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1
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Intraoperative fluorescence imaging with indocyanine green in hepatic resection for malignancy: a systematic review and meta-analysis of diagnostic test accuracy studies. Surg Endosc 2020; 34:2891-2903. [PMID: 32266547 DOI: 10.1007/s00464-020-07543-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 04/01/2020] [Indexed: 01/27/2023]
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2
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Liu Z, Peng Q, Li Y, Gao Y. Resveratrol enhances cisplatin-induced apoptosis in human hepatoma cells via glutamine metabolism inhibition. BMB Rep 2018. [PMID: 30103844 PMCID: PMC6177506 DOI: 10.5483/bmbrep.2018.51.9.114] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Cisplatin is one of the most effective chemotherapeutic drugs used in the treatment of HCC, but many patients will ultimately relapse with cisplatin-resistant disease. Used in combination with cisplatin, resveratrol has synergistic effect of increasing chemosensitivity of cisplatin in various cancer cells. However, the mechanisms of resveratrol enhancing cisplatin-induced toxicity have not been well characterized. Our study showed that resveratrol enhances cisplatin toxicity in human hepatoma cells via an apoptosis-dependent mechanism. Further studies reveal that resveratrol decreases the absorption of glutamine and glutathione content by reducing the expression of glutamine transporter ASCT2. Flow cytometric analyses demonstrate that resveratrol and cisplatin combined treatment leads to a significant increase in ROS production compared to resveratrol or cisplatin treated hepatoma cells alone. Phosphorylated H2AX (γH2AX) foci assay demonstrate that both resveratrol and cisplatin treatment result in a significant increase of γH2AX foci in hepatoma cells, and the resveratrol and cisplatin combined treatment results in much more γH2AX foci formation than either resveratrol or cisplatin treatment alone. Furthermore, our studies show that over-expression of ASCT2 can attenuate cisplatin-induced ROS production, γH2AX foci formation and apoptosis in human hepatoma cells. Collectively, our studies suggest resveratrol may sensitize human hepatoma cells to cisplatin chemotherapy via glutamine metabolism inhibition.
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Affiliation(s)
- Zhaoyuan Liu
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Qing Peng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Yang Li
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province; State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou 510515, China
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3
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Zhao T, Jia H, Cheng Q, Xiao Y, Li M, Ren W, Li C, Feng Y, Feng Z, Wang H, Zheng J. Nifuroxazide prompts antitumor immune response of TCL-loaded DC in mice with orthotopically-implanted hepatocarcinoma. Oncol Rep 2017; 37:3405-3414. [PMID: 28498414 DOI: 10.3892/or.2017.5629] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Accepted: 04/13/2017] [Indexed: 01/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis and high mortality. At present, vaccination with tumor cell lysate (TCL) loaded dendritic cells (DC) has been shown to be an effective therapy against HCC. However, the ability of promoting the specific T cell immune response is rather weak, influencing the antitumor response. Thus, it is necessary to find a strategy to improve the antitumor effect of TCL-loaded DC. Activation of signal transducer and activator of transcription 3 (STAT3) significantly inhibits antitumor immune response and DC maturity. Nifuroxazide, an antidiarrheal agent, has been proved to directly inhibit STAT3 activation. Thus, we investigated whether nifuroxazide could improve the antitumor immune response in mice vaccinated with TCL-loaded DC. The study provides the theoretical and experimental basis for developing an effective adjuvant for DC vaccine to treat HCC. Our results showed that the administration of nifuroxazide and DC-loaded TCL could significantly improve the survival rate, inhibit the tumor growth, and prompt the antitumor immune responses in mice with orthotopically implanted hepatocarcinomas, thus, possibly providing a new combination strategy to treat HCC.
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Affiliation(s)
- Tiesuo Zhao
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Huijie Jia
- Department of Pathology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Qian Cheng
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China
| | - Yali Xiao
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Minming Li
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Wenjing Ren
- Department of Dermatology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Chen Li
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Yuchen Feng
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Zhiwei Feng
- Department of Immunology, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Hui Wang
- Research Center for Immunology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Junnian Zheng
- Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou, Jiangsu 221002, P.R. China
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4
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Fidelman N, Kerlan RK, Hawkins RA, Pampaloni M, Taylor AG, Kohi MP, Kolli KP, Atreya CE, Bergsland EK, Kelley RK, Ko AH, Korn WM, Van Loon K, McWhirter RM, Luan J, Johanson C, Venook AP. Radioembolization with 90Y glass microspheres for the treatment of unresectable metastatic liver disease from chemotherapy-refractory gastrointestinal cancers: final report of a prospective pilot study. J Gastrointest Oncol 2016; 7:860-874. [PMID: 28078110 DOI: 10.21037/jgo.2016.08.04] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND This prospective pilot single-institution study was undertaken to document the feasibility, safety, and efficacy of radioembolization of liver-dominant metastatic gastrointestinal cancer using 90Y glass microspheres. METHODS Between June 2010 and October 2013, 42 adult patients (26 men, 16 women; median age 60 years) with metastatic chemotherapy-refractory unresectable colorectal (n=21), neuroendocrine (n=11), intrahepatic bile duct (n=7), pancreas (n=2), and esophageal (n=1) carcinomas underwent 60 lobar or segmental administrations of 90Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for up to 5.5 years after radioembolization. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Time to maximum response, response duration, progression-free survival (PFS) (hepatic and extrahepatic), and overall survival (OS) were measured. RESULTS Median target dose and activity were 109.4 Gy and 2.6 GBq per treatment session, respectively. Majority of clinical AE were grade 1 or 2 in severity. Patients with colorectal cancer had hepatic objective response rate (ORR) of 25% and a hepatic disease control rate (DCR) of 80%. Median PFS and OS were 1.0 and 4.4 months, respectively. Patients with neuroendocrine tumors (NET) had hepatic ORR and DCR of 73% and 100%, respectively. Median PFS was 8.9 months for this cohort. DCR and median PFS and OS for patients with cholangiocarcinoma were 86%, 1.1 months, and 6.7 months, respectively. CONCLUSIONS 90Y glass microspheres device has a favorable safety profile, and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort.
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Affiliation(s)
- Nicholas Fidelman
- Department of Radiology, University of California San Francisco, San Francisco, CA, USA
| | - Robert K Kerlan
- Department of Radiology, University of California San Francisco, San Francisco, CA, USA
| | - Randall A Hawkins
- Department of Radiology, University of California San Francisco, San Francisco, CA, USA
| | - Miguel Pampaloni
- Department of Radiology, University of California San Francisco, San Francisco, CA, USA
| | - Andrew G Taylor
- Department of Radiology, University of California San Francisco, San Francisco, CA, USA
| | - Maureen P Kohi
- Department of Radiology, University of California San Francisco, San Francisco, CA, USA
| | - K Pallav Kolli
- Department of Radiology, University of California San Francisco, San Francisco, CA, USA
| | - Chloe E Atreya
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Emily K Bergsland
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - R Kate Kelley
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Andrew H Ko
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - W Michael Korn
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Katherine Van Loon
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Ryan M McWhirter
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Jennifer Luan
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Curt Johanson
- Department of Radiology, University of California San Francisco, San Francisco, CA, USA
| | - Alan P Venook
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
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5
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Hsieh TC, Wu YC, Sun SS, Yen KY, Kao CH. Treating hepatocellular carcinoma with 90Y-bearing microspheres: a review. Biomedicine (Taipei) 2016; 6:19. [PMID: 27848114 PMCID: PMC5138159 DOI: 10.7603/s40681-016-0019-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 08/06/2016] [Indexed: 12/21/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a disease usually diagnosed in its advanced-stage, and is frequently not amenable to curative surgical treatment. Also, HCC is resistant to chemotherapy and less vulnerable to radiation therapy compared to normal hepatic parenchyma. Both of these facts render the efficacy of adjuvant and palliative treatments problematic. Selective internal radiation therapy (SIRT) with 90Y-bearing microspheres is characterized by preferentially delivering substantially high doses of radiation to a liver tumor dose simultaneously limiting the damage to its non-tumorous cells, providing an opportunity for effective local tumor control and even tumor regression therapy. The current article reviews the specific characters, dosimetry, possible applications, and special considerations toward the pre-existing radiation therapy of 90Y microsphere SIRT in treating HCC.
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Affiliation(s)
- Te-Chun Hsieh
- Department of Nuclear Medicine and PET Center, China Medical University Hospital, No. 2, Yuh-Der Rd., North Dist., Taichung, 404, Taiwan.,Department of Biomedical Imaging and Radiological Science, China Medical University, 404, Taichung, Taiwan
| | - Yu-Chin Wu
- Department of Nuclear Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu Branch, No. 25, Ln. 442. Sec. 1, Jingguo Rd., East Dist.,, Hsinchu City, 300, Taiwan.
| | - Shung-Shung Sun
- Department of Nuclear Medicine and PET Center, China Medical University Hospital, No. 2, Yuh-Der Rd., North Dist., Taichung, 404, Taiwan.,Department of Biomedical Imaging and Radiological Science, China Medical University, 404, Taichung, Taiwan
| | - Kuo-Yang Yen
- Department of Nuclear Medicine and PET Center, China Medical University Hospital, No. 2, Yuh-Der Rd., North Dist., Taichung, 404, Taiwan.,Department of Biomedical Imaging and Radiological Science, China Medical University, 404, Taichung, Taiwan
| | - Chia-Hung Kao
- Department of Nuclear Medicine and PET Center, China Medical University Hospital, No. 2, Yuh-Der Rd., North Dist., Taichung, 404, Taiwan. .,School of Medicine, China Medical University, 404, Taichung, Taiwan.
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Elevated Lung Shunt Fraction as a Prognostic Indicator for Disease Progression and Metastasis in Hepatocellular Carcinoma. J Vasc Interv Radiol 2016; 27:804-11. [DOI: 10.1016/j.jvir.2016.01.129] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 12/29/2015] [Accepted: 01/06/2016] [Indexed: 11/15/2022] Open
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7
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Yu G, Li H, Yang S, Wen J, Niu J, Zu Y. ssDNA Aptamer Specifically Targets and Selectively Delivers Cytotoxic Drug Doxorubicin to HepG2 Cells. PLoS One 2016; 11:e0147674. [PMID: 26808385 PMCID: PMC4726709 DOI: 10.1371/journal.pone.0147674] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 01/06/2016] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of death due to cancer worldwide with over 500,000 people affected annually. Although chemotherapy has been widely used to treat patients with HCC, alternate modalities to specifically deliver therapeutic cargos to cancer cells have been sought in recent years due to the severe side effects of chemotherapy. In this respect, aptamer-based tumor targeted drug delivery has emerged as a promising approach to increase the efficacy of chemotherapy and reduce or eliminate drug toxicity. In this study, we developed a new HepG2-specific aptamer (HCA#3) by a procedure known as systematic evolution of ligands by exponential enrichment (SELEX) and exploited its role as a targeting ligand to deliver doxorubicin (Dox) to HepG2 cells in vitro. The selected 76-base nucleotide aptamer preferentially bound to HepG2 hepatocellular carcinoma cells but not to control cells. The aptamer HCA#3 was modified with paired CG repeats at the 5′-end to carry and deliver a high payload of intercalated Dox molecules at the CG sites. Four Dox molecules (mol/mol) were fully intercalated in each conjugate aptamer-Dox (ApDC) molecule. Biostability analysis showed that the ApDC molecules are stable in serum. Functional analysis showed that ApDC specifically targeted and released Dox within HepG2 cells but not in control cells, and treatment with HCA#3 ApDC induced HepG2 cell apoptosis but had minimal effect on control cells. Our study demonstrated that HCA#3 ApDC is a promising aptamer-targeted therapeutic that can specifically deliver and release a high doxorubicin payload in HCC cells.
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Affiliation(s)
- Ge Yu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin Province, China
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, United States of America
| | - Huan Li
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, United States of America
- Xiangya Hospital of Central South University, Changsha, China
| | - Shuanghui Yang
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, United States of America
- Xiangya Hospital of Central South University, Changsha, China
| | - Jianguo Wen
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, United States of America
- * E-mail: (JW); (JN); (YZ)
| | - Junqi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin Province, China
- * E-mail: (JW); (JN); (YZ)
| | - Youli Zu
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, United States of America
- * E-mail: (JW); (JN); (YZ)
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8
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Nguyen QV, Lym JS, Huynh CT, Kim BS, Jae HJ, Kim YI, Lee DS. A novel sulfamethazine-based pH-sensitive copolymer for injectable radiopaque embolic hydrogels with potential application in hepatocellular carcinoma therapy. Polym Chem 2016. [DOI: 10.1039/c6py01141a] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
After transcatheter delivery through hepatic artery, a hydrogel can be formed within tumor vasculature by the decrease of environmental pH, block the blood vessel and control the release of loaded anticancer drugs.
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Affiliation(s)
- Quang Vinh Nguyen
- Theranostic Macromolecules Research Center and School of Chemical Engineering
- Sungkyunkwan University
- Suwon
- Korea
| | - Jae Seung Lym
- Theranostic Macromolecules Research Center and School of Chemical Engineering
- Sungkyunkwan University
- Suwon
- Korea
| | - Cong Truc Huynh
- Theranostic Macromolecules Research Center and School of Chemical Engineering
- Sungkyunkwan University
- Suwon
- Korea
- Department of Biomedical Engineering
| | - Bong Sup Kim
- Theranostic Macromolecules Research Center and School of Chemical Engineering
- Sungkyunkwan University
- Suwon
- Korea
| | - Hwan Jun Jae
- Department of Radiology
- Seoul National University Hospital
- Seoul
- Korea
| | - Young Il Kim
- Department of Radiology
- Seoul National University Hospital
- Seoul
- Korea
- Department of Radiology
| | - Doo Sung Lee
- Theranostic Macromolecules Research Center and School of Chemical Engineering
- Sungkyunkwan University
- Suwon
- Korea
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9
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CT Appearance of Hepatocellular Carcinoma after Locoregional Treatments: A Comprehensive Review. Gastroenterol Res Pract 2015; 2015:670965. [PMID: 26798332 PMCID: PMC4700180 DOI: 10.1155/2015/670965] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 09/09/2015] [Accepted: 09/14/2015] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major health problem worldwide, affecting more than 600,000 new patients per year. Curative treatments are available in a small percentage of patients, while most of them present in stages requiring locoregional treatments such as thermoablation, transarterial chemoembolization, and/or radioembolization. These therapies
result in specific imaging features that the general radiologist has to be aware of in order to assess the response to treatment and to correctly manage the follow-up of treated patients. Multiphasic helical computed tomography has become a popular imaging modality for detecting hypervascular tumors and characterizing liver lesions. On this basis, many staging and diagnostic systems have been proposed for evaluating response to all different existing strategies. Radiofrequencies and microwaves generate thermoablation of tumors, and transarterial chemoembolization exploits the double effect of the locoregional administration of drugs and embolizing particles. Eventually radioembolization uses a beta-emitting isotope to induce necrosis. Therefore, the aim of this comprehensive review is to analyze and compare CT imaging appearance of HCC after various locoregional treatments, with regard to specific indications for all possible procedures.
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10
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Waller LP, Deshpande V, Pyrsopoulos N. Hepatocellular carcinoma: A comprehensive review. World J Hepatol 2015; 7:2648-2663. [PMID: 26609342 PMCID: PMC4651909 DOI: 10.4254/wjh.v7.i26.2648] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 05/19/2015] [Accepted: 10/14/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is rapidly becoming one of the most prevalent cancers worldwide. With a rising rate, it is a prominent source of mortality. Patients with advanced fibrosis, predominantly cirrhosis and hepatitis B are predisposed to developing HCC. Individuals with chronic hepatitis B and C infections are most commonly afflicted. Different therapeutic options, including liver resection, transplantation, systemic and local therapy, must be tailored to each patient. Liver transplantation offers leading results to achieve a cure. The Milan criteria is acknowledged as the model to classify the individuals that meet requirements to undergo transplantation. Mean survival remains suboptimal because of long waiting times and limited donor organ resources. Recent debates involve expansion of these criteria to create options for patients with HCC to increase overall survival.
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Affiliation(s)
- Lisa P Waller
- Lisa P Waller, Vrushak Deshpande, Nikolaos Pyrsopoulos, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Vrushak Deshpande
- Lisa P Waller, Vrushak Deshpande, Nikolaos Pyrsopoulos, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Lisa P Waller, Vrushak Deshpande, Nikolaos Pyrsopoulos, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
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12
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Welte S, Urbanik T, Elßner C, Kautz N, Koehler BC, Waldburger N, Bermejo JL, Pinna F, Weiss KH, Schemmer P, Jaeger D, Longerich T, Breuhahn K, Schulze-Bergkamen H. Nuclear expression of the deubiquitinase CYLD is associated with improved survival in human hepatocellular carcinoma. PLoS One 2014; 9:e110591. [PMID: 25329885 PMCID: PMC4199737 DOI: 10.1371/journal.pone.0110591] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 09/19/2014] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND & AIMS The deubiquitinase CYLD removes (K-63)-linked polyubiquitin chains from proteins involved in NF-κB, Wnt/ß-catenin and Bcl-3 signaling. Reduced CYLD expression has been reported in different tumor entities, including hepatocellular carcinoma (HCC). Furthermore, loss of CYLD has been shown to contribute to HCC development in knockout animal models. This study aimed to assess subcellular CYLD expression in tumor tissues and its prognostic significance in HCC patients undergoing liver resection or liver transplantation. METHODS Subcellular localization of CYLD was assessed by immunohistochemistry in tumor tissues of 95 HCC patients undergoing liver resection or transplantation. Positive nuclear CYLD staining was defined as an immunohistochemical (IHC) score ≥ 3. Positive cytoplasmic CYLD staining was defined as an IHC score ≥ 6. The relationship with clinicopathological parameters was investigated. Cell culture experiments were performed to analyze subcellular CYLD expression in vitro. RESULTS Cytoplasmic CYLD expression was observed in 57 out of 95 (60%) HCC specimens (cyt°CYLD+). Nuclear CYLD staining was positive in 52 out of 95 specimens (55%, nucCYLD+). 13 out of 52 nucCYLD+ patients (25%) showed a lack of cytoplasmic CYLD expression. nucCYLD+ was associated with prolonged overall survival in patients after resection or liver transplantation (P = 0.007). 5-year overall survival rates were 63% in nucCYLD+ vs. 26% in nucCYLD- patients. Nuclear CYLD staining strongly correlated with tumor grading (P<0.001) and Ki67 positivity (P = 0.005). nucCYLD+ did not prove to be an independent prognostic parameter. In vitro, Huh7, Hep3B and HepG2 showed reduced CYLD levels compared to the non-malignant liver cell line THLE-2. Induction of CYLD expression by doxorubicin treatment led to increased cytoplasmic and nuclear expression of CYLD. CONCLUSIONS Expression of nuclear CYLD is a novel prognostic factor for improved survival in patients with HCC undergoing liver resection or transplantation.
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Affiliation(s)
- Stefan Welte
- National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany
| | - Toni Urbanik
- National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany
| | - Christin Elßner
- National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany
| | - Nicole Kautz
- National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany
| | - Bruno Christian Koehler
- National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany
| | - Nina Waldburger
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Justo Lorenzo Bermejo
- Institute of Medical Biometry and Informatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Federico Pinna
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Karl-Heinz Weiss
- Department of Gastroenterology, Toxicology, and Infectious Diseases, Heidelberg University Hospital, Internal Medicine IV, Heidelberg, Germany
| | - Peter Schemmer
- Department of General and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Dirk Jaeger
- National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Longerich
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Kai Breuhahn
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Henning Schulze-Bergkamen
- National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany
- Department of Gastroenterology, Diabetology and Rheumatology, Internal Medicine II, Marien-Hospital, Wesel, Germany
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13
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Méndez-Sánchez N, Ridruejo E, Alves de Mattos A, Chávez-Tapia NC, Zapata R, Paraná R, Mastai R, Strauss E, Guevara-Casallas LG, Daruich J, Gadano A, Parise ER, Uribe M, Aguilar-Olivos NE, Dagher L, Ferraz-Neto BH, Valdés-Sánchez M, Sánchez-Avila JF. Latin American Association for the Study of the Liver (LAASL) clinical practice guidelines: management of hepatocellular carcinoma. Ann Hepatol 2014; 13 Suppl 1:S4-S40. [PMID: 24998696 DOI: 10.1016/s1665-2681(19)30919-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer death, and accounts for 5.6% of all cancers. Nearly 82% of the approximately 550,000 liver cancer deaths each year occur in Asia. In some regions, cancer-related death from HCC is second only to lung cancer. The incidence and mortality of HCC are increasing in America countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Clinical care and survival for patients with HCC has advanced considerably during the last two decades, thanks to improvements in patient stratification, an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and the introduction of novel therapies and strategies in prevention. Nevertheless, HCC remains the third most common cause of cancer-related deaths worldwide. These LAASL recommendations on treatment of hepatocellular carcinoma are intended to assist physicians and other healthcare providers, as well as patients and other interested individuals, in the clinical decision-making process by describing the optimal management of patients with liver cancer.
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Affiliation(s)
| | - Ezequiel Ridruejo
- Hepatology Section, Department of Medicine. Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno "CEMIC". Ciudad Autónoma de Buenos Aires, Argentina; Hepatology and Liver Transplant Unit. Hospital Universitario Austral, Pilar, Argentina
| | | | | | - Rodrigo Zapata
- Hepatology and Liver Transplantation Unit. University of Chile School of Medicine, German Clinic. Santiago, Chile
| | - Raymundo Paraná
- Associate Professor of School of Medicine - Federal University of Bahia Head of the Gastro-Hepatologist Unit of the University Bahia University Hospital
| | - Ricardo Mastai
- Transplantation Unit. German Hospital.Buenos Aires, Argentina
| | - Edna Strauss
- Clinical hepatologist of Hospital do Coraçao - São Paulo - Brazil. Professor of the Post Graduate Course in the Department of Pathology at the School of Medicine, University of São Paulo
| | | | - Jorge Daruich
- Hepatology Department, Clinical Hospital San Martín. University of Buenos Aires Buenos Aires, Argentina
| | - Adrian Gadano
- Section of Hepatology, Italian Hospital of Buenos Aires. Buenos Aires, Argentina
| | - Edison Roberto Parise
- Professor Associado da Disciplina de Gastroenterologia da Universidade Federal de São Paulo, Presidente Eleito da Sociedade Brasileira de Hepatologia
| | - Misael Uribe
- Digestive Diseases and Obesity Clinic, Medica Sur Clinic Foundation. México City, Mexico
| | - Nancy E Aguilar-Olivos
- Digestive Diseases and Obesity Clinic, Medica Sur Clinic Foundation. México City, Mexico
| | - Lucy Dagher
- Consultant Hepatologist. Metropolitan Policlinic- Caracas- Venezuela
| | - Ben-Hur Ferraz-Neto
- Director of Liver Institute - Beneficencia Portuguesa de São Paulo. Chief of Liver Transplantation Team
| | - Martha Valdés-Sánchez
- Department of Pediatric Oncology National Medical Center "Siglo XXI". Mexico City, Mexico
| | - Juan F Sánchez-Avila
- Hepatology and Liver Transplantation Department National Institute of Nutrition and Medical Sciences "Salvador Zubirán" Mexico City, Mexico
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14
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Bester L, Meteling B, Boshell D, Saxena A, Morris DL. Current role of transarterial chemoembolization and radioembolization in the treatment of metastatic colorectal cancer. Hepat Oncol 2014; 1:215-228. [PMID: 30190956 DOI: 10.2217/hep.13.21] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
In this article, we review two liver-directed therapies that are currently used for the palliative treatment of primary and secondary hepatic malignancies, transcatheter arterial chemoembolization (TACE), including a new type of TACE with drug-eluting beads, and radioembolization. Important developments and administration techniques for all therapies are discussed, as well as their integration into the current routine clinical care for management of metastatic colorectal cancer. According to published data from clinical trials, as presented in this review, both radioembolization and TACE/TACE with drug-eluting beads have been proven to be safe and effective in selected patients with chemorefractory liver metastases from colorectal cancer. For patients with unresectable liver-only or liver-dominant disease who have failed standard chemotherapy options or for whom chemotherapy is contraindicated, new modalities, such as those discussed, are particularly valid and promising if clinical guidelines for patient selection and treatment administration are followed.
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Affiliation(s)
- Lourens Bester
- Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.,Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia
| | - Baerbel Meteling
- Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.,Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia
| | - David Boshell
- Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.,Department of Interventional Radiology, University of New South Wales, St. Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia
| | - Akshat Saxena
- Department of Surgery, University of New South Wales, St. George Hospital, Kogarah, New South Wales 2217, Australia.,Department of Surgery, University of New South Wales, St. George Hospital, Kogarah, New South Wales 2217, Australia
| | - David L Morris
- Department of Surgery, University of New South Wales, St. George Hospital, Kogarah, New South Wales 2217, Australia.,Department of Surgery, University of New South Wales, St. George Hospital, Kogarah, New South Wales 2217, Australia
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15
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Bester L, Meteling B, Boshell D, Chua TC, Morris DL. Transarterial chemoembolisation and radioembolisation for the treatment of primary liver cancer and secondary liver cancer: A review of the literature. J Med Imaging Radiat Oncol 2014; 58:341-52. [PMID: 24589204 DOI: 10.1111/1754-9485.12163] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 12/23/2013] [Indexed: 02/06/2023]
Affiliation(s)
- Lourens Bester
- Department of Interventional Radiology; St Vincent's Hospital; University of New South Wales; Sydney New South Wales Australia
| | - Baerbel Meteling
- Department of Interventional Radiology; St Vincent's Hospital; University of New South Wales; Sydney New South Wales Australia
| | - David Boshell
- Department of Interventional Radiology; St Vincent's Hospital; University of New South Wales; Sydney New South Wales Australia
| | - Terence C. Chua
- Department of Surgery; St George Hospital; University of New South Wales; Sydney New South Wales Australia
| | - David L. Morris
- Department of Surgery; St George Hospital; University of New South Wales; Sydney New South Wales Australia
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16
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90Y Glass Microspheres for the Treatment of Unresectable Metastatic Liver Disease from Chemotherapy-Refractory Gastrointestinal Cancers: A Pilot Study. J Gastrointest Cancer 2014; 45:168-80. [DOI: 10.1007/s12029-013-9566-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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17
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Imaging Assessment of Hepatocellular Carcinoma Response to Locoregional and Systemic Therapy. AJR Am J Roentgenol 2013; 201:80-96. [DOI: 10.2214/ajr.13.10706] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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18
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Wang Z, Li X, Chen J, Shi H, Pan J, Zhang X, Jin Z. Safety and effectiveness of repeat arterial closure using the StarClose vascular closure device in patients with hepatic malignancy. Clin Radiol 2013; 68:e498-501. [PMID: 23706825 DOI: 10.1016/j.crad.2013.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2012] [Revised: 03/31/2013] [Accepted: 04/05/2013] [Indexed: 11/30/2022]
Abstract
AIM To evaluate the safety and effectiveness of the use of the StarClose vascular closure device for repeat arterial closure in patients with hepatic malignancy undergoing transarterial chemoembolization (TACE). MATERIALS AND METHODS A retrospective analysis of patients with hepatic malignancy who had undergone arterial closure with the StarClose device was performed in Peking Union Medical College Hospital between January 2009 and March 2012. A total of 165 patients (94 men, 71 women; mean age 60.1 ± 17.2 years) had arterial puncture closure after TACE (using a 5 F sheath). Percutaneous closure of the common femoral artery with the StarClose device was performed in accordance with the manufacturer's recommendations. The patients were examined for complications on follow-up. Device success was defined as haemostasis achieved immediately after StarClose device deployment with or without applying 3 min or less of manual compression. All the patients were evaluated clinically for wound complications and follow-up angiograms of the puncture site were obtained at subsequent TACE sessions. RESULTS There were a total of 593 closures using StarClose devices in 165 patients who underwent TACE, including 194 (32.7%) single closures and 399 (67.3%) repeat closures for the same femoral access. The number of repeat closures for the same femoral access ranged from one to nine (median 2). Haemostasis was achieved in 571 closures, and success rate was 96.3% (96.9% in single closures and 96% in repeat closures). There was no statistically different haemostasis success rate between single closures or repeat closures. No severe complications occurred during follow-up. CONCLUSION The repeat use of the StarClose device is safe and effective in patients with hepatic malignancy undergoing TACE.
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Affiliation(s)
- Z Wang
- Department of Radiology, Peking Union Medical College Hospital, Beijing, China
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19
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Willatt JM, Francis IR, Novelli PM, Vellody R, Pandya A, Krishnamurthy VN. Interventional therapies for hepatocellular carcinoma. Cancer Imaging 2012; 12:79-88. [PMID: 22487698 PMCID: PMC3335329 DOI: 10.1102/1470-7330.2012.0011] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma is the third most common cause of cancer-related death. In the past few years, staging systems have been developed that enable patients to be stratified into treatment algorithms in a multidisciplinary setting. Several of these treatments involve minimally invasive image-guided therapy that can be performed by radiologists.
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Affiliation(s)
- Jonathon M Willatt
- University of Michigan, 1500 E Medical Center Drive, Ann Arbor, MI 48109, USA.
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20
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Allegretta M, Filmus J. Therapeutic potential of targeting glypican-3 in hepatocellular carcinoma. Anticancer Agents Med Chem 2011; 11:543-8. [PMID: 21554204 DOI: 10.2174/187152011796011109] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Accepted: 04/29/2011] [Indexed: 02/08/2023]
Abstract
Glypican-3 (GPC3) is a developmentally-regulated oncofetal protein that has been established as a clinically-relevant biomarker for early hepatocellular carcinoma (HCC). It is one of the first transcripts to appear during malignant hepatocyte transformation, and is expressed at the protein level in approximately half of high-grade dysplastic macronodules in cirrhotic liver. Several studies show it is expressed in most (75 to 100%) of HCCs confirmed by histopathology. The protein is anchored to the hepatocyte membrane by a glycosyl-phosphatidylinositol (GPI) anchor and shows consistent membrane immunostaining pattern, making it a viable target for immunotherapeutic approaches. Targeting GPC3 for therapeutic intervention is a promising approach for the clinical management of HCC and selected other tumors that express the marker.
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21
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Nambotin SB, Wands JR, Kim M. Points of therapeutic intervention along the Wnt signaling pathway in hepatocellular carcinoma. Anticancer Agents Med Chem 2011; 11:549-59. [PMID: 21554202 DOI: 10.2174/187152011796011019] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2011] [Accepted: 04/29/2011] [Indexed: 12/29/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. However, there is little known about targeted therapeutics for the treatment of this devastating tumor. Among the growth factor signaling cascades deregulated in HCC, evidences suggest that the WNT/Frizzled-mediated signaling pathway plays a key role in the hepatic carcinogenesis. Aberrant activation of the signaling in HCC is mostly due to deregulated expression of the Wnt/β-catenin signaling components. This leads to the activation of the β-catenin/TCF dependent target genes, which controls cell proliferation, cell cycle, apoptosis or motility. It has been shown that disruption of the Wnt/β-catenin signaling cascade displayed anti-cancer properties in HCC. Currently, no therapeutic molecules targeting the WNT pathway are available or under clinical evaluation for the treatment of HCC. This review will discuss the identified potential molecular targets related to the canonical WNT signaling pathway and their potential therapeutic usefulness.
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Affiliation(s)
- Sarah B Nambotin
- Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
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Abstract
Transcatheter arterial chemoembolization (TACE) is one of the most commonly performed procedures in interventional radiology and is currently used for the palliative treatment of primary and metastatic hepatic malignancies. A new type of TACE is TACE with drug-eluting microspheres, which is currently gaining wide acceptance worldwide. In this article, we will review some technical components, patient selection, current results, and future directions of TACE and TACE with drug-eluting microspheres for primary and metastatic liver cancer.
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Schwarz RE, Abou-Alfa GK, Geschwind JF, Krishnan S, Salem R, Venook AP. Nonoperative therapies for combined modality treatment of hepatocellular cancer: expert consensus statement. HPB (Oxford) 2010; 12:313-20. [PMID: 20590905 PMCID: PMC2951818 DOI: 10.1111/j.1477-2574.2010.00183.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Although surgical resection and liver transplantation are the only treatment modalities that enable prolonged survival in patients with hepatocellular carcinoma (HCC), the majority of HCC patients presents with advanced disease and do not undergo resective or ablative therapy. Transarterial chemoembolization (TACE) is indicated in intermediate/advanced stage unresectable HCC even in the setting of portal vein involvement (excluding main portal vein). Sorafenib has been shown to improve survival of patients with advanced HCC in two controlled randomized trials. Yttrium 90 is a safe microembolization treatment that can be used as an alternative to TACE in patients with advanced liver only disease or in case of portal vein thrombosis. External beam radiation can be helpful to provide local control in selected unresectable HCC. These different treatment modalities may be combined in the treatment strategy of HCC and also used as a bridge to resection or liver transplantation. Patients should undergo formal multidisciplinary evaluation prior to initiating any such treatment in order to individualize the best available options.
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Affiliation(s)
| | - Ghassan K Abou-Alfa
- Department of Medical Oncology, Memorial – Sloan Kettering Cancer CenterNew York, NY
| | - Jeffrey F Geschwind
- Department of Interventional Radiology, The Johns Hopkins University School of MedicineBaltimore, MD
| | - Sunil Krishnan
- Department of Radiation Oncology, MD Anderson Cancer CenterHouston, TX
| | - Riad Salem
- Department of Interventional Oncology, Department of Radiology, Northwestern Memorial HospitalChicago, IL
| | - Alan P Venook
- Division of Medical Oncology, University of CaliforniaSan Francisco, CA, USA
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24
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Liapi E, Geschwind JFH. Intra-arterial therapies for hepatocellular carcinoma: where do we stand? Ann Surg Oncol 2010; 17:1234-46. [PMID: 20405328 DOI: 10.1245/s10434-010-0977-4] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2009] [Indexed: 12/27/2022]
Abstract
PURPOSE AND DESIGN Intra-arterial therapies for unresectable hepatocellular carcinoma (HCC) consist of a catheter-based group of treatments where therapeutic and/or embolic agents are intra-arterially directed to target tumors. Here we review these therapies, which may be classified into embolotherapy/chemotherapy-based and radiotherapy-based treatments. Embolotherapy/chemotherapy-based treatments include transcatheter arterial embolization, transarterial chemoembolization, transcatheter arterial chemoeinfusion, and chemoembolization with drug-eluting beads. Radiotherapy-based treatments include radioembolization with yttrium-90 and injection of iodine-131-labeled lipiodol. RESULTS AND CONCLUSION Interpretation of the results of clinical trials as well as implementation of meta-analyses involving the efficacy of intra-arterial therapies for unresectable HCC has been challenging and difficult to perform. The levels of evidence for treatment recommendations in oncology provide a common framework to understand the current status of intra-arterial therapies for HCC. Here we use an evidence-based approach to critically review and comprehend the current role and future potential of intra-arterial therapies in unresectable HCC.
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Affiliation(s)
- Eleni Liapi
- The Russell H Morgan Department of Radiology and Radiological Science, Division of Vascular and Interventional Radiology, The Johns Hopkins Hospital, Baltimore, MD, USA
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25
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Ong LC, Song IC, Jin Y, Kee IHC, Siew E, Yu S, Thng CH, Huynh H, Chow PKH. Effective inhibition of xenografts of hepatocellular carcinoma (HepG2) by rapamycin and bevacizumab in an intrahepatic model. Mol Imaging Biol 2009; 11:334-42. [PMID: 19330383 PMCID: PMC2719751 DOI: 10.1007/s11307-009-0213-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2008] [Revised: 09/17/2008] [Accepted: 10/24/2008] [Indexed: 02/08/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) displays a characteristic hypervascularity and depends on angiogenesis for tumor growth, which thus provides a potential target for therapeutic approaches to HCC. In this study, through the use of combined micro-positron emission tomography (PET)/computed tomography (CT), we investigate if such a combined targeting of vascular endothelial growth factor (VEGF) activity and expression might retard HCC growth in an orthotopic intrahepatic xenograft model. PROCEDURES Xenograft models were created by intraportal vein injection of HepG2 cell suspensions in severe combined immunodeficient mice. The mice were then treated with (1) rapamycin (RAPA), a mammalian target of rapamycin pathway inhibitor; (2) bevazicumab (BEV), a VEGF monoclonal antibody; and (3) a RAPA/BEV combination. RESULTS Assessment of HCC progression using CT with Omnipaque and PET with 2-deoxy-2-(F-18)-fluoro-D: -glucose showed that mice treated with RAPA/BEV had the lowest standardized uptake values (SUVs). At week 2, mice treated with RAPA/BEV, RAPA, and BEV all showed a marked decrease in the SUV(max) readings with the greatest drop being observed in the RAPA/BEV group (1.33 + 0.26, 1.81 + 0.2, 2.05 + 0.4 vs. vehicle control 2.11 + 0.53). CONCLUSIONS Our results, supported by micro-PET/CT, suggest that RAPA/BEV represents a potential novel antiangiogenic therapy for the treatment of HCC.
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Affiliation(s)
- Lai-Chun Ong
- Singapore General Hospital, Outram Road, Singapore, 169608, Singapore
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26
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Abstract
Selective internal radiation therapy involves the intra-arterial delivery of radioactive beads to the tumor while minimizing dosing to the adjacent organ. Because this technique invariably results in some degree of embolization, it has also been termed radioembolization. More than 8000 patients have been treated worldwide, with a large body of experience with primary hepatocellular carcinoma (HCC) and metastatic colorectal carcinoma (MCRC) and growing experience with other tumors (metastatic neuroendocrine, breast carcinoma, cholangiocarcinoma). Response rates by FDG-PET are 80% to 90%. Complications are uncommon and most often consist of self-limited malaise. More significant complications, including radiation-induced liver disease, ischemic cholecystitis, and gastrointestinal ulceration may be seen in up to 10% of patients. This underscores the critical importance of patient selection and meticulous technique. Median survival times in patients who have HCC and MCRC are significantly improved compared with historic controls. Further study is required to determine the appropriate role of radioembolization in the context of state-of-the-art chemotherapy and other liver-directed therapies.
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Affiliation(s)
- Gregory J Dubel
- Department of Diagnostic Imaging, Warren Alpert School of Medicine Brown University, Division of Interventional Radiology, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA.
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27
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Thabet A, Kalva S, Gervais DA. Percutaneous image-guided therapy of intra-abdominal malignancy: imaging evaluation of treatment response. ACTA ACUST UNITED AC 2008; 34:593-609. [DOI: 10.1007/s00261-008-9448-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Reid T. Fighting Fire With Fire: Effects of Oncolytic Virotherapy on Underlying Viral Hepatitis in Hepatocellular Carcinoma. Mol Ther 2008; 16:1521-3. [DOI: 10.1038/mt.2008.176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
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Liapi E, Georgiades CC, Hong K, Geschwind JFH. Transcatheter arterial chemoembolization: current technique and future promise. Tech Vasc Interv Radiol 2008; 10:2-11. [PMID: 17980314 DOI: 10.1053/j.tvir.2007.08.008] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Transarterial chemoembolization is the mainstay of catheter based interventional oncologic therapies. This article describes the history of the procedure, selection of appropriate candidates, technical aspects of procedure performance, results, complications, and appropriate follow-up. In addition, the limitations and challenges of the procedure are outlined. Finally, the reader is introduced to novel and promising techniques and devices that hold future promise for transarterial therapy of malignancies.
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Affiliation(s)
- Eleni Liapi
- Russell H. Morgan Department of Radiology and Radiological Science, Division of Cardiovascular and Interventional Radiology, The Johns Hopkins Hospital, Baltimore, MD 21287, USA
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30
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Kalva SP, Thabet A, Wicky S. Recent advances in transarterial therapy of primary and secondary liver malignancies. Radiographics 2008; 28:101-17. [PMID: 18203933 DOI: 10.1148/rg.281075115] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The management of liver malignancies presents many challenges. Few patients with primary hepatocellular carcinoma or metastatic disease of the liver are eligible for surgery, which is the only curative therapeutic option. Because the hepatic tumor burden is often a determinant of eligibility for surgery and is a primary contributor to morbidity and mortality, an increasing number of innovative techniques based on the transarterial administration of liver-directed drug-eluting or radiation-emitting microspheres are being tested for use in cytoreductive and palliative therapy. The delivery of therapy via a transarterial route takes advantage of the fact that hepatic malignancies are primarily supplied by the hepatic artery. The early results of clinical trials are promising; the clinical effectiveness and safety of drug-eluting and yttrium-90-bearing microspheres have been demonstrated; however, further clinical investigation is needed to verify a benefit in survival. Transarterially administered gene therapy holds promise but is still in the early stages of investigation. For all transarterial therapies, the outcome depends heavily on meticulous patient selection, careful preparation and administration of therapy, and early and regular follow-up evaluations by using an interdisciplinary approach.
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Affiliation(s)
- Sanjeeva P Kalva
- Division of Cardiovascular Intervention, Department of Radiology, Massachusetts General Hospital, Gray 2, 55 Fruit St, GRB-290, Boston, MA 02114, USA.
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31
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Semela D, Piguet AC, Kolev M, Schmitter K, Hlushchuk R, Djonov V, Stoupis C, Dufour JF. Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. J Hepatol 2007; 46:840-8. [PMID: 17321636 DOI: 10.1016/j.jhep.2006.11.021] [Citation(s) in RCA: 167] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2006] [Revised: 09/26/2006] [Accepted: 11/02/2006] [Indexed: 12/11/2022]
Abstract
BACKGROUND/AIMS Hepatocellular carcinoma (HCC) is amenable to only few treatments. Inhibitors of the kinase mTOR are a new class of immunosuppressors already in use after liver transplantation. Their antiproliferative and antiangiogenic properties suggest that these drugs could be considered to treat HCC. We investigated the antitumoral effects of mTOR inhibition in a HCC model. METHODS Hepatoma cells were implanted into livers of syngeneic rats. Animals were treated with the mTOR inhibitor sirolimus for 4 weeks. Tumor growth was monitored by MR imaging. Antiangiogenic effects were assessed in vivo by microvessel density and corrosion casts and in vitro by cell proliferation, tube formation and aortic ring assays. RESULTS Treated rats had significantly longer survival and developed smaller tumors, fewer extrahepatic metastases and less ascites than controls. Sirolimus decreased intratumoral microvessel density resulting in extensive necrosis. Endothelial cell proliferation was inhibited at lower drug concentrations than hepatoma cells. Tube formation and vascular sprouting of aortic rings were significantly impaired by mTOR inhibition. Casts revealed that in tumors treated with sirolimus vascular sprouting was absent, whereas intussusception was observed. CONCLUSIONS mTOR inhibition significantly reduces HCC growth and improves survival primarily via antiangiogenic effects. Inhibitors of mTOR may have a role in HCC treatment.
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MESH Headings
- Angiogenesis Inhibitors/pharmacology
- Animals
- Antibiotics, Antineoplastic/pharmacology
- Capillaries/drug effects
- Carcinoma, Hepatocellular/blood supply
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/enzymology
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Enzyme Inhibitors/pharmacology
- Liver Neoplasms, Experimental/blood supply
- Liver Neoplasms, Experimental/drug therapy
- Liver Neoplasms, Experimental/enzymology
- Neoplasm Transplantation
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/enzymology
- Phosphorylation/drug effects
- Protein Kinases/drug effects
- Protein Kinases/metabolism
- Rats
- Regional Blood Flow/drug effects
- Sirolimus/pharmacology
- TOR Serine-Threonine Kinases
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Affiliation(s)
- David Semela
- Institute of Clinical Pharmacology, University of Berne, Murtenstrasse 35, CH-3010 Berne, Switzerland
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Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-of-the-art brachytherapy treatment for primary and secondary liver malignancies. Part 1: Technical and methodologic considerations. J Vasc Interv Radiol 2006; 17:1251-78. [PMID: 16923973 DOI: 10.1097/01.rvi.0000233785.75257.9a] [Citation(s) in RCA: 491] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Microsphere and particle technology represent the next-generation agents that have formed the basis of interventional oncology, an evolving subspecialty of interventional radiology. One of these platforms, yttrium-90 microspheres, is rapidly being adopted in the medical community as an adjunctive therapeutic tool in the management of primary and secondary liver malignancies. Given the complexity of the treatment algorithm of patients who may be candidates for this therapy and the need for clinical guidance, a comprehensive review of the methodologic and technical considerations was undertaken. This experience is based on more than 900 (90)Y infusions performed over a 5-year period.
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Affiliation(s)
- Riad Salem
- Department of Radiology, Robert H. Lurie Comprehensive Cancer, 676 North St Clair, Suite 800, Chicago, Illinois 60611, USA.
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33
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Liver transplantation for hepatocellular carcinoma in children. Curr Opin Organ Transplant 2006. [DOI: 10.1097/01.mot.0000244644.70222.80] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Cerwenka H, Bacher H, Mischinger HJ. Primary hepatoma – guidelines for interdisciplinary treatment. Eur Surg 2006; 38:94-99. [DOI: 10.1007/s10353-006-0227-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Shu X, McCulloch M, Xiao H, Broffman M, Gao J. Chinese herbal medicine and chemotherapy in the treatment of hepatocellular carcinoma: a meta-analysis of randomized controlled trials. Integr Cancer Ther 2006; 4:219-29. [PMID: 16113029 DOI: 10.1177/1534735405279927] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC), one of the most common malignancies worldwide, is highly resistant to standard therapy. It is unclear whether chemotherapy, arterial embolization, or arterial chemoembolization improve survival advantage enough to justify their high toxicity. Treatment with Chinese herbal medicine has been explored, combining herbs that stimulate host immune response with those that have cytotoxic activity against HCC cells. The authors sought to evaluate the effectiveness of Chinese herbal medicine combined with chemotherapy. The hypothesis was that Chinese herbal medicine added to chemotherapy for the treatment of HCC would improve survival and tumor response, when compared to treatment with chemotherapy alone. METHODS The authors searched the databases TCMLARS, PubMed, and EMBASE as well as the bibliographies of studies identified in the systematic search for potentially relevant titles or abstracts of studies in any language. They retained those that (1) treated only HCC patients, (2) were described as randomized or reported that there was no statistical difference between treatment groups, (3) gave patients either Chinese herbal medicine therapy combined with chemotherapy in the treatment group or chemotherapy alone in the control group, and (4) provided data on the number of enrolled subjects and responders and nonresponders for tumor response and survival. The authors used random effects meta-analysis to combine data. RESULTS Twenty-six studies representing 2079 patients met the inclusion criteria. Chinese herbal medicine combined with chemotherapy, compared to chemotherapy alone, improved survival at 12 months (relative risk [RR], 1.55; 95% confidence interval [CI], 1.39-1.72; P < .000), 24 months (RR, 2.15; 95% CI, 1.75-2.64; P < .000), and 36 months (RR, 2.76; 95% CI, 1.95-3.91; P < .000). Tumor response increased (RR, 1.39; 95% CI, 1.24-1.56; P < .000). CONCLUSIONS These findings provide promising evidence that combining Chinese herbal medicine with chemotherapy may benefit patients with HCC. Because of the low quality of these studies, these findings should be confirmed through conducting high-quality, rigorously controlled trials.
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Affiliation(s)
- Xiaojuan Shu
- Pine Street Foundation, San Anselmo, CA 94960, USA
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Abstract
BACKGROUND Surgical resection is the best established treatment known to provide long-term survival and possibility of cure for liver malignancy. Intraoperative blood loss has been the major concern during major liver resections, and mortality and morbidity of surgery are clearly associated with the amount of blood loss. Different techniques have been developed to minimize intraoperative blood loss during liver resection. The radiofrequency ablation (RFA) technique has been used widely in the treatment of unresectable liver tumors. This review concentrates on the use of RFA to provide an avascular liver resection plane. METHODS AND RESULTS The following review is based on two types of RFA device during liver resection: single needle probe RFA and the In-Line RFA device. CONCLUSION Liver resection assisted by RFA is safe and is associated with very limited blood loss.
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Affiliation(s)
- Peng Yao
- University of New South Wales, Department of Surgery, St George HospitalSydneyAustralia
| | - David L. Morris
- University of New South Wales, Department of Surgery, St George HospitalSydneyAustralia
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