Zhenhua Hu

Salvage Liver Transplantation Is a Reasonable Option for Selected Patients Who Have Recurrent Hepatocellular Carcinoma after Liver Resection

Background Salvage liver transplantation (SLT) has been reported as being feasible for patients who develop recurrent hepatocellular carcinoma (HCC) after primary liver resection, but this finding remains controversial. We retrospectively studied the clinical characteristics of SLT recipients and conducted a comparison between SLT recipients and primary liver transplantation (PLT) recipients. Methodology and Principal Findings A retrospective study examined data from the China Liver Transplant Registry (CLTR) for 6,975 transplants performed from January 1999 to December 2009. A total of 6,087 patients underwent PLT and 888 patients underwent SLT for recurrence. Living donor liver transplantation (LDLT) was performed in 389 patients, while 6,586 patients underwent deceased donor liver transplantation (DDLT). Kaplan-Meier curves were used to compare survival rates. The 1-year, 3-year, and 5-year overall survival of SLT recipients was similar to that of PLT recipients: 73.00%, 51.77%, and 45.84% vs. 74.49%, 55.10%, and 48.81%, respectively (P = 0.260). The 1-year, 3-year and 5-year disease-free survival of SLT recipients was inferior to that of PLT recipients: 64.79%, 45.57%, and 37.78% vs. 66.39%, 50.39%, and 43.50%, respectively (P = 0.048). Similar survival results were observed for SLT and PLT within both the LDLT and DDLT recipients. Within the SLT group, the 1-year, 3-year, and 5-year overall survival for LDLT and DDLT recipients was similar: 93.33%, 74.67%, and 74.67% vs. 80.13%, 62.10%, and 54.18% (P = 0.281), as was the disease-free survival: 84.85%, 62.85%, and 62.85% vs. 70.54%, 53.94%, and 43.57% (P = 0.462). Conclusions Our study demonstrates that for selected patients, SLT has similar survival to that of PLT, indicating that SLT is acceptable for patients with recurrent HCC after liver resection. Given the limited organ donor pool, salvage LDLT might be considered as a possible treatment.

Liver Ischemic Preconditioning (IPC) Improves Intestinal Microbiota Following Liver Transplantation in Rats through 16s rDNA-Based Analysis of Microbial Structure Shift

Background Ischemia-reperfusion (I/R) injury is associated with intestinal microbial dysbiosis. The “gut-liver axis” closely links gut function and liver function in health and disease. Ischemic preconditioning (IPC) has been proven to reduce I/R injury in the surgery. This study aims to explore the effect of IPC on intestinal microbiota and to analyze characteristics of microbial structure shift following liver transplantation (LT). Methods The LT animal models of liver and gut IPC were established. Hepatic graft function was assessed by histology and serum ALT/AST. Intestinal barrier function was evaluated by mucosal ultrastructure, serum endotoxin, bacterial translocation, fecal sIgA content and serum TNF-α. Intestinal bacterial populations were determined by quantitative PCR. Microbial composition was characterized by DGGE and specific bacterial species were determined by sequence analysis. Principal Findings Liver IPC improved hepatic graft function expressed as ameliorated graft structure and reduced ALT/AST levels. After administration of liver IPC, intestinal mucosal ultrastructure improved, serum endotoxin and bacterial translocation mildly decreased, fecal sIgA content increased, and serum TNF-α decreased. Moreover, liver IPC promoted microbial restorations mainly through restoring Bifidobacterium spp., Clostridium clusters XI and Clostridium cluster XIVab on bacterial genus level. DGGE profiles indicated that liver IPC increased microbial diversity and species richness, and cluster analysis demonstrated that microbial structures were similar and clustered together between the NC group and Liver-IPC group. Furthermore, the phylogenetic tree of band sequences showed key bacteria corresponding to 10 key band classes of microbial structure shift induced by liver IPC, most of which were assigned to Bacteroidetes phylum. Conclusion Liver IPC cannot only improve hepatic graft function and intestinal barrier function, but also promote restorations of intestinal microbiota following LT, which may further benefit hepatic graft by positive feedback of the “gut-liver axis”.

Nanosecond pulsed electric field (nsPEF) treatment for hepatocellular carcinoma: A novel locoregional ablation decreasing lung metastasis

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy. Nanosecond pulsed electric field (nsPEF) is a new technology destroying tumor cells with a non-thermal high voltage electric field using ultra-short pulses. The studys aim was to evaluate the ablation efficacy of nsPEFs with human HCC cell lines and a highly metastatic potential HCC xenograft model on BALB/c nude mice. The in vivo study showed nsPEFs induced HCC cell death in a dose dependent manner. On the high metastatic hepatocellular carcinoma cell line (HCCLM3) xenograft mice model, tumor growth was inhibited significantly in nsPEF-treated- groups (single dose and multi-fractionated dose). Besides a local effect, the nsPEF treatment reduced pulmonary metastases. The nsPEFs also enhanced HCC cell phagocytosis by human macrophage cell (THP1) in vitro. The nsPEF is efficient in controlling HCC progression and reducing its metastasis. NsPEF treatment may elicit a host immune response against tumor cells. This study suggests nsPEF therapy could be used as a potential locoregional therapy for hepatocellular carcinoma.

Use of hepatitis B surface antigen–positive grafts in liver transplantation: A matched analysis of the US National database

The scarcity of available donor organs is the key challenge in orthotopic liver transplantation (OLT). A viable way of expanding the donor pool is the use of liver grafts from hepatitis B surface antigen (HBsAg)–positive donors. The present study used the US Scientific Registry of Transplant Recipients database (1987‐2010), and each of the 78 patients who underwent OLT with HBsAg‐positive grafts was matched with 4 patients who received HBsAg‐negative grafts by urgent status, donor sex, recipient sex, donor age, recipient age, transplant date, Model for End‐Stage Liver Disease score, and warm ischemia time. The overall graft and patient survival rates were similar for recipients of HBsAg‐positive grafts and matched controls: the 5‐year graft survival rates were 66% and 64%, respectively (P = 0.95), and the 5‐year patient survival rates were 71% and 71%, respectively (P = 0.87). A Cox proportional hazards regression analysis that was adjusted for other variables showed no impact of the donor HBsAg status on graft or patient survival. The use of hepatitis B immunoglobulin (HBIG) was independently associated with better posttransplant graft survival [hazard ratio (HR) = 0.23, 95% confidence interval (CI) = 0.06‐0.81] and patient survival (HR = 0.16, 95% CI = 0.04‐0.75) for recipients of HBsAg‐positive grafts. In conclusion, the use of HBsAg‐positive liver grafts did not reduce posttransplant graft or patient survival. Moreover, matching these donors to recipients treated with HBIG may improve safety. Liver Transpl 20:35–45, 2014.

Nanosecond Pulsed Electric Field Inhibits Cancer Growth Followed by Alteration in Expressions of NF-κB and Wnt/β-Catenin Signaling Molecules

Cancer remains a leading cause of death worldwide and total number of cases globally is increasing. Novel treatment strategies are therefore desperately required for radical treatment of cancers and long survival of patients. A new technology using high pulsed electric field has emerged from military application into biology and medicine by applying nsPEF as a means to inhibit cancer. However, molecular mechanisms of nsPEF on tumors or cancers are still unclear. In this paper, we found that nsPEF had extensive biological effects in cancers, and clarified its possible molecular mechanisms in vitro and in vivo. It could not only induce cell apoptosis via dependent-mitochondria intrinsic apoptosis pathway that was triggered by imbalance of anti- or pro-apoptosis Bcl-2 family proteins, but also inhibit cell proliferation through repressing NF-κB signaling pathway to reduce expressions of cyclin proteins. Moreover, nsPEF could also inactivate metastasis and invasion in cancer cells by suppressing Wnt/β-Catenin signaling pathway to down-regulating expressions of VEGF and MMPs family proteins. More importantly, nsPEF could function safely and effectively as an anti-cancer therapy through inducing tumor cell apoptosis, destroying tumor microenvironment, and depressing angiogenesis in tumor tissue in vivo. These findings may provide a creative and effective therapeutic strategy for cancers.

Survival in Liver Transplant Recipients with Hepatitis B- or Hepatitis C-Associated Hepatocellular Carcinoma: The Chinese Experience from 1999 to 2010

Background Hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and hepatitis C virus (HCV)-HCC are the main indications for liver transplantation. We compared differences in survival outcomes between these two conditions. Methods and Findings The China Liver Transplant Registry (CLTR) contains data collated from all transplants performed in 86 liver transplantation centers across China. We analyzed CLTR data from January 1999 to December 2010. In all, 7,658 patients (7,162 with HBV-HCC and 496 with HCV-HCC) were included in this study. Clinical characteristics were compared between the HBV-HCC and HCV-HCC groups; Kaplan–Meier analysis was used to calculate the overall, tumor-free and hepatitis-free survival rates. The 1-year, 3-year and 5-year overall survival was significantly higher in HBV-HCC recipients than in HCV-HCC recipients (76.65%, 56.61% and 49.10% vs. 64.59%, 42.78% and 39.20%, respectively; P<0.001). The corresponding tumor-free survival rates (63.55%, 47.37%, 40.99% vs. 56.84%, 38.04%, 35.66%, respectively) and hepatitis-free survival rates (75.49%, 54.84%, 47.34% vs. 63.87%, 42.15%, 39.33%, respectively) were both superior in HBV-HCC recipients (both P<0.001). Multivariate analyses identified hepatitis, preoperative alpha-fetoprotein (AFP) level, size of largest tumor, number of tumor nodules, TNM stage, vascular invasion and preoperative model for end-stage liver disease (MELD) score as independent predictors of overall, tumor-free and hepatitis-free survival. Conclusions Survival outcomes after liver transplantation were significantly better in HBV-HCC patients than in HCV-HCC patients. This finding may be used to guide donor liver allocation in transplantation programs.

Spectrum of De Novo Cancers and Predictors in Liver Transplantation: Analysis of the Scientific Registry of Transplant Recipients Database.

Background De novo malignancies occur after liver transplantation because of immunosuppression and improved long-term survival. But the spectrums and associated risk factors remain unclear. Aims To describe the overall pattern of de novo cancers in liver transplant recipients. Methods Data from Scientific Registry of Transplant Recipients from October 1987 to December 2009 were analyzed. The spectrum of de novo cancer was analyzed and logistic-regression was used to identify predictors of do novo malignancies. Results Among 89,036 liver transplant recipients, 6,834 recipients developed 9,717 post-transplant malignancies. We focused on non-skin malignancies. A total of 3,845 recipients suffered from 4,854 de novo non-skin malignancies, including 1,098 de novo hematological malignancies, 38 donor-related cases, and 3,718 de novo solid-organ malignancies. Liver transplant recipients had more than 11 times elevated cancer risk compared with the general population. The long-term overall survival was better for recipients without de novo cancer. Multivariate analysis indicated that HCV, alcoholic liver disease, autoimmune liver disease, nonalcoholic steatohepatitis, re-transplantation, combined transplantation, hepatocellular carcinoma, immunosuppression regime of cellcept, cyclosporine, sirolimus, steroids and tacrolimus were independent predictors for the development of solid malignancies after liver transplantation. Conclusions De novo cancer risk was elevated in liver transplant recipients. Multiple factors including age, gender, underlying liver disease and immunosuppression were associated with the development of de novo cancer. This is useful in guiding recipient selection as well as post-transplant surveillance and prevention.

Liver Grafts for Transplantation from Donors with Diabetes: An Analysis of the Scientific Registry of Transplant Recipients Database

Patients with a history of diabetes mellitus (DM) have worse survival than those without DM after liver transplantation. However, the effect of liver grafts from DM donors on the post-transplantation survival of recipients is unclear. Using the Scientific Registry of Transplant Recipients database (2004–2008), 25,413 patients were assessed. Among them, 2,469 recipients received grafts from donors with DM. The demographics and outcome of patients were assessed. Patient survival was assessed using Kaplan–Meier methodology and Cox regression analyses. Recipients from DM donors experienced worse graft survival than recipients from non-DM donors (one-year survival: 81% versus 85%, and five-year survival: 67% versus 74%, P<0.001, respectively). Graft survival was significantly lower for recipients from DM donors with DM duration >5 years (P<0.001) compared with those with DM duration <5 years. Cox regression analyses showed that DM donors were independently associated with worse graft survival (hazard ratio, 1.11; 95% confidence interval, 1.02–1.19). The effect of DM donors was more pronounced on certain underlying liver diseases of recipients. Increases in the risk of graft loss were noted among recipients from DM donors with hepatitis-C virus (HCV) infection, whereas those without HCV experienced similar outcomes compared with recipients from non-DM donors. These data suggest that recipients from DM donors experience significantly worse patient survival after liver transplantation. However, in patients without HCV infection, using DM donors was not independently associated with worse post-transplantation graft survival. Matching these DM donors to recipients without HCV may be safe.

Time interval to recurrence as a predictor of overall survival in salvage liver transplantation for patients with hepatocellular carcinoma associated with hepatitis B virus.

BACKGROUND Salvage liver transplantation (SLT) has been proposed for recurrent hepatocellular carcinoma (HCC) after hepatectomy; however, it is unclear how the time interval to tumor recurrence from previous hepatectomy affects prognosis. METHODS We analyzed retrospectively the outcomes of 62 patients who underwent SLT in the Liver Transplantation Center of the First Affiliated Hospital of Zhejiang University between 2001 and 2012. SLT recipients were divided into 2 groups based on whether the time interval to recurrence was >1 year (L group) or <1 year (S group). RESULTS Baseline characteristics were similar between the 2 groups. The 1-, 3-, and 5-year overall survival rates were 81%, 45%, and 45% in the L group, which were better than in the S group, with 47%, 21%, and 21%, respectively (P = .005). The corresponding tumor-free survival rates were similar (P = .60) between 2 groups, with 71%, 51%, and 41% in the L group versus 55%, 55%, and 55% in the S group. Macrovascular invasion (hazard ratio [HR], 3.30), greatest tumor diameter (HR, 3.92), and time interval to tumor recurrence from previous hepatectomy (HR, 0.29) were independent predictors for overall survival. Furthermore, the diameter of the largest tumor was the only independent predictor of tumor-free survival (HR, 25.64). CONCLUSION The time interval to HCC recurrence from a previous hepatectomy is an important factor associated with survival after SLT. This finding should be helpful in guiding patient selection criteria for SLT in patients with previous hepatectomy.

Association of family history of HBV with resectability of hepatocellular carcinoma.

BACKGROUND/AIMS This study aims to address the relationship between a positive family history of liver cancer or hepatitis B virus (HBV) infection and the operative resectability of hepatocellular carcinoma (HCC) in the Chinese population. METHODOLOGY Two hundred and sixty-two HCC patients underwent operative or non-operative therapies in our hospital. One hundred and eighteen of the patients were clinically considered as resectable patients. The remaining 144 patients were clinically unresectable. Statistical analysis was performed in SPSS 15.0 for Windows. RESULTS A family history of HBV infection is significantly associated with the resectability of HCC (AOR=2.332; 95% CI, 1.051-5.177). There was also has a significant association between the first degree relatives infected with HBV and the resectability of HCC (AOR=2.334; 95% CI, 1.050-5.190), especially a patients sibling having a history of HBV infection is significantly related to the resectability of HCC (AOR=2.727; 95% CI, 1.092-6.808). CONCLUSIONS A family history of HBV infection is associated with the resectability of HCC, and in particular, if a patients sibling has a history of HBV infection, this indicates a reduced opportunity to receive curative liver resection.