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      Salvage Liver Transplantation for Recurrent Hepatocellular Carcinoma after Liver Resection: Retrospective Study of the Milan and Hangzhou Criteria

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          Salvage liver transplantation (SLT) has recently been proposed for recurrent hepatocellular carcinoma after liver resection; however, criteria for candidate assessment in SLT have not been thoroughly evaluated.

          Methods and Findings

          We retrospectively analyzed outcomes and factors affecting survival of 53 recipients who received SLT in the Liver Transplantation Center, The First Affiliated Hospital of Zhejiang University between 2004 and 2012. Thirty recipients fulfilled the Hangzhou criteria, of which 16 also fulfilled the Milan criteria, while the remaining 23 exceeded both criteria. The 1-year, 3-year and 5-year overall survival rates and tumor-free survival rates were both superior in patients fulfilling Milan or Hangzhou criteria compared with those exceeding the criteria. For recipients outside Milan criteria but within Hangzhou criteria, the 1-year, 3-year overall survival rates were 70.1%, 70.1%, similar to recipients within Milan criteria, with the 1-year, 3-year and 5-year overall survival of 93.8%%, 62.1% and 62.1% (P = 0.586). The tumor-free survival rates were also similar between these two subgroups, with 51.9% and 51.9% vs. 85.6%, 85.6% and 64.2% during the same time interval, respectively (P = 0.054). Cox regression analysis identified Hangzhou criteria (within vs. outside, hazard ratio (HR) 0.376) and diameter of the largest tumor (HR 3.523) to be independent predictors for overall survival. The only predictor for tumor-free survival was diameter of the largest tumor (HR 22.289).


          Hangzhou criteria safely expanded the candidate pool and are feasible in assessment of candidates for SLT. This is helpful in donor liver allocation in transplant practice.

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          Most cited references 23

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          Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.

          The role of orthotopic liver transplantation in the treatment of patients with cirrhosis and hepatocellular carcinoma is controversial, and determining which patients are likely to have a good outcome after liver transplantation is difficult. We studied 48 patients with cirrhosis who had small, unresectable hepatocellular carcinomas and who underwent liver transplantation. In 94 percent of the patients, the cirrhosis was related to infection with hepatitis B virus, hepatitis C virus, or both. The presence of tumor was confirmed by biopsy or serum alpha-fetoprotein assay. The criteria for eligibility for transplantation were the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than three tumor nodules, each 3 cm or less in diameter, in patients with multiple tumors. Thirty-three patients with sufficient hepatic function underwent treatment for the tumor, mainly chemoembolization, before transplantation. After liver transplantation, the patients were followed prospectively for a median of 26 months (range, 9 to 54). No anticancer treatment was given after transplantation. The overall mortality rate was 17 percent. After four years, the actuarial survival rate was 75 percent and the rate of recurrence-free survival was 83 percent. Hepatocellular carcinoma recurred in four patients (8 percent). The overall and recurrence-free survival rates at four years among the 35 patients (73 percent of the total) who met the predetermined criteria for the selection of small hepatocellular carcinomas at pathological review of small hepatocellular carcinomas at pathological review of the explanted liver wer 85 percent and 92 percent, respectively, whereas the rates in the 13 patients (27 percent) whose tumors exceeded these limits were 50 percent and 59 percent, respectively (P=0.01 for overall survival; P=0.002 for recurrence-free survival). In this group of 48 patients with early-stage tumors, tumor-node-metastasis status, the number of tumors, the serum alphafetoprotein concentration, treatment received before transplantation, and 10 other variables were not significantly correlated with survival. Liver transplantation is an effective treatment for small, unresectable hepatocellular carcinomas in patients with cirrhosis.
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            Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.

            The precise staging of hepatocellular carcinoma (HCC) based on the size and number of lesions that predict recurrence after orthotopic liver transplantation (OLT) has not been clearly established. We therefore analyzed the outcome of 70 consecutive patients with cirrhosis and HCC who underwent OLT over a 12-year period at our institution. Pathologic tumor staging of the explanted liver was based on the American Tumor Study Group modified Tumor-Node-Metastases (TNM) Staging Classification. Tumor recurrence occurred in 11.4% of patients after OLT. The Kaplan-Meier survival rates at 1 and 5 years were 91.3% and 72.4%, respectively, for patients with pT1 or pT2 HCC; and 82.4% and 74.1%, respectively, for pT3 tumors (P =.87). Patients with pT4 tumors, however, had a significantly worse 1-year survival of 33.3% (P =.0001). An alpha-fetoprotein (AFP) level > 1,000 ng/mL, total tumor diameter > 8 cm, age > or = 55 years and poorly differentiated histologic grade were also significant predictors for reduced survival in univariate analysis. Only pT4 stage and total tumor diameter remained statistically significant in multivariate analysis. Patients with HCC meeting the following criteria: solitary tumor < or = 6.5 cm, or < or = 3 nodules with the largest lesion < or = 4.5 cm and total tumor diameter < or = 8 cm, had survival rates of 90% and 75.2%, at 1 and 5 years, respectively, after OLT versus a 50% 1-year survival for patients with tumors exceeding these limits (P =.0005). We conclude that the current criteria for OLT based on tumor size may be modestly expanded while still preserving excellent survival after OLT.
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              Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.

              Patients undergoing liver transplantation for hepatocellular carcinoma within the Milan criteria (single tumour

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                27 January 2014
                : 9
                : 1
                [1 ]Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
                [2 ]Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang Province, Hangzhou, China
                [3 ]Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China
                University of Pisa, Italy
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SZ ZH. Performed the experiments: JZ. Analyzed the data: ZL. Contributed reagents/materials/analysis tools: JX ZQ MZ. Wrote the paper: ZH JZ JW.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 7
                This study was sponsored by grants from National S&T Major Project (No. 2012ZX10002017), the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (Grant No.81121002) and the National Natural Science Foundation of China (Grant No.81200331). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Statistical Methods
                Clinical Research Design
                Retrospective Studies
                Gastroenterology and Hepatology
                Liver Diseases
                Cancers and Neoplasms
                Gastrointestinal Tumors
                Hepatocellular Carcinoma
                Transplant Surgery



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