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Lin KY, Chen QJ, Tang SC, Lin ZW, Zhang JX, Zheng SM, Li YT, Wang XM, Lu Q, Fu J, Guo LB, Zheng LF, You PH, Wu MM, Lin KC, Zhou WP, Yang T, Zeng YY. Prognostic implications of alpha-fetoprotein and C-reactive protein elevation in hepatocellular carcinoma following resection (PACE): a large cohort study of 2770 patients. BMC Cancer 2023; 23:1190. [PMID: 38053048 PMCID: PMC10696803 DOI: 10.1186/s12885-023-11693-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/28/2023] [Indexed: 12/07/2023] Open
Abstract
BACKGROUND Routine clinical staging for hepatocellular carcinoma (HCC) incorporates liver function, general health, and tumor morphology. Further refinement of prognostic assessments and treatment decisions may benefit from the inclusion of tumor biological marker alpha-fetoprotein (AFP) and systemic inflammation indicator C-reactive protein (CRP). METHODS Data from a multicenter cohort of 2770 HCC patients undergoing hepatectomy were analyzed. We developed the PACE risk score (Prognostic implications of AFP and CRP Elevation) after initially assessing preoperative AFP and CRP's prognostic value. Subgroup analyzes were performed in BCLC cohorts A and B using multivariable Cox analysis to evaluate the prognostic stratification ability of the PACE risk score and its complementary utility for BCLC staging. RESULTS Preoperative AFP ≥ 400ng/mL and CRP ≥ 10 mg/L emerged as independent predictors of poorer prognosis in HCC patients who underwent hepatectomy, leading to the creation of the PACE risk score. PACE risk score stratified patients into low, intermediate, and high-risk groups with cumulative 5-year overall (OS) and recurrence-free survival (RFS) rates of 59.6%/44.9%, 43.9%/38.4%, and 20.6%/18.0% respectively (all P < 0.001). Increased PACE risk scores correlated significantly with early recurrence and extrahepatic metastases frequency (all P < 0.001). The multivariable analysis identified intermediate and high-risk PACE scores as independently correlating with poor postoperative OS and RFS. Furthermore, the PACE risk score proficiently stratified the prognosis of BCLC stages A and B patients, with multivariable analyses demonstrating it as an independent prognostic determinant for both stages. CONCLUSION The PACE risk score serves as an effective tool for postoperative risk stratification, potentially supplementing the BCLC staging system.
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Affiliation(s)
- Kong-Ying Lin
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Qing-Jing Chen
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Shi-Chuan Tang
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Zhi-Wen Lin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Jian-Xi Zhang
- Department of Hepatobiliary Surgery, Xiamen Hospital, Beijing University of Chinese Medicine, Xiamen, 361000, China
| | - Si-Ming Zheng
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Ningbo University, Ningbo, 315000, China
| | - Yun-Tong Li
- Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, 361000, China
| | - Xian-Ming Wang
- Department of General Surgery, First Affiliated Hospital of Shandong First Medical University, Shandong, 250014, China
| | - Qiang Lu
- Department of Hepatopancreatobiliary Surgery, Third Hospital of Zhangzhou, Zhangzhou, 363000, China
| | - Jun Fu
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Luo-Bin Guo
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Li-Fang Zheng
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Peng-Hui You
- Biobank in Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Meng-Meng Wu
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Ke-Can Lin
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China
| | - Wei-Ping Zhou
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, 200000, China
| | - Tian Yang
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University (Second Military Medical University), Shanghai, 200000, China.
| | - Yong-Yi Zeng
- Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, China.
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350000, China.
- Liver Disease Research Center of Fujian Province, Fuzhou, 350000, China.
- Department of Hepatopancreatobiliary Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China.
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Yoon JH, Choi SK. Management of early-stage hepatocellular carcinoma: challenges and strategies for optimal outcomes. JOURNAL OF LIVER CANCER 2023; 23:300-315. [PMID: 37734717 PMCID: PMC10565545 DOI: 10.17998/jlc.2023.08.27] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 08/24/2023] [Accepted: 08/27/2023] [Indexed: 09/23/2023]
Abstract
Although hepatocellular carcinoma (HCC) is associated with a poor prognosis, management of early-stage HCC is often successful with highly efficacious treatment modalities such as liver transplantation, surgical resection, and radiofrequency ablation. However, unfavorable clinical outcomes have been observed under certain circumstances, even after efficient treatment. Factors that predict unsuitable results after treatment include tumor markers, inflammatory markers, imaging findings reflecting tumor biology, specific outcome indicators for each treatment modality, liver functional reserve, and the technical feasibility of the treatment modalities. Various strategies may overcome these challenges, including the application of reinforced treatment indication criteria with predictive markers reflecting tumor biology, compensation for technical issues with up-to-date technologies, modification of treatment modalities, downstaging with locoregional therapies (such as transarterial chemotherapy or radiotherapy), and recently introduced combination immunotherapies. In this review, we discuss the challenges to achieving optimal outcomes in the management of early-stage HCC and suggest strategies to overcome these obstacles.
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Affiliation(s)
- Jae Hyun Yoon
- Department of Gastroenterology and hepatology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
| | - Sung Kyu Choi
- Department of Gastroenterology and hepatology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea
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Yang YQ, Wen ZY, Liu XY, Ma ZH, Liu YE, Cao XY, Hou L, Xie H. Current status and prospect of treatments for recurrent hepatocellular carcinoma. World J Hepatol 2023; 15:129-150. [PMID: 36926237 PMCID: PMC10011906 DOI: 10.4254/wjh.v15.i2.129] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/13/2022] [Accepted: 01/23/2023] [Indexed: 02/24/2023] Open
Abstract
Owing to its heterogeneous and highly aggressive nature, hepatocellular carcinoma (HCC) has a high recurrence rate, which is a non-negligible problem despite the increasing number of available treatment options. Recent clinical trials have attempted to reduce the recurrence and develop innovative treatment options for patients with recurrent HCC. In the event of liver remnant recurrence, the currently available treatment options include repeat hepatectomy, salvage liver transplantation, tumor ablation, transcatheter arterial chemoembolization, stereotactic body radiotherapy, systemic therapies, and combination therapy. In this review, we summarize the strategies to reduce the recurrence of high-risk tumors and aggressive therapies for recurrent HCC. Additionally, we discuss methods to prevent HCC recurrence and prognostic models constructed based on predictors of recurrence to develop an appropriate surveillance program.
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Affiliation(s)
- Yu-Qing Yang
- Department of Epidemiology and Biostatistics, Jilin University, Changchun 130021, Jilin Province, China
| | - Zhen-Yu Wen
- Department of Occupational and Environmental Health, Jilin University, Changchun 130021, Jilin Province, China
| | - Xiao-Yan Liu
- Senior Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Zhen-Hu Ma
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Yan-E Liu
- Department of Epidemiology and Biostatistics, Jilin University, Changchun 130021, Jilin Province, China
| | - Xue-Ying Cao
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Li Hou
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Hui Xie
- Senior Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
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Immunological Markers, Prognostic Factors and Challenges Following Curative Treatments for Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms221910271. [PMID: 34638613 PMCID: PMC8508906 DOI: 10.3390/ijms221910271] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortalities worldwide. Patients with early-stage HCC are eligible for curative treatments, such as surgical resection, liver transplantation (LT) and percutaneous ablation. Although curative treatments provide excellent long-term survival, almost 70–80% of patients experience HCC recurrence after curative treatments. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease, are well-known risk factors for recurrence following curative therapies. Moreover, the tumor microenvironment (TME) also plays a key role in the recurrence of HCC. Many immunosuppressive mechanisms, such as an increase in regulatory T cells and myeloid-derived suppressor cells with a decrease in cytotoxic T cells, are implicated in HCC recurrence. These suppressive TMEs are also modulated by several factors and pathways, including mammalian target of rapamycin signaling, vascular endothelial growth factor, programmed cell death protein 1 and its ligand 1. Based on these mechanisms and the promising results of immune checkpoint blockers (ICBs) in advanced HCC, there have been several ongoing adjuvant studies using a single or combination of ICB following curative treatments in HCC. In this review, we strive to provide biologic and immunological markers, prognostic factors, and challenges associated with clinical outcomes after curative treatments, including resection, LT and ablation.
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Thompson CP, Jagdale A, Walcott G, Iwase H, Foote JB, Cron RQ, Hara H, Cleveland DC, Cooper DKC. A perspective on the potential detrimental role of inflammation in pig orthotopic heart xenotransplantation. Xenotransplantation 2021; 28:e12687. [PMID: 33786912 DOI: 10.1111/xen.12687] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/26/2021] [Accepted: 03/18/2021] [Indexed: 02/06/2023]
Abstract
There is a critical shortage of deceased human donor organs for transplantation. The need is perhaps most acute in neonates and infants with life-threatening congenital heart disease, in whom mechanical support devices are largely unsuccessful. If orthotopic (life-supporting) heart transplantation (OHTx) were consistently successful in the genetically engineered pig-to-nonhuman primate (NHP) model, a clinical trial of bridging with a pig heart in such patients might be justified. However, the results of pig OHTx in NHPs have been mixed and largely poor. We hypothesise that a factor is the detrimental effects of the inflammatory response that is known to develop (a) during any surgical procedure that requires cardiopulmonary bypass, and (b) immediately after an NHP recipient is exposed to a pig xenograft. We suggest that the combination of these two inflammatory responses has a direct detrimental effect on pig heart graft function, but also, and possibly of more importance, on recipient baboon pulmonary function, which further impacts survival of the pig heart graft. In addition, the inflammatory response almost certainly adversely impacts the immune response to the graft. If our hypothesis is correct, the potential steps that could be taken to reduce the inflammatory response or its effects (with varying degrees of efficacy) include (a) white blood cell filtration, (b) complement depletion or inactivation, (c) immunosuppressive therapy, (d) high-dose corticosteroid therapy, (e) cytokine/chemokine-targeted therapy, (f) ultrafiltration or CytoSorb hemoperfusion, (g) reduction in the levels of endogenous catecholamines, (h) triiodothyronine therapy and (i) genetic engineering of the organ-source pig. Prevention of the inflammatory response, or attenuation of its effects, by judicious anti-inflammatory therapy may contribute not only to early survival of the recipient of a genetically engineered pig OHTx, but also to improved long-term pig heart graft survival. This would open the possibility of initiating a clinical trial of genetically engineered pig OHTx as a bridge to allotransplantation.
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Affiliation(s)
- Charles P Thompson
- Xenotransplantation Program, Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Abhijit Jagdale
- Xenotransplantation Program, Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Gregory Walcott
- Department of Medicine/Cardiovascular Diseases, the University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hayato Iwase
- Xenotransplantation Program, Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jeremy B Foote
- Department of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Randall Q Cron
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hidetaka Hara
- Xenotransplantation Program, Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David C Cleveland
- Division of Cardiothoracic Surgery, Children's Hospital of Alabama, and Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David K C Cooper
- Xenotransplantation Program, Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
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Shavelle RM, Kwak JH, Saur R, Brooks JC, Rosenthal P. Life Expectancy after Liver Transplantation for Non-Cirrhotic Hepatocellular Carcinoma. Prog Transplant 2021; 31:117-125. [PMID: 33722096 DOI: 10.1177/15269248211002793] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Hepatocelluar carcinoma typically occurs with underlying cirrhosis. However roughly 20% of cases arise in a non-cirrhotic liver. There is limited literature that addresses the long-term survival of the narrow subgroup who received transplantation. For such patients we sought to calculate life expectancies both at time of transplant and several years later, stratified by key risk factors, and to determine if survival has improved in recent years. Such information can be helpful in making treatment decisions. METHODS Data on 4,373 non-cirrhotic HCC patients who underwent liver transplantation in the MELD era (2002-2018) from the United States OPTN database were analyzed using the Cox proportional hazards regression model and life table methods. RESULTS Demographic and past medical history factors related to survival were patient age, donor age over 20, and the presence of ascites or severe hepatic encephalopathy. Survival did not vary by race or sex. HCC-specific factors significantly related to survival were the total number of tumors, extrahepatic spread, lymph node involvement, satellite lesions, micro- or macrovascular invasion, tumor differentiation (grade), and pre-transplant treatment. Survival improved over the study period, at 4% per calendar year during the first 5 years post transplant and 1% per year thereafter. CONCLUSIONS Life expectancy in non-cirrhotic HCC transplant patients is much reduced from normal, and varies according to age and tumor-related factors. Survival improved modestly over the study period.
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Affiliation(s)
| | - Ji Hun Kwak
- Life Expectancy Project, San Francisco, CA, USA
| | - Rachel Saur
- Life Expectancy Project, San Francisco, CA, USA
| | | | - Philip Rosenthal
- Pediatric Hepatology, 8785University of California, San Francisco, CA, USA
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C-reactive protein can predict dose intensity, time to treatment failure and overall survival in HCC treated with lenvatinib. PLoS One 2020; 15:e0244370. [PMID: 33351844 PMCID: PMC7755182 DOI: 10.1371/journal.pone.0244370] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 12/08/2020] [Indexed: 12/19/2022] Open
Abstract
Background and aim Lenvatinib has become a first line treatment for unresectable hepatocellular carcinoma (HCC). However, continued administration is impossible in many patients due to treatment resistance and severe adverse events. This study aimed to identify predicting factors to select patients likely to benefit from lenvatinib treatment. Methods We retrospectively analyzed 53 patients who were treated with lenvatinib for unresectable HCC. They were divided to two groups; low C-reactive protein (CRP) group with pretreatment serum CRP level < 1.0 mg/dL and high CRP group with serum CRP level ≥ 1.0 mg/dl. Overall survival (OS), total amount administered, and period of treatment were compared between the two groups. Results The high CRP group showed a significantly poorer OS than the low CRP group (0.0% vs 71.5%/ 1year, p < 0.01). Multivariate analyses revealed that high CRP was a significant negative factor for OS (HR: 7.69, 95% confidence interval: 2.43–24.3, p < 0.001), and this result was independent of Child-Pugh score and existing tumor factors. Relative dose intensity at 8 weeks was lower (p = 0.01) and time to treatment failure was shorter (P < 0.001) in the high CRP group. Conclusions CRP level was associated with OS in HCC patients treated with lenvatinib. CRP could be a useful marker to identify patients most likely to benefit from lenvatinib treatment.
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Moon YJ, Kwon HM, Jung KW, Kim KS, Shin WJ, Jun IG, Song JG, Hwang GS. Preoperative high-sensitivity troponin I and B-type natriuretic peptide, alone and in combination, for risk stratification of mortality after liver transplantation. Korean J Anesthesiol 2020; 74:242-253. [PMID: 32846082 PMCID: PMC8175877 DOI: 10.4097/kja.20296] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 08/23/2020] [Indexed: 01/11/2023] Open
Abstract
Background Given the severe shortage of donor liver grafts, coupled with growing proportion of cardiovascular death after liver transplantation (LT), precise cardiovascular risk assessment is pivotal for selecting recipients who gain the greatest survival benefit from LT surgery. We aimed to determine the prognostic value of pre-LT combined measurement of B-type natriuretic peptide (BNP) and high-sensitivity troponin I (hsTnI) in predicting early post-LT mortality. Methods We retrospectively evaluated 2,490 consecutive adult LT patients between 2010 and 2018. Cut-off values of BNP and hsTnI for predicting post-LT 90-day mortality were calculated. According to the derived cut-off values of two cardiac biomarkers, alone and in combination, adjusted hazard ratios (aHR) of post-LT 90-day mortality were determined using multivariate Cox regression analysis. Results Mortality rate after 90 days was 2.9% (72/2,490). Rounded cut-off values for post-LT 90-day mortality were 400 pg/ml for BNP (aHR 2.02 [1.15, 3.52], P = 0.014) and 60 ng/L for hsTnI (aHR 2.65 [1.48, 4.74], P = 0.001), respectively. Among 273 patients with BNP ≥ 400 pg/ml, 50.9% of patients were further stratified into having hsTnI ≥ 60 ng/L. Combined use of pre-LT cardiac biomarkers predicted post-LT 90-day mortality rate; both non-elevated: 1.0% (21/2,084), either one is elevated: 9.0% (24/267), and both elevated: 19.4% (27/139, log-rank P < 0.001; aHR vs non-elevated 4.23 [1.98, 9.03], P < 0.001). Conclusions Concomitant elevation of both cardiac biomarkers posed significantly higher risk of 90-day mortality after LT. Pre-LT assessment cardiac strain and myocardial injury, represented by BNP and hsTnI values, would contribute to prioritization of LT candidates and help administer target therapies that could modify early mortality.
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Affiliation(s)
- Young-Jin Moon
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hye-Mee Kwon
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyeo-Woon Jung
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyoung-Sun Kim
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Won-Jung Shin
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In-Gu Jun
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jun-Gol Song
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gyu-Sam Hwang
- Department of Anesthesiology and Pain Medicine, Laboratory for Cardiovascular Dynamics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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A Systematic Review for Variables to Be Collected in a Transplant Database for Improving Risk Prediction. Transplantation 2020; 103:2591-2601. [PMID: 30768569 DOI: 10.1097/tp.0000000000002652] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND This systematic review was commissioned to identify new variables associated with transplant outcomes that are not currently collected by the Organ Procurement and Transplantation Network (OPTN). METHODS We identified 81 unique studies including 1 193 410 patients with median follow-up of 36 months posttransplant, reporting 108 unique risk factors. RESULTS Most risk factors (104) were recipient related; few (4) were donor related. Most risk factors were judged to be practical and feasible to routinely collect. Relative association measures were small to moderate for most risk factors (ranging between 1.0 and 2.0). The strongest relative association measure for a heart transplant outcome with a risk factor was 8.6 (recipient with the previous Fontan operation), for a kidney transplant 2.8 (sickle cell nephropathy as primary cause of end-stage renal disease), for a liver transplant 14.3 (recipient serum ferritin >500 µg/L), and for a lung transplant 6.3 (Burkholderia cepacia complex infection for 1 y or less). OPTN may consider some of these 108 variables for future collection to enhance transplant research and clinical care. CONCLUSIONS Evidence-based approaches can be used to determine variables collected in databases and registries. Several candidate variables have been identified for OPTN.
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Lee HM, Kim T, Choi HJ, Park J, Shim JW, Kim YS, Moon YE, Hong SH, Chae MS. Influence of intraoperative oxygen content on early postoperative graft dysfunction in living donor liver transplantation: A STROBE-compliant retrospective observational study. Medicine (Baltimore) 2020; 99:e20339. [PMID: 32481323 PMCID: PMC7249939 DOI: 10.1097/md.0000000000020339] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The aim of the present study was to investigate the role of intraoperative oxygen content on the development of early allograft dysfunction (EAD) in patients undergoing living donor liver transplantation (LDLT).This retrospective review included 452 adult patients who underwent elective LDLT. Our study population was classified into 2 groups: EAD and non-EAD. Arterial blood gas analysis was routinely performed 3 times during surgery: during the preanhepatic phase (ie, immediately after anesthetic induction); during the anhepatic phase (ie, at the onset of hepatic venous anastomosis); and during the neohepatic phase (ie, 1 hour after graft reperfusion). Arterial oxygen content (milliliters per deciliters) was derived using the following equation: (1.34 × hemoglobin [gram per deciliters] × SaO2 [%] × 0.01) + (0.0031 × PaO2 [mmHg]).The incidence of EAD occurrence was 13.1% (n = 59). Although oxygen contents at the preanhepatic phase were comparable between the 2 groups, the oxygen contents at the anhepatic and neohepatic phases were lower in the EAD group than in the non-EAD group. Patients with postoperative EAD had lower oxygen content immediately before and continuously after graft reperfusion, compared to patients without postoperative EAD. After the preanhepatic phase, oxygen content decreased in the EAD group but increased in the non-EAD group. The oxygen content and prevalence of normal oxygen content gradually increased during surgery in the non-EAD group, but not in the EAD group. Multivariable analysis revealed that oxygen content during the anhepatic phase and higher preoperative CRP levels were factors independently associated with the occurrence of EAD (area under the receiver-operating characteristic curve: 0.754; 95% confidence interval: 0.681-0.826; P < .001 in the model). Postoperatively, patients with EAD had a longer duration of hospitalization, higher incidences of acute kidney injury and infection, and experienced higher rates of patient mortality, compared to patients without EAD.Lower arterial oxygen concentration may negatively impact the functional recovery of the graft after LDLT, despite preserved hepatic vascular flow. Before graft reperfusion, the levels of oxygen content components, such as hemoglobin content, PaO2, and SaO2, should be regularly assessed and carefully maintained to ensure proper oxygen delivery into transplanted liver grafts.
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Affiliation(s)
- Hyung Mook Lee
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital
| | - Taehee Kim
- Department of Anesthesiology and Pain Medicine, Bucheon St. Mary's Hospital
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jaesik Park
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital
| | - Jung-Woo Shim
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital
| | - Yong-Suk Kim
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital
| | - Young Eun Moon
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital
| | - Sang Hyun Hong
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital
| | - Min Suk Chae
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital
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Li S, Feng X, Cao G, Wang Q, Wang L. Prognostic significance of inflammatory indices in hepatocellular carcinoma treated with transarterial chemoembolization: A systematic review and meta-analysis. PLoS One 2020; 15:e0230879. [PMID: 32214401 PMCID: PMC7098645 DOI: 10.1371/journal.pone.0230879] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 03/10/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES To investigate the association between inflammatory indices and clinical outcomes of hepatocellular carcinoma (HCC) patients treated with transarterial chemoembolization (TACE) by performing meta-analysis. METHODS A systematic literature search for relevant studies published up to August 2019 was performed by using PubMed, Web of Science, EMBASE, China National Knowledge Internet (CNKI) and Wanfang databases. Pooled hazard ratios (HR) or odds ratio (OR) and 95% confidence intervals (95% CI) were calculated. RESULTS A total of 5280 patients from 22 studies were finally enrolled in the meta-analysis. The results demonstrated that elevated preoperative NLR, PLR, and CRP was associated with poor OS in HCC patients treated by TACE (HR = 1.81, P<0.00001; HR = 1.56, P = 0.007; HR = 1.45, P<0.00001, respectively). In addition, high NLR was significantly correlated with the presence of tumor vascular invasion (OR = 1.49, P = 0.002). Elevated PLR tended to be correlated with higher incidence of tumor size>3 cm (OR = 2.42, P = 0.005). CONCLUSIONS Elevated preoperative NLR, PLR, and CRP are associated with poor prognosis in HCC patients treated with TACE. These inflammatory indices may be convenient, accessible, affordable and dependable biomarkers with prognostic potential for HCC patients treated by TACE.
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Affiliation(s)
- Shuangshuang Li
- Department of Microbiology and Center of Infectious Disease, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
| | - Xudong Feng
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang province, People’s Republic of China
| | - Guodong Cao
- Department of Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China
| | - Qianhui Wang
- Department of Infectious Diseases, Taiyuan No. 3 Hospital, Taiyuan, Shanxi Province, People’s Republic of China
| | - Ling Wang
- Department of Microbiology and Center of Infectious Disease, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People’s Republic of China
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12
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DNA methylation of SOCS1/2/3 predicts hepatocellular carcinoma recurrence after liver transplantation. Mol Biol Rep 2020; 47:1773-1782. [PMID: 32006198 DOI: 10.1007/s11033-020-05271-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 01/20/2020] [Indexed: 02/07/2023]
Abstract
DNA methylation status of SOCS1/SOCS2/SOCS3 is intensely involved in the development and progression of hepatocellular carcinoma (HCC). This study explored its prognostic value for HCC recurrence after liver transplantation (LT). Clinical data from 62 HCC patients who underwent LT at our centre were retrospectively collected. The SOCS1/2/3 methylation level were determined using next generation sequencing. Overall, 244 methylated sites at the SOCS1/2/3 promoter were identified. Multivariate analysis yielded the methylated sites SOCS2-1-90 (Chromosome 12, Position 93963982; HR 0.386, 95% CI 0.149-0.998) and SOCS1-1-68 (Chromosome 16, Position 11350699; HR 4.376, 95% CI 1.324-14.459) as independent predictors of post-LT HCC recurrence. Patients were divided into highly- and lowly methylated groups according to the median SOCS1-1-68 (0.95%) and SOCS2-1-90 (1.05%) methylation levels. Highly methylated SOCS2-1-90 was associated with significantly lower AFP levels (P = 0.008), decreased proportion of maximal tumour size > 8 cm (P = 0.02), and better pathological grading (P = 0.06). Conversely, patients in the highly methylated SOCS1-1-68 group had higher AFP levels (P = 0.043). Kaplan-Meier analyses revealed that patients with highly methylated SOCS2-1-90 had increased recurrence free survival (RFS) and overall survival (OS) rates when compared with those with lowly methylated SOCS2-1-90 (P = 0.0041 and 0.012, respectively). Nevertheless, the correlation between methylated SOCS1-1-68 and cumulative recurrence rates was less pronounced (P = 0.098). Subgroup analyses demonstrated that patients meeting the Milan criteria, UCSF criteria, Metroticket 2.0 Model or Hangzhou criteria with highly methylated SOCS2-1-90 had the best RFS rates. DNA methylation of SOCS2-1-90 is a novel biomarker for predicting post-transplant HCC recurrence.
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13
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Kim JY. Macrophages in xenotransplantation. KOREAN JOURNAL OF TRANSPLANTATION 2019; 33:74-82. [PMID: 35769982 PMCID: PMC9188951 DOI: 10.4285/jkstn.2019.33.4.74] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 12/19/2019] [Accepted: 12/19/2019] [Indexed: 11/25/2022] Open
Abstract
Xenotransplantation refers to organ transplantation across species. Immune rejection of xenografts is stronger and faster than that of allografts because of significant molecular differences between species. Recent studies have revealed the involvement of macrophages in xenograft and allograft rejections. Macrophages have been shown to play a critical role in inflammation, coagulation, and phagocytosis in xenograft rejection. This review presents a recent understanding of the role of macrophages in xenograft rejection and possible strategies to control macrophage-mediated xenograft rejection.
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Affiliation(s)
- Jae Young Kim
- Department of Life Science, Gachon University, Seongnam, Korea
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14
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Meischl T, Rasoul-Rockenschaub S, Györi G, Sieghart W, Reiberger T, Trauner M, Soliman T, Berlakovich G, Pinter M. C-reactive protein is an independent predictor for hepatocellular carcinoma recurrence after liver transplantation. PLoS One 2019; 14:e0216677. [PMID: 31141535 PMCID: PMC6541257 DOI: 10.1371/journal.pone.0216677] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 04/26/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Serum C-reactive protein (CRP) is a prognostic factor for overall survival (OS) and recurrence of hepatocellular carcinoma (HCC) in patients treated with resection or non-surgical treatment. Here, we investigated the association of elevated CRP (≥1 vs. <1 mg/dL) with (i) recurrence of HCC and (ii) OS after liver transplantation (LT). METHODS Adult HCC patients undergoing orthotopic deceased donor LT at the Medical University of Vienna between 1997 and 2014 were retrospectively analysed. RESULTS Among 216 patients included, 132 (61.1%) were transplanted within the Milan criteria and forty-two patients (19.4%) had microvascular invasion on explant histology. Seventy patients (32.4%) showed elevated CRP (≥ 1 mg/dL). On multivariate analysis, a CRP ≥ 1 mg/dL was an independent risk factor for HCC recurrence with a 5-year recurrence rate of 27.4% vs. 16.4% (HR 2.33; 95% CI 1.13-4.83; p = 0.022). OS was similar in patients with normal vs. elevated CRP levels. CONCLUSIONS Elevated serum CRP is associated with HCC recurrence after LT and may be a marker for more aggressive tumor biology. Future studies should evaluate whether patients with elevated pre-transplant CRP levels benefit from closer monitoring for HCC recurrence.
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Affiliation(s)
- Tobias Meischl
- Division of Gastroenterology und Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | | | - Georg Györi
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Sieghart
- Division of Gastroenterology und Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology und Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology und Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Soliman
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Gabriela Berlakovich
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology und Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Liver Cancer (HCC) Study Group Vienna, Medical University of Vienna, Vienna, Austria
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15
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Evidence for the important role of inflammation in xenotransplantation. JOURNAL OF INFLAMMATION-LONDON 2019; 16:10. [PMID: 31148951 PMCID: PMC6537172 DOI: 10.1186/s12950-019-0213-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 05/02/2019] [Indexed: 12/17/2022]
Abstract
There is increasing evidence of a sustained state of systemic inflammation after pig-to-nonhuman primate (NHP) xenotransplantation (that has been termed systemic inflammation in xenograft recipients [SIXR]). Increases in inflammatory markers, e.g., C-reactive protein, histones, serum amyloid A, D-dimer, cytokines, chemokines, and a decrease in free triiodothyronine, have been demonstrated in the recipient NHPs. The complex interactions between inflammation, coagulation, and the immune response are well-recognized, but the role of inflammation in xenograft recipients is not fully understood. The evidence suggests that inflammation can promote the activation of coagulation and the adaptive immune response, but the exact mechanisms remain uncertain. If prolonged xenograft survival is to be achieved, anti-inflammatory strategies (e.g., the administration of anti-inflammatory agents, and/or the generation of genetically-engineered organ-source pigs that are protected from the effect of inflammation) may be necessary to prevent, control, or negate the effect of the systemic inflammation that develops in xenograft recipients. This may allow for a reduction in the intensity of exogenous immunosuppressive therapy. If immunological tolerance to a xenograft is to be obtained, then control of inflammation may be essential.
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16
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Citores MJ, Lucena JL, de la Fuente S, Cuervas-Mons V. Serum biomarkers and risk of hepatocellular carcinoma recurrence after liver transplantation. World J Hepatol 2019; 11:50-64. [PMID: 30705718 PMCID: PMC6354126 DOI: 10.4254/wjh.v11.i1.50] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/13/2018] [Accepted: 12/05/2018] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is the only potentially curative treatment for selected patients with cirrhosis and hepatocellular carcinoma (HCC) who are not candidates for resection. When the Milan criteria are strictly applied, 75% to 85%of 3- to 4-year actuarial survival rates are achieved, but up to 20% of the patients experience HCC recurrence after transplantation. The Milan criteria are based on the preoperative tumor macromorphology, tumor size and number on computed tomography or magnetic resonance imaging that neither correlate well with posttransplant histological study of the liver explant nor accurately predict HCC recurrence after LT, since they do not include objective measures of tumor biology. Preoperative biological markers, including alpha-fetoprotein, des-gamma-carboxiprothrombin or neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio, can predict the risk for HCC recurrence after transplantation. These biomarkers have been proposed as surrogate markers of tumor differentiation and vascular invasion, with varied risk magnitudes depending on the defined cutoffs. Different studies have shown that the combination of one or several biomarkers integrated into prognostic models predict the risk of HCC recurrence after LT more accurately than Milan criteria alone. In this review, we focus on the potential utility of these serum biological markers to improve the performance of Milan criteria to identify patients at high risk of tumoral recurrence after LT.
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Affiliation(s)
- Maria J Citores
- Department of Internal Medicine, Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana, Majadahonda 28222, Spain
| | - Jose L Lucena
- Liver Transplantation Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
- Department of Surgery, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
| | - Sara de la Fuente
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
| | - Valentin Cuervas-Mons
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda 28222, Spain
- Department of Medicine, Universidad Autónoma de Madrid, Madrid 28029, Spain
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17
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Le Y, Shen JX, Zhang YF, He MK, Kan A, Chen HL, Yu ZS, Li QJ, Shi M. Transarterial Chemoembolization related to Good Survival for Selected Patients with advanced Hepatocellular Carcinoma. J Cancer 2019; 10:665-671. [PMID: 30719164 PMCID: PMC6360434 DOI: 10.7150/jca.28528] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 10/03/2018] [Indexed: 01/10/2023] Open
Abstract
Background & aims: It remains controversial whether patients with advanced-stage hepatocellular carcinoma could be benefit from transarterial chemoembolization (TACE) treatment. The purpose of the present study is to identify predictors of survival following TACE in patients with advanced HCC. Methods: Overall, 303 patients with Barcelona Clinic Liver Cancer (BCLC) stage C HCC who were first treated with TACE from Sun Yat-sen University Cancer Centre between January 2009 and December 2013 were reviewed and enrolled in this study. We carried out Kaplan-Meier and Cox proportional hazard model analyses of prognostic factors. Results: The median survival of the whole cohort was 8.4 months. Multivariable Cox regression analyses confirmed that four risk factors, high serum levels of gamma-glutamyl transpeptidase (GGT), C-reactive protein (CRP), alkaline phosphatase (ALP) and presence of portal vein tumour thrombosis (PVTT), were independent prognostic factors for overall survival. The expected median survival among patients with 0-1 and 2-4 risk factors were 18.1 (95% CI: 15.5-20.7) and 6.8 (95% CI: 5.8-7.8) months, respectively. Objective tumor response among patients with 0-1 and 2-4 risk factors were 38.9% and 17.3%, respectively. Conclusion: We found four risk factors were associated with dismal overall survival for advanced HCC patients: serum GGT level, serum CRP, serum ALP and presence of PVTT. TACE may be recommended for patients with advanced HCC with 0-1 risk factors due to the favourable prognosis.
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Affiliation(s)
- Yong Le
- Department of Hepatobiliary Oncology, Cancer Centre, Sun Yat-sen University, Guangzhou, China.,Collaborative Innovation Centre for Cancer Medicine, Cancer Centre, Sun Yat-sen University, Guangzhou, China.,Sate Key Laboratory of Oncology in South China, Guangzhou, China
| | - Jing-Xian Shen
- Collaborative Innovation Centre for Cancer Medicine, Cancer Centre, Sun Yat-sen University, Guangzhou, China.,Department of Radiology, Sun Yat-sen University Cancer Centre, Guangzhou, China
| | - Yong-Fa Zhang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Min-Ke He
- Department of Hepatobiliary Oncology, Cancer Centre, Sun Yat-sen University, Guangzhou, China.,Collaborative Innovation Centre for Cancer Medicine, Cancer Centre, Sun Yat-sen University, Guangzhou, China
| | - Anna Kan
- Collaborative Innovation Centre for Cancer Medicine, Cancer Centre, Sun Yat-sen University, Guangzhou, China.,Sate Key Laboratory of Oncology in South China, Guangzhou, China
| | - Hai-Long Chen
- Collaborative Innovation Centre for Cancer Medicine, Cancer Centre, Sun Yat-sen University, Guangzhou, China.,Sate Key Laboratory of Oncology in South China, Guangzhou, China
| | - Zi-Shan Yu
- Department of Hepatobiliary Oncology, Cancer Centre, Sun Yat-sen University, Guangzhou, China.,Collaborative Innovation Centre for Cancer Medicine, Cancer Centre, Sun Yat-sen University, Guangzhou, China
| | - Qi-Jiong Li
- Department of Hepatobiliary Oncology, Cancer Centre, Sun Yat-sen University, Guangzhou, China.,Collaborative Innovation Centre for Cancer Medicine, Cancer Centre, Sun Yat-sen University, Guangzhou, China.,Sate Key Laboratory of Oncology in South China, Guangzhou, China
| | - Ming Shi
- Department of Hepatobiliary Oncology, Cancer Centre, Sun Yat-sen University, Guangzhou, China.,Collaborative Innovation Centre for Cancer Medicine, Cancer Centre, Sun Yat-sen University, Guangzhou, China.,Sate Key Laboratory of Oncology in South China, Guangzhou, China
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18
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Kornberg A, Schernhammer M, Kornberg J, Friess H, Thrum K. Serological Risk Index Based on Alpha-Fetoprotein and C-Reactive Protein to Indicate Futile Liver Transplantation Among Patients with Advanced Hepatocellular Carcinoma. Dig Dis Sci 2019; 64:269-280. [PMID: 30259282 DOI: 10.1007/s10620-018-5296-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 09/17/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND The aim of this study was to establish a preoperatively available serological risk index using alpha-fetoprotein (AFP) and C-reactive protein (CRP) for predicting oncologically futile liver transplantation (LT) in hepatocellular carcinoma (HCC) patients. METHODS A total of 119 liver transplant patients with HCC were retrospectively analyzed. The prognostic impact of clinical and histopathologic factors including pre-LT serum AFP and CRP values was determined. RESULTS Apart from microvascular tumor invasion (MVI; odds ratio [OR] 15.77), pretransplant serum levels of AFP > 100 ng/ml (OR 13.31) and CRP > 0.8 mg/dl (OR 13.97) were identified as independent predictors of HCC recurrence. The cumulative risk of HCC relapse at 5 years post-LT was 2.3% in low serological tumor activity (STA) index (AFP ≤ 100 ng/ml + CRP ≤ 0.8 mg/dl), 17.1% in intermediate STA (AFP ≤ 100 ng/ml or CRP ≤ 0.8 mg/dl), and 91.6% in high STA index (AFP > 100 ng/ml + CRP > 0.8 mg/dl; p < 0.001), respectively. High STA index was identified as most powerful pre-LT available predictor of MVI (OR 15.31) and posttransplant HCC recurrence (OR 54.44). Five-year recurrence-free survival rate in Milan Out patients with high STA was 0%, compared to 91.7% and 83.6% in those with low or intermediate STA index (p < 0.001), respectively. CONCLUSION Our proposed serological risk index based on pretransplant serum AFP and CRP values is able to predict oncologically futile LT among advanced HCC patients.
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Affiliation(s)
- Arno Kornberg
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaningerstr. 22, 81675, Munich, Germany.
| | - Martina Schernhammer
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaningerstr. 22, 81675, Munich, Germany
| | - Jennifer Kornberg
- Department of Anaesthesiology, Klinikum Großhadern, LMU Munich, Munich, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaningerstr. 22, 81675, Munich, Germany
| | - Katharina Thrum
- Institute of Pathology, Helios Klinikum Berlin, Berlin, Germany
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19
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Amado V, Rodríguez-Perálvarez M, Ferrín G, De la Mata M. Selecting patients with hepatocellular carcinoma for liver transplantation: incorporating tumor biology criteria. J Hepatocell Carcinoma 2018; 6:1-10. [PMID: 30613572 PMCID: PMC6306074 DOI: 10.2147/jhc.s174549] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Liver transplantation (LT) is the optimal therapeutic option for patients with liver cirrhosis and hepatocellular carcinoma (HCC). Due to universal donor shortage, only the patients with limited tumor burden (under the so-called Milan criteria) are considered as potential candidates for LT in most institutions. It is expected that in the near future, more liver grafts will be available for patients with HCC due to the implementation of new direct antivirals against hepatitis C, leaving a prone scenario to consider expanding Milan criteria. A moderate expansion of Milan criteria could be implemented without increasing the risk of tumor recurrence if patients with favorable biological behavior are carefully selected. Incorporating information regarding tumor biology in the decision-making algorithm would result in a more rational use of LT in patients with HCC. In the present review, surrogate markers of tumor biology are critically evaluated as potential tools to be combined with existing radiological criteria. In addition, the current state of liquid biopsy is discussed, as this cutting-edge technology may reshape the management of HCC in the upcoming years.
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Affiliation(s)
- Víctor Amado
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Manuel Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Gustavo Ferrín
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
| | - Manuel De la Mata
- Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, IMIBIC, CIBERehd, Córdoba, Spain,
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20
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Magistri P, Rosenblatt R, Halazun KJ. Liver Transplantation for HCC Beyond Milan. CURRENT TRANSPLANTATION REPORTS 2018. [DOI: 10.1007/s40472-018-0212-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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21
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Mano Y, Yoshizumi T, Yugawa K, Ohira M, Motomura T, Toshima T, Itoh S, Harada N, Ikegami T, Soejima Y, Maehara Y. Lymphocyte-to-Monocyte Ratio Is a Predictor of Survival After Liver Transplantation for Hepatocellular Carcinoma. Liver Transpl 2018; 24:1603-1611. [PMID: 29893464 DOI: 10.1002/lt.25204] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 01/29/2018] [Accepted: 05/09/2018] [Indexed: 12/24/2022]
Abstract
Recent studies revealed that systemic inflammation was correlated with poorer prognosis in various cancers. We investigated the prognostic value of the lymphocyte-to-monocyte ratio (LMR) in patients who underwent living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC). We retrospectively analyzed the records of 216 patients who underwent LDLT for HCC. Patients were divided into high (n = 126) and low (n = 90) LMR groups. Their clinicopathological parameters and survival times were compared. To determine the mechanisms of the change in the LMR, we performed immunohistochemical analyses of CD3 and CD68 expression. A low LMR was significantly associated with a high Model for End-Stage Liver Disease score; a high Child-Pugh score; elevation of alpha-fetoprotein, des-gamma-carboxyprothrombin, and neutrophil-to-lymphocyte ratio; larger tumor size; more tumors; and poorer prognosis. A low LMR was associated with poor prognosis and represented an independent prognostic factor, particularly among patients beyond the Milan criteria. The ratio of CD3-positive to CD68-positive cells was significantly lower in the low-LMR group. In conclusion, our results show that the LMR was an independent predictor of survival of patients with HCC beyond the Milan criteria who underwent LDLT. The LMR reflected the immune status of the tumor microenvironment.
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Affiliation(s)
- Yohei Mano
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kyohei Yugawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Ohira
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takashi Motomura
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Noboru Harada
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuji Soejima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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22
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Lorente L. New prognostic biomarkers of mortality in patients undergoing liver transplantation for hepatocellular carcinoma. World J Gastroenterol 2018; 24:4230-4242. [PMID: 30310256 PMCID: PMC6175764 DOI: 10.3748/wjg.v24.i37.4230] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/18/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
The outcome prediction of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) was classically established using various macromorphological factors and serum alpha-fetoprotein levels prior to LT. However, other biomarkers have recently been reported to be associated with the prognosis of HCC patients undergoing to LT. This review summarizes clinical data on these new biomarkers. High blood levels of malondialdehyde, total antioxidant capacity, caspase-cleaved cytokeratin-18, soluble CD40 ligand, substance P, C-reactive protein, and vascular endothelial growth factor, increased neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in blood, high peripheral blood expression of human telomerase reverse transcriptase messenger ribonucleic acid, and high HCC expression of dickkopf-1 have recently been associated with decreased survival rates. In addition, high blood levels of des-gamma-carboxy prothrombin, and high HCC expression of glypican-3, E-cadherin and beta-catenin have been associated with increased HCC recurrence. Additional research is necessary to establish the prognostic role of these biomarkers in HCC prior to LT. Furthermore, some of these biomarkers are also interesting because their potential modulation could help to create new research lines for improving the outcomes of those patients.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife 38320, Spain
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23
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Lee HW, Song GW, Lee SG, Kim JM, Joh JW, Han DH, Kim SI, Kim SH, Kim DS, Cho JY, Suh KS. Patient Selection by Tumor Markers in Liver Transplantation for Advanced Hepatocellular Carcinoma. Liver Transpl 2018; 24:1243-1251. [PMID: 29575509 DOI: 10.1002/lt.25056] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 02/22/2018] [Indexed: 02/07/2023]
Abstract
Although far advanced hepatocellular carcinoma (HCC) is generally considered a contraindication for liver transplantation (LT), biologically favorable tumors among them could show acceptable results. However, it is still unclear which tumors can be treated with LT. Data were collected on adult patients who underwent LT for HCC beyond the Milan criteria in 8 Korean LT centers between January 2000 and June 2013. Far advanced HCC was defined as HCC with the largest tumor ≥ 10 cm, 10 or more tumor nodules, or accompanying macrovascular invasion. A total of 688 patients, including 169 with far advanced HCC, were enrolled in this study. The 5-year overall and recurrence-free survival rates were 60.4% and 55.1%, respectively, for all patients but only 28.7% and 24.8%, respectively, for patients with far advanced HCC (P < 0.001). Both preoperative alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II (PIVKA-II) were significant risk factors for HCC recurrence after LT. In particular, AFP + PIVKA-II combined was a better predictor than either marker alone. Of all far advanced HCC patients with available AFP and PIVKA-II levels, 45 (30.8%) had low AFP + PIVKA-II (≤300) and their 5-year overall and recurrence-free survival rate were 47.8% and 53.4%, respectively, which were acceptable and significantly superior to those of patients with AFP (ng/mL) + PIVKA-II (nAU/mL) > 300 (21.0% and 10.8%, respectively; P < 0.001). In conclusion, patients with favorable HCC had acceptable outcomes after LT even when their tumors were extremely advanced. AFP + PIVKA-II gave reliable information about the tumor biology of far advanced HCC. Liver Transplantation 00 000-000 2018 AASLD.
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Affiliation(s)
- Hae Won Lee
- Department of Surgery, Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Gi-Won Song
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Gyu Lee
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dai Hoon Han
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Soon Il Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Seong Hoon Kim
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| | - Dong-Sik Kim
- Department of Surgery, Korea University College of Medicine, Seoul, Korea
| | - Jai Young Cho
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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Chae MS, Kim Y, Lee N, Chung HS, Park CS, Lee J, Choi JH, Hong S. Graft Regeneration and Functional Recovery in Patients with Early Allograft Dysfunction After Living-Donor Liver Transplantation. Ann Transplant 2018; 23:481-490. [PMID: 30013021 PMCID: PMC6248034 DOI: 10.12659/aot.909112] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Successful graft regeneration is important in living-donor liver transplantation (LDLT) because partial liver grafts are used. Early allograft dysfunction (EAD) is an intermediate outcome that affects the long-term postoperative course in liver transplantation. The aim of the present study was to investigate liver graft regeneration under EAD development in LDLT. Material/Methods The data of 226 patients who underwent LDLT from September 2010 to July 2014 were retrospectively analyzed. The patients were classified into 2 groups: one with and one without EAD. Graft regeneration, functional recovery, and long-term patient survival were compared between the 2 groups. Results The grafts grew more vigorously in the EAD group than in the non-EAD group, as evidenced by the larger absolute (ALV) and relative liver volumes (RLV) of the former on postoperative days (POD) 7 and 21. The median (interquartile range) RLVs of the non-EAD group versus the EAD group were as follows: 55.2 (47.9–65.8) vs. 53.7 (46.6–64.5)% preoperatively, p>0.05; 76.1 (66.9–85.7) vs. 86.7 (73.9–96.8)% on POD 7, p<0.01; 79.6 (69.3–91.2) vs. 93.7 (79.6–101.6)%, p<0.01 on POD 21. In the early postoperative period, hepatic function, measured as total bilirubin and international normalized ratio, was higher in the EAD group; however, after EAD development, graft function recovered in these patients. In the follow-up period, overall patient survival was comparable between the 2 groups. Conclusions The liver grafts of EAD patients steadily regenerated, such that the development of EAD did not affect long-term patient survival after LDLT.
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Affiliation(s)
- Min Suk Chae
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Youngchan Kim
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Nuri Lee
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Hyun Sik Chung
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Chul Soo Park
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jaemin Lee
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jong Ho Choi
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sanghyun Hong
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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Rosenblatt RE, Tafesh ZH, Halazun KJ. Role of inflammatory markers as hepatocellular cancer selection tool in the setting of liver transplantation. Transl Gastroenterol Hepatol 2017; 2:95. [PMID: 29264433 DOI: 10.21037/tgh.2017.10.04] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 10/17/2017] [Indexed: 12/12/2022] Open
Abstract
Since the advent of the Milan criteria in 1996 and its widespread adoption for selection of patients with hepatocellular carcinoma (HCC) who would benefit from transplant, there has been an extensive hunt for the ideal clinical biomarker to predict HCC recurrence. This is because Milan lack does not include tumor biology indices and recurrence rates remain in the 15-20% range worldwide. While a 'silver-bullet' biomarker has not been found, several useful inflammatory markers have been identified and used in scoring systems that supersede Milan in their ability to predict HCC recurrence post liver transplantation (LT). In this review, we aim to summarize the role of inflammatory markers paly in the selection of HCC patients awaiting LT.
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Affiliation(s)
- Russell E Rosenblatt
- Division of gastroenterology and hepatology, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA
| | - Zaid H Tafesh
- Division of gastroenterology and hepatology, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA
| | - Karim J Halazun
- Department of surgery, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA
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Kornberg A, Witt U, Schernhammer M, Kornberg J, Ceyhan GO, Mueller K, Friess H, Thrum K. Combining 18F-FDG positron emission tomography with Up-to-seven criteria for selecting suitable liver transplant patients with advanced hepatocellular carcinoma. Sci Rep 2017; 7:14176. [PMID: 29074969 PMCID: PMC5658419 DOI: 10.1038/s41598-017-14430-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 10/10/2017] [Indexed: 02/06/2023] Open
Abstract
The Up-to-seven (UTS) criteria (sum of tumor size and number not exceeding 7) for indicating liver transplantation (LT) in hepatocellular carcinoma (HCC) were originally based on explant pathology features and absence of microvascular invasion (MVI). 18F-fludeoxyglucose (18F-FDG) positron emission tomography (PET) was shown to indicate the risk of MVI and tumor recurrence. The aim of this study was to analyze the prognostic significance of the clinical UTS criteria when being combined with PET-status of the tumor. Data of 116 liver transplant patients were subject to retrospective analysis. Five-year recurrence-free survival (RFS) rates in patients meeting (n = 85) and exceeding (n = 21) the radiographic UTS criteria were 81% and 55.1%, respectively (p = 0.014). In the UTS In subset, RFS was significantly better in PET-negative (94.9%) than in PET-positive patients (48.3%; p < 0.001). In the UTS Out subset, 5-year RFS rates were 87.1% and 19% in patients with non- 18F-FDG-avid and 18F-FDG-avid tumors (p < 0.001), respectively. Positive PET-status was identified as the only independent clinical predictor of tumor recurrence in beyond UTS patients (Hazard ratio [HR] 19.25; p < 0.001). Combining radiographic UTS criteria with FDG-PET may safely expand the HCC selection criteria for LT.
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Affiliation(s)
- Arno Kornberg
- Department of Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany.
| | - Ulrike Witt
- Department of Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany
| | - Martina Schernhammer
- Department of Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany
| | - Jennifer Kornberg
- Department of Anaesthesiology, Klinikum Großhadern, LMU, Munich, Germany
| | - Gueralp O Ceyhan
- Department of Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany
| | | | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany
| | - Katharina Thrum
- Institute of Pathology, Helios Klinikum Berlin, Berlin, Germany
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Kirstein MM, Schweitzer N, Winter T, Lappas K, Graen N, Kunstmann I, Voigtländer T, Reineke-Plaaß T, Manns MP, Lehner F, Rodt T, Vogel A. Patterns and challenges of treatment sequencing in patients with hepatocellular carcinoma: Experience from a German referral center. J Gastroenterol Hepatol 2017; 32:1730-1738. [PMID: 28185302 DOI: 10.1111/jgh.13761] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 01/11/2017] [Accepted: 02/08/2017] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers. Several local and systemic therapies are available for patients with HCC depending on the stage of the disease. In clinical practice, treatment decision-making, and sequencing may be very heterogeneous. METHODS In this study, we retrospectively analyzed treatment algorithms in 2101 patients with HCC treated from 2000 to 2015 at Hannover Medical School, Germany. RESULTS Transarterial chemoembolization was the most common initial treatment (n = 545; 25.9%), followed by resection (n = 435, 20.7%), local-ablative procedures (n = 283, 13.5%), systemic therapies (n = 275, 13.1%), and liver transplantation (n = 52; 2.5%). Most patients were treated only once (n = 960; 59.6%). A total of 433 (26.9%) and 160 (9.9%) patients received a second line and third line treatment after recurrent or progressive disease. Patients with more than one treatment line were diagnosed at significantly earlier disease stages (P < 0.001). Using binary logistic regression, AFP ≤ 200 μg/L, albumin > 36 g/L, and small tumor size (≤50 mm) were identified as predictors of achieving more than one treatment line. Subsequent treatment stage migration to a therapy suggested for the next advanced stage occurred only in 56.9%, whereas 43.1% received treatments suggested for earlier disease stages. Only 16% of all treated patients received systemic therapy in the salvage setting. CONCLUSION Most patients were treated only once, and only a minority of patients received systemic treatment. The high dropout rate for subsequent therapies needs to be considered within therapy decision-making. There is an urgent need for prospective studies to define the best time point when to switch patients from local to systemic therapies.
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Affiliation(s)
- Martha M Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Nora Schweitzer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Theresa Winter
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katerina Lappas
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Nathalie Graen
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Isabell Kunstmann
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Torsten Voigtländer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | | | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Frank Lehner
- Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Thomas Rodt
- Institute for Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Donat M, Alonso S, Pereira F, Ferrero E, Carrión L, Acin-Gándara D, Moreno E. Impact of Histological Factors of Hepatocellular Carcinoma on the Outcome of Liver Transplantation. Transplant Proc 2017; 48:1968-77. [PMID: 27569930 DOI: 10.1016/j.transproceed.2016.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 04/10/2016] [Accepted: 04/27/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND The aim of this study was to identify predictors of overall survival (OS), disease-free survival (DFS), and recurrence in a cohort of 151 patients with hepatocellular carcinoma (HCC) and cirrhosis who were treated by liver transplantation (LT). PATIENTS AND METHODS A retrospective database of patients undergoing LT for radiologically diagnosed HCC at "12 de Octubre" Hospital, Madrid during 1986-2006 was analyzed. RESULTS The median follow-up was 67.44 months (SD = 55.7 months). Overall 1-, 3-, 5-, and 10-year survival was 87.5%, 73.7%, 64.1% and 43.4%, respectively. The 5-year OS of patients beyond the Milan criteria was 47.14%, whereas that of patients within the Milan criteria was 70.13% (P = .011). The 5-year OS of patients beyond the Milan criteria and with microvascular invasion (MVI) was 27.27%, whereas that of patients beyond the Milan criteria and without MVI criteria was 57.89% (P = .003). Multivariate analysis of prognostic factors revealed MVI and G3 to be independent and statistically significant factors affecting OS (P < .0001 and P = .045, respectively), DFS (P < .0001 and P = .004, respectively), and recurrence (P = .0002 and P = .028, respectively). Multivariate analysis of prognostic factors also revealed preoperative fine-needle aspiration (FNA) to be an independent negative statistically significant factor affecting recurrence (P = .0022). Multivariate analysis of predictive MVI factors revealed preoperative α-fetoprotein (AFP) levels >200 ng/mL to be an independent positive and statistically significant predictor of MVI (P = .0004). CONCLUSION MVI and G3 are independent negative factors affecting OS, DFS, and recurrence. The presence of MVI or AFP levels >200 ng/mL represent a contraindication for LT, as long as the patient is beyond the Milan criteria.
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Affiliation(s)
- M Donat
- Department of General and Visceral Surgery, Infanta Leonor Hospital, Madrid, Spain
| | - S Alonso
- Department of General and Visceral Surgery, Fuenlabrada University Hospital, Madrid, Spain.
| | - F Pereira
- Department of General and Visceral Surgery, Fuenlabrada University Hospital, Madrid, Spain
| | - E Ferrero
- Department of General and Visceral Surgery, "12 de Octubre" University Hospital, Madrid, Spain
| | - L Carrión
- Department of General and Visceral Surgery, Fuenlabrada University Hospital, Madrid, Spain
| | - D Acin-Gándara
- Department of General and Visceral Surgery, Fuenlabrada University Hospital, Madrid, Spain
| | - E Moreno
- Department of General and Visceral Surgery, "12 de Octubre" University Hospital, Madrid, Spain
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Omran MM, Emran TM, Farid K, Eltaweel FM, Omar MA, Bazeed FB. An Easy and Useful Noninvasive Score Based on α-1-acid Glycoprotein and C-Reactive Protein for Diagnosis of Patients with Hepatocellular Carcinoma Associated with Hepatitis C Virus Infection. J Immunoassay Immunochem 2016; 37:273-88. [PMID: 26685049 DOI: 10.1080/15321819.2015.1132229] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
This study aimed to evaluate the diagnostic value of α-1-acid glycoprotein (AGP) and C-reactive protein (CRP) and develop a predictive score to improve the diagnosis of hepatocellular carcinoma (HCC). AGP and CRP were measured in serum of 53 HCC patients and 20 liver cirrhosis (LC) patients, in addition to 15 healthy individuals. Area under receiver-operating characteristic curves (AUCs) was used to create a predictive score comprising AGP, CRP, alpha fetoprotein, and albumin. The diagnostic performances of score was determined and compared with AFP alone for the diagnosis of HCC. The combination of AGP, albumin, CRP, and AFP had AUC 0.92 and sensitivity 85% which was higher than AFP alone. The odds ratio of having HCC was 8.4 for AGP, 5.8 for CRP, 12.5 for AFP and 6.5 for albumin. Our score predicted HCC with an OR of 50.6 for HCC. The AUC of score in HCC with single tumor, absent vascular invasion and CLIP score (0-1) were 0.9, 0.9, 0.82, respectively, compared with 0.71, 0.71, 0.68, respectively, for AFP. In conclusion, a non-invasive and simple score based on AGP, CRP, AFP, and albumin could improve the accuracy of HCC diagnosis.
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Affiliation(s)
| | - Tarek M Emran
- b Clinical Pathology Department , Al-Azhar University , New Damietta , Egypt
| | - Khaled Farid
- c Tropical Medicine Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | | | - Mona A Omar
- d Chemistry Department , Damietta University , Egypt
| | - Fagr B Bazeed
- e Medical Biochemistry Department , Mansoura University , Egypt
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30
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Nakanishi H, Kurosaki M, Tsuchiya K, Yasui Y, Higuchi M, Yoshida T, Komiyama Y, Takaura K, Hayashi T, Kuwabara K, Nakakuki N, Takada H, Ueda M, Tamaki N, Suzuki S, Itakura J, Takahashi Y, Izumi N. Novel Pretreatment Scoring Incorporating C-reactive Protein to Predict Overall Survival in Advanced Hepatocellular Carcinoma with Sorafenib Treatment. Liver Cancer 2016; 5:257-268. [PMID: 27781198 PMCID: PMC5075810 DOI: 10.1159/000449337] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVES This study aimed to build a prediction score of prognosis for patients with advanced hepatocellular carcinoma (HCC) after sorafenib treatment. METHODS A total of 165 patients with advanced HCC who were treated with sorafenib were analyzed. Readily available baseline factors were used to establish a scoring system for the prediction of survival. RESULTS The median survival time (MST) was 14.2 months. The independent prognostic factors were C-reactive protein (CRP) <1.0 mg/dL [hazard ratio (HR) =0.51], albumin >3.5 g/dL (HR =0.55), alpha-fetoprotein <200 ng/mL (HR =0.45), and a lack of major vascular invasion (HR =0.39). Each of these factors had a score of 1, and after classifying the patients into five groups, the total scores ranged from 0 to 4. Higher scores were linked to significantly longer survival (p<0.0001). Twenty-nine patients (17.6%) with a score of 4 had a MST as long as 36.5 months, whereas MST was as short as 2.4 and 3.7 months for seven (4.2%) and 22 (13.3%) patients with scores of 0 and 1, respectively. CONCLUSIONS A novel prognostic scoring system, which includes the CRP level, has the ability to stratify the prognosis of patients with advanced stage HCC after treatment with sorafenib.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Namiki Izumi
- *Namiki Izumi, MD, PhD, Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo (Japan), Tel. +81 422 32 3111, E-Mail
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Lee HW, Suh KS. Liver transplantation for advanced hepatocellular carcinoma. Clin Mol Hepatol 2016; 22:309-318. [PMID: 27729631 PMCID: PMC5066382 DOI: 10.3350/cmh.2016.0042] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 08/10/2016] [Indexed: 12/12/2022] Open
Abstract
There has been ongoing debate that the Milan criteria may be too strict that a significant number of patients who could benefit from liver transplantation (LT) might have been excluded. Based on this idea, various studies have been conducted to further expand the Milan criteria and give more HCC patients a chance of cure. In deceased donor LT (DDLT) setting, expansion of the criteria is relatively tempered because the results of LT for HCC should be comparable to those of patients with non-malignant indications. On the other hand, in living donor LT (LDLT) situation, liver grafts are not public resources. The acceptable target outcomes for LDLT might be much lower than those for DDLT. Patients with biologically favorable tumors might have excellent survivals after LT despite morphological advanced HCCs. Therefore, the significance and utility of biological tumor parameters for selecting suitable LT candidates have been increased to predict HCC recurrence after LT. Although there is no consensus regarding the use of prognostic biomarkers in LT selection criteria for HCC, the combination of conventional morphological parameters and new promising biomarkers could help us refine and expand the LT criteria for HCC in the near future.
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Affiliation(s)
- Hae Won Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.,Department of Surgery, Seoul National University Boramae Medical Center, Seoul, Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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32
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Expansion of the criteria for living donor liver transplantation for hepatocellular carcinoma. Curr Opin Organ Transplant 2016; 21:231-7. [PMID: 26918880 DOI: 10.1097/mot.0000000000000294] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Several expanded criteria for liver transplantation for hepatocellular carcinoma (HCC) have been suggested out of concern that the Milan criteria may be too strict, and thereby exclude patients who could benefit from this surgical procedure. However, most expanded criteria were designed for deceased donor liver transplantation. Living donor liver transplantation (LDLT) differs from that of deceased donor liver transplantation primarily because LDLT liver grafts are not public resources. RECENT FINDINGS In Asian countries, where HCC is endemic, LDLT is the main currently available treatment option for HCC. High-volume LDLT centers throughout Asia have adopted their own expanded selection criteria for LDLT for HCC with acceptable long-term results. Some centers utilize tumor markers as one of the criterion to help select suitable candidates. Indeed, such adjunctive biomarkers may have prognostic relevance for patients with HCC. The use of both biological and histomorphologic parameters may increase the number of transplantable patients. SUMMARY The overall chance of survival, and recipient/donor preferences as well as the risk of recurrence are considered in the LDLT setting. Therefore, the selection criteria for liver transplantation for HCC could benefit from expansion for LDLT.
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Higher Bilirubin Levels of Healthy Living Liver Donors Are Associated With Lower Posttransplant Hepatocellular Carcinoma Recurrence. Transplantation 2016; 100:1933-8. [DOI: 10.1097/tp.0000000000001293] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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Craig SM, Fry JK, Rodrigues Hoffmann A, Manino P, Heilmann RM, Suchodolski JS, Steiner JM, Hottinger HA, Hunter SL, Lidbury JA. Serum C-reactive protein and S100A12 concentrations in dogs with hepatic disease. J Small Anim Pract 2016; 57:459-64. [PMID: 27271454 DOI: 10.1111/jsap.12504] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 03/03/2016] [Accepted: 03/04/2016] [Indexed: 01/19/2023]
Abstract
OBJECTIVES To describe serum C-reactive protein and S100A12 concentrations in dogs with hepatic disease and to determine whether there is a relationship between the concentration of either and the severity of hepatic necroinflammation. METHODS Serum C-reactive protein and S100A12 concentrations were measured in 46 dogs undergoing hepatic biopsy. Dogs were divided into three groups: congenital portosystemic shunts, chronic hepatitis and hepatic neoplasia. The histological severity of hepatic necroinflammation was scored. RESULTS C-reactive protein and S100A12 concentrations were greater than the upper limit of the reference intervals in 39 and 26% of dogs, respectively. There was no association of disease group with C-reactive protein (P=0·1733) or S100A12 (P=0·1513) concentrations. There was a positive correlation between serum C-reactive protein concentration and hepatic necroinflammatory activity (rs =0·428, P=0·006). CLINICAL SIGNIFICANCE Increased serum C-reactive protein and S100A12 concentrations were observed in a subpopulation of dogs with various types of hepatic diseases, suggesting acute-phase inflammation and activation of phagocytic cells, respectively. Dogs with higher hepatic necroinflammatory activity scores tended to have higher serum C-reactive protein concentrations. Further studies are needed to confirm this finding in a larger group of dogs.
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Affiliation(s)
- S M Craig
- Gulf Coast Veterinary Specialists, Houston, Texas, 77027, USA
| | - J K Fry
- Gulf Coast Veterinary Specialists, Houston, Texas, 77027, USA
| | - A Rodrigues Hoffmann
- Department of Pathobiology, College of Veterinary Medicine & Biomedical Sciences, College Station, Texas, 77843-4474, USA
| | - P Manino
- Gulf Coast Veterinary Specialists, Houston, Texas, 77027, USA
| | - R M Heilmann
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, College Station, Texas, 77843-4474, USA
| | - J S Suchodolski
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, College Station, Texas, 77843-4474, USA
| | - J M Steiner
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, College Station, Texas, 77843-4474, USA
| | - H A Hottinger
- Gulf Coast Veterinary Specialists, Houston, Texas, 77027, USA
| | - S L Hunter
- Gulf Coast Veterinary Specialists, Houston, Texas, 77027, USA
| | - J A Lidbury
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, College Station, Texas, 77843-4474, USA
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Liver transplantation for hepatobiliary malignancies: a new era of "Transplant Oncology" has begun. Surg Today 2016; 47:403-415. [PMID: 27130463 DOI: 10.1007/s00595-016-1337-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 04/06/2016] [Indexed: 01/10/2023]
Abstract
The indications of liver transplantation for hepatobiliary malignancies have been carefully expanded in a stepwise fashion, despite the fundamental limitations in oncological, immunological, and technical aspects. A new era of "Transplant Oncology," the fusion of transplant surgery and surgical oncology, has begun, and we stand at the dawn of a paradigm shift in multidisciplinary cancer treatment. For hepatocellular carcinoma, new strategies have been undertaken to select recipients based on biological and dynamic markers instead of conventional morphological and static parameters, opening the doors for a more deliberate expansion of the Milan criteria and locoregional therapies before liver transplantation. Neoadjuvant chemoradiation therapy followed by liver transplantation for unresectable perihilar cholangiocarcinoma developed by the Mayo Clinic provided excellent outcomes in a US multicenter study; however, the surgical indications are not necessarily universal and await international validation. Similarly, an aggressive multidisciplinary approach has been applied for other tumors, including intrahepatic cholangiocarcinoma, hepatoblastoma, liver metastases from colorectal and neuroendocrine primary and gastrointestinal stromal tumors as well as rare tumors, such as hepatic undifferentiated embryonal sarcoma and infantile choriocarcinoma. In conclusion, liver transplantation is an important option for hepatobiliary malignancies; however, prospective studies are urgently needed to ensure the appropriate patient selection, organ allocation and living donation policies, and administration of antineoplastic immunosuppression.
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Pommergaard HC, Burcharth J, Rosenberg J, Rasmussen A. Serologic and molecular biomarkers for recurrence of hepatocellular carcinoma after liver transplantation: A systematic review and meta-analysis. Transplant Rev (Orlando) 2016; 30:171-7. [PMID: 27118303 DOI: 10.1016/j.trre.2016.03.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 03/13/2016] [Accepted: 03/25/2016] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Recurrence after liver transplantation (LT) for hepatocellular carcinoma (HCC) is a major cause of mortality. Knowledge on biomarkers may contribute to better surveillance based on the patients' risk of recurrence. Reviewing the literature, we aimed to identify serological and molecular biomarkers for recurrence of hepatocellular carcinoma after liver transplantation. METHODS A literature search was performed in the databases PubMed and Scopus to identify observational studies evaluating serological or molecular biomarkers for recurrence of HCC after LT using adjusted analysis to correct for confounding. RESULTS Of 502 records, 69 mainly retrospective studies were included with a total of 15,213 patients. Of these, 41 studies were suitable for meta-analyses, which showed that the serum markers pre-transplant α-fetoprotein (AFP) (hazard ratio (HR) 2.69 [2.08-3.47]), pre-transplant des-gamma-carboxy prothrombin (DCP) (HR 5.99 [3.27-10.98]), and allelic imbalance in microsatellites in DNA of tumor tissue (HR 13.49 [3.17-57.30]) were related to recurrence. CONCLUSIONS AFP, DCP and allelic imbalance in microsatellites may be used to predict recurrence. Together with other modalities, biomarkers may be used in future transplantation criteria to optimize selection of suitable patients.
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Affiliation(s)
- Hans-Christian Pommergaard
- Hvidovre Hospital - University of Copenhagen, Department of Surgery, Kettegård Allé 30, 2650 Hvidovre, Denmark.
| | - Jakob Burcharth
- Herlev Hospital - University of Copenhagen, Department of Surgery, Herlev Ringvej 75, 2730 Herlev, Denmark
| | - Jacob Rosenberg
- Herlev Hospital - University of Copenhagen, Department of Surgery, Herlev Ringvej 75, 2730 Herlev, Denmark
| | - Allan Rasmussen
- Rigshospitalet - University of Copenhagen, Department of Surgical Gastroenterology and Transplantation, Abdominal Centre, Blegdamsvej 9, 2100 Copenhagen, Denmark
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Xu DW, Wan P, Xia Q. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: A review. World J Gastroenterol 2016; 22:3325-34. [PMID: 27022214 PMCID: PMC4806190 DOI: 10.3748/wjg.v22.i12.3325] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 12/14/2015] [Accepted: 01/30/2016] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) has been accepted as an effective therapy for hepatocellular carcinoma (HCC). The Milan criteria (MC) are widely used across the world to select LT candidates in HCC patients. However, the MC may be too strict because a substantial subset of patients who have HCC exceed the MC and who would benefit from LT may be unnecessarily excluded from the waiting list. In recent years, many extended criteria beyond the MC were raised, which were proved to be able to yield similar outcomes compared with those patients meeting the MC. Because the simple use of tumor size and number was insufficient to indicate HCC biological features and to predict the risk of tumor recurrence, some biological markers such as Alpha-fetoprotein, Des-Gamma-carboxy prothrombin and the neutrophil-to-lymphocyte ratio were useful in selecting LT candidates in HCC patients beyond the MC. For patients with advanced HCC, downstaging therapy is an effective way to reduce the tumor stage to fulfill the MC by using liver-directed therapy such as transarterial chemoembolization, radiofrequency ablation and percutaneous ethanol injection. This article reviews the recent advances in LT for HCC beyond the MC.
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Andrassy J, Wolf S, Hoffmann V, Rentsch M, Stangl M, Thomas M, Pratschke S, Frey L, Gerbes A, Meiser B, Angele M, Werner J, Guba M. Rescue management of early complications after liver transplantation-key for the long-term success. Langenbecks Arch Surg 2016; 401:389-96. [PMID: 26960592 DOI: 10.1007/s00423-016-1398-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Accepted: 03/01/2016] [Indexed: 11/30/2022]
Abstract
PURPOSE Postoperative complications may have not only immediate but also long-term effects on the outcomes. Here, we analyzed the effect of postoperative complications requiring a reoperation (grade 3b) within the first 30 days on patients' and graft survival following liver transplantation. METHODS Graft and patient survival in relation to donor and recipient variables and the need of reoperation for complications of 277 consecutive liver transplants performed from January 2007 to December 2012 were analyzed. RESULTS Two hundred seventy-seven liver transplants were performed in 252 patients. Overall patient and graft survival at 1, 2, and 3 years were significantly reduced in patients requiring a reoperation. The labMELD score was significantly elevated (p = 0.04) and cold ischemia time was prolonged (p = 0.03) in recipients undergoing reoperations. Kaplan-Meier curves indicate that complications impact the outcome primarily within the first 3 months after transplantation. In multivariate analyses, the actual need of reoperation (p < 0.001), the labMELD score (p = 0.05), cold ischemia time (p = 0.02), and the need for hemodialysis pre-transplant (p = 0.05) were the only variables which correlated with the overall survival. CONCLUSION Postoperative complications resulting in reoperations have a significant impact on the outcome primarily in the early phase after liver transplantation. Successful management of postoperative complications is key to every successful liver transplant program.
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Affiliation(s)
- Joachim Andrassy
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University, Munich, Germany.
| | - Sebastian Wolf
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University, Munich, Germany
| | - Verena Hoffmann
- Institute of Medical Information Sciences, Biometry and Epidemiology (IBE), Ludwig Maximilian University, Munich, Germany
| | - Markus Rentsch
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University, Munich, Germany
| | - Manfred Stangl
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University, Munich, Germany
| | - Michael Thomas
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University, Munich, Germany
| | - Sebastian Pratschke
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University, Munich, Germany
| | - Lorenz Frey
- Department of Anesthesiology, Ludwig Maximilian University, Munich, Germany
| | - Alexander Gerbes
- Department of Medicine, MED II, Ludwig Maximilian University, Munich, Germany
| | - Bruno Meiser
- Transplant Center, Ludwig Maximilian University, Munich, Germany
| | - Martin Angele
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University, Munich, Germany
| | - Markus Guba
- Department of General, Visceral, and Transplant Surgery, Ludwig Maximilian University, Munich, Germany
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Na GH, Kim EY, Hong TH, You YK, Kim DG. Effects of loco regional treatments before living donor liver transplantation on overall survival and recurrence-free survival in South Korean patients with hepatocellular carcinoma. HPB (Oxford) 2016; 18:98-106. [PMID: 26776857 PMCID: PMC4750233 DOI: 10.1016/j.hpb.2015.08.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 06/18/2015] [Accepted: 08/09/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND We evaluated the effects of pre-transplant locoregional treatment on survival in living donor liver transplantation (LDLT), and the most accurate method for predicting survival after LDLT in patients who received pre-transplant locoregional treatment. METHODS From December 2003 to December 2012, 234 patients underwent LDLT for hepatocellular carcinoma (HCC) at our transplant center. We retrospectively reviewed 86 patients newly diagnosed with HCC and who received pre-transplant locoregional treatments at our hospital. RESULTS Of the 33 patients with HCC initially beyond the Milan criteria, 12 experienced successful down-staging after locoregional treatments, and the 5-year recurrence-free survival was 81.8%, which was comparable to those in patients with HCC initially within the Milan criteria. A bad responder according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) [HR, 4.874 (1.059-22.442), p = 0.042], and increased AFP levels [HR 4.002 (1.540-10.397), p = 0.004] during pre-transplant locoregional treatments were independent risk factors for HCC recurrence after LDLT in multivariate analysis. CONCLUSIONS Liver transplantation may be considered after successful down-staging in patients with HCC initially beyond the Milan criteria. The mRECIST and serum AFP level changes are better selection criteria for LDLT in patients who have received locoregional treatments.
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Affiliation(s)
| | | | | | | | - Dong G. Kim
- Correspondence Dong G. Kim, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea. Tel: +82 2 2258 6096. Fax: +82 2 595 2822.
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Kornberg A, Witt U, Kornberg J, Müller K, Friess H, Thrum K. Postoperative peak serum C-reactive protein is a predictor of outcome following liver transplantation for hepatocellular carcinoma. Biomarkers 2015; 21:152-9. [PMID: 26643974 DOI: 10.3109/1354750x.2015.1118548] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
CONTEXT C-reactive protein (CRP), a biomarker of inflammation, may correlate with prognosis in several malignancies. OBJECTIVE To investigate the prognostic impact of early postoperative peak serum levels of CRP on tumor-specific outcome in 106 liver transplant patients with hepatocellular carcinoma (HCC). METHODS AND RESULTS In multivariate Cox regression analysis, a posttransplant elevated peak CRP level (>versus ≤ 3.5 mg/dl) was identified as an independent predictor of poor recurrence-free survival (p = 0.01; HR = 4.04; CI = 1.399-11.640). CONCLUSION Early postoperative serum CRP may serve as a useful inflammation-based biomarker of outcome in liver transplant patients with HCC.
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Affiliation(s)
- Arno Kornberg
- a Department of Surgery, Klinikum Rechts Der Isar, Technical University , Munich , Germany
| | - Ulrike Witt
- a Department of Surgery, Klinikum Rechts Der Isar, Technical University , Munich , Germany
| | - Jennifer Kornberg
- b Department of Anaesthesiology , Klinikum Großhadern, LMU Munich , Germany
| | | | - Helmut Friess
- a Department of Surgery, Klinikum Rechts Der Isar, Technical University , Munich , Germany
| | - Katharina Thrum
- d Institute of Pathology , Helios Klinikum, Berlin , Germany
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Pretransplant serum levels of C-reactive protein predict prognoses in patients undergoing liver transplantation for hepatocellular carcinoma. Transplant Proc 2015; 47:686-93. [PMID: 25891712 DOI: 10.1016/j.transproceed.2014.11.048] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Revised: 11/12/2014] [Accepted: 11/25/2014] [Indexed: 12/28/2022]
Abstract
BACKGROUND Preoperative absolute C-reactive protein (CRP) has been shown to correlate with prognoses in various malignancies, including hepatocellular carcinoma (HCC). METHODS The aim of this study was to investigate whether pretransplant CRP levels predict prognoses in patients undergoing liver transplantation (LT) for HCC. We retrospectively analyzed clinicopathological factors in 211 patients with available pretransplant serum CRP levels who underwent LT for HCC between January 2005 and April 2012. RESULTS By means of receiver operating characteristic curve analysis, a CRP level of >0.3 mg/dL was considered to be elevated. By multivariate analysis, the high CRP level, the maximal tumor size >5 cm, the presence of intrahepatic metastasis, and positive findings in pretransplant (18)fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) were related to tumor recurrence, whereas the high CRP level, the presence of intrahepatic metastasis, and positive findings in pretransplant (18)F-FDG PET/CT were related to poor overall survival. When subgroup analysis was conducted according to the Milan criteria, the high CRP level was an independent factor for predicting poor outcomes in patients with HCC beyond the Milan criteria (P = .001 for recurrence-free survival and P = .010 for overall survival), and not for patients within the criteria. CONCLUSIONS Pretransplant serum CRP levels can predict prognoses in patients undergoing LT for HCC, especially in patients with HCC exceeding the Milan criteria.
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Liu YB, Ying J, Kuang SJ, Jin HS, Yin Z, Chang L, Yang H, Ou YL, Zheng JH, Zhang WD, Li CS, Jian ZX. Elevated Preoperative Serum Hs-CRP Level as a Prognostic Factor in Patients Who Underwent Resection for Hepatocellular Carcinoma. Medicine (Baltimore) 2015; 94:e2209. [PMID: 26656354 PMCID: PMC5008499 DOI: 10.1097/md.0000000000002209] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
To evaluate the effects of preoperative highly sensitive C-reactive protein (Hs-CRP) in serum on the prognostic outcomes of patients with hepatocellular carcinoma (HCC) following hepatic resection in Chinese samples.From January 2004 to December 2008, a total of 624 consecutive HCC patients who underwent hepatic resection were incorporated. Serum levels of Hs-CRP were tested at preoperation via a collection of venous blood samples. Survival analyses adopted the univariate and multivariate analyses.In our study, among the 624 screened HCC patients, 516 patients were eventually incorporated and completed follow-up. Positive correlations were found regarding preoperative serum Hs-CRP level and tumor size, Child-Pugh class, or tumor stage (all P < 0.0001). Patients with recurrence outcomes and nonsurvivors had increased Hs-CRP levels at preoperation (both P < 0.0001). When compared to the Hs-CRP-normal group, the overall survival (OS) and recurrence-free survival rates were evidently decreased in the Hs-CRP-elevated group. Further, preoperative serum Hs-CRP level might be having possible prediction effect regarding survival and recurrence of HCC patients after hepatic section in the multivariate analysis.Preoperative increased serum Hs-CRP level was an independent prognostic indicator in patients with HCC following hepatic resection in Chinese samples.
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Affiliation(s)
- Yu-Bin Liu
- From the Department of Hepatobiliary Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, P.R. China (Y-BL, S-JK, H-SJ, ZY, LC, HY, Y-LO, J-HZ, Z-XJ) and Department of Infectious, People's Hospital of Xuyi, Jiangsu, P.R. China (JY, W-DZ, C-SL)
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The usefulness of C-reactive protein and neutrophil-to-lymphocyte ratio for predicting the outcome in hospitalized patients with liver cirrhosis. BMC Gastroenterol 2015; 15:146. [PMID: 26498833 PMCID: PMC4619077 DOI: 10.1186/s12876-015-0378-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 10/15/2015] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The role of clinical parameters such as systemic inflammatory response syndrome (SIRS) criteria in predicting the infection remains unclear in cirrhosis patients. The aim was to evaluate the usefulness of inflammatory markers including C-reactive protein (CRP) and the neutrophil-to-lymphocyte ratio (NLR) for diagnosis of infection and predicting the outcomes in hospitalized cirrhotic patients. METHODS The study included 184 cirrhotic patients consecutively hospitalized from 2011 to 2012. The presence of overt infection and survival was evaluated. CRP concentration, NLR, Model for End-Stage Liver Disease (MELD) score and the presence of SIRS were assessed. RESULTS The main cause of admission was uncontrolled ascites (36.4 %), followed by varix bleeding (23.9 %), and hepatic encephalopathy (13.6 %). Fifty-eight patients (31.5 %) had overt infection during hospitalization and thirty-two patients (17.4 %) expired during the follow up period (median 38 months). Ninety-two patients (52.2 %) fulfilled the SIRS criteria and among them, only 32 patients (38.5 %) had the overt infection. For diagnose of the infection, baseline CRP concentration was a significant factor compared to the presence of SIRS (odds ratio 1.202, P = 0.003). For predicting one-month short-term survival, MELD score, NLR and WBC count were significant factors but in Child-Pugh class C patients, NLR was only an independent factor. CONCLUSIONS CRP was a significant indicator of infection in hospitalized cirrhotic patients and a NLR was a useful predictor of 1-month survival, particularly in Child-Pugh class C patients. This study suggests that the inflammatory markers such as CRP and NLR can help identify cirrhotic patients at risk of unfavorable outcomes.
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Mazzola A, Costantino A, Petta S, Bartolotta TV, Raineri M, Sacco R, Brancatelli G, Cammà C, Cabibbo G. Recurrence of hepatocellular carcinoma after liver transplantation: an update. Future Oncol 2015; 11:2923-36. [PMID: 26414336 DOI: 10.2217/fon.15.239] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver transplantation is the only curative alternative for selected patients with hepatocellular carcinoma (HCC) who are not eligible for resection and/or with decompensated cirrhosis. According to Milan criteria the 5-year survival rate is 70-85%, with a recurrence-free survival of 75%. However, HCC recurrence rate after liver transplantation remains a significant problem in the clinical practice. The prognosis in patients with HCC recurrence is poor. The treatment of choice for HCC recurrence is surgery, but it seems that a systemic treatment based on combination of an mTOR inhibitor with sorafenib can be used. Data on safety and efficacy are limited, clinical monitoring is necessary. The aim of this review is to underline the main concerns, pitfalls and warnings for these patients.
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Affiliation(s)
- Alessandra Mazzola
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy.,Unité Médicale de Transplantation Hépatique AP-HP, Hôpital Pitié-Salpêtrière, UPMC Paris, Paris, France
| | - Andrea Costantino
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Salvatore Petta
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | | | - Maurizio Raineri
- Section of Anesthesiology, Analgesia, Intensive Care & Emergency, Department of Biopathology, Medical & Forensic Biotechnologies (DIBIMEF), Policlinico 'P Giaccone', University of Palermo, Palermo, Italy
| | - Rodolfo Sacco
- Gastroenterology Unit, Cisanello Hospital, Pisa, Italy
| | | | - Calogero Cammà
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology - Di.Bi.M.I.S., University of Palermo, Palermo, Italy
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Prediction of gross post-transplant outcomes based on the intra-operative decline in C-reactive protein in living donor liver transplantation. Transplant Proc 2015; 47:431-7. [PMID: 25769586 DOI: 10.1016/j.transproceed.2015.01.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 01/14/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND C-reactive protein (CRP), a marker of infection and inflammation, is produced mainly in the liver. Its slow onset and various influencing factors have limited studies on the intra-operative changes in CRP in living donor liver transplantation (LDLT). In this study, we asked whether the intra-operative changes in CRP predicts post-transplant outcome. METHODS The peri-transplant data of 263 LDLT patients were reviewed. "Intra-operative CRP decline" was calculated by subtracting the pretransplant CRP from the 1-day post-transplant CRP. A negative value defined an intra-operative decline. Peri-transplant variables were compared between patients with and without gross post-transplant outcomes (GPOs), including death, allograft dysfunction, infection, and kidney injury. Multivariate logistic regression was used to develop a model to predict GPO, and area receiver operating characteristic curve (AUC) analysis was used to evaluate the prognostic accuracies for GPO. RESULTS GPOs were determined in 95 LDLT patients (36.1%). GPO-positive patients had a lesser change in CRP levels (0.51 versus 1.16 mg/dL) and a higher incidence of a decline in CRP (34.7% versus 13.7%) during LDLT (P < .05) than did GPO-negative patients. The AUC of the intra-operative CRP change (0.585; P = .018) did not significantly differ from that of the pretransplant CRP. After multivariate adjustment, a patient with an intra-operative decline in CRP had a 3.21-fold higher risk for GPO occurrence (P = .001). CONCLUSIONS GPO occurrence was related to the intra-operative decline of CRP in LDLT patients. However, multivariate compensation might be required for the clinical utilization of intra-operative decline in CRP as a prognostic indicator.
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Fujiwara N, Tateishi R, Nakagawa H, Nakagomi R, Kondo M, Minami T, Sato M, Uchino K, Enooku K, Kondo Y, Asaoka Y, Shiina S, Yoshida H, Koike K. Slight elevation of high-sensitivity C-reactive protein to predict recurrence and survival in patients with early stage hepatitis C-related hepatocellular carcinoma. Hepatol Res 2015; 45:645-55. [PMID: 25070147 DOI: 10.1111/hepr.12398] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Revised: 07/13/2014] [Accepted: 07/22/2014] [Indexed: 12/29/2022]
Abstract
AIM Hepatocellular carcinoma (HCC) is associated with chronic inflammation derived from various origins. We investigated whether high-sensitivity C-reactive protein (hsCRP) could predict recurrence and survival after curative treatment for early stage hepatitis C virus-related HCC (C-HCC). METHODS We enrolled 387 patients with three or fewer C-HCC nodules, none of which exceeded 3 cm, and of Child-Pugh class A or B who underwent radiofrequency ablation. We divided the patients into high and low hsCRP groups based on the optimal cut-off value for recurrence using a split-sample method and maximally selected rank statistics. Differences in recurrence and survival rates were evaluated by the Kaplan-Meier method and the log-rank test. Hazard ratios of hsCRP were adjusted with confounding factors using a multiple Cox regression model. We also assessed the correlations between hsCRP levels and clinical parameters. RESULTS The optimal hsCRP cut-off value was 0.08 mg/dL. The cumulative recurrence rates after 5 years in the high and low hsCRP groups were 90.0% and 82.2%, respectively (P = 0.028), and the corresponding survival rates were 50.9% and 71.8%, respectively (P < 0.001). Higher hsCRP was an independent predictor for recurrence (adjusted hazard ratio [aHR], 1.32; 95% confidence interval [CI], 1.03-1.67; P = 0.026) and survival (aHR, 1.59; 95% CI, 1.14-2.22; P = 0.007). hsCRP was correlated with central obesity as well as tumor burden and liver dysfunction. CONCLUSION Slight elevation of the hsCRP level, even within the normal range, can predict recurrence and survival after curative treatment among patients with early stage C-HCC.
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Affiliation(s)
- Naoto Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryo Nakagomi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mayuko Kondo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tatsuya Minami
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Koji Uchino
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kenichiro Enooku
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuji Kondo
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshinari Asaoka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shuichiro Shiina
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
| | - Haruhiko Yoshida
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Smirne C, Grossi G, Pinato DJ, Burlone ME, Mauri FA, Januszewski A, Oldani A, Minisini R, Sharma R, Pirisi M. Evaluation of the red cell distribution width as a biomarker of early mortality in hepatocellular carcinoma. Dig Liver Dis 2015; 47:488-94. [PMID: 25864774 DOI: 10.1016/j.dld.2015.03.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 03/06/2015] [Accepted: 03/11/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND The red cell distribution width is a biomarker of early mortality across various disease states. AIM To verify whether it may refine estimates of survival in hepatocellular carcinoma. METHODS The red cell distribution width measured at diagnosis was analyzed in relationship to mortality by any cause both in a retrospective training cohort (N=208), and in an independent prospectively collected validation cohort (N=106) of patients with hepatocellular carcinoma. Based on Cox proportional hazards modelling, a prognostic index was validated. RESULTS In the training and the validation cohort, median survival time was respectively 1026 and 868 days in patients with red cell distribution width ≤14.6%, vs. 282 and 340 days in patients with red cell distribution width >14.6%; the corresponding hazard ratios were 0.43 (95% CI: 0.31-0.60), p<0.0001 and 0.28 (95% CI: 0.17-0.47), p<0.0001. At multivariate analysis, the red cell distribution width remained an independent predictor of survival (p<0.001) in a Cox model including other widely accepted prognostic factors. Applying to the validation dataset the prognostic index derived from the training dataset, the ability of the model to discriminate the survival probabilities of patients was confirmed (Harrell's C=0.769). CONCLUSIONS The red cell distribution width is a novel, reproducible, prospectively validated predictor of survival in patients with hepatocellular carcinoma.
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Affiliation(s)
- Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Glenda Grossi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - David J Pinato
- Division of Experimental Medicine, Hammersmith Campus of Imperial College London, London, UK
| | - Michela E Burlone
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy; CRRF Monsignor Luigi Novarese, Moncrivello, Italy
| | - Francesco A Mauri
- Department of Histopathology, Hammersmith Campus of Imperial College London, London, UK
| | - Adam Januszewski
- Department of Oncology, Hammersmith Campus of Imperial College London, London, UK
| | - Alberto Oldani
- Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy
| | - Rohini Sharma
- Division of Experimental Medicine, Hammersmith Campus of Imperial College London, London, UK
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.
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Takada Y, Tohyama T, Watanabe J. Biological markers of hepatocellular carcinoma for use as selection criteria in liver transplantation. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2014; 22:279-86. [PMID: 25408520 DOI: 10.1002/jhbp.195] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The Milan criteria (MC) have been widely accepted as an effective way of selecting patients with early-stage hepatocellular carcinoma (HCC) for curative liver transplantation (LT). However, since a substantial subset of HCC patients exists that is beyond the MC but with the potential for good outcomes after LT, several institutions have recently proposed new extended criteria. To explore optimal criteria that can reasonably predict the risk of recurrence, it is considered that new markers of biological behavior are needed in addition to morphological tumor size and number. Several promising candidates for such biological markers have been reported, including serum tumor markers such as alpha-fetoprotein and des-gamma-carboxy prothrombin, inflammatory markers such as C-reactive protein and neutrophil-to-lymphocyte ratio, response to pre-transplant treatments for bridging therapy or down-staging, and fluorine-18-fluorodeoxyglucose positron emission tomography. However, the role of these biological markers in patient selection criteria for LT has yet to be clarified. This review article aims to summarize the results of recent reported studies and to display perspectives for the establishment of optimal criteria that incorporate such biological markers.
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Affiliation(s)
- Yasutsugu Takada
- Department of HPB and Breast Surgery, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
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Cholongitas E, Mamou C, Rodríguez-Castro KI, Burra P. Mammalian target of rapamycin inhibitors are associated with lower rates of hepatocellular carcinoma recurrence after liver transplantation: a systematic review. Transpl Int 2014; 27:1039-49. [PMID: 24943720 DOI: 10.1111/tri.12372] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 04/13/2014] [Accepted: 06/08/2014] [Indexed: 12/13/2022]
Abstract
Calcineurin inhibitors (CNIs) have been associated in a dose-dependent fashion with an increased risk of post-transplant hepatocellular carcinoma (HCC) recurrence. The mammalian target of rapamycin inhibitors (mTORi) (sirolimus/everolimus) might represent an alternative immunosuppressive regimen with antineoplastic effect. In the present systematic review, the association between mTORi and HCC recurrence after liver transplantation (LT) was evaluated and compared against that of CNIs-treated patients. In total, 3666 HCC liver transplant recipients from 42 studies met the inclusion criteria. Patients under CNIs developed HCC recurrence significantly more frequently, compared with patients under mTORi (448/3227 or 13.8% vs. 35/439 or 8%, P < 0.001), although patients treated with CNIs had a higher proportion of HCC within Milan criteria (74% vs. 69%) and lower rates of microvascular invasion, compared with mTORi-treated patients (22% vs. 44%) (P < 0.05). Patients on everolimus had significantly lower recurrence rates of HCC, compared with those on sirolimus or CNIs (4.1% vs. 10.5% vs. 13.8%, respectively, P < 0.05), but everolimus-treated recipients had shorter follow-up period (13 vs. 30 vs. 43.2 months, respectively) and more frequently been transplanted for HCC within Milan criteria (84% vs. 60.5% vs. 74%, respectively, P < 0.05). Our findings favor the use of mTORi instead of CNIs to control HCC recurrence after LT, but comparative studies with longer follow-up are needed for final conclusions.
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Affiliation(s)
- Evangelos Cholongitas
- 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece
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Hepatocellular cancer: how to expand safely inclusion criteria for liver transplantation. Curr Opin Organ Transplant 2014; 19:229-34. [PMID: 24811435 DOI: 10.1097/mot.0000000000000085] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW The Milan criteria are still considered to be the best ones to select patients with hepatocellular cancer (HCC) for liver transplantation. Although the Milan criteria allowed lowering the incidence of tumor recurrence to a remarkable 10%, there is growing evidence that high numbers of patients were unrightfully excluded from a curative liver transplantation when exceeding these criteria. New strategies have been advocated during recent years with the intent not only to enlarge the number of potential transplant candidates, but also to select recipients with the lowest biological risk of recurrence. RECENT FINDINGS Different 'biological' and 'dynamic' parameters have been proposed both in western and eastern scenarios, such as α-fetoprotein dynamics, radiological response to locoregional treatments and several inflammatory markers, the neutrophil-to-lymphocyte ratio being the most promising one. SUMMARY The paradigm that HCC patients should be selected according to morphological aspects (tumor numbers and diameters) only, based on the almost 20-year old success story of the Milan criteria, should be modified by combining these parameters with newer biological tumor markers in order to further refine the selection for liver transplantation. Such therapeutic algorithm will allow to further improve selection for and thus outcome after liver transplantation for HCC patients.
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