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Gadallah EA, Elkomos BE, Khalil A, Fawzy FS, Abdelaal A. Central hepatectomy versus major hepatectomy for patients with centrally located hepatocellular carcinoma: a systematic review and meta-analysis. BMC Surg 2023; 23:2. [PMID: 36600282 DOI: 10.1186/s12893-022-01891-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 12/20/2022] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND AND AIM For those with a centrally located HCC, the two types of liver sectionectomy that can be performed are extended hepatectomy (EH) and central hepatectomy (CH). This meta-analysis aimed to compare the short- and long-term outcomes between patients treated with CH and patients treated with EH for those with centrally located HCC. METHOD We searched PubMed, Scopus, Web of Science, and Cochrane library for eligible studies from inception to 1 April 2022 and a systematic review and meta-analysis were done to compare the outcomes between the two groups. RESULTS we included 9 studies with a total of 1674 patients in this study. The pooled results in this meta-analysis showed equal long-term overall survival, Disease-free survival, recurrence and mortality between the two groups (5-year OS, RR = 1.14, 95% CI = 0.96-1.35, P = 0.12; I2 = 56%), (5-year DFS, RR = 0.81, 95% CI = 0.61-1.08, P = 0.15; I2 = 60%), (Recurrence, RR = 1.04, 95% CI = 0.94-1.15, P = 0.45; I2 = 27%), and (Mortality, RR = 0.55, 95% CI = 0.26-1.15, P = 0.11; I2 = 0%). In addition to that, no significant difference could be detected in the overall incidence of complications between the two groups (Complications, RR = 0.94, 95% CI = 0.76-1.16, P = 0.57; I2 = 0%). However, CH is associated with a remarkable increase in the rate of biliary fistula (Biliary fistula, RR = 1.90, 95% CI = 1.07-3.40, P = 0.03; I2 = 0%). And Liver cell failure was higher in the case of EH (LCF, RR = 0.47, 95% CI = 0.30-0.76, P = 0.002; I2 = 0%). Regarding the operative details, CH is associated with longer operative time (Time of the operation, Mean difference = 0.82, 95% CI = 0.36, 1.27, P = 0.0004; I2 = 57%). CONCLUSION No significant difference in the short and long-term survival and recurrence between CH and MH for CL-HCC. However, CH is associated with greater future remnant liver volume that decreases the incidence of LCF and provides more opportunities for a repeat hepatectomy after tumour recurrence.
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Affiliation(s)
| | | | - Ahmed Khalil
- General Surgery Department, Ain Shams University Hospital, Cairo, Egypt
| | - Fawzy Salah Fawzy
- General Surgery Department, Ain Shams University Hospital, Cairo, Egypt
| | - Amr Abdelaal
- General Surgery Department, Ain Shams University Hospital, Cairo, Egypt
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Kong J, Li G, Chai J, Yu G, Liu Y, Liu J. Impact of Postoperative Complications on Long-Term Survival After Resection of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Ann Surg Oncol 2021; 28:8221-8233. [PMID: 34160708 DOI: 10.1245/s10434-021-10317-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/06/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Controversy exists over the relationship between postoperative complications (POCs) and long-term survival for hepatocellular carcinoma (HCC) after hepatectomy. This study aimed to evaluate the impact of POCs on overall survival (OS) and disease-free survival (DFS) for HCC after liver resection. PATIENTS AND METHODS The PubMed, EMBASE, and Cochrane Library databases were used to search for eligible studies published through 18 April 2020, and studies comparing the long-term outcomes between HCC patients with and without POCs after hepatectomy were included. A random-effects model was used to calculate the pooled hazard ratio (HR) with a 95% confidence interval (CI). Subgroup analysis and meta-regression were performed to assess the potential influence of study-, patient-, and tumor-related factors on the relationship between POCs and oncologic outcomes and to adjust their effect. This study was registered at the International Prospective Register of Systematic Reviews (CRD42019136109). RESULTS Thirty-seven studies, including 14,096 patients, were deemed eligible and included in this study. Compared with those without POCs, patients who developed POCs had a significant reduction in OS (HR 1.39, 95% CI 1.28-1.50, P < 0.001; prediction interval 1.04-1.85) and tended to have worse DFS (HR 1.25, 95% CI 1.16-1.35, P < 0.001; prediction interval 0.98-1.60). Contour-enhanced funnel plots suggested a risk of publication bias. Subgroup analysis and meta-regression showed that POCs remained a threat to OS and DFS regardless of the influence of clinicopathological factors. CONCLUSION This study demonstrated that POCs had an adverse impact on OS and DFS in HCC patients after liver resection.
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Affiliation(s)
- Junjie Kong
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China.,Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Guangbing Li
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Jiawei Chai
- Department of Breast and Thyroid Surgery, Shandong Maternity and Child Care Hospital, Jinan, Shandong Province, China
| | - Guangsheng Yu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Yong Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Jun Liu
- Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China. .,Department of Liver Transplantation and Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China.
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Predictors of complications after liver surgery: a systematic review of the literature. HPB (Oxford) 2021; 23:645-655. [PMID: 33485797 DOI: 10.1016/j.hpb.2020.12.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/21/2020] [Accepted: 12/11/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Numerous potential predictors of adverse outcomes have been reported but their performance and utilization in practice seem heterogenous. This study aimed to systematically review the literature on the role and value of predictors of complications after hepatectomy. METHODS A systematic review following the PRISMA guidelines was performed. Studies on liver transplant were excluded. Only studies assessing overall or major complications were included. RESULTS A total of 10'965 abstracts were screened. After application of exclusion criteria, 72 articles including 68'480 patients were included. A total of 72 markers with 48 pre-, 9 intra- and 15 postoperative factors were identified as predictors of complications. Preoperative and intraoperative predictive markers retrieved several times with the highest odds ratios (OR) were ASA score (OR range: 1.3-7.5, significant in 8 studies) and intraoperative need for red blood cell transfusion (OR range: 1.2-17.1, significant in 24 studies), respectively. CONCLUSION Numerous markers have been described to predict the complication risk after hepatectomy. Because of their intrinsic characteristics, most markers such as ASA score and need for red blood cell transfusion are of limited clinical interest. There is a clear need to identify new biomarkers and to develop scores that could easily be implemented in clinical practice.
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SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET. Oncogene 2020; 39:7279-7295. [PMID: 33046796 DOI: 10.1038/s41388-020-01500-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 08/25/2020] [Accepted: 09/30/2020] [Indexed: 12/13/2022]
Abstract
Metastasis is the main reason for high mortality in hepatocellular carcinoma (HCC) patients and the molecular mechanism remains unclear. Therefore, it is important to elucidate the mechanism underlying HCC metastasis. Here, we report a novel role of SIX homeobox 4 (SIX4), one of the SIX gene family, in promoting HCC metastasis. The elevated expression of SIX4 was positively correlated with loss of tumor encapsulation, microvascular invasion, higher TNM stage, and poor prognosis in human HCC. SIX4 expression was an independent and significant risk factor for the recurrence and survival in HCC patients. Upregulation of SIX4 promoted HCC invasion and metastasis, whereas downregulation of SIX4 decreased HCC invasion and metastasis. SIX4 transactivated Yes1 associated transcriptional regulator (YAP1) and MET proto-oncogene, receptor tyrosine kinase (MET) expression through directly binding to their promoters. Knockdown of YAP1 and c-MET inhibited SIX4-medicated HCC metastasis, while the stable overexpression of YAP1 and c-MET reversed the decreased metastasis induced by SIX4 knockdown. Hepatocyte growth factor (HGF), the specific ligand of c-MET, upregulated SIX4 expression through ERK/NF-κB pathway. Knockdown of SIX4 significantly decreased HGF-enhanced HCC metastasis. In human HCC tissues, SIX4 expression was positively correlated with nuclear YAP1, c-MET and HGF expression. Patients with positive coexpression of SIX4/ nuclear YAP1, SIX4/c-MET or HGF/SIX4 had the poorest prognosis. Moreover, the combination treatment of YAP1 inhibitor Verteporfin and c-MET inhibitor Capmatinib significantly suppressed SIX4-mediated HCC metastasis. In conclusion, SIX4 is a prognostic biomarker in HCC patients and targeting the HGF-SIX4-c-MET positive feedback loop may provide a promising strategy for the treatment of SIX4-driven HCC metastasis.
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Kabir T, Syn NL, Tan ZZX, Tan HJ, Yen C, Koh YX, Kam JH, Teo JY, Lee SY, Cheow PC, Chow PKH, Chung AYF, Ooi LL, Chan CY, Goh BKP. Predictors of post-operative complications after surgical resection of hepatocellular carcinoma and their prognostic effects on outcome and survival: A propensity-score matched and structural equation modelling study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2020; 46:1756-1765. [PMID: 32345496 DOI: 10.1016/j.ejso.2020.03.219] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 01/31/2020] [Accepted: 03/23/2020] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Although hepatectomy is the mainstay of curative therapy for hepatocellular carcinoma (HCC), post-operative complications remain high. Presently there is conflicting data on the impact of morbidity on oncologic outcomes. We sought to identify predictors for the occurrence of post-hepatectomy complications, as well as to analyse the impact on overall survival (OS) and recurrence-free survival (RFS). MATERIALS AND METHODS We performed a retrospective review of 888 patients who underwent resection for HCC from 2001 to 2016 in our institution. RESULTS A total of 237 patients (26.7%) developed 254 complications of Clavien-Dindo Grade ≥2. Hepatitis B (p = 0.0397), elevated ASA score (p = 0.0002), higher platelet counts (p = 0.0277), raised pre-operative APRI scores (p = 0.0105) and bloodloss (p < 0.0001) were independently associated with the development of complications. After propensity-score matching, 458 patients were compared in a 1:1 ratio (229 with complications versus 229 without). Patients with complications had significantly longer median length of stay (9 days [IQR 7-15] versus 6 days [IQR 5-8], p < 0.0001), higher 90-day mortality rates as well as inferior OS (p = 0.0139), but there was no difference in RFS (p = 0.4577). Age (p = 0.0006), elevated Child Pugh points (p < 0.0001), microvascular invasion (p = 0.0002), multifocal tumours (p = 0.0002), R1 resection (p = 0.0443) and development of complications (p = 0.0091) were independent predictors of inferior OS. CONCLUSION Post-operative morbidity affected both short-term and OS outcomes after hepatectomy for HCC. Hepatitis B, higher ASA scores, elevated preoperative APRI and increased blood loss were found to predict a higher likelihood of developing complications. This may potentially be mitigated by careful patient selection and adopting strict measures to minimise intraoperative bleeding.
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Affiliation(s)
- Tousif Kabir
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Department of General Surgery, Sengkang General Hospital, Singapore
| | | | - Zoe Z X Tan
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Hiang-Jin Tan
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Clarence Yen
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Ye-Xin Koh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore
| | - Juinn Huar Kam
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Department of General Surgery, Sengkang General Hospital, Singapore
| | - Jin-Yao Teo
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Ser-Yee Lee
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore
| | - Peng-Chung Cheow
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Pierce K H Chow
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore
| | - Alexander Y F Chung
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore
| | - London L Ooi
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Department of General Surgery, Sengkang General Hospital, Singapore; Yong Loo Lin School of Medicine, Singapore; Duke NUS Medical School, Singapore
| | - Chung-Yip Chan
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore
| | - Brian K P Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke NUS Medical School, Singapore.
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Qiao W, Leng F, Liu T, Wang X, Wang Y, Chen D, Wei J. Prognostic Value of Prealbumin in Liver Cancer: A Systematic Review and Meta-Analysis. Nutr Cancer 2019; 72:909-916. [PMID: 31507226 DOI: 10.1080/01635581.2019.1661501] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Accumulated studies have reported the prognostic significance of prealbumin in liver cancer, but the results were not conclusive. The aim of this study was to evaluate the association between pretreatment serum prealbumin and clinical outcome of liver cancer patients through a meta-analysis. We comprehensively searched EMBASE, PubMed, Web of Science and the Cochrane library to identify eligible studies. The pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were utilized to evaluate the prognostic value of pretreatment serum prealbumin in overall survival (OS) and recurrence-free survival (RFS) of liver cancer patients. A total of 3470 patients from 10 eligible studies were finally included for analysis. The combined effects of prealbumin on liver cancer patients' OS and RFS were HR = 1.83, 95% CI: 1.46-2.30, P < 0.001 and HR = 1.47, 95% CI: 1.01-2.14, P = 0.045, respectively. Sensitivity and subgroup analysis showed that the pooled HR of prealbumin on liver cancer patients' OS was stable. Since potential publication bias was identified in the OS studies, the trim-and-fill method therefore was performed to explore publication bias, and the results showed reliability. This meta-analysis shows that low pretreatment serum prealbumin is significantly associated with poor prognosis of liver cancer patients.
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Affiliation(s)
- Weizhou Qiao
- Department of Clinical Laboratory, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, PR China
| | - Feng Leng
- Department of Clinical Laboratory, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, PR China
| | - Tong Liu
- Department of Clinical Laboratory, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, PR China
| | - Xuan Wang
- Department of Clinical Laboratory, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, PR China
| | - Yueying Wang
- Department of Clinical Laboratory, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, PR China
| | - Dongjie Chen
- Department of Clinical Laboratory, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, PR China
| | - Jinlong Wei
- Department of Clinical Laboratory, Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, Liaoning, PR China
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Prognostic Value of Pretreatment Serum Transthyretin Level in Patients with Gastrointestinal Cancers. DISEASE MARKERS 2019; 2019:7142065. [PMID: 31275452 PMCID: PMC6589268 DOI: 10.1155/2019/7142065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 04/18/2019] [Indexed: 01/19/2023]
Abstract
Background Many studies have shown the link between the pretreatment serum transthyretin and prognosis in gastrointestinal (GI) cancers. However, based on the conclusion, the initial findings were inconsistent. Hence, this meta-analysis was performed to identify the prognostic values of the pretreatment serum transthyretin in GI cancers. Methods Previous studies published before November 2018 were collected from a comprehensive literature search of several databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were applied in the assessment of the intensity of associations. Also, the publication bias and the robustness of merged data were assessed. All statistical analyses were undertaken using STATA/SE 14.1. Results The combined data indicated that the pretreatment serum transthyretin level was related to the prognosis in GI cancers. The group with reduced pretreatment transthyretin had a significantly worse overall survival (OS) (HR = 1.71, 95% CI: 1.37-2.05). The subgroup analysis for OS further showed the predictive value of transthyretin. In addition, the low serum transthyretin level could be an unfavorable factor for recurrence-free survival (RFS) or progression-free survival (PFS) (HR = 1.66, 95% CI: 1.14-2.18) in GI cancers. Conclusion The low pretreatment serum transthyretin level implies an unfavorable prognosis for patients with GI cancers. The monitoring of pretreatment transthyretin level could contribute to the risk stratification and individualized therapy in GI cancers.
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Braunwarth E, Primavesi F, Göbel G, Cardini B, Oberhuber R, Margreiter C, Maglione M, Schneeberger S, Öfner D, Stättner S. Is bile leakage after hepatic resection associated with impaired long-term survival? Eur J Surg Oncol 2019; 45:1077-1083. [PMID: 30803908 DOI: 10.1016/j.ejso.2019.02.021] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Revised: 01/31/2019] [Accepted: 02/17/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Bile leakage (BL) is a frequent and severe complication following liver surgery. The aim of this study was to evaluate risk factors for BL, related other complications and association with long-term survival. METHODS This study included all patients undergoing hepatectomy in a single centre from 2005 to 2016. Perioperative risk factors related to BL were identified using univariable and multivariable analysis. Kaplan-Meier method was used for survival analysis. RESULTS BL occurred in 48 of 458 patients (11%). BLs were more frequent in patients after major hepatectomy (p = 0.001). Portal vein embolization, bilioenteric-anastomosis, lymphadenectomy, vascular reconstruction and operative time were significant factors for developing BL. Comparing patients with or without BL, BL was more commonly associated with other postoperative complications (p = 0.001), especially acute kidney failure and surgical-site-infections. There was no difference in 90-day-mortality (p = 0.124). The median disease-free survival was comparable (17 vs. 15 months, p = 0.976), also no difference was observed when stratifying for different tumour entities. There was no difference in median overall survival (OS) among malignant disease (35 vs. 47 months, p = 0.200) and in 3-year OS (46% vs. 59%). Multivariate analysis confirmed that postoperative liver failure and major hepatectomy were risk factors for reduced OS (p = 0.010). CONCLUSIONS Many concerns have been raised regarding tumour progression after major complications. In this study, we only found a relevant influence of BL on OS in pCC, whereas no association was seen in other cancer types, indicating that tumour progression might be triggered by BL in cancer types arising from the bile ducts itself.
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Affiliation(s)
- Eva Braunwarth
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Florian Primavesi
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Georg Göbel
- Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Innsbruck, Austria
| | - Benno Cardini
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Rupert Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Christian Margreiter
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Manuel Maglione
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Dietmar Öfner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Stättner
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria.
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Zhang Y, Gao X, Zhu Y, Kadel D, Sun H, Chen J, Luo Q, Sun H, Yang L, Yang J, Sheng Y, Zheng Y, Zhu K, Dong Q, Qin L. The dual blockade of MET and VEGFR2 signaling demonstrates pronounced inhibition on tumor growth and metastasis of hepatocellular carcinoma. J Exp Clin Cancer Res 2018; 37:93. [PMID: 29712569 PMCID: PMC5925844 DOI: 10.1186/s13046-018-0750-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 04/03/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The application of VEGF signaling inhibitors have been associated with more invasive or metastatic behavior of cancers including hepatocellular carcinoma (HCC). We explored the contribution of MET pathway to the enhanced HCC invasion and metastasis by VEGF signaling inhibition, and investigated the antitumor effects of NZ001, a novel dual inhibitor of MET and VEGFR2, in HCC. METHODS Immunocompetent orthotopic mice model of hepal-6 was established to investigate the effects of either VEGF antibody alone or in combination with the selective MET inhibitor on tumor aggressiveness. The antitumor effects of NZ001 were examined in cultured HCC cells as well as in vivo models. MET gene amplification was determined by SNP 6.0 assay. MET/P-MET expression was detected by IHC. RESULTS Selective VEGF signaling inhibition by VEGF antibody significantly reduced in vivo tumor growth of the orthotopic mice models, simultaneously also enhanced tumor invasion and metastasis, but inhibiting MET signaling attenuated this side-effect. Further study revealed that hypoxia caused by VEGF signaling inhibition induced HIF-1α nuclear accumulation, subsequently leading to elevated total-MET expression, and synergized with HGF in inducing invasion. NZ001, a novel dual inhibitor of MET and VEGFR2, markedly inhibited both tumor growth and metastasis of HCC, which showed obvious advantages over sorafenib in not inducing more invasive and metastatic behaviors. This effect is more pronounced in HCC with MET amplification and overexpression. CONCLUSIONS The activation of MET is responsible for the metastasis-promoting effects induced by VEGF inhibition. MET and VEGFR2 dual blockade, NZ001, has advantages over sorafenib in not inducing more invasive and metastatic behaviors; MET amplification and overexpression can be used to identify the subgroup of patients most likely to get the optimal benefit from NZ001 treatment.
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Affiliation(s)
- Yu Zhang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Xiaomei Gao
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Ying Zhu
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Dhruba Kadel
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Haoran Sun
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Jing Chen
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Duke University, Durham, NC, USA
- Duke Cancer Institute, Duke University, Durham, NC, USA
| | - Qin Luo
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Haoting Sun
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Luyu Yang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Jing Yang
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Yuanyuan Sheng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Yan Zheng
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China
| | - Kejin Zhu
- Kanion Research Institute, 58 Kangyuan Road, Lianyungang, 222002, Jiangsu, China.
| | - Qiongzhu Dong
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
| | - Lunxiu Qin
- Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Institutes of Biomedical Sciences, Fudan University, 12 Urumqi Road (M), Shanghai, 200040, China.
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Deng YR, Liu WB, Lian ZX, Li X, Hou X. Sorafenib inhibits macrophage-mediated epithelial-mesenchymal transition in hepatocellular carcinoma. Oncotarget 2018; 7:38292-38305. [PMID: 27203677 PMCID: PMC5122390 DOI: 10.18632/oncotarget.9438] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Accepted: 05/01/2016] [Indexed: 02/06/2023] Open
Abstract
Tumor-associated macrophages, crucial components of the microenvironment in hepatocellular carcinoma, hamper anti-cancer immune responses. The aim of the present study was to investigate the effect of sorafenib on the formation of the tumor microenvironment, especially the relationship between polarized macrophages and hepatocytes. Macrophage infiltration was reduced in patients with hepatocellular carcinoma who were treated with sorafenib. In vitro, sorafenib abolished polarized macrophage-induced epithelial mesenchymal transition (EMT) and migration of hepatocellular carcinoma cells but not normal hepatocytes. Moreover, sorafenib attenuated HGF secretion in polarized macrophages, and decreased plasma HGF in patients with hepatocellular carcinoma. Additionally, sorafenib abolished the polarized macrophage-induced activation of the HGF receptor Met in hepatocellular carcinoma cells. Our findings suggest that sorafenib inhibits polarized macrophage-induced EMT in hepatocellular carcinoma cells via the HGF-Met signaling pathway. These results contribute to our understanding of the immunological mechanisms that underlie the protective effects of sorafenib in hepatocellular carcinoma therapy.
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Affiliation(s)
- Yan-Ru Deng
- Intensive Care Unit, Affiliated Provincial Hospital of Anhui Medical University, Hefei, China
| | - Wen-Bin Liu
- Department of Hepatic Surgery and Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Affiliated Provincial Hospital of Anhui Medical University, Hefei, China
| | - Zhe-Xiong Lian
- Liver Immunology Laboratory, Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Xingsheng Li
- Department of Gerontology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xin Hou
- Anhui Provincial Laboratory of Microbiology and Parasitology, Department of Microbiology and Parasitology, Anhui Medical University, Hefei, Anhui, China
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11
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Pravisani R, Baccarani U, Isola M, Adani G, Lorenzin D, Terrosu G, Risaliti A. Impact of surgical complications on the risk of hepatocellular carcinoma recurrence after hepatic resection. Updates Surg 2017; 70:57-66. [DOI: 10.1007/s13304-017-0486-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 08/10/2017] [Indexed: 12/12/2022]
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12
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Margonis GA, Sasaki K, Andreatos N, Nishioka Y, Sugawara T, Amini N, Buettner S, Hashimoto M, Shindoh J, Pawlik TM. Prognostic impact of complications after resection of early stage hepatocellular carcinoma. J Surg Oncol 2017; 115:791-804. [PMID: 28205284 DOI: 10.1002/jso.24576] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 01/11/2017] [Accepted: 01/13/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Resection is the most effective treatment for HCC. However, postoperative morbidity is common and its impact on long-term oncological outcome remains unclear. METHODS Long-term outcomes of 774 patients who underwent curative resection for early stage HCC at Johns Hopkins Hospital and Toranomon Hospital were investigated after stratifying by the development of postoperative overall and infectious complications. RESULTS A minor or major postoperative complication developed in 281 and 65 patients, respectively, while postoperative mortality was 1.3% (n = 10). The 5-year cumulative recurrence and overall survival(OS) rates were 57.2% and 76.4%, respectively. Overall postoperative complications independently predicted worse OS in multivariable analysis (HR = 1.42, P = 0.021). Complication severity did not correlate with OS (P > 0.05). While infectious complications were not independent predictors of OS, the combination of blood transfusion and infectious complications led to significantly worse OS (66.3% vs. 44.9%, P = 0.008). Postoperative complications also correlated with increased recurrence risk, but only in patients with non-cirrhotic parenchyma (55.0% vs. 47.7%, P = 0.035) or non-viral hepatitis (55.6% vs. 44.4%, P = 0.002). CONCLUSIONS Post-operative morbidity independently predicted poor OS following hepatectomy for early stage HCC. A similar effect on recurrence was noted only in patients with favorable etiopathologic factors. Finally, the combination of peri-operative transfusion and subsequent infectious complications was associated with a synergistic negative effect on prognosis.
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Affiliation(s)
| | - Kazunari Sasaki
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nikolaos Andreatos
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yujiro Nishioka
- Hepatobiliary Surgery Division, Department of Digestive Surgery, Toranomon Hospital, Tokyo, Japan
| | - Toshitaka Sugawara
- Hepatobiliary Surgery Division, Department of Digestive Surgery, Toranomon Hospital, Tokyo, Japan
| | - Neda Amini
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Stefan Buettner
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Masaji Hashimoto
- Hepatobiliary Surgery Division, Department of Digestive Surgery, Toranomon Hospital, Tokyo, Japan
| | - Junichi Shindoh
- Hepatobiliary Surgery Division, Department of Digestive Surgery, Toranomon Hospital, Tokyo, Japan
| | - Timothy M Pawlik
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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13
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Usefulness of Mac-2 Binding Protein Glycosylation Isomer for Prediction of Posthepatectomy Liver Failure in Patients With Hepatocellular Carcinoma. Ann Surg 2017; 265:1201-1208. [DOI: 10.1097/sla.0000000000001836] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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14
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Furuyama T, Kudo A, Matsumura S, Mitsunori Y, Aihara A, Ban D, Ochiai T, Tanaka S, Tanabe M. Preoperative direct bilirubin to prothrombin time ratio index to prevent liver failure after minor hepatectomy. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2016; 23:763-770. [PMID: 27717165 DOI: 10.1002/jhbp.400] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 09/12/2016] [Indexed: 01/27/2023]
Abstract
BACKGROUND The most reliable index to predict the safety of hepatectomy for patients with poor liver function remains unknown. We aimed to construct a novel preoperative index to predict early liver failure (ELF) and mortality due to recurrence-free liver failure (MLF) after hepatectomy. METHODS Between 2000 and 2012, 385 consecutive patients with hepatocellular carcinoma undergoing curative minor hepatectomy were divided into two sequential cohorts: training set (n = 143) and validation set (n = 242), and observed until 2015. RESULTS Prothrombin time and direct bilirubin were independent predictors of both ELF and MLF in the training set. Thus we devised a novel index, the direct bilirubin to prothrombin time ratio index (DBPTRI). The areas under ROC curves of DBPTRI for predicting ELF and MLF were 0.78 and 0.93, respectively, in the validation set. Using a preoperative DBPTRI cut off of 4.2, we accurately predicted ELF and MLF in 86.8% and 88.4% of patients, respectively. DBPTRI was the best predictor of ELF and MLF when compared with conventional indices such as ICG-R15 and Child-Pugh score. Moreover, the 5-year overall survival rates of the patients with low and high DBPTRI were 59% and 36%, respectively (P < 0.0001). CONCLUSIONS DBPTRI may serve as a simple, non-invasive index for estimating liver failure after hepatectomy.
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Affiliation(s)
- Takaki Furuyama
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Atsushi Kudo
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Satoshi Matsumura
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Yusuke Mitsunori
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Arihiro Aihara
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Daisuke Ban
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Takanori Ochiai
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
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15
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Cheng J, Zhao P, Liu J, Liu X, Wu X. Preoperative aspartate aminotransferase-to-platelet ratio index (APRI) is a predictor on postoperative outcomes of hepatocellular carcinoma. Medicine (Baltimore) 2016; 95:e5486. [PMID: 27902606 PMCID: PMC5134803 DOI: 10.1097/md.0000000000005486] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Preoperative aspartate aminotransferase-to-platelet ratio index (APRI) has been identified as a biochemical marker for histological fibrogenesis and fibrosis in cirrhosis and prognosis of hepatocellular carcinoma (HCC). Whether preoperative APRI can predict postoperative short-term outcomes has not been studied. The purpose of this study was to investigate the ability of preoperative APRI to predict short-term outcomes following liver resection for HCC. APRI was evaluated in 360 patients undergoing liver resection for HCC. The receiver operating characteristic curve analysis was conducted to determine the cutoff value of the APRI in predicting postoperative morbidity. Univariate and multivariate analysis was performed to identify the risk factors for postoperative outcomes. The correlation of the preoperative APRI value with clinicopathological parameters was also examined. We found that the optimal cutoff value of the APRI was set at 9.5 for postoperative complications. APRI was an independent risk factor for overall complications by univariate and multivariate analyses. HCC patients with elevated APRI (>9.5) had a worse liver function and significantly higher postoperative complication rate. In conclusion, preoperative APRI is a useful biochemical marker to predict postoperative outcomes in HCC patients.
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Affiliation(s)
- JiWen Cheng
- Department of Pediatric Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University
| | - Pu Zhao
- Department of Neonatology, Shaanxi Provincial People's Hospital, Xi’an, Shaanxi Province
| | - JiangBo Liu
- Department of General Surgery, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan Province
| | - Xi Liu
- Department of Pathology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
| | - XuanLin Wu
- Department of Pediatric Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University
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16
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Yao H, Bian X, Mao L, Zi X, Yan X, Qiu Y. Preoperative Enteral Nutritional Support in Patients Undergoing Hepatectomy for Hepatocellular Carcinoma: A Strengthening the Reporting of Observational Studies in Epidemiology Article. Medicine (Baltimore) 2015; 94:e2006. [PMID: 26579806 PMCID: PMC4652815 DOI: 10.1097/md.0000000000002006] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
To compare the short-term outcomes between hepatocellular carcinoma (HCC) patients with and those without preoperative nutrition on the basis of postoperative enteral nutrition.HCC patients with postoperative enteral nutrition who underwent liver resection between February 2010 and December 2014 in Nanjing Drum Tower Hospital were considered for the study: 43 patients with and 36 patients without preoperative nutrition. Primary endpoint was the incidence of overall complications. Secondary endpoints were infectious and major complications.In the preoperative enteral nutrition group, shorter length of postoperative hospital stay (10.5 ± 2.7 versus 13.7 ± 6.3 days, P = 0.007), less exogenous albumin infusion (10.2 ± 22.4 versus 47.8 ± 97.7 g, P = 0.030), earlier first exhaust time (2.7 ± 0.8 versus 3.0 ± 0.9 days, P = 0.043), and first defection time (3.5 ± 0.9 versus 4.4 ± 1.4 days, P = 0.001) were observed. No significant differences were observed in the incidence of overall complications (32.6% versus 52.8%, P = 0.070), infectious complications (7.0% versus 8.3%, P = 1), and major complications (14.0% versus 11.1%, P = 0.969) between the preoperative enteral nutrition and control group.Preoperative enteral nutrition could improve short-term outcomes of HCC patients via accelerating the recovery of gastrointestinal function and shortening the length of postoperative hospital stay.
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Affiliation(s)
- Hui Yao
- From the Department of Hepatopancreatobiliary Surgery, Drum Tower Hospital, Medical School of Nanjing University (HY, XB, LM, XY, YQ) and Department of Hepatopancreatobiliary Surgery, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China (XZ)
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17
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Zhou YM, Zhang XF, Li B, Sui CJ, Yang JM. Postoperative complications affect early recurrence of hepatocellular carcinoma after curative resection. BMC Cancer 2015; 15:689. [PMID: 26466573 PMCID: PMC4604633 DOI: 10.1186/s12885-015-1720-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 10/08/2015] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Postoperative recurrence remains the major cause of death after curative resection for hepatocellular carcinoma (HCC). This study was conducted to evaluate the impact of postoperative complications on HCC recurrence after curative resection. METHODS The postoperative outcomes of 274 HCC patients who underwent curative resection were analysed retrospectively. RESULTS Of the 247 HCC patients, 103 (37.6 %) patients developed postoperative complications. The occurrence of postoperative complications was found to be associated with a significantly higher tumor recurrence (76.2 % vs. 56.6 %, P = 0.002) and a lower 5-year overall survival rate (27.7 % vs. 42.1 %; P = 0.037) as compared with those without complications. Regarding the recurrence pattern, early recurrence (≤2 years) was more frequently seen in patients with complications than that in patients without complications (54.5 % vs.38.6 %; P = 0.011). Multivariate analysis indicated that postoperative complications occurrence was an independent risk factor for early recurrence (odds ratio [OR] 2.223; 95 % confidence intervals [95 % CI] 1.161-4.258, P = 0.016) and poor overall survival (OR 1.413; 95 % CI, 1.012-1.971, P = 0.042). CONCLUSIONS The results of the present study indicate that the occurrence of postoperative complications is a predictive factor for HCC recurrence after curative hepatectomy, especially for early recurrence.
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Affiliation(s)
- Yan-Ming Zhou
- Department of Hepatobiliary & Pancreatovascular Surgery, First affiliated Hospital of Xiamen University, Xiamen, China.
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Xiao-Feng Zhang
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Bin Li
- Department of Hepatobiliary & Pancreatovascular Surgery, First affiliated Hospital of Xiamen University, Xiamen, China.
| | - Cheng-Jun Sui
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
| | - Jia-Mei Yang
- Department of Special Treatment, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
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18
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Bouattour M, Payancé A, Wassermann J. Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging. World J Hepatol 2015; 7:2245-2263. [PMID: 26380650 PMCID: PMC4568486 DOI: 10.4254/wjh.v7.i20.2245] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 05/16/2015] [Accepted: 08/30/2015] [Indexed: 02/06/2023] Open
Abstract
Many years after therapeutic wilderness, sorafenib finally showed a clinical benefit in patients with advanced hepatocellular carcinoma. After the primary general enthusiasm worldwide, some disappointments emerged particularly since no new treatment could exceed or at least match sorafenib in this setting. Without these new drugs, research focused on optimizing care of patients treated with sorafenib. One challenging research approach deals with identifying prognostic and predictive biomarkers of sorafenib in this population. The task still seems difficult; however appropriate investigations could resolve this dilemma, as observed for some malignancies where other drugs were used.
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Affiliation(s)
- Mohamed Bouattour
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Audrey Payancé
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
| | - Johanna Wassermann
- Mohamed Bouattour, Audrey Payancé, Department of Hepatology, Beaujon University Hospital (AP-HP - Paris 7 Diderot), 92110 Clichy, France
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19
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Cheng V, Inaba K, Haltmeier T, Gutierrez A, Siboni S, Benjamin E, Lam L, Demetriades D. Serum transthyretin is a predictor of clinical outcomes in critically ill trauma patients. Surgery 2015; 158:438-44. [PMID: 26003908 DOI: 10.1016/j.surg.2015.02.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2015] [Revised: 01/27/2015] [Accepted: 02/04/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND In surgery patients, low preoperative serum transthyretin (TTR) level is associated with greater rates of infection and mortality. However, the predictive value of TTR on surgical outcomes after major trauma has not yet been studied. METHODS Critically ill trauma patients who underwent surgery for trauma and had TTR preoperatively measured after admission to the surgical intensive care unit (ICU) at the LAC+USC Medical Center (01/2008-05/2014) were identified retrospectively. Univariable and multivariable regression analyses determined the significance of TTR on outcomes. RESULTS We identified 348 patients. Univariable analysis indicated that patients with lower TTR had more infections (P < .001), higher mortality (P = .007), longer hospital stay (P < .001), longer ICU stay (P < .001), and increased ventilator days (P < .001). Even after adjusting for differences in patient characteristics, lower TTR level was associated with greater infectious complication rates (P = .001), greater mortality (P = .005), longer hospital stay (P = .013), longer ICU stay (P = .030), and increased ventilator days (P = .044). CONCLUSION In critically ill trauma patients, low serum TTR level is associated with poorer clinical outcomes, and its prognostic utility warrants further study.
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Affiliation(s)
- Vincent Cheng
- Division of Trauma and Surgical Critical Care, Department of Surgery, LAC+USC Medical Center, University of Southern California, Los Angeles, CA
| | - Kenji Inaba
- Division of Trauma and Surgical Critical Care, Department of Surgery, LAC+USC Medical Center, University of Southern California, Los Angeles, CA.
| | - Tobias Haltmeier
- Division of Trauma and Surgical Critical Care, Department of Surgery, LAC+USC Medical Center, University of Southern California, Los Angeles, CA
| | - Adam Gutierrez
- Division of Trauma and Surgical Critical Care, Department of Surgery, LAC+USC Medical Center, University of Southern California, Los Angeles, CA
| | - Stefano Siboni
- Division of Trauma and Surgical Critical Care, Department of Surgery, LAC+USC Medical Center, University of Southern California, Los Angeles, CA
| | - Elizabeth Benjamin
- Division of Trauma and Surgical Critical Care, Department of Surgery, LAC+USC Medical Center, University of Southern California, Los Angeles, CA
| | - Lydia Lam
- Division of Trauma and Surgical Critical Care, Department of Surgery, LAC+USC Medical Center, University of Southern California, Los Angeles, CA
| | - Demetrios Demetriades
- Division of Trauma and Surgical Critical Care, Department of Surgery, LAC+USC Medical Center, University of Southern California, Los Angeles, CA
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20
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Mizuguchi T, Mitaka T, Hirata K. Role of Branched Chain Amino Acids in Cellular and Organ Damage: The Prognostic Significance of the Preoperative Branched Chain Amino Acid to Tyrosine Ratio. BRANCHED CHAIN AMINO ACIDS IN CLINICAL NUTRITION 2015:65-77. [DOI: 10.1007/978-1-4939-1914-7_5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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21
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Abstract
As the number of liver resections in the United States has increased, operations are more commonly performed on older patients with multiple comorbidities. The advent of effective chemotherapy and techniques such as portal vein embolization, have compounded the number of increasingly complex resections taking up to 75% of healthy livers. Four potentially devastating complications of liver resection include postoperative hemorrhage, venous thromboembolism, bile leak, and post-hepatectomy liver failure. The risk factors and management of these complications are herein explored, stressing the importance of identifying preoperative factors that can decrease the risk for these potentially fatal complications.
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Affiliation(s)
- Maria C Russell
- Division of Surgical Oncology, Department of Surgery, Emory University Hospital, 550 Peachtree Street Northeast, 9th Floor MOT, Atlanta, GA 30308, USA.
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22
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Ishii M, Mizuguchi T, Harada K, Ota S, Meguro M, Ueki T, Nishidate T, Okita K, Hirata K. Comprehensive review of post-liver resection surgical complications and a new universal classification and grading system. World J Hepatol 2014; 6:745-751. [PMID: 25349645 PMCID: PMC4209419 DOI: 10.4254/wjh.v6.i10.745] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 09/01/2014] [Accepted: 09/16/2014] [Indexed: 02/06/2023] Open
Abstract
Liver resection is the gold standard treatment for certain liver tumors such as hepatocellular carcinoma and metastatic liver tumors. Some patients with such tumors already have reduced liver function due to chronic hepatitis, liver cirrhosis, or chemotherapy-associated steatohepatitis before surgery. Therefore, complications due to poor liver function are inevitable after liver resection. Although the mortality rate of liver resection has been reduced to a few percent in recent case series, its overall morbidity rate is reported to range from 4.1% to 47.7%. The large degree of variation in the post-liver resection morbidity rates reported in previous studies might be due to the lack of consensus regarding the definitions and classification of post-liver resection complications. The Clavien-Dindo (CD) classification of post-operative complications is widely accepted internationally. However, it is hard to apply to some major post-liver resection complications because the consensus definitions and grading systems for post-hepatectomy liver failure and bile leakage established by the International Study Group of Liver Surgery are incompatible with the CD classification. Therefore, a unified classification of post-liver resection complications has to be established to allow comparisons between academic reports.
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Affiliation(s)
- Masayuki Ishii
- Masayuki Ishii, Toru Mizuguchi, Kohei Harada, Shigenori Ota, Makoto Meguro, Tomomi Ueki, Toshihiko Nishidate, Kenji Okita, Koichi Hirata, Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Postgraduate School of Medicine, Sapporo, Hokkaido 060-8543, Japan
| | - Toru Mizuguchi
- Masayuki Ishii, Toru Mizuguchi, Kohei Harada, Shigenori Ota, Makoto Meguro, Tomomi Ueki, Toshihiko Nishidate, Kenji Okita, Koichi Hirata, Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Postgraduate School of Medicine, Sapporo, Hokkaido 060-8543, Japan
| | - Kohei Harada
- Masayuki Ishii, Toru Mizuguchi, Kohei Harada, Shigenori Ota, Makoto Meguro, Tomomi Ueki, Toshihiko Nishidate, Kenji Okita, Koichi Hirata, Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Postgraduate School of Medicine, Sapporo, Hokkaido 060-8543, Japan
| | - Shigenori Ota
- Masayuki Ishii, Toru Mizuguchi, Kohei Harada, Shigenori Ota, Makoto Meguro, Tomomi Ueki, Toshihiko Nishidate, Kenji Okita, Koichi Hirata, Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Postgraduate School of Medicine, Sapporo, Hokkaido 060-8543, Japan
| | - Makoto Meguro
- Masayuki Ishii, Toru Mizuguchi, Kohei Harada, Shigenori Ota, Makoto Meguro, Tomomi Ueki, Toshihiko Nishidate, Kenji Okita, Koichi Hirata, Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Postgraduate School of Medicine, Sapporo, Hokkaido 060-8543, Japan
| | - Tomomi Ueki
- Masayuki Ishii, Toru Mizuguchi, Kohei Harada, Shigenori Ota, Makoto Meguro, Tomomi Ueki, Toshihiko Nishidate, Kenji Okita, Koichi Hirata, Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Postgraduate School of Medicine, Sapporo, Hokkaido 060-8543, Japan
| | - Toshihiko Nishidate
- Masayuki Ishii, Toru Mizuguchi, Kohei Harada, Shigenori Ota, Makoto Meguro, Tomomi Ueki, Toshihiko Nishidate, Kenji Okita, Koichi Hirata, Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Postgraduate School of Medicine, Sapporo, Hokkaido 060-8543, Japan
| | - Kenji Okita
- Masayuki Ishii, Toru Mizuguchi, Kohei Harada, Shigenori Ota, Makoto Meguro, Tomomi Ueki, Toshihiko Nishidate, Kenji Okita, Koichi Hirata, Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Postgraduate School of Medicine, Sapporo, Hokkaido 060-8543, Japan
| | - Koichi Hirata
- Masayuki Ishii, Toru Mizuguchi, Kohei Harada, Shigenori Ota, Makoto Meguro, Tomomi Ueki, Toshihiko Nishidate, Kenji Okita, Koichi Hirata, Department of Surgery, Surgical Oncology and Science, Sapporo Medical University Postgraduate School of Medicine, Sapporo, Hokkaido 060-8543, Japan
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23
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Zhang F, Wu G, Sun H, Ding J, Xia F, Li X, Ma K, Wang S, Bie P. Radiofrequency ablation of hepatocellular carcinoma in elderly patients fitting the Milan criteria: a single centre with 13 years experience. Int J Hyperthermia 2014; 30:471-9. [PMID: 25314335 DOI: 10.3109/02656736.2014.961042] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
PURPOSE The aim of this study was to evaluate the safety and outcomes of radiofrequency ablation (RFA) in treating elderly patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS This was a retrospective analysis of 391 patients with HCC fitting the Milan criteria and treated with RFA for the first time from 1999 to 2012 at the Southwest Hospital, China. The patients were divided into two groups, an elderly group (age ≥70 years, n = 102) and a non-elderly group (age <70 years, n = 289). Long-term outcomes were assessed on all patients and survival rates were calculated. RESULTS The overall survival rates of the two groups differed significantly. The recurrence-free survival rates of the two groups did not differ significantly. There was no significant difference between the two groups. Excluding comorbid diseases related deaths, the overall survival rates of the two groups did not differ significantly. CONCLUSIONS The safety and outcomes of RFA in treating early HCC were similar among elderly and non-elderly patients. Co-morbid diseases, such as cardiovascular disease and respiratory disease, rather than HCC or liver diseases, contributed to the relatively low overall survival rate found in elderly patients.
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Affiliation(s)
- Fengshen Zhang
- Department of Hepatobiliary Surgery, 324 Hospital of the People's Liberation Army , Chongqing , China and
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Fukushima K, Fukumoto T, Kuramitsu K, Kido M, Takebe A, Tanaka M, Itoh T, Ku Y. Assessment of ISGLS definition of posthepatectomy liver failure and its effect on outcome in patients with hepatocellular carcinoma. J Gastrointest Surg 2014; 18:729-36. [PMID: 24297653 DOI: 10.1007/s11605-013-2423-y] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 11/18/2013] [Indexed: 01/31/2023]
Abstract
BACKGROUND Posthepatectomy liver failure (PHLF) is a major complication after hepatectomy. As there was no standardized definition, the International Study Group of Liver Surgery (ISGLS) defined PHLF as increased international normalized ratio and hyperbilirubinemia on or after postoperative day 5 in 2010. We evaluated the impact of the ISGLS definition of PHLF on hepatocellular carcinoma (HCC) patients. METHODS We retrospectively analyzed 210 consecutive HCC patients who underwent curative hepatectomy at our facility from 2005 to 2010. The median follow-up period after hepatectomy was 35.2 months. RESULTS Thirty-nine (18.6%) patients fulfilled the ISGLS definition of PHLF. Overall survival (OS) rates at 1, 3, and 5 years in patients with/without PHLF were 69.1/93.5, 45.1/72.5, and 45.1/57.8%, respectively (P = 0.002). Recurrence-free survival (RFS) rates at 1, 3, and 5 years in patients with/without PHLF were 40.9/65.9, 15.7/38.3, and 15.7/20.3%, respectively (P = 0.003). Multivariate analysis revealed that PHLF was significantly associated with both OS (P = 0.047) and RFS (P = 0.019). Extent of resection (P < 0.001), intraoperative blood loss (P = 0.002), and fibrosis stage (P = 0.040) were identified as independent risk factors for developing PHLF. CONCLUSION The ISGLS definition of PHLF was associated with OS and RFS in HCC patients, and long-term survival will be improved by reducing the incidence of PHLF.
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Affiliation(s)
- Kenji Fukushima
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
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Liver stiffness measurement by transient elastography as a predictor on posthepatectomy outcomes. Ann Surg 2013; 257:922-8. [PMID: 23001077 DOI: 10.1097/sla.0b013e318269d2ec] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Liver fibrosis and cirrhosis are well-known risk factors for morbidity after hepatectomy. Liver stiffness measurement (LSM) using transient elastography is a new method for detection of hepatic fibrosis and cirrhosis with high accuracy. Whether LSM can predict posthepatectomy outcomes has not been studied. METHODS This was a prospective cohort study in which consecutive patients underwent hepatectomy for various indications from February 2010 to July 2011. All patients received detailed preoperative assessments including LSM and indocyanine green (ICG) clearance test. The primary outcome was major postoperative complication. RESULTS One hundred five patients with a mean age of 59 years were included; 75 (71.4%) had chronic viral hepatitis and 76 (72.4%) had hepatocellular carcinoma. Thirty-four patients (32.4%) received major hepatectomy. The median ICG retention rate at 15 minutes was 4.2 (0.1%-32%) and the median LSM was 9.4 (3.3-75 kPa). For posthepatectomy outcomes, only LSM but not ICG showed significant correlation with major postoperative complications on receiver operating characteristic curves, with area under the curve of 0.79 (P < 0.001). Using the calculated cutoff at 12.0 kPa, LSM had sensitivity of 85.7% and specificity of 71.8% in the prediction of major postoperative complications. It was also an independent prognostic factor for major postoperative complications by multivariate analysis. The operative blood loss and transfusion rate were also significantly higher in patients with LSM >12.0 kPa. CONCLUSIONS High LSM (>12.0 kPa) predicted worse posthepatectomy outcomes. Preoperative LSM was better than ICG test in the prediction of major postoperative complications. It was a useful preoperative investigation for risk stratification before hepatectomy.
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Mizuguchi T, Kawamoto M, Meguro M, Nakamura Y, Ota S, Hui TT, Hirata K. Prognosis and predictors of surgical complications in hepatocellular carcinoma patients with or without cirrhosis after hepatectomy. World J Surg 2013; 37:1379-1387. [PMID: 23479099 DOI: 10.1007/s00268-013-1989-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Although poor liver function is associated with a high morbidity rate and poor prognosis in hepatocellular carcinoma (HCC) patients, the exact effects of liver pathology on the surgical outcomes of HCC patients are poorly understood. The purpose of this study was to assess how the liver pathology of HCC patients affects their prognosis and complications rate after liver resection. METHODS Between January 2006 and November 2010, 149 consecutive hepatocellular carcinoma patients, including 79 noncirrhosis patients and 70 cirrhosis patients, were enrolled in this study. RESULTS Among the noncirrhotic patients, operative time, fresh frozen plasma (FFP) transfusion requirement, tumor size, and serum retinol binding protein (RBP) levels were significantly higher in the complications group than in the complications-free groups. On the other hand, in the cirrhotic patients the prothrombin time (PT) and indocyanine green retention value at 15 min (ICGR15) of the complications group were significantly lower and higher, respectively, than those of the complications-free group. In the noncirrhotic patients, recurrence-free survival and overall survival did not differ between the complications and complications-free groups. On the other hand, in the cirrhotic patients, the recurrence-free survival and overall survival of the complications-free group were significantly longer than those of the complications group. CONCLUSIONS In the noncirrhotic patients, surgical complications had no prognostic effect, whereas they had a significant survival impact in the cirrhotic patients. The surgical strategy for HCC should be based on the patient's pathological background.
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Affiliation(s)
- Toru Mizuguchi
- Department of Surgery I, Sapporo Medical University Hospital, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, Hokkaido, 060-8543, Japan.
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Abstract
Hepatocellular carcinoma (HCC) is a significant cause of cancer-related morbidity and mortality worldwide. Despite improvements in local therapies, including surgical resection, liver transplantation, and transarterial embolization, the prognosis remains poor for the majority of patients who develop recurrence or present with advanced disease. Systemic therapy with the tyrosine kinase inhibitor sorafenib represents a milestone in advanced HCC but provides a limited survival benefit. Ongoing efforts to study hepatocarcinogenesis have identified an important role for c-MET signaling in the promotion of tumor growth, angiogenesis, and metastasis. In this review, we summarize the preclinical data from human tissue, cell lines, and animal models that implicate c-MET in the pathogenesis of HCC. We also evaluate potential biomarkers that may estimate prognosis or predict response to c-MET inhibitors for more rational clinical trial design. Finally, we discuss the latest clinical trials of c-MET inhibitors in advanced HCC.
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Affiliation(s)
- Lipika Goyal
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA
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Harada K, Mizuguchi T, Katagiri Y, Kawamoto M, Nakamura Y, Meguro M, Ota S, Sasaki S, Miyanishi K, Sonoda T, Mori M, Shinomura Y, Kato J, Hirata K. Area between the hepatic and heart curves of (99m)Tc-galactosyl-human serum albumin scintigraphy represents liver function and disease progression for preoperative evaluation in hepatocellular carcinoma patients. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2012; 19:667-673. [PMID: 22179579 DOI: 10.1007/s00534-011-0486-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND/PURPOSE We developed software to calculate the pixels of interest in the area between the hepatic and heart curves (ABC) of (99m)Tc-galactosyl human serum albumin (GSA) scintigraphy. The aim of this study was to examine the accuracy of the ABC to evaluate liver function before hepatectomy. METHODS Between January 2005 and December 2010, 205 consecutive patients who underwent initial hepatectomy were enrolled in this study. The ABC was calculated using original computer software. The area under the receiver operating characteristic curve (AUC) was calculated for evaluation of Child-Pugh score grade B (Child B), pathological chronic hepatitis (CH), and liver cirrhosis (LC). RESULTS The AUC of any indicator for Child B was more than 0.900 except bilirubin. The AUC of ABC for CH and LC (AUC 0.734 each) was comparable to those of HH15 (clearance index; AUC 0.704 and 0.700, respectively) and LHL15 (receptor index; AUC 0.703 and 0.706, respectively) in multiple receiver operating characteristic comparison. CONCLUSIONS We have developed a novel liver function indicator, the ABC, to count radioactivity in sequence. The ABC reflects liver function according to pathological deterioration of the liver. Although the ABC gave no significant advantage compared to HH15 and LHL15, it improved the AUC evaluation by 0.028-0.034.
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Affiliation(s)
- Kohei Harada
- Department of Surgery I, Sapporo Medical University Hospital, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
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Llovet JM, Peña CEA, Lathia CD, Shan M, Meinhardt G, Bruix J. Plasma Biomarkers as Predictors of Outcome in Patients with Advanced Hepatocellular Carcinoma. Clin Cancer Res 2012; 18:2290-300. [PMID: 22374331 DOI: 10.1158/1078-0432.ccr-11-2175] [Citation(s) in RCA: 441] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Josep M Llovet
- Barcelona Clínic Liver Cancer Group, Liver Unit, CIBERehd, Institut d'Investigacions Biomèdiques, August Pi i Sunyer, Hospital Clínic Barcelona, Barcelona, Spain.
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Sun R, Zhang Q, Guo L, Chen MY, Sun Y, Cao B, Sun J. HGF stimulates proliferation through the HGF/c-Met pathway in nasopharyngeal carcinoma cells. Oncol Lett 2012; 3:1124-1128. [PMID: 22783404 DOI: 10.3892/ol.2012.613] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Accepted: 01/16/2012] [Indexed: 01/05/2023] Open
Abstract
Hepatocyte growth factor (HGF) and its receptor c-Met are important in the development and homeostasis of a variety of human malignancies. However, the role of the HGF/c-Met signaling pathway in nasopharyngeal carcinoma (NPC) has not been clearly elucidated. This study examined the effect of HGF/c-Met on proliferation and migration in several NPC cell lines. RT-PCR was used to detect the HGF gene in CNE-1, CNE-2, HK-1, HONE-1 and SUNE-1 NPC cells. However, HGF gene expression was not detected in any of these cells. Using immunoblotting analysis, the Met25 protein was identified in HONE-1, HK-1 and CNE-1 cells. Results from fluorescence-activated cell sorting (FACS) analysis revealed that anti-Met25 mAb specifically bound Met-expressing HONE-1, HK-1 and CNE-1 cells. It was further demonstrated that exogenous HGF was able to stimulate the proliferation of HONE-1 and HK-1 cells and the healing of scrape wounds in HONE-1 NPC cells. Our results reveal the potential therapeutic applications of combination therapy with antibodies targeting HGF in NPC patients.
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Affiliation(s)
- Rui Sun
- State Key Laboratory of Oncology in Southern China
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Moselli NM, Baricocchi E, Ribero D, Sottile A, Suita L, Debernardi F. Intraoperative epidural analgesia prevents the early proinflammatory response to surgical trauma. Results from a prospective randomized clinical trial of intraoperative epidural versus general analgesia. Ann Surg Oncol 2011; 18:2722-2731. [PMID: 21479690 DOI: 10.1245/s10434-011-1700-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2010] [Indexed: 01/04/2025]
Abstract
BACKGROUND The intraoperative epidural analgesia (EA) has the potential to reduce stress response to surgical trauma which induces a transient immunoactivation that has a negative impact on the outcome. This study investigates the effect of intraoperative EA versus intravenous analgesia (IA) on the immune function. METHODS A total of 35 consecutive patients candidated to undergo major surgery for colon cancer were randomly assigned to intraoperative EA (n = 18) or IA (n = 17). Blood samples for TNF-α, IFN-γ, IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, and GM-CSF were obtained before surgery (T(pre)), 3 h (T(3h)), and 24 h (T(24h)) after skin incision. Data on postoperative complications were prospectively collected and analyzed. RESULTS In the EA group, IL-4 increased from T(pre) to T(3h) and from T(3h) to T(24h), IL-10 increased from T(pre) to T(3h) and persisted unmodified thereafter. At all time-points, IL-4 and IL-10 serum levels were significantly higher than those in the IA group. Conversely, in the IA group, IL-4 and IL-10 serum levels did not change while all other cytokines levels were significantly higher compared with the EA group. In particular, IL-6 progressively reached a 7-fold increase of its basal value at T(24h). Complications were significantly more common in IA patients (13 of 17) compared with EA patients (7 of 18) (P = .024). CONCLUSIONS Our results indicate that in cancer patients undergoing major elective colon surgery, the EA attenuates the surgery-induced proinflammatory response and the typical postoperative transient immunosuppression and seems associated with a reduced rate of postoperative complications compared with IA.
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Affiliation(s)
- Nora Maria Moselli
- Department of Anesthesiology, Intensive Care and Pain Therapy, IRCC-Institute for Cancer Research and Treatment, Candiolo, Italy
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Nakamura Y, Mizuguchi T, Kawamoto M, Meguro M, Harada K, Ota S, Hirata K. Cluster analysis of indicators of liver functional and preoperative low branched-chain amino acid tyrosine ration indicate a high risk of early recurrence in analysis of 165 hepatocellular carcinoma patients after initial hepatectomy. Surgery 2011; 150:250-262. [PMID: 21801962 DOI: 10.1016/j.surg.2011.06.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2010] [Accepted: 06/13/2011] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cluster analysis is used for dividing many prognostic indicators, including liver function, tumor progression, and operative variables, into specific clusters. The albumin (ALB), hepatocyte growth factor (HGF), and branched chain amino-acid to tyrosine ratio (BTR) may represent the severity of liver disease and function of the hepatic reserve. We developed the ALB-BTR and HGF-BTR classifications depending on each level to find specific unique subgroups. Our aim was to identify specific subgroups destined for favorable and poor prognoses after initial hepatectomy. METHODS Between 2002 and 2008, 165 patients were analyzed retrospectively. Liver function indicators, including BTR, tumor-related factors, and operative variables, were evaluated by cluster analysis with Ward's criterion. The ALB-BTR classification was divided into 4 groups depending on ALB (cutoff value, 4.0 g/dL) and BTR (cutoff value, 6.0). The HGF-BTR classification was also divided into 4 groups depending on HGF (cutoff value, 0.35 ng/mL) and BTR (cutoff value, 6.0). The prognoses of the subgroups were compared by the log-rank test. RESULTS Cluster analysis divided multiple indicators into 5 different clusters. In each cluster, we further analyzed subgroups using the ALB-BTR and HGF-BTR classification. Mean recurrence-free survival times in ALB-GI (19.1 ± 2.4 months) and HGF-GIII (29.4 ± 3.8 months) were less than their mean overall survival times. CONCLUSION Cluster analysis is useful to find similar and different indicators. Even though liver function was well preserved, low BTR could identify early recurrence in hepatocellular carcinoma patients after resection.
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Affiliation(s)
- Yukio Nakamura
- Department of Surgery I, Sapporo Medical University Hospital, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
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Mizuguchi T, Kawamoto M, Meguro M, Nakamura Y, Harada K, Kukita K, Hirata K. Prognostic impact of preoperative the branched-chain amino acid to the tyrosine ratio in hepatocellular carcinoma patients after initial hepatectomy. J Gastrointest Surg 2011; 15:1433-1439. [PMID: 21607795 DOI: 10.1007/s11605-011-1566-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2010] [Accepted: 05/11/2011] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The branched-chain amino acid/tyrosine ratio (BTR) reflects the amino acid balance and the severity of liver disease. The aim of the present study was to determine the relationship between BTR and liver function in patients with hepatocellular carcinoma (HCC). Furthermore, we evaluated the clinical usefulness of BTR as a prognostic indicator of disease-free and overall patient survival after initial hepatectomy. METHODS Between January 2004 and December 2008, 105 consecutive HCC patients who underwent initial hepatectomy were enrolled in this study. The correlation between BTR and preoperative liver functional indicators was evaluated. The cutoff levels of BTR for 2-year survival prediction were evaluated using a dot blot diagram. The patients were divided into high BTR (4.5 or higher) and low BTR (4.4 or lower) groups and these were compared in terms of clinical variables such as liver functional indicators, operative variables, and tumor characteristics. RESULTS The preoperative BTR level decreased according to the severity of liver disease. BTR was correlated with the albumin, bilirubin, and prealbumin levels, as well as the prothrombin time. Although the preoperative liver function was significantly different between the high BTR and low BTR groups, the operative variables and tumor-related variables were not found to be significantly different. Postoperative complications in the high BTR group were significantly less frequent than in the low BTR group (p = 0.003). Disease-free and overall patient survival in the high BTR group were significantly longer than in the low BTR group (p < 0.001 and p = 0.021, respectively). CONCLUSIONS BTR reflected the pathological liver background with a high correlation to the other liver functional indicators. BTR is thus considered to be a useful marker to predict postoperative complications, disease-free survival, and overall survival of HCC patients after initial hepatectomy. It is, therefore, a useful indicator of liver function and a predictor for the risk of cancer recurrence and overall survival in HCC patients.
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Affiliation(s)
- Toru Mizuguchi
- Department of Surgery I, Sapporo Medical University Hospital, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, 060-8543, Japan.
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Nagai T, Arao T, Furuta K, Sakai K, Kudo K, Kaneda H, Tamura D, Aomatsu K, Kimura H, Fujita Y, Matsumoto K, Saijo N, Kudo M, Nishio K. Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma. Mol Cancer Ther 2011; 10:169-77. [PMID: 21220499 DOI: 10.1158/1535-7163.mct-10-0544] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The epithelial mesenchymal transition (EMT) has emerged as a pivotal event in the development of the invasive and metastatic potentials of cancer progression. Sorafenib, a VEGFR inhibitor with activity against RAF kinase, is active against hepatocellular carcinoma (HCC); however, the possible involvement of sorafenib in the EMT remains unclear. Here, we examined the effect of sorafenib on the EMT. Hepatocyte growth factor (HGF) induced EMT-like morphologic changes and the upregulation of SNAI1 and N-cadherin expression. The downregulation of E-cadherin expression in HepG2 and Huh7 HCC cell lines shows that HGF mediates the EMT in HCC. The knockdown of SNAI1 using siRNA canceled the HGF-mediated morphologic changes and cadherin switching, indicating that SNAI1 is required for the HGF-mediated EMT in HCC. Interestingly, sorafenib and the MEK inhibitor U0126 markedly inhibited the HGF-induced morphologic changes, SNAI1 upregulation, and cadherin switching, whereas the PI3 kinase inhibitor wortmannin did not. Collectively, these findings indicate that sorafenib downregulates SNAI1 expression by inhibiting mitogen-activated protein kinase (MAPK) signaling, thereby inhibiting the EMT in HCC cells. In fact, a wound healing and migration assay revealed that sorafenib completely canceled the HGF-mediated cellular migration in HCC cells. In conclusion, we found that sorafenib exerts a potent inhibitory activity against the EMT by inhibiting MAPK signaling and SNAI1 expression in HCC. Our findings may provide a novel insight into the anti-EMT effect of tyrosine kinase inhibitors in cancer cells.
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Affiliation(s)
- Tomoyuki Nagai
- Kazuto Nishio, Department of Genome Biology, Kinki University School of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka 589-8511, Japan
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Breuhahn K, Schirmacher P. Signaling networks in human hepatocarcinogenesis--novel aspects and therapeutic options. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2011; 97:251-77. [PMID: 21074736 DOI: 10.1016/b978-0-12-385233-5.00009-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) represents one of the most common human malignancies with poor prognosis. Because therapeutic strategies are insufficient for most HCC patients, there is a great need to determine the central molecular mechanisms and pathways in order to derive novel targets for systemic therapy. There is vast evidence that not only the dysregulation of distinct signaling cascades, but also their interactions at different levels, affect tumor cell function. Through these interactions, the effects of pathways can be increased, and even new tumor-supporting qualities acquired that further facilitate HCC progression. Although several approaches for the modulation of these relevant pathways are under development, future therapeutic strategies should take into account that oncogenic stimuli cannot be understood in a monodimensional manner. In order to avoid escape mechanisms during therapy, strategies based on comprehensive knowledge of the interactive regulatory network in hepatocarcinogenesis are necessary.
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Affiliation(s)
- K Breuhahn
- Institute of Pathology, University Hospital, Heidelberg, Germany
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Okamura Y, Takeda S, Fujii T, Sugimoto H, Nomoto S, Nakao A. Prognostic significance of postoperative complications after hepatectomy for hepatocellular carcinoma. J Surg Oncol 2011; 104:814-21. [DOI: 10.1002/jso.21977] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2011] [Accepted: 04/22/2011] [Indexed: 12/15/2022]
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Okamura Y, Takeda S, Fujii T, Sugimoto H, Nomoto S, Nakao A. Impact of the Thoracoabdominal Approach on Peri- and Postoperative Outcomes of Hepatectomy for Hepatocellular Carcinoma. World J Surg 2011; 35:1042-9. [DOI: 10.1007/s00268-011-1023-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Aune G, Lian AM, Tingulstad S, Torp SH, Forsmo S, Reseland JE, Stunes AK, Syversen U. Increased circulating hepatocyte growth factor (HGF): a marker of epithelial ovarian cancer and an indicator of poor prognosis. Gynecol Oncol 2011; 121:402-6. [PMID: 21284996 DOI: 10.1016/j.ygyno.2010.12.355] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Revised: 12/20/2010] [Accepted: 12/22/2010] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Hepatocyte growth factor (HGF) has been described to be increased in different cancers. In the present study we wanted to investigate whether HGF in serum can distinguish between benign and malignant ovarian tumors, and whether serum HGF levels can predict the outcome in patients with ovarian carcinomas. METHODS We included 123 consecutive patients appointed for laparotomy due to a pelvic mass. Preoperative levels of serum cancer antigen 125 (CA 125), HGF and HGF activator (HGFA) were quantified with immunological methods. We performed immunohistochemical analyses of HGFα, HGFβ and the receptor c-Met. Five-year survival of patients with advanced disease (stage III and stage IV) was analyzed with the Kaplan-Meier method. RESULTS Sixty patients had ovarian carcinomas, 23 borderline tumors, and 40 benign ovarian tumors. Patients with ovarian carcinomas had significantly higher preoperative HGF and CA 125 serum levels than patients with benign ovarian tumors, and borderline tumors. Patients with borderline tumors had significantly higher CA 125 values than benign cases. A combination of CA 125 and HGF increased the specificity in predicting carcinoma. We observed abundant HGFα, HGFβ and c-Met expressions in all ovarian tumors. Patients with advanced disease and preoperative serum HGF values ≥2SD above reference value had a shorter disease-free survival than patients with advanced disease and serum HGF <2SD above reference value. CONCLUSIONS HGF in serum is an indicator of ovarian carcinoma in women with a pelvic mass, and of a poor prognosis in advanced ovarian cancer.
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Affiliation(s)
- Guro Aune
- Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
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Mizuguchi T, Kawamoto M, Meguro M, Shibata T, Nakamura Y, Kimura Y, Furuhata T, Sonoda T, Hirata K. Laparoscopic hepatectomy: a systematic review, meta-analysis, and power analysis. Surg Today 2011; 41:39-47. [PMID: 21191689 DOI: 10.1007/s00595-010-4337-6] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2009] [Accepted: 03/16/2010] [Indexed: 12/15/2022]
Abstract
PURPOSE A previous meta-analysis study demonstrated that bleeding and the duration of the hospital stay following laparoscopic hepatectomy (Lap) were significantly smaller and shorter, respectively, than for patients undergoing an open approach (Op). The aim of the present study was to re-evaluate perioperative variables and adverse outcomes in patients undergoing Lap versus (vs) Op after 2000. METHODS A PubMed and Ovid Medline search identified clinical studies that compared the outcomes of Lap vs Op patients after 2000. A meta-analysis and power analysis were performed. RESULTS Operative time was not significantly different between the two approaches (95% confidence interval [CI]: -0.063 to 0.992). Patient bleeding in the Lap group was significantly lower than in the Op group (95% CI: -1.027 to -0.390). Complications with Lap patients were significantly less frequent (95% CI: 0.231-0.642), and the duration of the hospital stay for Lap patients was significantly shorter (95% CI: -0.950 to -0.530) than for Op patients. Only one paper presented 80% power with 0.05 α-errors in all four outcomes, whereas four studies did not have sufficient statistical power. CONCLUSIONS The clinical benefits of Lap include a smaller incidence of complications and a shorter duration of hospital stay at the current time. Several studies had too few cases to sufficiently evaluate these factors, although other studies were appropriately analyzed.
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Affiliation(s)
- Toru Mizuguchi
- Department of Surgery I, Sapporo Medical University, S-1, W-16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
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