intermediate and advanced HCC. Further investigations would be important to better understand the effective health care resource usage.
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Affiliation(s)
| | - Calogero Cammà
- Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | | | - Roberto Ganga
- Clinical Medicine Division, Ospedale Brotzu, Cagliari, Italy
| | | | | | | | - Marco Volpe
- Business Integration Partners S.p.A., Milan, Italy
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17
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Yamakado K, Hirota S. Sub-classification of intermediate-stage (Barcelona Clinic Liver Cancer stage-B) hepatocellular carcinomas. World J Gastroenterol 2015; 21:10604-10608. [PMID: 26457020 PMCID: PMC4588082 DOI: 10.3748/wjg.v21.i37.10604] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 06/17/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the fifth most common cancer in the world, shows increasing incidence worldwide. Curative treatments such as hepatectomy, liver transplantation, and radiofrequency ablation are applied in only 30%-60% of cases. Most remaining patients receive transarterial chemoembolization (TACE). Patients with intermediate-stage HCCs are regarded as good candidates for TACE. However, the intermediate stage includes non-homogeneous patients. Some movements are underway to stratify patients using prognostic factors to identify patient groups exhibiting greater benefit from TACE than other patient groups. This review describes two substaging systems that subclassify intermediate-stage HCCs and discusses the importance of dividing intermediate-stage patients.
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18
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Tampaki M, Doumba PP, Deutsch M, Koskinas J. Circulating biomarkers of hepatocellular carcinoma response after locoregional treatments: New insights. World J Hepatol 2015; 7:1834-1842. [PMID: 26207165 PMCID: PMC4506941 DOI: 10.4254/wjh.v7.i14.1834] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 06/24/2015] [Accepted: 07/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular cancer is the 5(th) most common cancer in the world and the third cause of death by malignant disease. Locoregional therapies are the most usual treatment of choice for patients with early or intermediate stage of disease. The main diagnostic tools for the detection of recurrence are the radiological techniques such as 4-phase computed tomography or dynamic contrast enhanced magnetic resonance imaging. However, in order to achieve best evaluation of treatment outcome and recurrence rates, there is a great need for the identification of specific and easily measured circulating biomarkers. The aim of this review is to analyze the existing data considering the prognostic significance of changes of serum diagnostic markers such as alpha-fetoprotein, des-gamma-carboxy prothrombin, alpha-fetoprotein-L3, angiogenetic factors (vascular endothelial growth factor, hypoxia inducible factor-1a) and immune parameters before and after radiofrequency ablation or transarterial chemoembolization.
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Affiliation(s)
- Maria Tampaki
- Maria Tampaki, Polyxeni P Doumba, Melanie Deutsch, John Koskinas, Academic Department of Medicine, Medical School of Athens, Hippokration General Hospital, 11527 Athens, Greece
| | - Polyxeni P Doumba
- Maria Tampaki, Polyxeni P Doumba, Melanie Deutsch, John Koskinas, Academic Department of Medicine, Medical School of Athens, Hippokration General Hospital, 11527 Athens, Greece
| | - Melanie Deutsch
- Maria Tampaki, Polyxeni P Doumba, Melanie Deutsch, John Koskinas, Academic Department of Medicine, Medical School of Athens, Hippokration General Hospital, 11527 Athens, Greece
| | - John Koskinas
- Maria Tampaki, Polyxeni P Doumba, Melanie Deutsch, John Koskinas, Academic Department of Medicine, Medical School of Athens, Hippokration General Hospital, 11527 Athens, Greece
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19
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Hepatic Resection Improved the Long-Term Survival of Patients with BCLC Stage B Hepatocellular Carcinoma in Asia: a Systematic Review and Meta-Analysis. J Gastrointest Surg 2015; 19:1271-80. [PMID: 25943910 DOI: 10.1007/s11605-015-2811-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 03/20/2015] [Indexed: 01/31/2023]
Abstract
OBJECTIVE Hepatic resection has been increasingly performed in patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC), but the current evidence supporting its efficacy remains controversial. The aim of this systematic review was to investigate the long-term survival and safety of hepatic resection compared to transarterial chemoembolization (TACE) alone for BCLC stage B HCC. METHODS Eligible trials that compared hepatic resection with TACE alone for intermediate HCC were identified from the Embase, PubMed, Web of Science, and Cochrane databases. The study outcomes included overall survival (OS) rate and treatment-related complication rate. Hazard ratios (HRs) with a 95% confidence interval were used to measure the pooled effect according to a random-effects or fixed-effects model, depending on the heterogeneity among the included studies. The heterogeneity among these trials statistically was evaluated using the χ(2) and I (2) tests. Sensitivity analyses were also performed. RESULTS A total of 9 studies containing 4958 patients were included. The comparison between hepatic resection and TACE revealed a pooled HR for 3-year OS of 0.403 (95% CI 0.364-0.446, p = 0.000; I (2) = 0 %, p = 0.643) and a pooled HR for 5-year OS of 0.433 (95% CI 0.394-0.475, p = 0.000; I (2) = 0%, p = 0.468). An AFP level >400 ng/ml and being HBV-positive were factors significantly correlated with overall survival. For treatment-related complications, the overall odds ratio (OR) for hepatic resection versus TACE was 0.990 (95% CI 0.934-1.049; p = 0.728; I (2) = 64.5%, p = 0.060). CONCLUSION Hepatic resection likely improved overall survival compared with TACE alone in BCLC stage B HCC patients, but did not increase the incidence of treatment-related complications. An AFP level >400 ng/ml and HBV positivity were significantly correlated with poor OS.
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20
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Di Costanzo GG, Tortora R. Intermediate hepatocellular carcinoma: How to choose the best treatment modality? World J Hepatol 2015; 7:1184-1191. [PMID: 26019734 PMCID: PMC4438493 DOI: 10.4254/wjh.v7.i9.1184] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 10/16/2014] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Intermediate stage, or stage B according to Barcelona Clinic Liver Cancer classification, of hepatocellular carcinoma (HCC) comprises a heterogeneous population with different tumor burden and liver function. This heterogeneity is confirmed by the large variability of treatment choice and disease-relate survival. The aim of this review was to highlight the existing evidences regarding this specific topic. In a multidisciplinary evaluation, patients with large (> 5 cm) solitary HCC should be firstly considered for liver resection (LR). When LR is unfeasible, locoregional treatments are evaluable therapeutic options, being transarterial chemoembolization (TACE), the most used procedure. Percutaneous ablation can be an evaluable treatment for large HCC. However, the efficacy of all ablative procedures decrease as tumor size increases over 3 cm. In clinical practice, a combination treatment strategy [TACE or transarterial radioembolization (TARE)-plus percutaneous ablation] is “a priori” preferred in a relevant percentage of these patients. On the other hands, sorafenib is the treatment of choice in patients who are unsuitable to surgery and/or with a contraindication to locoregional treatments. In multifocal HCC, TACE is the first-line treatment. The role of TARE is still undefined. Surgery may have also a role in the treatment of multifocal HCC in selected cases (patients with up to three nodules, multifocal HCC involving 2-3 adjacent liver segments). In some patients with bilobar disease the combination of LR and ablative treatment may be a valuable option. The choice of the best treatment in the patient with intermediate stage HCC should be “patient-tailored” and made by a multidisciplinary team.
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21
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Gomaa AI, Waked I. Recent advances in multidisciplinary management of hepatocellular carcinoma. World J Hepatol 2015; 7:673-87. [PMID: 25866604 PMCID: PMC4388995 DOI: 10.4254/wjh.v7.i4.673] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/17/2014] [Accepted: 01/15/2015] [Indexed: 02/06/2023] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) is increasing, and it is currently the second leading cause of cancer-related death worldwide. Potentially curative treatment options for HCC include resection, transplantation, and percutaneous ablation, whereas palliative treatments include trans-arterial chemoembolization (TACE), radioembolization, and systemic treatments. Due to the diversity of available treatment options and patients' presentations, a multidisciplinary team should decide clinical management of HCC, according to tumor characteristics and stage of liver disease. Potentially curative treatments are suitable for very-early- and early-stage HCC. However, the vast majority of HCC patients are diagnosed in later stages, where the tumor characteristics or progress of liver disease prevent curative interventions. For patients with intermediate-stage HCC, TACE and radioembolization improve survival and are being evaluated in addition to potentially curative therapies or with systemic targeted therapy. There is currently no effective systemic chemotherapy, immunologic, or hormonal therapy for HCC, and sorafenib is the only approved molecular-targeted treatment for advanced HCC. Other targeted agents are under investigation; trials comparing new agents in combination with sorafenib are ongoing. Combinations of systemic targeted therapies with local treatments are being evaluated for further improvements in HCC patient outcomes. This article provides an updated and comprehensive overview of the current standards and trends in the treatment of HCC.
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Affiliation(s)
- Asmaa I Gomaa
- Asmaa I Gomaa, Imam Waked, Hepatology Department, National Liver Institute, Menoufiya University, Shebeen El-Kom 35111, Egypt
| | - Imam Waked
- Asmaa I Gomaa, Imam Waked, Hepatology Department, National Liver Institute, Menoufiya University, Shebeen El-Kom 35111, Egypt
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22
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Zhong JH, Rodríguez AC, Ke Y, Wang YY, Wang L, Li LQ. Hepatic resection as a safe and effective treatment for hepatocellular carcinoma involving a single large tumor, multiple tumors, or macrovascular invasion. Medicine (Baltimore) 2015; 94:e396. [PMID: 25621684 PMCID: PMC4602643 DOI: 10.1097/md.0000000000000396] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/25/2014] [Accepted: 11/26/2014] [Indexed: 01/27/2023] Open
Abstract
This systematic review examined whether the available evidence justifies using hepatic resection (HR) during later stages of hepatocellular carcinoma (HCC), which contravenes treatment guidelines but is current practice at many medical centers.Official guidelines and retrospective studies recommend different roles for HR for patients with large/multinodular HCC or with HCC involving macrovascular invasion (MVI).Several databases were systematically searched for studies examining the safety and efficacy of HR for treating HCC involving a single large tumor (>5 cm) or multiple tumors, or for treating HCC involving MVI.We identified 50 studies involving 14, 808 patients that investigated the use of HR to treat large/multinodular HCC, and 24 studies with 4389 patients that investigated HR to treat HCC with MVI. Median in-hospital mortality for patients with either type of HCC was significantly lower in Asian studies (2.7%) than in non-Asian studies (7.3%, P < 0.001). Median overall survival (OS) was significantly higher for all Asian patients with large/multinodular HCC than for all non-Asian patients at both 1 year (81% vs 65%, P < 0.001) and 5 years (42% vs 32%, P < 0.001). Similar results were obtained for median disease-free survival at 1 year (61% vs 50%, P < 0.001) and 5 years (26% vs 24%, P < 0.001). However, median OS was similar for Asian and non-Asian patients with HCC involving MVI at 1 year (50% vs 52%, P = 0.45) and 5 years (18% vs 14%, P = 0.94). There was an upward trend in 5-year OS in patients with either type of HCC.HR is reasonably safe and effective at treating large/multinodular HCC and HCC with MVI. The available evidence argues for expanding the indications for HR in official treatment guidelines.
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Affiliation(s)
- Jian-Hong Zhong
- From the Department of Hepatobiliary Surgery (J-HZ, ACR, Y-YW, L-QL), Affiliated Tumor Hospital of Guangxi Medical University, Nanning; Department of Research (ACR), Creaducate Enterprises Ltd, Kowloon, Hong Kong; and Department of Hepatobiliary Surgery (YK, LW), The Second Affiliated Hospital of Kunming Medical University, Kunming, PR China
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Xie ZB, Ma L, Wang XB, Bai T, Ye JZ, Zhong JH, Li LQ. Transarterial embolization with or without chemotherapy for advanced hepatocellular carcinoma: a systematic review. Tumour Biol 2014; 35:8451-8459. [PMID: 25038916 DOI: 10.1007/s13277-014-2340-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2014] [Accepted: 07/10/2014] [Indexed: 01/27/2023] Open
Abstract
Transarterial chemoembolization (TACE) and transarterial embolization (TAE) are commonly used as first-line treatment for patients with advanced hepatocellular carcinoma (HCC) and have been shown to improve overall survival (OS). However, there remain concerns regarding whether the benefit of the prolonged survival achieved with TACE is superior to the maximum cytotoxic effect of the associated chemotherapeutics. This systematic review aims to compare the efficiency of TACE and TAE based on randomized controlled trials (RCTs). MEDLINE, EMBASE, the Cochrane library, the Science Citation Index, and the Chinese National Knowledge Infrastructure databases were systematically searched through the end of April 2014. Risk ratios (RRs) and 95 % confidence intervals (CIs) were calculated. Meta-analysis of the RCTs was conducted to estimate the mortality and survival rate between the TACE and TAE groups. The analysis included five RCTs involving 582 patients. For all-cause mortality, TACE did not result in a statistically significant reduced incidence of adverse events than TAE with a pooled RR of 1.21 (95 % CI = 0.74-1.98, P = 0.16). In addition, 6-, 9-, 12-, 24-, and 36-month OS of the TACE group were not significantly higher than that of the TAE group (all P > 0.05). Interestingly, TACE resulted in a significantly higher rate of advanced events. The efficacy of TACE is not superior to TAE in advanced HCC patients. Moreover, TACE was associated with an increased rate of adverse events than TAE. Improved strategies are needed to reduce the risk of post-TACE complications.
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Affiliation(s)
- Zhi-Bo Xie
- Hepatobiliary Surgery Department, Affiliated Tumor Hospital of Guangxi Medical University, He Di Rd. #71, Nanning, 530021, People's Republic of China
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Nasser F, Cavalcante RN, Galastri FL, de Rezende MB, Felga GG, Travassos FB, De Fina B, Affonso BB. Safety and feasibility of same-day discharge of patients with hepatocellular carcinoma treated with transarterial chemoembolization with drug-eluting beads in a liver transplantation program. J Vasc Interv Radiol 2014; 25:1012-7. [PMID: 24704346 DOI: 10.1016/j.jvir.2014.02.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Revised: 02/18/2014] [Accepted: 02/20/2014] [Indexed: 12/12/2022] Open
Abstract
PURPOSE To evaluate the safety and feasibility of same-day discharge of patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization with the use of drug-eluting beads (DEBs) and elucidate the prognostic factors for hospital admission. MATERIALS AND METHODS A total of 266 DEB chemoembolization procedures in 154 consecutive patients listed for liver transplantation or identified for potential HCC downstaging were performed with the outpatient treatment protocol. Endpoints evaluated were admission to the hospital after the procedure for clinical reasons, readmission to the hospital within 1 month of the procedure, and procedure-related morbidity and mortality. In the evaluation of prognostic factors for admission, parameters of patients discharged the same day were compared with those of patients admitted overnight. RESULTS Same-day discharge was feasible in 238 cases (89.5%), and 28 (10.5%) needed overnight admission. The main reason for overnight admission was postprocedural abdominal pain (n = 23; 67.8%). The procedure-related complication rate was 2.6%, and there were no readmissions or deaths during the first 30 days after chemoembolization. Chemoembolization performed for downstaging and the use of more than one vial of embolic agent were associated with an increased need for overnight admission (P = .012 and P = .007, respectively). CONCLUSIONS Same-day discharge of patients with HCC treated with DEB chemoembolization in a liver transplantation program is safe and feasible, with low complication and admission rates. Treatment for HCC downstaging and the use of more than one vial of embolic agent were associated with an increased need for hospital admission.
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Affiliation(s)
- Felipe Nasser
- Department of Interventional Radiology, São Paulo SP 05652-900, Brazil
| | | | | | - Marcelo B de Rezende
- Liver Transplantation, Hospital Israelita Albert Einstein, 627 Albert Einstein St., São Paulo SP 05652-900, Brazil
| | - Guilherme G Felga
- Liver Transplantation, Hospital Israelita Albert Einstein, 627 Albert Einstein St., São Paulo SP 05652-900, Brazil
| | | | - Bruna De Fina
- Department of Interventional Radiology, São Paulo SP 05652-900, Brazil
| | - Breno B Affonso
- Department of Interventional Radiology, São Paulo SP 05652-900, Brazil
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ZHANG LILI, YU SU, DUAN ZHIJUN, WANG QIUMING, TIAN GE, TIAN YAN, ZHAO WEI, WANG HUI, ZHANG CUILING, GUO SHIBIN, LIU QIGUI, HE GAOHONG, BIAN TENGFEI, CHANG JIUYANG, JIN XUE, CUI DONGSHENG. Treatment of liver cancer in mice by the intratumoral injection of an octreotide-based temperature-sensitive gel. Int J Mol Med 2013; 33:117-27. [DOI: 10.3892/ijmm.2013.1542] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Accepted: 08/21/2013] [Indexed: 11/06/2022] Open
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Wang YG, Li L, Liu CH, Hong S, Zhang MJ. Peroxiredoxin 3 is resistant to oxidation-induced apoptosis of Hep-3b cells. Clin Transl Oncol 2013; 16:561-6. [DOI: 10.1007/s12094-013-1117-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Accepted: 09/22/2013] [Indexed: 12/21/2022]
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Cheung F, Wang X, Wang N, Yuen MF, Ziea TC, Tong Y, Wong VT, Feng Y. Chinese Medicines as an Adjuvant Therapy for Unresectable Hepatocellular Carcinoma during Transarterial Chemoembolization: A Meta-Analysis of Randomized Controlled Trials. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2013; 2013:487919. [PMID: 23956773 PMCID: PMC3730382 DOI: 10.1155/2013/487919] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 06/06/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023]
Abstract
Objective. To conduct a comprehensive PRISMA-compliant systematic review and meta-analysis to evaluate the efficacy and safety of Chinese medicines (CMs) as an adjuvant therapy for unresectable HCC during transarterial chemoembolization (TACE). Methods. Main databases were searched up to October 2012 for randomized controlled trials (RCTs) evaluating the effects of CMs plus TACE on unresectable HCC compared with TACE alone. References of relevant reviews and eligible studies were also assessed. Risk ratios with 95% confidence intervals and mean difference were calculated. Heterogeneity and publication bias were examined. Results. Sixty-seven trials (N = 5,211) were included in the meta-analysis. Sensitivity analysis and random-effects model were performed for assessing significant heterogeneity. CMs plus TACE showed beneficial effects on tumor response, survival at 6, 12, 18, 24, and 36 months, quality of life, and TACE toxicity reduction compared with TACE alone. Conclusion. The results show that the use of CMs may increase the efficacy and reduce the toxicity of TACE in treating patients with unresectable HCC. These findings suggest that CMs could be considered as an adjuvant therapy for unresectable HCC patients during TACE. Larger-scale RCTs using standard methods and long-term follow-up are warranted to confirm these findings.
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Affiliation(s)
- Fan Cheung
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Xuanbin Wang
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
- Laboratory of Chinese Herbal Pharmacology, Renmin Hospital and School of Pharmacy, Hubei University of Medicine, Hubei 442000, China
| | - Ning Wang
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong
| | - Tat-chi Ziea
- Chinese Medicine Department, Hospital Authority, Hong Kong
| | - Yao Tong
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Vivian Taam Wong
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Yibin Feng
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong
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Naringenin (citrus flavonone) induces growth inhibition, cell cycle arrest and apoptosis in human hepatocellular carcinoma cells. Pathol Oncol Res 2013; 19:763-70. [PMID: 23661153 DOI: 10.1007/s12253-013-9641-1] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 04/11/2013] [Indexed: 12/22/2022]
Abstract
Search for new substances with antiproliferative activity and apoptosis inducing potential towards HepG2 cells is important since HCC is notoriously resistant to conventional chemotherapy. Dietary phytochemicals with significant anti-proliferative and apoptosis inducing potential are considered as agents promising for cancer therapy. Naringenin, a common dietary flavonoid abundantly present in fruits and vegetables, is believed to possess strong cytotoxic activity in numerous types of cancer cells. However, the detailed molecular mechanisms of its antiproliferative effects and apoptosis induction are still unclear. In this study, we investigated antiproliferative and apoptosis-inducing effect of naringenin in human hepatocellular carcinoma HepG2 cells. Naringenin was shown to inhibit the proliferation of HepG2 cells resulted partly from an accumulation of cells in the G0/G1 and G2/M phase of the cell cycle. Naringenin induced a rapid accumulation of p53, which might account for the naringenin-induced G0/G1 and G2/M phase arrests in Hep G2 cells. In addition, naringenin have been shown to induce apoptosis as evidenced by nuclei damage and increased proportion of apoptotic cells detected by flow cytometry analysis. Naringenin triggered the mitochondrial-mediated apoptosis pathway as shown by an increased ratio of Bax/Bcl-2, subsequent release of cytochrome C, and sequential activation of caspase-3. Our results showed that naringenin had inhibitory effect on the growth of HepG2 cell line through inhibition of cell proliferation and apoptosis induction. The elucidation of the drug targets of naringenin on inhibition of tumor cells growth should enable further development of naringenin for liver cancer therapy.
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Zhou Y, Lu N, Zhang H, Wei L, Tao L, Dai Q, Zhao L, Lin B, Ding Q, Guo Q. HQS-3, a newly synthesized flavonoid, possesses potent anti-tumor effect in vivo and in vitro. Eur J Pharm Sci 2013; 49:649-58. [PMID: 23619285 DOI: 10.1016/j.ejps.2013.04.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 03/22/2013] [Accepted: 04/14/2013] [Indexed: 12/21/2022]
Abstract
HQS-3 is a newly baicalein derivative with a benzene substitution. We investigated the anticancer effect of HQS-3 in vivo and in vitro. HQS-3 significantly decreased tumor growth in mice inoculated with Heps and HepG2 cells; and had little influence on the state and weight of animals. After treatment with 20 mg/kg HQS-3, the inhibitory rate of tumor weight in mice inoculated with Heps and HepG2 cells were 63.62% and 68.03%, respectively. Meanwhile, HQS-3 inhibited the viability of various kinds of tumor cells with IC50 values in the range of 22.98-54.32 μM after 48 h treatment measured by MTT-assay. HQS-3 remarkably inhibited viability of hepatoma cells in a concentration- and time-dependent manner and induced apoptosis in HepG2 cells by DAPI staining and Annexin V/PI double staining. The apoptosis-induction effect of HQS-3 was attributed to its ability to modulate the activity of caspase-9, caspase-3 and PARP. Moreover, the expression of bax protein was increased while the bcl-2 protein was decreased, leading to an increase in Bax/Bcl-2 ratio. The accumulation of ROS induced by HQS-3 in HepG2 cells was also observed. The further results suggested that HQS-3 induced mitochondrial-mediated apoptosis by increasing ROS level and inhibiting the expression of anti-oxidative protein SOD2. HQS-3 exerted anti-tumor activity both in vitro and in vivo via inducing tumor cells apoptosis, and these results suggested that it deserves further investigation as a novel chemotherapy for human tumors.
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Affiliation(s)
- Yuxin Zhou
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
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Dufour JF, Bargellini I, De Maria N, De Simone P, Goulis I, Marinho R. Intermediate hepatocellular carcinoma: current treatments and future perspectives. Ann Oncol 2013; 24 Suppl 2:ii24-9. [DOI: 10.1093/annonc/mdt054] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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31
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Phytochemical, cytotoxic, hepatoprotective and antioxidant properties of Delonix regia leaves extract. Med Chem Res 2013. [DOI: 10.1007/s00044-012-0420-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Knieling F, Waldner MJ, Goertz RS, Strobel D. Quantification of dynamic contrast-enhanced ultrasound in HCC: prediction of response to a new combination therapy of sorafenib and panobinostat in advanced hepatocellular carcinoma. BMJ Case Rep 2012; 2012:bcr-2012-007576. [PMID: 23257272 DOI: 10.1136/bcr-2012-007576] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Here, we report the case of a patient, who showed an antitumour response to a new combination therapy of sorafenib and the histon deacetylase inhibitor panobinostat (LBH-589). D-CEUS (Dynamic contrast-enhanced ultrasonography) was able to predict response to the new therapy regime and may be an interesting tool in the early evaluation of response to therapy. It might be especially useful to differentiate between responders and non-responders of new-targeted pharmaceuticals like multikinase inhibitors in hepatocellular carcinomas.
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies, with an increasing incidence. With advances in surgical techniques and instrumentation and the development of molecular-target drugs, a number of potentially curative treatments have become available. Management of HCC patients depends on the stage of their tumor. Liver resection remains the first choice for very early-stage HCC, but it is being challenged by local ablative therapy. For early-stage HCC that meet the Milan criteria, liver transplantation still offers a better outcome; however, local ablative therapy can be a substitute when transplantation is not feasible. Local ablation is also used as a bridging therapy toward liver transplantation. HCC recurrence is the main obstacle to successful treatment, and there is currently no effective means of preventing or treating HCC recurrence. Transarterial therapy is considered suitable for intermediate-stage HCC, while sorafenib is recommended for advanced-stage HCC. This stage-based approach to therapy not only provides acceptable outcomes but also improves the quality of life of HCC patients. Because of the complexity of HCC, therapeutic approaches must be adapted according to the characteristics of each individual patient. This review discusses the current standards and trends in the treatment of HCC.
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Affiliation(s)
| | | | - Peter Schemmer
- *Deptment of General and Transplant Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, Heidelberg 69120 (Germany), Tel. +49 0 6221 56 6110, E-Mail
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Ozen E, Gozukizil A, Erdal E, Uren A, Bottaro DP, Atabey N. Heparin inhibits Hepatocyte Growth Factor induced motility and invasion of hepatocellular carcinoma cells through early growth response protein 1. PLoS One 2012; 7:e42717. [PMID: 22912725 PMCID: PMC3418296 DOI: 10.1371/journal.pone.0042717] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Accepted: 07/11/2012] [Indexed: 12/16/2022] Open
Abstract
The Hepatocyte Growth Factor (HGF)/c-Met signaling pathway regulates hepatocyte proliferation, and pathway aberrations are implicated in the invasive and metastatic behaviors of hepatocellular carcinoma (HCC). In addition to c-Met, heparin acts as a co-receptor to modulate pathway activity. Recently, anti-metastatic and anti-cancer effects of heparin have been reported. However, the role of heparin in the regulation of HGF signaling remains controversial and the effects of heparin on HGF-induced biological responses during hepatocarcinogenesis is not yet defined. In this study we determined the effects of heparin on HGF-induced activities of HCC cells and the underlying molecular mechanisms. Here, we report for the first time that heparin inhibits HGF-induced adhesion, motility and invasion of HCC cells. In addition, heparin reduced HGF-induced activation of c-Met and MAPK in a dose-dependent manner, as well as decreased transcriptional activation and expression of Early growth response factor 1 (Egr1). HGF-induced MMP-2 and MMP-9 activation, and MT1-MMP expression, also were inhibited by heparin. Stable knockdown of Egr1 caused a significant decrease in HGF-induced invasion, as well as the activation and expression of MMPs. Parallel to these findings, the overexpression of Egr1 increased the invasiveness of HCC cells. Our results suggest that Egr1 activates HGF-induced cell invasion through the regulation of MMPs in HCC cells and heparin inhibits HGF-induced cellular invasion via the downregulation of Egr1. Therefore, heparin treatment might be a therapeutic approach to inhibit invasion and metastasis of HCC, especially for patients with active HGF/c-Met signaling.
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Affiliation(s)
- Evin Ozen
- Department of Medical Biology and Genetics, School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Aysim Gozukizil
- Department of Medical Biology and Genetics, School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Esra Erdal
- Department of Medical Biology and Genetics, School of Medicine, Dokuz Eylul University, Izmir, Turkey
| | - Aykut Uren
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, D.C., United States of America
| | - Donald P. Bottaro
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National, Institutes of Health, Bethesda, Maryland, United States of America
| | - Nese Atabey
- Department of Medical Biology and Genetics, School of Medicine, Dokuz Eylul University, Izmir, Turkey
- * E-mail:
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Nishikawa H, Osaki Y, Inuzuka T, Takeda H, Nakajima J, Matsuda F, Henmi S, Sakamoto A, Ishikawa T, Saito S, Kita R, Kimura T. Branched-chain amino acid treatment before transcatheter arterial chemoembolization for hepatocellular carcinoma. World J Gastroenterol 2012; 18:1379-84. [PMID: 22493552 PMCID: PMC3319965 DOI: 10.3748/wjg.v18.i12.1379] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2011] [Revised: 09/26/2011] [Accepted: 12/31/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the significance of branched-chain amino acid (BCAA) treatment before transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).
METHODS: This study included 99 patients who underwent TACE therapy for HCC at our hospital and were followed up without treatment for at least 6 mo between January 2004 and January 2010. They were divided into 2 groups: those receiving BCAA granules (n = 40) or regular diet (n = 59, control). Data obtained were retrospectively analyzed (prior to TACE, and 1 wk, 1, 3, and 6 mo after TACE) in terms of nutritional condition and clinical laboratory parameters (serum albumin level and Child-Pugh score), both of which are determinants of hepatic functional reserve.
RESULTS: The BCAA group comprised 27 males and 13 females with a mean age of 69.9 ± 8.8 years. The patients of the BCAA group were classified as follows: Child-Pugh A/B/C in 22/15/3 patients, and Stage II/III/IVA HCC in 12/23/5 patients, respectively. The control group comprised 32 males and 27 females with a mean age of 73.2 ± 10.1 years. In the control group, 9 patients had chronic hepatitis, Child-Pugh A/B/C in 39/10/1 patients, and StageI/II/III/IVA HCC in 1/11/35/12 patients, respectively. Overall, both serum albumin level and Child-Pugh score improved significantly in the BCAA group as compared with the control 3 and 6 mo after TACE (P < 0.05). Further analysis was performed by the following categorization: (1) child-Pugh classification; (2) liver cirrhosis subgroup with a serum albumin level > 3.5 g/dL; and (3) epirubicin dose. A similar trend indicating a significant improvement of all variables in the BCAA group was noted (P < 0.05).
CONCLUSION: Treatment with BCAA granules in patients who have undergone TACE for HCC is considered useful to maintain their hepatic functional reserve.
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Minami Y, Kudo M. Review of dynamic contrast-enhanced ultrasound guidance in ablation therapy for hepatocellular carcinoma. World J Gastroenterol 2011; 17:4952-9. [PMID: 22174544 PMCID: PMC3236587 DOI: 10.3748/wjg.v17.i45.4952] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2011] [Revised: 06/09/2011] [Accepted: 06/16/2011] [Indexed: 02/06/2023] Open
Abstract
Local ablative techniques-percutaneous ethanol injection, microwave coagulation therapy and radiofrequency ablation (RFA)-have been developed to treat unresectable hepatocellular carcinoma (HCC). The success rate of percutaneous ablation therapy for HCC depends on correct targeting of the tumor via an imaging technique. However, probe insertion often is not completely accurate for small HCC nodules, which are poorly defined on conventional B-mode ultrasound (US) alone. Thus, multiple sessions of ablation therapy are frequently required in difficult cases. By means of two breakthroughs in US technology, harmonic imaging and the development of second-generation contrast agents, dynamic contrast-enhanced harmonic US imaging with an intravenous contrast agent can depict tumor vascularity sensitively and accurately, and is able to evaluate small hypervascular HCCs even when B-mode US cannot adequately characterize the tumors. Therefore, dynamic contrast-enhanced US can facilitate RFA electrode placement in hypervascular HCC, which is poorly depicted by B-mode US. The use of dynamic contrast-enhanced US guidance in ablation therapy for liver cancer is an efficient approach. Here, we present an overview of the current status of dynamic contrast-enhanced US-guided ablation therapy, and summarize the current indications and outcomes of reported clinical use in comparison with that of other modalities.
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