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Qi Y, Fang Q, Li Q, Ding H, Shu Q, Hu Y, Xin W, Fang L. MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway. J Gastrointest Oncol 2021; 12:1873-1883. [PMID: 34532135 PMCID: PMC8421902 DOI: 10.21037/jgo-21-362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 07/29/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The toll-like receptor (TLR) is an emerging signaling pathway in tumor invasion and metastasis. The activation of TLRs requires specific accessory proteins, such as the small secreted glycoprotein myeloid differentiation protein 2 (MD2), which contributes to ligand responsiveness. However, the role of MD2 in tumorigenesis and metastasis has rarely been reported. This study aimed to investigate the effects and underlying mechanisms of MD2 on the proliferation, migration, and invasion of hepatocellular carcinoma (HCC). METHODS Cell counting kit 8 (CCK8), cell colony formation, wound healing, and transwell assays were conducted to determine cell viability, proliferation, migration, and invasion, respectively. Quantitative real-time PCR (qRT-PCR) was performed to assess the expression of MD2 in HCC cell lines and human normal liver cell lines as well as the silencing efficiency of MD2 blockage. Western blot and qRT-PCR assays were performed to detect the protein and mRNA expression levels of epithelial mesenchymal transformation (EMT) markers and epidermal growth factor receptor (EGFR) signaling molecules. RESULTS MD2 was highly expressed in HCC tissues and cell lines. High expression of MD2 was associated with poor prognosis of HCC patients. In addition, MD2 silencing slightly inhibited the proliferation of HepG2 and HCCLM3, and significantly suppressed cell migration and invasion. Furthermore, MD2 blockage could distinctly prevent the EMT process by increasing the protein and mRNA levels of E-cadherin and Occludin, and decreasing the levels of Vimentin, N-cadherin, and Snail. Finally, the phosphorylation level of EGFR as well as its downstream molecular Src, Akt, I-κBα, and p65 were downregulated in HCC cells with MD2 silencing. CONCLUSIONS Our findings suggest that high expression of MD2 may affect the EMT, migration, and invasion via modulation of the EGFR pathway in HCC cells.
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Affiliation(s)
- Yajun Qi
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Qilu Fang
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Qinglin Li
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Department of Comprehensive Medical Oncology, Key Laboratory of Head and Neck Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
| | - Haiying Ding
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Qi Shu
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Yan Hu
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Wenxiu Xin
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Department of Comprehensive Medical Oncology, Key Laboratory of Head and Neck Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
| | - Luo Fang
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
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Propofol suppresses hepatocellular carcinoma by inhibiting NET1 through downregulating ERK/VEGF signaling pathway. Sci Rep 2020; 10:11208. [PMID: 32641699 PMCID: PMC7343826 DOI: 10.1038/s41598-020-67693-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 06/08/2020] [Indexed: 11/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of tumor death in China with high mortality since its strong metastatic potential. Currently, treatment against advanced HCC is poorly efficient and thus screening new drugs to prevent the HCC invasion is of great significance to improve the survival rate of patients with HCC. From the results of this study, we concluded that propofol, a widely used anesthetics could prevent the proliferation by MTT assay. The scratch wound and invasion assays showed that migratory property and invasiveness in HCC cells SMMC-7721 was inhibited by propofol. This process was probably mediated by NET1 since NET1 overexpression offset the repressive effect of propofol on the invasiveness and migratory ability of SMMC-7721 cells. Furthermore, propofol treatment also reduced p-ERK1/2 and VEGF level by western blot analysis. Similar observation was found when NET1 was silenced. Thus, the results of this study provided valuable clinical therapy potential of propofol against liver cancer. We also disclosed molecular mechanism underlying the regulation of invasion and migration in HCC cells by NET1.
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Santopaolo F, Lenci I, Milana M, Manzia TM, Baiocchi L. Liver transplantation for hepatocellular carcinoma: Where do we stand? World J Gastroenterol 2019; 25:2591-2602. [PMID: 31210712 PMCID: PMC6558441 DOI: 10.3748/wjg.v25.i21.2591] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 04/09/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma represents an important cause of morbidity and mortality worldwide. It is the sixth most common cancer and the fourth leading cause of cancer death. Liver transplantation is a key tool for the treatment of this disease in human therefore hepatocellular carcinoma is increasing as primary indication for grafting. Although liver transplantation represents an outstanding therapy for hepatocellular carcinoma, due to organ shortage, the careful selection and management of patients who may have a major survival benefit after grafting remains a fundamental question. In fact, only some stages of the disease seem amenable of this therapeutic option, stimulating the debate on the appropriate criteria to select candidates. In this review we focused on current criteria to select patients with hepatocellular carcinoma for liver transplantation as well as on the strategies (bridging) to avoid disease progression and exclusion from grafting during the stay on wait list. The treatments used to bring patients within acceptable criteria (down-staging), when their tumor burden exceeds the standard criteria for transplant, are also reported. Finally, we examined tumor reappearance following liver transplantation. This occurrence is estimated to be approximately 8%-20% in different studies. The possible approaches to prevent this outcome after transplant are reported with the corresponding results.
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Affiliation(s)
- Francesco Santopaolo
- Hepatology Unit, Department of Medicine, Policlinico Universitario Tor Vergata, Rome 00133, Italy
| | - Ilaria Lenci
- Hepatology Unit, Department of Medicine, Policlinico Universitario Tor Vergata, Rome 00133, Italy
| | - Martina Milana
- Hepatology Unit, Department of Medicine, Policlinico Universitario Tor Vergata, Rome 00133, Italy
| | - Tommaso Maria Manzia
- Transplant Surgery Unit, Department of Surgery, Policlinico Universitario Tor Vergata, Rome 00133, Italy
| | - Leonardo Baiocchi
- Hepatology Unit, Department of Medicine, Policlinico Universitario Tor Vergata, Rome 00133, Italy
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Coletta M, Nicolini D, Benedetti Cacciaguerra A, Mazzocato S, Rossi R, Vivarelli M. Bridging patients with hepatocellular cancer waiting for liver transplant: all the patients are the same? Transl Gastroenterol Hepatol 2017; 2:78. [PMID: 29034351 PMCID: PMC5639014 DOI: 10.21037/tgh.2017.09.01] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 08/28/2017] [Indexed: 12/13/2022] Open
Abstract
Liver transplant (LT) is considered the best curative treatment for patients with cirrhosis and hepatocellular carcinoma (HCC) within Milan criteria. The possibility to perform LT in HCC patients is limited by the liver grafts supply; indeed, the shortage of donors often leads to a long time on waiting list and then to dropout because of tumor progression. Bridging therapies are neo-adjuvant treatments given to patients on LT waitlist, with the aim to prevent tumor progression and to reduce dropout rate. Many bridging modalities have been proposed. The choice of each treatment is based on the characteristics of the patient, liver function, comorbidities and on the number, dimensions and localization of HCC. This review article describes several types of bridging therapies, focusing on the indications for different kind of patients.
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Affiliation(s)
- Martina Coletta
- Hepato-biliary and Abdominal Transplantation Surgery, Department of Gastroenterology and Transplantation, Polytechnic University of Marche, A.O.U. "Ospedali Riuniti", Ancona, Italy
| | - Daniele Nicolini
- Hepato-biliary and Abdominal Transplantation Surgery, Department of Gastroenterology and Transplantation, Polytechnic University of Marche, A.O.U. "Ospedali Riuniti", Ancona, Italy
| | - Andrea Benedetti Cacciaguerra
- Hepato-biliary and Abdominal Transplantation Surgery, Department of Gastroenterology and Transplantation, Polytechnic University of Marche, A.O.U. "Ospedali Riuniti", Ancona, Italy
| | - Susanna Mazzocato
- Hepato-biliary and Abdominal Transplantation Surgery, Department of Gastroenterology and Transplantation, Polytechnic University of Marche, A.O.U. "Ospedali Riuniti", Ancona, Italy
| | - Roberta Rossi
- Hepato-biliary and Abdominal Transplantation Surgery, Department of Gastroenterology and Transplantation, Polytechnic University of Marche, A.O.U. "Ospedali Riuniti", Ancona, Italy
| | - Marco Vivarelli
- Hepato-biliary and Abdominal Transplantation Surgery, Department of Gastroenterology and Transplantation, Polytechnic University of Marche, A.O.U. "Ospedali Riuniti", Ancona, Italy
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Treatment Options in Patients Awaiting Liver Transplantation with Hepatocellular Carcinoma and Cholangiocarcinoma. Clin Liver Dis 2017; 21:231-251. [PMID: 28364811 DOI: 10.1016/j.cld.2016.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Liver transplantation (LT) provides a good chance of cure for selected patients with hepatocellular carcinoma (HCC) and perihilar cholangiocarcinoma (pCCA). Patients with HCC on a waiting list for LT are at risk for tumor progression and dropout. Treatment of HCC with locoregional therapies may lessen dropout due to tumor progression. Strict selection and adherence to the LT criteria for patients with pCCA before and after neoadjuvant chemotherapy are critical for optimal outcome with LT. This article reviews the existing data for the various treatment strategies used for patients with HCC and pCCA awaiting LT.
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Ou W, Lv J, Zou X, Yao Y, Wu J, Yang J, Wang Z, Ma Y. Propofol inhibits hepatocellular carcinoma growth and invasion through the HMGA2-mediated Wnt/β-catenin pathway. Exp Ther Med 2017; 13:2501-2506. [PMID: 28565871 DOI: 10.3892/etm.2017.4253] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 12/23/2016] [Indexed: 12/11/2022] Open
Abstract
Propofol is a commonly used intravenous anesthetic in tumor surgery. Recently, studies have confirmed that propofol has an antitumor effect on hepatocellular carcinoma (HCC); however, the molecular mechanism underlying this effect has not been elucidated until now. The present study aimed to investigate the mechanism of propofol on HepG2 cell proliferation, apoptosis and invasion, focusing on High Mobility Group AT-Hook 2 (HMGA2)-mediated Wnt/β-catenin pathway. The HepG2 cells were treated with various concentrations of propofol for 24 h, the relative protein levels of HMGA2, Wnt3a, β-catenin, Snail Family Zinc Finger 1 and c-myc were determined by western blot analysis. HMGA2-pcDNA3.1 plasmid was transfected into the HepG2 cells to overexpress HMGA2. Cell proliferation, apoptosis and invasion were examined by MTT assays, flow cytometry and Transwell-matrigel invasion assays, respectively. The results showed that propofol suppressed HMGA2 expression and Wnt/β-catenin signaling in a dose-dependent manner. Propofol was able to inhibit cell proliferation and invasion, and induce cell apoptosis of HepG2 cells; however, these effects were attenuated by HMGA2 overexpression. The suppressed Wnt/β-catenin signaling in HepG2 cells by treatment with propofol was also reversed by HMGA2 overexpression. In conclusion, this study provided a novel mechanism underlying the anti-tumor function of propofol on HCC. To the best of our knowledge, the present study is the first to demonstrate that propofol could downregulate the expression of HMGA2, which inhibited the Wnt/β-catenin pathway, thus leading to the inhibition of cell proliferation and invasion, as well as the apoptosis of HepG2 cells.
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Affiliation(s)
- Wei Ou
- Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guizhou, Guiyang 550001, P.R. China
| | - Jie Lv
- Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guizhou, Guiyang 550001, P.R. China
| | - Xiaohua Zou
- Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guizhou, Guiyang 550001, P.R. China
| | - Yin Yao
- Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guizhou, Guiyang 550001, P.R. China
| | - Jinli Wu
- Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guizhou, Guiyang 550001, P.R. China
| | - Jian Yang
- Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guizhou, Guiyang 550001, P.R. China
| | - Zhumei Wang
- Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guizhou, Guiyang 550001, P.R. China
| | - Yan Ma
- Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guizhou, Guiyang 550001, P.R. China
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Ai DL, Li BT, Peng XM, Zhang LZ, Wang JY, Zhao Y, Yang B, Yu Q, Liu CZ, Yang N, Wang HM, Zhou L. Acquired amegakaryocytic thrombocytopenic purpura induced by percutaneous ethanol injection during treatment of hepatocellular carcinoma: A case report. Oncol Lett 2016; 11:798-800. [PMID: 26870287 DOI: 10.3892/ol.2015.3934] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 10/23/2015] [Indexed: 01/31/2023] Open
Abstract
Percutaneous ethanol injection is an important localized treatment method for patients presenting with hepatocellular carcinoma (HCC). Among the advantages of percutaneous ethanol injection are its minimal invasiveness, simplicity, low cost and low risk of complications. However, the increasing popularity of percutaneous ethanol injection has resulted in serious adverse effects attributed to individual variations. The present study describes the case of a patient who exhibited acquired amegakaryocytic thrombocytopenic purpura, caused by percutaneous ethanol injection treatment for HCC. This complication was promptly identified, and platelet transfusion and injection of recombinant human interleukin-11 resulted in a rapid recovery of the patient's platelet count. Attention should be given to this rare complication in patients administered percutaneous ethanol injection treatment for HCC.
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Affiliation(s)
- Ding-Lun Ai
- Department of Interventional Radiology, Beijing 302nd Hospital, Beijing 100039, P.R. China
| | - Bo-Tao Li
- Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital to the Chinese Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Xiao-Ming Peng
- Department of Interventional Radiology, Beijing 302nd Hospital, Beijing 100039, P.R. China
| | - Lin-Zhi Zhang
- Department of Interventional Radiology, Beijing 302nd Hospital, Beijing 100039, P.R. China
| | - Jing-Yan Wang
- Department of Interventional Radiology, Beijing 302nd Hospital, Beijing 100039, P.R. China
| | - Yun Zhao
- Department of Interventional Radiology, Beijing 302nd Hospital, Beijing 100039, P.R. China
| | - Bin Yang
- Department of Interventional Radiology, Beijing 302nd Hospital, Beijing 100039, P.R. China
| | - Qiang Yu
- Department of Interventional Radiology, Beijing 302nd Hospital, Beijing 100039, P.R. China
| | - Chun-Zi Liu
- Department of Interventional Radiology, Beijing 302nd Hospital, Beijing 100039, P.R. China
| | - Ning Yang
- Department of Clinical Laboratory, Beijing 302nd Hospital, Beijing 100039, P.R. China
| | - Hua-Ming Wang
- Department of Interventional Radiology, Beijing 302nd Hospital, Beijing 100039, P.R. China
| | - Lin Zhou
- Department of Interventional Radiology, Beijing 302nd Hospital, Beijing 100039, P.R. China
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Hackl C, Schlitt HJ, Kirchner GI, Knoppke B, Loss M. Liver transplantation for malignancy: Current treatment strategies and future perspectives. World J Gastroenterol 2014; 20:5331-5344. [PMID: 24833863 PMCID: PMC4017048 DOI: 10.3748/wjg.v20.i18.5331] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 12/31/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
In 1967, Starzl et al performed the first successful liver transplantation for a patient diagnosed with hepatoblastoma. In the following, liver transplantation was considered ideal for complete tumor resection and potential cure from primary hepatic malignancies. Several reports of liver transplantation for primary and metastatic liver cancer however showed disappointing results and the strategy was soon dismissed. In 1996, Mazzaferro et al introduced the Milan criteria, offering liver transplantation to patients diagnosed with limited hepatocellular carcinoma. Since then, liver transplantation for malignant disease is an ongoing subject of preclinical and clinical research. In this context, several aspects must be considered: (1) Given the shortage of deceased-donor organs, long-term overall and disease free survival should be comparable with results obtained in patients transplanted for non-malignant disease; (2) In this regard, living-donor liver transplantation may in selected patients help to solve the ethical dilemma of optimal individual patient treatment vs organ allocation justice; and (3) Ongoing research focusing on perioperative therapy and anti-proliferative immunosuppressive regimens may further reduce tumor recurrence in patients transplanted for malignant disease and thus improve overall survival. The present review gives an overview of current indications and future perspectives of liver transplantation for malignant disease.
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Watanabe S, Morishita A, Deguchi A, Nakai S, Sakamoto T, Fujita K, Maeda E, Nomura T, Tani J, Miyoshi H, Yoneyama H, Fujiwara S, Kobara H, Mori H, Himoto T, Masaki T. Ethanol injection therapy for small hepatocellular carcinomas located beneath a large vessel using a curved percutaneous ethanol injection therapy needle. Oncol Lett 2014; 7:1831-1834. [PMID: 24932242 PMCID: PMC4049773 DOI: 10.3892/ol.2014.2053] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Accepted: 03/14/2014] [Indexed: 11/16/2022] Open
Abstract
Percutaneous ethanol injection therapy (PEIT) has been administered as a safe therapeutic modality for patients with small hepatocellular carcinoma (HCC). Due to the nature of the straight approaching line of a PEIT or radiofrequency ablation needle, penetrating the vessels that are interposed between the dermal insertion point and the nodule is unavoidable. A device with an overcoat needle and coaxial curved PEIT needle was created that facilitated a detour around interposing large vessels in order to avoid unnecessary harmful effects that result from the PEIT procedure. Two cases of HCC located adjacent to a neighboring large vessel were treated with a curved PEIT needle. The curved PEIT needle, which is connected to an outer needle, enabled deviation around the interposing vessels and successful connection with the HCC. Careful use of the curved line of the PEIT needle enabled the safe and successful performance of the PEIT without any requirement for specific training. This hand-assisted technique may be an applicable treatment for small HCC located beneath large vessels as a direct therapeutic method using ultrasound guidance.
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Affiliation(s)
- Seishiro Watanabe
- Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa 760-8557, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Akihiro Deguchi
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Seiji Nakai
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Emiko Maeda
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Hisaaki Miyoshi
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Shintaro Fujiwara
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Hirohito Mori
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Takashi Himoto
- Department of Integrated Medicine, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Miki-cho, Kida-gun, Kagawa 761-0793, Japan
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Pompili M, Francica G, Ponziani FR, Iezzi R, Avolio AW. Bridging and downstaging treatments for hepatocellular carcinoma in patients on the waiting list for liver transplantation. World J Gastroenterol 2013; 19:7515-7530. [PMID: 24282343 PMCID: PMC3837250 DOI: 10.3748/wjg.v19.i43.7515] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 09/30/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023] Open
Abstract
Several therapeutic procedures have been proposed as bridging treatments for patients with hepatocellular carcinoma (HCC) awaiting liver transplantation (LT). The most used treatments include transarterial chemoembolization and radiofrequency ablation. Surgical resection has also been successfully used as a bridging procedure, and LT should be considered a rescue treatment in patients with previous HCC resection who experience tumor recurrence or post-treatment severe decompensation of liver function. The aims of bridging treatments include decreasing the waiting list dropout rate before transplantation, reducing HCC recurrence after transplantation, and improving post-transplant overall survival. To date, no data from prospective randomized studies are available; however, for HCC patients listed for LT within the Milan criteria, prolonging the waiting time over 6-12 mo is a risk factor for tumor spread. Bridging treatments are useful in containing tumor progression and decreasing dropout. Furthermore, the response to pre-LT treatments may represent a surrogate marker of tumor biological aggressiveness and could therefore be evaluated to prioritize HCC candidates for LT. Lastly, although a definitive conclusion can not be reached, the experiences reported to date suggest a positive impact of these treatments on both tumor recurrence and post-transplant patient survival. Advanced HCC may be downstaged to achieve and maintain the current conventional criteria for inclusion in the waiting list for LT. Recent studies have demonstrated that successfully downstaged patients can achieve a 5-year survival rate comparable to that of patients meeting the conventional criteria without requiring downstaging.
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Fortune BE, Umman V, Gilliland T, Emre S. Liver transplantation for hepatocellular carcinoma: a surgical perspective. J Clin Gastroenterol 2013; 47 Suppl:S37-S42. [PMID: 23632344 DOI: 10.1097/mcg.0b013e318286ff8e] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality in the world. Early detection and timely treatment of HCC is critical for better patient outcomes. Curative therapy consists of surgical hepatic resection or liver transplantation (LTx); however, both are restricted to explicit selective criteria. Liver resection is the gold standard of treatment for noncirrhotic patients but can be done in only a small fraction of cirrhotic patients depending on synthetic dysfunction, degree of portal hypertension, and number and location(s) of tumor(s). Therefore, the best treatment modality in cirrhotic patients with HCC is LTx as it will cure both HCC and the underlying cirrhosis. The limitation to offer transplant to all cirrhotic patients with HCC is the shortage of available donor organs. While these patients are waiting for transplant, their tumors may progress and develop distant metastases and may lead to patients losing their candidacy for LTx. Various ablation therapies can be used to treat HCC, prevent tumor progression, and thus, avoid patients losing the option of LTx. Future directions to improve HCC patient outcomes include advancement in tumor gene analysis and histopathology for better prediction of tumor behavior, improved immunosuppression regimens to reduce tumor recurrence in the posttransplant setting, and efficient use of an expanded donor pool that includes living donor organs. This paper will review the current methods of HCC diagnosis, selection for either hepatic resection or LTx, and will also summarize posttreatment outcomes. We will suggest future directions for the field as we strive to improve outcomes for our HCC patients.
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Affiliation(s)
- Brett E Fortune
- Department of Medicine, Division of Digestive Disease, Yale School of Medicine, New Haven, CT 06520, USA
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Percutaneous laser ablation of hepatocellular carcinoma in patients with liver cirrhosis awaiting liver transplantation. Eur J Radiol 2009; 74:e6-e11. [PMID: 19345541 DOI: 10.1016/j.ejrad.2009.03.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2008] [Revised: 01/30/2009] [Accepted: 03/06/2009] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The aim of this study was to determine the effectiveness and safety of percutaneous laser ablation for the treatment of cirrhotic patients with hepatocellular carcinoma awaiting liver transplantation. MATERIALS AND METHODS The data of 9 male cirrhotic patients (mean age 50 years, range 45-60 years) with 12 biopsy proven nodules of hepatocellular carcinoma (mean diameter 2.0 cm, range 1.0-3.0 cm) treated by laser ablation before liver transplantation between June 2000 and January 2006 were retrospectively reviewed. Laser ablation was carried out by inserting 300 nm optical fibers through 21-Gauge needles (from two to four) positioned under ultrasound guidance into the target lesions. A continuous wave Neodymium:Yttrium Aluminium Garnet laser was used. Transarterial chemoembolization prior to liver transplantation was performed in two incompletely ablated tumors. RESULTS No procedure-related major complications were recorded. During the waiting time to liver transplantation local tumor progression after ablation occurred in 3 nodules (25%). At histological examination of the explanted livers complete necrosis was found in 8 nodules (66.7%, all treated exclusively with laser ablation), partial necrosis >50% in 3 nodules (25%), and partial necrosis <50% in 1 nodule. CONCLUSION In patients with cirrhotic livers awaiting liver transplantation, percutaneous laser ablation is safe and effective for the management of small hepatocellular carcinoma.
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Abstract
Liver transplantation (LT) is the treatment of choice for many patients with unresectable hepatocellular carcinoma (HCC), but long waiting time due to the shortage of donor organs can result in tumor progression and drop-out from LT candidacy. Furthermore, even in candidates meeting the restrictive Milan criteria there is risk of HCC recurrence; this risk rises significantly when patients with more advanced HCC are included. In an effort to address these issues, treatment of HCC in patients awaiting LT has become widespread practice. In this review the various modalities employed in the pre-LT setting are presented, and the evidence for benefit with regard to (1) improvement of post-LT survival, (2) down-staging of advanced HCC to within Milan criteria and (3) preventing waiting list drop-out is considered. Chemoembolization, radiofrequency ablation and ethanol injection all have well-documented antitumor activity; however, there is no high level evidence that waiting list HCC treatment with these modalities is effective in achieving any of the three above-mentioned aims. Nevertheless, particularly in the United States, where continued waiting list priority depends on maintaining HCC within Milan criteria, use of nonsurgical HCC treatment will likely continue in an effort to forestall tumor progression and waiting list drop-out.
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Affiliation(s)
- M Schwartz
- Mount Sinai Medical Center, Surgery/Transplant, New York, NY, USA.
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14
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Stigliano R, Marelli L, Yu D, Davies N, Patch D, Burroughs AK. Seeding following percutaneous diagnostic and therapeutic approaches for hepatocellular carcinoma. What is the risk and the outcome? Seeding risk for percutaneous approach of HCC. Cancer Treat Rev 2007; 33:437-47. [PMID: 17512669 DOI: 10.1016/j.ctrv.2007.04.001] [Citation(s) in RCA: 211] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2006] [Revised: 03/30/2007] [Accepted: 04/03/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND Tumour biopsy is usually considered mandatory for patient management by oncologists. Currently percutaneous ablation is used therapeutically for cirrhotic patients with small hepatocellular carcinoma (HCC), not suitable for resection or waiting for liver transplantation. However malignant seeding is a recognized complication of both diagnostic and therapeutic procedures in patients with HCC. Although percutaneous therapy whether with or without biopsy of a suspected HCC nodule may minimize the risk of seeding, this has not been confirmed. AIM To evaluate the risk of seeding, defined as new neoplastic disease occurring outside the liver capsule, either in the subcutaneous tissue or peritoneal cavity following needle biopsy and/or local ablation therapy (LAT). METHODS A literature search resulted in 179 events in 99 articles between January 1983 and February 2007: 66 seedings followed liver biopsy, 26 percutaneous ethanol injection (PEI), 1 microwave, 22 radiofrequency ablation (RFA), and 64 after combined biopsy and percutaneous treatment (5 microwave; 33 PEI; 26 RFA). RESULTS In 41 papers specifying the total number of patients biopsied and/or treated, the median risk of seeding was 2.29% (range 0-11%) for biopsy group; 1.4% (1.15-1.85%) for PEI when used with biopsy and 0.61% (0-5.56%) for RFA without biopsy, 0.95% (0-12.5%) for RFA with biopsy and 0.72% (0-10%) for liver nodules (including non-HCC nodules) biopsied and ablated. CONCLUSION Risk of seeding with HCC is substantial and appears greater with using diagnostic biopsy alone compared to therapeutic percutaneous procedures. This risk is particularly relevant for patients being considered for liver transplantation.
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Affiliation(s)
- R Stigliano
- Liver Transplantation and Hepatobiliary Medicine Unit, Royal Free Hospital, Pond Street, NW3 2QG London, UK.
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15
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Dharancy S, Boitard J, Decaens T, Sergent G, Boleslawski E, Duvoux C, Vanlemmens C, Meyer C, Gugenheim J, Durand F, Boillot O, Declerck N, Louvet A, Canva V, Romano O, Ernst O, Mathurin P, Pruvot FR. Comparison of two techniques of transarterial chemoembolization before liver transplantation for hepatocellular carcinoma: a case-control study. Liver Transpl 2007; 13:665-71. [PMID: 17427172 DOI: 10.1002/lt.21109] [Citation(s) in RCA: 27] [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
Supraselective transarterial chemoembolization (STACE) more efficiently targets chemotherapy delivered via the feeding arterial branches of the tumor than does conventional transarterial chemoembolization (TACE). However, the hypothesis of its greater efficacy compared with the latter is subject to controversy. The aim of the present study was to compare STACE to conventional TACE in a controlled study of candidates for liver transplantation (LT) for hepatocellular carcinoma (HCC). Patients were matched for factors associated with HCC recurrence and survival. Sixty patients were included: 30 who were treated with STACE and 30 treated with conventional TACE. The 2 groups were similar in terms of matched criteria. In the overall population (uni- and multinodular HCC), there was no marked difference between the 2 groups in 5-year disease-free survival: 76.8% vs. 74.8%. In sensitivity analysis of patients considered to be the best candidates for TACE (uninodular HCC < or =5 cm), there was a trend toward significance between STACE and TACE in 5-year disease-free survival: 87% vs. 64% (P = 0.09). The only factor associated with complete tumor necrosis was STACE in the overall population (30.8% vs. 6.9%, P = 0.02), with a similar trend in the subgroup of patients with a single nodule (33.3% vs. 6.7%, P = 0.06), whereas the mean number of procedures was similar in the 2 groups (mean, 1.3 procedures; range 1-5 procedures; P = NS). STACE is more efficient at inducing complete tumor necrosis in the liver. This study observed trends toward improvement in the disease-free survival of patients with uninodular HCC < or =5 cm. Future studies focusing on such patients are warranted.
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Affiliation(s)
- Sébastien Dharancy
- Service des Maladies de l'Appareil Digestif et de la Nutrition, Hôpital Huriez, CHU Lille, France.
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16
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Laser Literature Watch. Photomed Laser Surg 2006; 24:222-48. [PMID: 16706704 DOI: 10.1089/pho.2006.24.222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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