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Tomino T, Itoh S, Okamoto D, Yoshiya S, Nagao Y, Harada N, Fujita N, Ushijima Y, Ishigami K, Yoshizumi T. Impact of portal-phase signal intensity of dynamic gadoxetic acid-enhanced magnetic resonance imaging in hepatocellular carcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2023; 30:1089-1097. [PMID: 37548316 DOI: 10.1002/jhbp.1345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 03/25/2023] [Accepted: 03/31/2023] [Indexed: 08/08/2023]
Abstract
PURPOSE To evaluate the prognostic impact of dynamic gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) in patients with hepatocellular carcinoma (HCC). METHODS We retrospectively reviewed the data of 206 patients with HCC who underwent preoperative Gd-EOB-DTPA-enhanced MRI and hepatectomy and quantitatively evaluated the signal intensity ratio of the tumor to the surrounding liver tissue in the portal phase (SIRPP). We verified the survival rates and assessed the prognostic factors associated with overall survival (OS) and recurrence-free survival (RFS) using SIRPP. RESULTS Multivariate analysis revealed that the independent predictive factors for poorly-differentiated HCC were α-fetoprotein > 20 ng/mL (hazard ratio [HR]: 3.1909, 95% confidence interval [CI]: 1.3464-7.5622, p = .0084) and SIRPP ≤ 0.85 (HR: 3.7155, 95% CI: 1.521-9.076, p = .004). The 5-year OS and RFS rates in the high and low SIRPP groups were 83.2 and 52.1%, respectively (p < .0001) and 49.7 and 18.5%, respectively (p = .0003). Multivariate analysis revealed that SIRPP ≤ 0.68 was an independent prognostic factor related to OS (HR: 4.4537, 95% CI: 1.6581-11.9626, p = .003). CONCLUSION The SIRPP of preoperative Gd-EOB-DTPA-enhanced MRI might predict the histological differentiation and prognosis of HCC.
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Affiliation(s)
- Takahiro Tomino
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Daisuke Okamoto
- Departments of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shohei Yoshiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Nagao
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noboru Harada
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Nobuhiro Fujita
- Departments of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuhiro Ushijima
- Departments of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kousei Ishigami
- Departments of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Downstaging to Liver Transplant: Success Involves Choosing the Right Patient. Clin Liver Dis 2020; 24:665-679. [PMID: 33012452 DOI: 10.1016/j.cld.2020.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatocellular carcinoma is a rising indication for liver transplantation in the United States. Downstaging, defined as the reduction of tumor burden using local-regional therapy into Milan criteria, opens an avenue to access cure through transplant for patients who traditionally would not qualify. Approaching the selection of downstaging candidates through an assessment of hepatic function, staying within a modest expansion of tumor burden, and incorporation of serologic/imaging markers for tumor biology provide the best chance for successful downstaging. Following well-defined downstaging protocols with built-in failure criteria ensures excellent post-transplant outcomes.
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Effect of palonosetron and dexamethasone administration on the prevention of gastrointestinal symptoms in hepatic arterial chemoembolization with epirubicin. Support Care Cancer 2019; 28:3251-3257. [PMID: 31732854 DOI: 10.1007/s00520-019-05178-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 10/16/2019] [Indexed: 02/08/2023]
Abstract
PURPOSE There are several studies on premedication to prevent postembolization syndromes which occurs after transcatheter arterial chemoembolization (TACE), but the medication to be used is still not established. This study aimed to examine the effect of palonosetron and dexamethasone on the prevention of gastrointestinal symptoms induced by TACE. METHODS Patients with hepatocellular carcinoma who were treated with TACE with epirubicin were retrospectively evaluated. The complete response rate of antiemetic drugs and incidence and severity of gastrointestinal symptoms were compared between the antiemetic group (AE group), which includes 51 patients prophylactically administered with palonosetron 0.75 mg and dexamethasone 9.9 mg intravenously before TACE on day 1 and dexamethasone 6.6 mg intravenously on days 2 and 3, and control group with 101 patients without antiemetic premedication. RESULTS Complete response rate in the entire evaluation period was significantly higher in the AE group compared with that in the control group. In the acute phase, the incidence and severity of nausea, vomiting, and anorexia significantly decreased in the AE group, but only anorexia improved in the delay phase. Additionally, postembolization syndromes, such as abdominal pain and fever, were significantly attenuated in the AE group; however, constipation worsened in this group. CONCLUSIONS Premedication of palonosetron and dexamethasone significantly prevents the incidence and reduces the severity of gastrointestinal symptoms especially in the acute phase. Further studies will be needed to determine the most recommended 5-HT3 antagonist or dosage of dexamethasone in establishing the optimal antiemetic regimen.
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Huang X, Xie W, Yu X, Fan C, Wang J, Cao Y, Li J. Methyl-Cantharidimide Inhibits Growth of Human Hepatocellular Carcinoma Cells by Inducing Cell Cycle Arrest and Promoting Apoptosis. Front Oncol 2019; 9:1234. [PMID: 31803617 PMCID: PMC6873211 DOI: 10.3389/fonc.2019.01234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 10/28/2019] [Indexed: 12/28/2022] Open
Abstract
Methyl-Cantharidimide (MCA) is a derivative of cantharidin which has potential anticancer activity. This study investigates the effect of MCA on the growth and metastasis of human hepatocellular carcinoma (HCC) cells. Human HCC HepG2 and Hep3B2.1-7 cells, and normal hepatocytes (L02) were treated with a series of concentrations of MCA. The inhibition ability of these cells was examined by CCK-8 assay. Cell cycle and cell apoptosis were determined using Flow Cytometry. The effect of MCA on cell migration and invasion was evaluated through scratch wound healing and transwell migration assays. Furthermore, Western blot was used to evaluate biomarkers associated with cell cycle and apoptosis. It was found that: (i) MCA inhibited cell proliferation in HCC cells in a dose- and time-dependent manner, especially in HepG2 cells; (ii) MCA arrested HCC cells in G-1 phase cell cycle; (iii) MCA induced HCC cells apoptosis; (iv) MCA inhibited the migration ability of HCC cells; and (v) MCA treatment significantly increased cleaved-caspase3 and decreased NF-κB protein in HCC cells. These results suggest that MCA has cytotoxic effect on HCC cells by inducing cell cycle arrest and promoting apoptosis. MCA could be developed as an previous anticancer drug for the treatment of human hepatocellular carcinoma.
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Affiliation(s)
- Xiangzhong Huang
- Department of Interventional Therapy, Affiliated Jiangyin Hospital, Medical College of Southeast University, Jiangyin, China
| | - Wen Xie
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Xiaofan Yu
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Caiyun Fan
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Jin Wang
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Yi Cao
- School of Public Health, Medical College of Soochow University, Suzhou, China
| | - Jianxiang Li
- School of Public Health, Medical College of Soochow University, Suzhou, China
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Luo H, Li C, Chen L. Preoperative albumin-bilirubin grade combined with aspartate aminotransferase-to-platelet count ratio index predict outcomes of patients with hepatocellular carcinoma within Milan criteria after liver resection. Biosci Trends 2019; 13:176-181. [PMID: 31061272 DOI: 10.5582/bst.2019.01088] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
There is little information concerning the prognostic significance of combined albumin- bilirubin (ALBI) grade and aspartate aminotransferase-to-platelet count ratio index (APRI) in hepatocellular carcinoma (HCC). Therefore, we performed this study to assess the prognostic utility of combining ALBI and APRI (ALBI-APRI score) for predicting the prognosis of patients with HCC within Milan criteria after liver resection. Two hundred thirty-nine patients were involved in this study. Patients with a high APRI score were allocated a score of 1, whereas patients with a low APRI score were allocated a score of 0. The ALBI-APRI score is the summation of APRI score and ALBI grade. The area under the receiver operating characteristic curve (AUC) was used to estimate the predictive accuracy of different models. During the study period, 132 patients experienced recurrence, and 52 patients died. Multivariate analysis revealed the ALBI-APRI score (HR = 1.753, 95% CI = 1.293-2.377, p < 0.001), presence of microvascular invasion (MVI, HR = 2.693, 95%CI = 1.832-3.960, p < 0.001) and multiple tumors (HR = 1.973, 95% CI = 1.300-2.995, p = 0.001) were all associated with recurrence. In addition, blood transfusion (HR = 3.113, 95% CI = 1.677-5.778, p < 0.001), high preoperative alpha-fetoprotein (AFP, HR = 2.272, 95% CI = 1.298-3.976, p = 0.004), ALBI-APRI score (HR = 2.046, 95% CI = 1.237-3.382, p = 0.005) and presence of MVI (HR = 4.524, 95% CI = 2.514-8.140, p < 0.001) were correlated with postoperative mortality. The AUCs of ALBI-APRI score were significantly higher than either ALBI or APRI alone for predicting both postoperative recurrence and mortality. ALBI-APRI score may be a predictor for the prognosis of patients with HCC within Milan criteria following liver resection. A more well-designed and large-scale study are warranted to prove our findings.
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Affiliation(s)
- Hongmei Luo
- Department of Nursing, West China Hospital of Sichuan University
| | - Chuan Li
- Department of General Surgery, West China Hospital of Sichuan University
| | - Liping Chen
- Department of General Surgery, West China Hospital of Sichuan University
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Magistri P, Rosenblatt R, Halazun KJ. Liver Transplantation for HCC Beyond Milan. CURRENT TRANSPLANTATION REPORTS 2018. [DOI: 10.1007/s40472-018-0212-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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Correnti M, Raggi C. Stem-like plasticity and heterogeneity of circulating tumor cells: current status and prospect challenges in liver cancer. Oncotarget 2018; 8:7094-7115. [PMID: 27738343 PMCID: PMC5351693 DOI: 10.18632/oncotarget.12569] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 10/04/2016] [Indexed: 12/12/2022] Open
Abstract
Poor prognosis and high recurrence remain leading causes of primary liver cancerassociated mortality. The spread of circulating tumor cells (CTCs) in the blood plays a major role in the initiation of metastasis and tumor recurrence after surgery. Nevertheless, only a subset of CTCs can survive, migrate to distant sites and establish secondary tumors. Consistent with cancer stem cell (CSC) hypothesis, stem-like CTCs might represent a potential source for cancer relapse and distant metastasis. Thus, identification of stem-like metastasis-initiating CTC-subset may provide useful clinically prognostic information. This review will emphasize the most relevant findings of CTCs in the context of stem-like biology associated to liver carcinogenesis. In this view, the emerging field of stem-like CTCs may deliver substantial contribution in liver cancer field in order to move to personalized approaches for diagnosis, prognosis and therapy.
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Affiliation(s)
- Margherita Correnti
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy
| | - Chiara Raggi
- Center for Autoimmune Liver Diseases, Humanitas Clinical and Research Center, Rozzano, Italy
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Tao R, Sun WY, Yu DH, Qiu W, Yan WQ, Ding YH, Wang GY, Li HJ. Sodium cantharidinate induces HepG2 cell apoptosis through LC3 autophagy pathway. Oncol Rep 2017; 38:1233-1239. [DOI: 10.3892/or.2017.5779] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 06/20/2017] [Indexed: 11/05/2022] Open
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9
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Ryu T, Takami Y, Wada Y, Tateishi M, Matsushima H, Mikagi K, Saitsu H. Double- and Triple-Positive Tumor Markers Predict Early Recurrence and Poor Survival in Patients with Hepatocellular Carcinoma within the Milan Criteria and Child-Pugh Class A. J Gastrointest Surg 2017; 21:957-966. [PMID: 28299619 DOI: 10.1007/s11605-017-3394-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/06/2017] [Indexed: 01/31/2023]
Abstract
The prognostic implications of the expression patterns of three tumor markers, alpha-fetoprotein (AFP), the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-γ-carboxy prothrombin (DCP), have been evaluated in patients with hepatocellular carcinoma (HCC). From January 1994 to December 2014, 1182 consecutive patients underwent hepatic resection and surgical microwave ablation for HCC at our institution. This study analyzed 475 patients within the Milan criteria and Child-Pugh class A. Cumulative overall survival (OS) and disease-free survival (DFS) rates were analyzed relative to the number of positive tumor markers. OS and DFS at 5 years postoperatively were 85.3 and 44.2% in triple-negative patients, 79.4 and 48.0% in single-positive patients, 56.2 and 32.9% in double-positive patients, and 61.7 and 35.7% in triple-positive patients with statistical significance. OS in triple-negative or single-positive patients was 85.3%, and that in all double- or triple-positive patients was 58.0% (P < 0.0001); DFS at 5 years postoperatively in these two groups was 45.9 and 34.0%, respectively (P < 0.0013). Both double- and triple-positive tumor markers are associated with early recurrence and poor survival in HCC patients within the Milan criteria and Child-Pugh class A.
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Affiliation(s)
- Tomoki Ryu
- Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama Chuo-ku, Fukuoka, 810-8563, Japan.
| | - Yuko Takami
- Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama Chuo-ku, Fukuoka, 810-8563, Japan
| | - Yoshiyuki Wada
- Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama Chuo-ku, Fukuoka, 810-8563, Japan
| | - Masaki Tateishi
- Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama Chuo-ku, Fukuoka, 810-8563, Japan
| | - Hajime Matsushima
- Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama Chuo-ku, Fukuoka, 810-8563, Japan
| | - Kazuhiro Mikagi
- Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama Chuo-ku, Fukuoka, 810-8563, Japan
| | - Hideki Saitsu
- Department of Hepato-Biliary-Pancreatic Surgery, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama Chuo-ku, Fukuoka, 810-8563, Japan
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Tao R, Wang ZF, Qiu W, He YF, Yan WQ, Sun WY, Li HJ. Role of S100A3 in human hepatocellular carcinoma and the anticancer effect of sodium cantharidinate. Exp Ther Med 2017; 13:2812-2818. [PMID: 28588665 PMCID: PMC5450779 DOI: 10.3892/etm.2017.4294] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 11/15/2016] [Indexed: 12/11/2022] Open
Abstract
The fifth most common cancer worldwide is hepatocellular carcinoma (HCC), which has an annual mortality rate of ~800,000. Although surgical procedures for HCC, such as hepatic resection and liver transplantation, have progressed and the outcomes of patients have improved, HCC is still characterized by frequent recurrence, even after liver transplantation. In the present study the expression of the protein coding gene, S100 calcium binding protein A3 (S100A3), was observed in 62 HCC tissues and tumor-surrounding tissues. The present study indicated that S100A3 activation was involved in tumorigenesis and tumor aggressiveness. The protein and mRNA expression levels of S100A3 in the human HCC cell line (HepG2) were investigated using western blotting and reverse transcription-quantitative polymerase chain reaction analysis, respectively. The function of sodium cantharidinate in inducing HCC cell apoptosis was also investigated. Sodium cantharidinate inhibited the protein and gene expression of S100A3 in HepG2 cells in vitro. These data suggested that S100A3 has an important role in human HCC. The present study indicates that the functional properties of sodium cantharidinate are promising for the development of a novel drug that may control the expression of S100A3 and improve the treatment of human HCC in the near future.
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Affiliation(s)
- Ran Tao
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.,Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Zhong-Feng Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wei Qiu
- Department of Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
| | - Yu-Fang He
- Institute of Phytochemistry, Jilin Academy of Chinese Medicine Sciences, Changchun, Jilin 130012, P.R. China
| | - Wei-Qun Yan
- Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Wen-Yi Sun
- Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
| | - Hai-Jun Li
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China
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Wang Q, Cheng F, Ma TT, Xiong HY, Li ZW, Xie CL, Liu CY, Tu ZG. Interleukin-12 inhibits the hepatocellular carcinoma growth by inducing macrophage polarization to the M1-like phenotype through downregulation of Stat-3. Mol Cell Biochem 2016; 415:157-68. [PMID: 27003285 DOI: 10.1007/s11010-016-2687-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 03/12/2016] [Indexed: 12/17/2022]
Abstract
Hepatocellular carcinoma is the third most common cause of cancer death worldwide. Novel early detection biomarkers and efficacious therapy strategies are needed. Macrophages recruited from circulation monocytes are the major component of solid cancer and play an important role in the carcinogenesis. Whether overexpression of L-12 in monocytes could induce the phenotype directional differentiation into tumoricidal M1 macrophages and inhibit HCC growth in tumor microenvironment was investigated in this study. For the establishment of the monocyte/IL-12 and polarization of M1-like macrophage, the IL-12 overexpressing recombinant monocyte/IL-12 cells were established by infecting with pAd5F35-CMV/IL-12 adenovirus and co-cultured with HCC SMMC-7721 and Hep3B cells. It was found that the phenotype of monocyte/IL-12 polarized to M1-like macrophages with CD197high IL-12high CD206low IL-10low, and decreased expression of TGF-β, VEGF-A, and MMP-9. In order to explore the mechanism underlying the macrophages polarization, we detected the Stat-3 pathway and its downstream transcription factor c-myc, and found that the p-Stat-3 and c-myc were down-regulated. To evaluate the effects of monocyte/IL-12 on inhibiting HCC growth, various assays including CCK8, flow cytometry, colony-forming and Transwell assays in vitro, and xenograft mouse models and immunohistochemical analyses in vivo were used to detect the HCC growth and relative markers. Treated with IL-12 overexpressing monocytes, the xenograft tumor growth was significantly inhibited in vivo. These results have proven that IL-12-overexpressed monocytes could directionally differentiate to M1-like macrophages through downregulation of Stat-3 and result in the inhibition of HCC growth.
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Affiliation(s)
- Qin Wang
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Feng Cheng
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Ting-Ting Ma
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Hai-Yu Xiong
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Zi-Wei Li
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Chang-Li Xie
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Cui-Ying Liu
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
| | - Zhi-Guang Tu
- Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
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Cillo U, Giuliani T, Polacco M, Herrero Manley LM, Crivellari G, Vitale A. Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation. World J Gastroenterol 2016; 22:232-252. [PMID: 26755873 PMCID: PMC4698488 DOI: 10.3748/wjg.v22.i1.232] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 08/14/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023] Open
Abstract
Morphological criteria have always been considered the benchmark for selecting hepatocellular carcinoma (HCC) patients for liver transplantation (LT). These criteria, which are often inappropriate to express the tumor’s biological behavior and aggressiveness, offer only a static view of the disease burden and are frequently unable to correctly stratify the tumor recurrence risk after LT. Alpha-fetoprotein (AFP) and its progression as well as AFP-mRNA, AFP-L3%, des-γ-carboxyprothrombin, inflammatory markers and other serological tests appear to be correlated with post-transplant outcomes. Several other markers for patient selection including functional imaging studies such as 18F-FDG-PET imaging, histological evaluation of tumor grade, tissue-specific biomarkers, and molecular signatures have been outlined in the literature. HCC growth rate and response to pre-transplant therapies can further contribute to the transplant evaluation process of HCC patients. While AFP, its progression, and HCC response to pre-transplant therapy have already been used as a part of an integrated prognostic model for selecting patients, the utility of other markers in the transplant setting is still under investigation. This article intends to review the data in the literature concerning predictors that could be included in an integrated LT selection model and to evaluate the importance of biological aggressiveness in the evaluation process of these patients.
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Lim KC, Wang VW, Siddiqui FJ, Shi L, Chan ESY, Oh HC, Tan SB, Chow PKH. Cost-effectiveness analysis of liver resection versus transplantation for early hepatocellular carcinoma within the Milan criteria. Hepatology 2015; 61:227-37. [PMID: 24638991 DOI: 10.1002/hep.27135] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 03/13/2014] [Indexed: 12/13/2022]
Abstract
UNLABELLED Both liver resection (LR) and cadaveric liver transplantation (CLT) are potentially curative treatments for patients with hepatocellular carcinoma (HCC) within the Milan criteria and with adequate liver function. Adopting either as a first-line therapy carries major cost and resource implications. The objective of this study was to estimate the relative cost-effectiveness of LR against CLT for patients with HCC within the Milan criteria using a decision analytic model. A Markov cohort model was developed to simulate a cohort of patients aged 55 years with HCC within the Milan criteria and Child-Pugh A/B cirrhosis, undergoing LR or CLT, and followed up over their remaining life expectancy. Analysis was performed in different geographical cost settings: the USA, Switzerland and Singapore. Transition probabilities were obtained from systematic literature reviews, supplemented by databases from Singapore and the Organ Procurement and Transplantation Network (USA). Utility and cost data were obtained from open sources. LR produced 3.9 quality-adjusted life years (QALYs) while CLT had an additional 1.4 QALYs. The incremental cost-effectiveness ratio (ICER) of CLT versus LR ranged from $111,821/QALY in Singapore to $156,300/QALY in Switzerland, and was above thresholds for cost-effectiveness in all three countries. Sensitivity analysis revealed that CLT-related 5-year cumulative survival, one-time cost of CLT, and post-LR 5-year cumulative recurrence rates were the most sensitive parameters in all cost scenarios. ICERs were reduced below threshold when CLT-related 5-year cumulative survival exceeded 84.9% and 87.6% in Singapore and the USA, respectively. For Switzerland, the ICER remained above the cost-effectiveness threshold regardless of the variations. CONCLUSION In patients with HCC within the Milan criteria and Child-Pugh A/B cirrhosis, LR is more cost-effective than CLT across three different costing scenarios: the USA, Switzerland, Singapore.
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Affiliation(s)
- Kheng Choon Lim
- Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore; Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore
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Nakagawa S, Beppu T, Okabe H, Sakamoto K, Kuroki H, Mima K, Nitta H, Imai K, Hayashi H, Sakamoto Y, Hashimoto D, Chikamoto A, Ishiko T, Watanabe M, Baba H. Triple positive tumor markers predict recurrence and survival in early stage hepatocellular carcinoma. Hepatol Res 2014; 44:964-74. [PMID: 24245496 DOI: 10.1111/hepr.12277] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 10/17/2013] [Accepted: 11/10/2013] [Indexed: 12/13/2022]
Abstract
AIM Hepatectomy is feasible for patients with hepatocellular carcinoma (HCC) with good hepatic function who meet the Milan criteria. Several studies have indicated that tumor markers of HCC, α-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP percentage and protein induced by vitamin K absence/antagonist-II were good predictors of malignant potential. It is important to identify highly malignant cases of HCC, and the aim of this study was to clarify the impact of triple positive tumor markers as the prognostic factors for early stage HCC within the Milan criteria. METHODS This study investigated 199 patients who underwent hepatectomy for HCC within the Milan criteria between January 2001 and May 2009. Cumulative recurrence-free survival (RFS), overall survival (OS) and clinicopathological parameters were analyzed according to the number of positive tumor markers. RESULTS In patients with triple positive tumor markers, 5-year RFS and OS was poor (17.1 and 61.4%, respectively). Multivariate analyses revealed independent risk factors for recurrence to be hepatitis C virus antibody positivity, non-initial treatment for HCC and triple positive tumor markers, and the independent risk factors for OS were high indocyanine green retention rate at 15 min value, maximum tumor size and triple positive tumor markers. Pathologically invasive growth, microvascular invasion and moderate to poor differentiation were significantly related to the number of the three tumor markers. CONCLUSION Triple positive tumor markers for early stage HCC within the Milan criteria showed poor prognosis and malignant characteristics. These markers could be a useful predictor for the degree of malignant potential in early stage HCC.
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Affiliation(s)
- Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
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15
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Zhong JH, Mo XS, Xiang BD, Yuan WP, Jiang JF, Xie GS, Li LQ. Postoperative use of the chemopreventive vitamin K2 analog in patients with hepatocellular carcinoma. PLoS One 2013; 8:e58082. [PMID: 23505456 PMCID: PMC3591458 DOI: 10.1371/journal.pone.0058082] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Accepted: 01/31/2013] [Indexed: 01/27/2023] Open
Abstract
Aim To evaluate the chemopreventive efficacy of vitamin K2 (VK2) analog in patients with hepatocellular carcinoma (HCC) after curative hepatic resection or local ablation, since a recent randomized control trial (RCT) and systematic review have given contradictory results. Methods MEDLINE, EMBASE and Cochrane library databases were systematically searched through the end of May 2012. Meta-analysis of RCTs and cohort studies was performed to estimate the effects of the VK2 analog on tumor recurrence rate and overall survival (OS). Risk ratios (RRs) and 95% confidence intervals (95% CIs) were calculated. Results Six RCTs and one cohort study involving a total of 930 patients were included. VK2 analog therapy did not reduce the 1-year recurrence rate, with a pooled RR of 0.67 (95% CI 0.39–1.13, p = 0.13). However, VK2 analog therapy was associated with a significant reduction in the 2- and 3-year tumor recurrence rates, with respective pooled RRs of 0.65 (95% CI 0.51–0.83, p<0.001) and 0.70 (95% CI = 0.58–0.85, p<0.001). The therapy was also associated with a significant improvement in 1-, 2-, and 3-year OS, with respective pooled RRs of 1.03 (95% CI 1.01–1.05, p = 0.02), 1.11 (95% CI 1.03–1.19, p = 0.005) and 1.14 (95% CI 1.02–1.28, p = 0.02). None of the studies reported adverse effects attributable to VK2 analog therapy. Conclusion The VK2 analog may reduce recurrence rate after 1 year and improve OS in HCC patients as early as 1 year. However, these findings should be considered preliminary since the majority of patients came from an RCT with survival data out to only 1 year. More extensive studies with larger sample sizes and longer follow-up are needed.
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Affiliation(s)
- Jian-Hong Zhong
- Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Xin-Shao Mo
- Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Bang-De Xiang
- Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Wei-Ping Yuan
- Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Jin-Fang Jiang
- Chemotherapy Department, Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Gui-Sheng Xie
- General Surgery Department, The Third Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Le-Qun Li
- Hepatobiliary Surgery Department, Tumor Hospital of Guangxi Medical University, Nanning, People's Republic of China
- * E-mail:
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16
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Lerut J, Julliard O, Ciccarelli O, Lannoy V, Gofette P. Hepatocellular cancer and liver transplantation: a Western experience. Recent Results Cancer Res 2013; 190:127-144. [PMID: 22941018 DOI: 10.1007/978-3-642-16037-0_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Orthotopic liver transplantation is the preferred treatment option in patients with hepatocellular carcinoma developing in chronic liver disease. Unfortunately, based on classical transplantation criteria (Milan criteria), only a minority of patients with hepatocellular carcinoma are candidate to orthotopic liver transplantation. Major improvements in treatment strategy and surgical technique including the use of neoadjuvant locoregional therapies and progresses of post-transplant immunosuppressive treatment have contributed to safely expand transplantation criteria preserving acceptable surgical morbidity-mortality and good oncologic outcome. Further extension of transplantation criteria may have advantages including an increase in the number of transplant candidates and improvement of the prognosis of the disease and also disadvantages including an increase of surgical morbidity and deterioration of global oncologic outcome of orthotopic liver transplantation in hepatocellular carcinoma. In the future, identification of imaging or molecular prognostic markers could help to better define transplantation criteria.
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Affiliation(s)
- Jan Lerut
- Department of Imaging - Interventional Radiology, Université catholique de Louvain-UCL, Brussels, Belgium.
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17
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Abstract
The main methods of treatment for hepatocellular carcinoma (HCC) in Japan are hepatic resection, radiofrequency ablation (RFA) and transcatheter arterial chemoembolization (TACE). Meticulous follow up is then undertaken to check for recurrence, which is treated using repeated RFA or TACE. Hepatic arterial infusion chemotherapy has been introduced as treatment for advanced HCC, and the molecular-targeted drug sorafenib is also now available. Rigorous medical care using these treatment methods and early diagnosis mean that the prognosis for HCC in Japan is the best in the world. This paper reviews the treatment strategies for HCC in Japan.
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Affiliation(s)
- Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
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18
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Lim KC, Chow PKH, Allen JC, Siddiqui FJ, Chan ESY, Tan SB. Systematic review of outcomes of liver resection for early hepatocellular carcinoma within the Milan criteria. Br J Surg 2012; 99:1622-9. [PMID: 23023956 DOI: 10.1002/bjs.8915] [Citation(s) in RCA: 164] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND Long-term overall survival after liver resection in patients with hepatocellular carcinoma (HCC) within the Milan criteria has been reported to improve in recent years. This study systematically reviewed the outcomes of surgical resection for HCC in patients with good liver function and meeting the Milan criteria for early HCC, published in the past 10 years. METHODS A literature search was conducted in PubMed for papers on outcomes of surgical resection for HCC published between January 2000 and December 2010. Cochrane systematic review methodology was used for this review. The primary outcome was overall survival. Secondary outcomes included operative mortality and disease-free survival. Studies that focused on geriatric populations, paediatric populations, a subset of the Milan criteria (such solitary tumours) or included patients with incidental tumours were excluded, as were case reports, conference abstracts, and studies with a large proportion of Child-Pugh grade C liver cirrhosis or unknown Child-Pugh status. RESULTS Of 152 studies reviewed, two randomized clinical trials and 27 retrospective case series were eligible for inclusion. The 5-year overall survival rate after resection of HCC ranged from 27 to 81 (median 67) per cent, and the median disease-free survival rate from 21 to 57 (median 37) per cent. There was a trend towards improved overall survival in recent years. The operative mortality rate ranged from 0 to 5 (median 0·7) per cent. CONCLUSION Surgical resection offers good overall survival for patients with HCC within the Milan criteria and with good liver function, although recurrence rates remain high. Outcomes have tended to improve in more recent years.
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Affiliation(s)
- K-C Lim
- Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore
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19
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Zhong JH, Li LQ, You XM, Xiang BD, Ma L, Gong WF. Oral vitamin K2 analogs for hepatocellular carcinoma after surgery: A meta-analysis. Shijie Huaren Xiaohua Zazhi 2012; 20:2420-2426. [DOI: 10.11569/wcjd.v20.i25.2420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy and safety of oral vitamin K2 (VK2) analogs for patients with hepatocellular carcinoma (HCC) after surgery.
METHODS: Sources such as Chinese National Knowledge Infrastructure, Medline, Embase and Cochrane library were systematically searched. All clinical trials comparing curative treatments alone with curative treatments plus VK2 analogs for HCC patients were identified. Meta-analysis was performed to estimate the effects of VK2 analogs on tumor recurrence and overall survival (OS). Risk ratios (RR) and 95% confidence intervals (95% CI) were calculated.
RESULTS: Six randomized clinical trials and one cohort study involving 930 patients were included. VK2 analogs did not statistically reduced the 1-year tumor recurrence rate, with a pooled RR of 0.67 (95% CI: 0.39-1.13, P = 0.13). However, hepatic resection plus VK2 analogs were associated with significantly lower 2- and 3-year tumor recurrence rates, with pooled RRs of 0.65 (95% CI: 0.51-0.83, P < 0.001) and 0.70 (95% CI: 0.58-0.85, P < 0.001). Moreover, for the 1-, 2-, and 3-year OS, VK2 analogs also demonstrated statistically significant results (RR = 1.03, 95% CI: 1.01-1.05, P = 0.02; RR = 1.11, 95% CI: 1.03-1.19, P = 0.005; RR = 1.14, 95% CI: 1.02-1.28, P = 0.02). Oral VK2 analogs were safe and were not associated with adverse events.
CONCLUSION: Current evidence suggests that postoperative VK2 analogs have appreciable efficacy in patients with HCC after curative treatment.
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20
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Inagaki Y, Xu HL, Hasegawa K, Aoki T, Beck Y, Sugawara Y, Tang W, Kokudo N. Des-gamma-carboxyprothrombin in patients with hepatocellular carcinoma and liver cirrhosis. J Dig Dis 2011; 12:481-8. [PMID: 22118699 DOI: 10.1111/j.1751-2980.2011.00521.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To ascertain serum and tissue expression of des-gamma-carboxyprothrombin (DCP) in patients with hepatocellular carcinoma (HCC) and liver cirrhosis and clarify the relationship between DCP expression and prognosis. METHODS Expression of DCP in tissues was evaluated with immunohistochemical staining using anti-DCP antibody in 74 patients with a single primary HCC nodule and liver cirrhosis. Their serum DCP levels were determined using an enzyme immunoassay with a double antibody sandwich system. RESULTS Positive DCP expression in cancerous and non-cancerous tissues was related to a worse prognosis for patients with HCC and liver cirrhosis. The combined evaluation of tissue DCP expression and serum DCP level showed that prognosis was the worst for patients with positive tissue DCP expression and a high serum DCP level. Univariate analysis indicated that a lower 5-year survival rate was significantly correlated with positive tissue DCP expression, a high serum DCP level and the combined factor of positive tissue DCP expression and a high serum DCP level. Multivariate analysis indicated that the combined factor of positive tissue DCP expression and a high serum DCP level was a significant prognostic factor. CONCLUSION The combined evaluation of tissue DCP expression and serum DCP level is more useful than either factor alone in predicting prognosis for patients with HCC and liver cirrhosis.
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Affiliation(s)
- Yoshinori Inagaki
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan
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Shirabe K, Mano Y, Muto J, Matono R, Motomura T, Toshima T, Takeishi K, Uchiyama H, Yoshizumi T, Taketomi A, Morita M, Tsujitani S, Sakaguchi Y, Maehara Y. Role of tumor-associated macrophages in the progression of hepatocellular carcinoma. Surg Today 2011; 42:1-7. [PMID: 22116397 DOI: 10.1007/s00595-011-0058-8] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Accepted: 02/16/2011] [Indexed: 12/12/2022]
Affiliation(s)
- Ken Shirabe
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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22
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Masuoka HC, Rosen CB. Liver transplantation for hepatocellular carcinoma: expanding frontiers and building bridges. Clin Liver Dis 2011; 15:385-93, vii-x. [PMID: 21689620 DOI: 10.1016/j.cld.2011.03.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Despite significant advances in nonsurgical treatments of hepatocellular carcinoma, these approaches rarely result in cure. Surgery remains the mainstay of curative therapy for hepatocellular carcinoma. Liver transplantation, in particular, has emerged as one of the most beneficial therapeutic modalities. Questions remain, however, regarding hepatocellular carcinoma surveillance, the choice of surgical resection versus transplantation, the role of chemotherapy, optimal selection criteria for transplantation, and the role of ablative therapies to halt tumor progression and downsize tumors exceeding transplant criteria.
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Affiliation(s)
- Howard C Masuoka
- Division of Gastroenterology and Hepatology, William J. von Liebig Transplant Center, Mayo Clinic and Mayo Clinic College of Medicine, Rochester, MN 55905, USA
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