Xiao-min Shi

A single-center retrospective analysis of liver transplantation on 255 patients with hepatocellular carcinoma.

Wang Z‐X, Song S‐H, Teng F, Wang G‐H, Guo W‐Y, Shi X‐M, Ma J, Wu Y‐M, Ding G‐S, Fu Z‐R. A single‐center retrospective analysis of liver transplantation on 255 patients with hepatocellular carcinoma. 
Clin Transplant 2010: 24: 752–757.

Suppression of Allograft Rejection by Tim-1-Fc through Cross-Linking with a Novel Tim-1 Binding Partner on T Cells

Engagement of T-cell immunoglobulin mucin (Tim)-1 on T cells with its ligand, Tim-4, on antigen presenting cells delivers positive costimulatory signals to T cells. However, the molecular mechanisms for Tim-1-mediated regulation of T-cell activation and differentiation are relatively poorly understood. Here we investigated the role of Tim-1 in T-cell responses and allograft rejection using recombinant human Tim-1 extracellular domain and IgG1-Fc fusion proteins (Tim-1-Fc). In vitro assays confirmed that Tim-1-Fc selectively binds to CD4+ effector T cells, but not dendritic cells or natural regulatory T cells (nTregs). Tim-1-Fc was able to inhibit the responses of purified CD4+ T cells that do not express Tim-4 to stimulation by anti-CD3/CD28 mAbs, and this inhibition was associated with reduced AKT and ERK1/2 phosphorylation, but it had no influence on nTregs. Moreover, Tim-1-Fc inhibited the proliferation of CD4+ T cells stimulated by allogeneic dendritic cells. Treatment of recipient mice with Tim-1-Fc significantly prolonged cardiac allograft survival in a fully MHC-mismatched strain combination, which was associated with impaired Th1 response and preserved Th2 and nTregs function. Importantly, the frequency of Foxp3+ cells in splenic CD4+ T cells was increased, thus shifting the balance toward regulators, even though Tim-1-Fc did not induce Foxp3 expression in CD4+CD25− T cells directly. These results indicate that Tim-1-Fc can inhibit T-cell responses through an unknown Tim-1 binding partner on T cells, and it is a promising immunosuppressive agent for preventing allograft rejection.

Criteria-specific long-term survival prediction model for hepatocellular carcinoma patients after liver transplantation

AIM To establish a model to predict long-term survival of hepatocellular carcinoma (HCC) patients after liver transplantation (MHCAT). METHODS Two hundred and twenty-three patients with HCC were followed for at least six years to identify independent risk factors for long-term survival after liver transplantation (LT). The criteria for HCC liver transplantation included the Milan, University of California San Francisco, Hangzhou and Shanghai Fudan criteria. The Cox regression model was used to build MHCAT specifying these criteria. A survival analysis was carried out for patients with high or low risk. RESULTS The one-, three- and five-year cumulative survival of HCC patients after LT was 78.9%, 53.2% and 46.4%, respectively. Of the HCC patients, the proportion meeting the Hangzhou and Fudan criteria was significantly higher than the proportion meeting the Milan criteria (64.6% vs 39.5%, 52.0% vs 39.5%, P < 0.05). Moreover, the proportion meeting the Hangzhou criteria was also significantly higher than the proportion meeting other criteria (P < 0.01). Pre-operative alfa-fetoprotein level, intraoperative blood loss and retransplantation were common significant predictors of long-term survival in HCC patients with reference to the Milan, University of California San Francisco and Fudan criteria, whereas in MHCAT based on the Hangzhou criteria, total bilirubin, intraoperative blood loss and retransplantation were independent predictors. The c-statistic for MHCAT was 0.773-0.824, with no statistical difference among these four criteria. According to the MHCAT scoring system, patients with low risk showed a higher five-year survival than those with high risk (P < 0.001). CONCLUSION MHCAT can effectively predict long-term survival for HCC patients, but needs to be verified by multi-center retrospective or randomized controlled trials.

The therapeutic effect of monocyte chemoattractant protein-1 delivered by an electrospun scaffold for hyperglycemia and nephrotic disorders

Here, we investigated in diabetic mice the therapeutic effect of monocyte chemoattractant protein-1 (MCP-1), locally delivered by an electrospun scaffold, on transplanted islets. This therapeutic scheme is expected to exert a synergistic effect to ameliorate hyperglycemia and its associated nephrotic disorders. The cumulative amount of MCP-1 released from the scaffold in vitro within a 3-week window was 267.77±32.18 ng, without a compromise in bioactivity. After 8 weeks following the transplantation, the islet population stimulated by MCP-1 was 35.14%±7.23% larger than the non-stimulated islet population. Moreover, MCP-1 increased concentrations of blood insulin and C-peptide 2 by 49.83%±5.29% and 43.49%±9.21%, respectively. Consequently, the blood glucose concentration in the MCP-1 group was significantly lower than that in the control group at week 2 post-surgery. MCP-1 also enhanced the tolerance of sudden oral glucose challenge. The rapid decrease of blood creatinine, urine creatinine, and blood urea nitrogen suggested that the recovery of renal functions compromised by hyperglycemia could also be attributed to MCP-1. Our study shed new light on a synergistic strategy to alleviate hyperglycemia and nephrotic disorders in diabetic patients.

Reconstruction of the middle hepatic vein tributary in adult right lobe living donor liver transplantation.

BACKGROUND In adult-to-adult living donor liver transplantation (LDLT), the use of a right lobe graft without the middle hepatic vein (MHV) can cause hepatic congestion and disturbance of venous drainage. To solve this problem, we successfully used cadaveric venous allografts preserved in 4 °C University of Wisconsin (UW) solution within 10 days as interposition veins for drainage of the paramedian portion of the right lobe in adult LDLT. METHODS From June 2007 to January 2008, 11 adult LDLT patients received modified right liver grafts. The major MHV tributaries (greater than 5 mm in diameter) of 9 cases were preserved and reconstructed using cadaveric interposition vein allografts that had been stored for 1 to 10 days in 4 °C UW solution. The regeneration of the paramedian sector of the grafts and the patency of the interposition vein allografts were examined by Doppler ultrasonography after the operation. RESULTS MHV tributaries were reconstructed in 9 recipients. Only 1 recipient died of renal failure and severe pulmonary infection on day 9 after transplantation without any hemiliver venous outflow obstruction. The other 8 recipients achieved long-term survival with a median follow-up of 30 months. The cumulative patency rates of the 8 recipients were 63.63% (7/11), 45.45% (5/11), 45.45% (5/11) and 36.36% (4/11) at 3, 6, 12 and 24 months, respectively. Regeneration of the paramedian sectors was equivalent. CONCLUSION The cadaveric venous allograft preserved in 4 °C UW solution within 10 days serves as a useful alternative for interposition veins in facilitating implantation of a right lobe graft and guarantees outflow of the MHV.

Validation of a criteria-specific long-term survival prediction model for hepatocellular carcinoma patients after liver transplantation.

The aim of this study was to validate a criteria-specific long-term survival prediction model (MHCAT) in a large cohort of hepatocellular carcinoma (HCC) patients after liver transplantation (LT) in China. Independent risk factors in MHCAT were retrospectively analysed for HCC patients recorded in the China Liver Transplant Registry. Survival predictions for each patient were calculated using MHCAT scores and the Metroticket formula separately, and the prediction efficacy of MHCAT and Metroticket was compared using the area under ROC curve (c-statistic). A total of 1371 LTs for HCC were analysed in the study, with a median follow-up of 22.2 months (IQR 6.1–72.4 months). The proportions meeting the Milan, UCSF, Fudan and Hangzhou criteria were 34.4%, 39.7%, 44.2% and 51.9%, respectively. The c-statistics for MHCAT predictions of 3- and 5-year survival rates of HCC recipients were 0.712–0.727 and 0.726–0.741, respectively. Among these patients, 1298 LTs for HCC were ultimately selected for the comparison analysis for prediction efficacy. The c-statistic of MHCAT for predictions of 3-year survival with reference to the Milan, UCSF and Fudan criteria was significantly increased compared with that for Metroticket (p < 0.05). In conclusion, MHCAT can effectively predict long-term survival for HCC recipients after LT.

Favorable effect of thrombocytopenia on outcomes of liver transplantation for hepatocellular carcinoma

Platelets may affect tumor cell proliferation and angiogenesis by releasing several cytokines including plateletderived growth factor and vascular endothelial growth factor, among others. [1] Studies have shown that the platelet count (PLT) is a risk factor for hepatic carcinogenesis. [2,3] Moreover, a recent meta-analysis by Pang et al. [4] indicated that preoperative thrombocytopenia was significantly associated with poor overall survival (OS) and recurrence-free survival (RFS) in patients with hepatocellular carcinoma (HCC). However, all studies included in that meta-analysis focused on HCC patients treated with hepatectomy or radiofrequency ablation, without addressing patients treated with liver transplantation (LT). We therefore aimed to evaluate the efficacy of the PLT in predicting outcomes of HCC patients undergoing LT. The medical records of 402 HCC patients who underwent LT at our transplant center between 2001 and 2012 were retrospectively reviewed. This study was approved by the Research Ethics Committee of Changzheng Hospital. PLT absolute values were taken the day before surgery. Patient characteristics are reported in Table 1. There was a predominance of hepatitis B virus-related HCC (n1⁄4380, 94.5%), and 263 patients (65.4%) did not satisfy the Milan criteria. The mean PLT was 103 10/L. Using the Martingale residuals of the Cox model, we classified patients into three categories according to the PLT:565, 65–130 and4130 ( 10/L). Kaplan–Meier survival curves indicated that patients with a low PLT had better OS (Figure 1a) and RFS (Figure 1b). Furthermore, multivariate analysis by Cox proportional hazards regression indicated that a PLT565 10/L was independently associated with a favorable OS [hazard ratio, 0.549; 95% confidence interval (CI), 0.366–0.824; p1⁄40.004] and RFS (hazard ratio, 0.598; 95% CI, 0.407–0.879; p1⁄40.009). In addition, a significant correlation was detected between the PLT and tumor biology. Patients with a low PLT (5130 10/L) had less frequent vascular invasion (p1⁄40.033), lower levels of serum alpha-fetoprotein (AFP;5400 ng/mL, p50.001) and satisfied the preoperative Milan criteria more frequently (p50.001). In contrast to previous studies, [5,6] our findings showed a favorable outcome for HCC patients with preoperative thrombocytopenia after LT. There are several potential explanations. Thrombocytopenia is correlated with poor liver function and relevant portal hypertension, [7] contraindicating extensive hepatic resection as well as anatomical resection. [8] Thus, these potentially curative treatments might not lead to a cure in patients with thrombocytopenia. LT could cure not only the tumor, but also the underlying cirrhosis, and the effectiveness of LT is not affected by the degree of liver function impairment. [9] Our study showed that

Relationship of chemokine IP-10 and its soluble CXCR3 in bile with acute graft rejection after liver transplantation: Relationship of chemokine IP-10 and its soluble CXCR3 in bile with acute graft rejection after liver transplantation

Objective:To observe the dynamic changes of chemokine IP-10 and its soluble receptor CXCR3 in bile,and to explore its relationship with acute graft rejection(AR)after liver transplantation.Methods:A total of 28 patients who underwent orthotopic liver transplantation in our hospital between October 2007 and March 2008 were included in the present study.They were divided into 2 groups according to the presence of AR:AR(n=8)and NAR(n=20).Another 10 patients who underwent endoscopic nasobiliary drainage(ENBD)for cholelithiasis in our hospital served as controls.The levels of chemokine IP-10 and sCXCR3 in the bile were determined by ELISA assay on 1,3,5,and 7 days after transplantation in all the patients and on 1,3,and 7 days after the anti-rejection therapy with glucocorticoid in patients of AR group;the relationship between their levels and the rejection active index(RAI)obtained by Banff criteria were evaluated;and its diagnostic value for AR was assessed.Results:The levels of IP-10 and sCXCR3 in bile gradually increased after liver transplantation and reached the peak on the 5th day after transplantation,and starting from day 5 after transplantation,their levels were significantly higher in the AR group than in the NAR group and ENBD group(P0.05).Besides,the levels of IP-10 and sCXCR3 in bile were significantly decreased after treatment with glucocorticoid(P0.05).On the day of AR diagnosis,the the levels of IP-10 and sCXCR3 in bile were significantly correlated with RAI(P0.05).On the 5th day after transplantation,the diagnostic sensitivity and specificity of IP-10 level for AR were 87.5% and 100%,respectively(cut-off point=964.45 pg/ml);on the 7th day after transplantation,the diagnostic sensitivity and specificity of sCXCR3 were 87.5% and 80%,respectively(cut-off point=819.35 pg/ml).Conclusion:The levels of IP-10 and sCXCR3 in bile are closed related with early graft acute rejection,and their levels may serve as a non-invasive diagnostic indicator for AR and outcome of anti-rejection therapy.