BACKGROUND: Liver transplantation is the definite treatment for end-stage liver diseases with satisfactory results. However, untoward effects of life-long immunosuppression prevent the development of alternative strategies to achieve better long-term outcome. Achieving clinical operational tolerance is the ultimate goal.
DATA SOURCES: A PubMed and Google Scholar search using terms: "immune tolerance", "liver transplantation", "clinical trial", "operational tolerance" and "immunosuppression withdrawal" was performed, and relevant articles published in English in the past decade were reviewed. Full-text publications relevant to the field were selected and relevant articles from reference lists were also included. Priority was given to those articles which are relevant to the review.
RESULTS: Because of the inherent tolerogenic property, around 20%-30% of liver transplantation recipients develop spontaneous operational tolerance after immunosuppression withdrawal, and the percentage may be even higher in pediatric living donor liver transplantation recipients. Several natural killer and γδT cell related markers have been identified to be associated with the tolerant state in liver transplantation patients. Despite the progress, clinical operational tolerance is still rare in liver transplantation. Reprogramming the recipient immune system by creating chimerism and regulatory cell therapies is among newer promising means to achieve clinical liver transplantation tolerance in the future.
CONCLUSION: Although clinical operational tolerance is still rare in liver transplantation recipients, ongoing basic research and collaborative clinical trials may help to decipher the mystery of transplantation tolerance and extend the potential benefits of drug withdrawal to an increasing number of patients in a more predictable fashion.

BACKGROUND: Locoregional therapies (LRTs) are treatments to achieve local control of hepatocellular carcinoma (HCC). Correlation between radiologic response to LRT and degree of induced tumor necrosis is not well understood. The aim of this study was to evaluate different levels of radiologic response after pre-liver transplant (LT) LRT and its correlation with percentage of tumor necrosis on explanted histopathology.
METHODS: Institutional Review Board approved LT database was queried for treated HCC in patients undergoing LT. Radiologic response was evaluated to predict tumor necrosis in the explanted liver. Tumor response was evaluated 1 to 3 months after LRT with computed tomography or MRI via Response Evaluation Criteria in Solid Tumors (RECIST), and European Association for the Study of the Liver (EASL) guidelines. LRT was repeated as needed until time of LT. Histological tumor necrosis was graded as complete (100%), partial (50%-99%), or poor (<50%).
RESULTS: Between 2002 and 2011, 128 patients (97 men and 31 women) received pre-LT LRT including transarterial therapy (93), radiofrequency ablation (20), or combination of both (15). The mean age of the patients was 58±9 years. Their mean follow-up was 35±27 months. The median waitlist time was 55 days. One hundred (78%) patients had HCC within the Milan criteria at the initial radiologic diagnosis. Nineteen (15%) of the patients had complete tumor necrosis on histopathology analysis. Fifty (39%) of the patients exhibited partial necrosis, 52 (41%) showed poor or no necrosis and 7 (5%) showed progressive disease. The overall pre-LT radiologic staging was correlated with explant pathology in 73 (57%) of the patients. Underestimated tumor stage was noted in 49 (38%) patients, and overestimated tumor stage in 6 (5%) patients. The post-LT 3-year overall survival and disease free survival were 82% and 80%, and the rates for complete and partial tumor necrosis were 100% vs 78% (P=0.02) and 100% vs 75% (P=0.03), respectively.
CONCLUSIONS: In the current era, interpretation of radiologic response after LRT for HCC does not correlate accurately with histologic tumor necrosis. Total tumor necrosis is the goal of LRT; therefore, evolution in its performance is needed. Similarly, ways to predict therapy induced tumor necrosis via radiological investigation need to be improved.

BACKGROUND: Conversion hepaticojejunostomy is considered the salvage intervention for biliary anastomotic stricture, a common complication of right-liver living donor liver transplantation with duct-to-duct anastomosis, after failed endoscopic treatment. The aim of this study is to compare the outcomes of side-to-side hepaticojejunostomy with those of end-to-side hepaticojejunostomy.
METHODS: Prospectively collected data of 402 adult patients who had undergone right-liver living donor liver transplantation with duct-to-duct anastomosis were reviewed. Diagnosis of biliary anastomotic stricture was made based on clinical, biochemical, histological and radiological results. Endoscopic treatment was the first-line treatment of biliary anastomotic stricture.
RESULTS: Interventional radiological or endoscopic treatment failed to correct the biliary anastomotic stricture in 13 patients, so they underwent conversion hepaticojejunostomy. Ten of them received end-to-side hepaticojejunostomy and three received side-to-side hepaticojejunostomy. In the end-to-side group, two patients sustained hepatic artery injury requiring repeated microvascular anastomosis, two developed re-stenosis requiring further percutaneous transhepatic biliary drainage and balloon dilatation, and two required revision hepaticojejunostomy. In the side-to-side group, one patient developed re-stenosis requiring further endoscopic retrograde cholangiography and balloon dilatation. No re-operation was needed in this group. Otherwise, outcomes in the two groups were similar in terms of liver function and graft survival.
CONCLUSIONS: Despite the similar outcomes, side-to-side hepaticojejunostomy may be a better option for bile duct reconstruction after failed interventional radiological or endoscopic treatment because it can decrease the chance of hepatic artery injury and allows future endoscopic treatment if re-stricture develops. However, more large-scale studies are warranted to validate the results.

BACKGROUND: Biliary atresia (BA) is a major cause of chronic cholestasis, a fatal disorder in infants. This study was undertaken to evaluate the safety and effectiveness of primary living donor liver transplantation (LDLT) in comparison with the traditional first-line treatment, the Kasai procedure.
METHODS:  We assessed 28 children with BA at age of less than two years (3-21.3 months) who had undergone LDLT in two hospitals in Southwest China during the period of 2008-2011. Eighteen children who had had primary LDLT were included in a primary LDLT group, and ten children who had undergone the Kasai operation in a pre-Kasai group. All patients were followed up after discharge from the hospital. The records of the BA patients and donors were reviewed.
RESULTS: The time of follow-up ranged 12-44.5 months with a median of 31 months. The 30-day and 1-year survival rates were 85.7% and 78.6%, respectively. There was no significant difference in the 30-day or 1-year survival between the two groups (83.3% vs 90% and 77.8% vs 80%, P>0.05). The main cause of death was hepatic artery thrombosis. There were more patients with complications who required intensive medical care or re-operation in the pre-Kasai group (8, 80%) than in the primary LDLT group (9, 50%) (P=0.226). But no significant differences were observed in operating time (9.3 vs 8.9 hours, P=0.77), intraoperative blood loss (208.6 vs 197.0 mL, P=0.84) and blood transfusion (105.6 vs 100.0 mL, P=0.91) between the two groups. The durations of ICU and hospital stay in the primary LDLT group and pre-Kasai group were 180.4 vs 157.7 hours (P=0.18) and 27 vs 29 days (P=0.29), respectively.
CONCLUSIONS: Primary LDLT is a safe and efficient management for young pediatric patients with BA. Compared with the outcome of LDLT for patients receiving a previous Kasai operation, a similar survival rate and a low rate of re-operation and intensive medical care for patients with BA can be obtained.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains one of the most common causes of poor long-term survival. However, the host genetic factors affecting increased risk of tumor recurrence after transplantation have not been thoroughly elucidated. The present study was designed to investigate the association of cytokine gene polymorphisms with the risk of tumor recurrence in LT patients for HCC.
METHODS: Eleven single-nucleotide polymorphisms within the promoter regions of 7 cytokine genes, i.e., the IL-1 family (IL-1α and IL-1β), IL-6, IL-8, IL-10, TNF-α, and TGF-β1, were genotyped in 93 HCC patients treated with LT using DNA sequencing. The association between these polymorphisms and the risk of tumor recurrence was evaluated while controlling confounding clinical variables.
RESULTS: The genotype frequency of IL-10 -1082 A/G in patients with and without recurrence of HCC was AA 83.3%, GA 16.7% and AA 97.6%, GA 2.4%, respectively. The association between IL-10 -1082 GA and recurrence was significant (P=0.033). No other single-nucleotide polymorphism in the cytokine gene was found to be associated with recurrence. Kaplan-Meier survival curves showed that the homozygous AA patients had a significantly longer mean recurrence-free survival than heterozygous GA patients (23.5 vs 5.7 months, P=0.001). However, multivariate analysis failed to reveal that the GA genotype of IL-10 -1082 A/G was an independent indicator of recurrence.
CONCLUSIONS: This study suggests the lack of association of selected cytokine gene polymorphisms with HCC recurrence after LT in the Han Chinese population. The finding does not exclude the idea that other cytokine polymorphisms could act as candidate biomarkers of disease prognosis.

BACKGROUND: Adipose-derived stem cells (ADSCs) are particularly attractive in future clinical applications of stem cell-based therapy for acute-on-chronic liver failure (ACLF). This study was undertaken to evaluate the therapeutic potential of ADSCs on ACLF.
METHODS:  ADSCs isolated from porcine fat tissue were expanded and labeled with BrdU. Rabbit models of ACLF were created by administration of D-Gal following CCl4-induced cirrhosis. One day after administration of D-Gal, rabbits of the ACLF/ADSCs group (n=15) were received ADSCs transplantation, while those in the ACLF/saline group (n=15) were treated with the same volume of saline. Biochemical parameters and histomorphological scoring were evaluated; the distribution and characteristics of transplanted ADSCs as well as the pathology of the liver were examined.
RESULTS: ADSCs transplantation improved the survival rate and the liver function of rabbits with ACLF. Biochemical parameters of the ACLF/ADSCs group were improved compared with those of the ACLF/saline group, and histomorphological scoring of the ACLF/ADSCs group was significantly lower than that of the ACLF/saline group. ADSCs were identified in the periportal region of the liver after cell transplantation.
CONCLUSION: Xenogenic ADSCs have therapeutic efficacy in the ACLF rabbit model.

BACKGROUND: Predictors of poor prognosis of solitary hepatocellular carcinoma (SHCC), a subgroup encompassing most patients with the malignancy, are still controversial. Hence, risk factors for portal vein tumor thrombosis (PVTT) in SHCC are obscure. The present study was designed to address this issue.
METHOD: Clinicopathological and follow-up data for 156 consecutive patients with SHCC following curative hepatic resection were analyzed using uni- and multi-variate analyses.
RESULTS: Univariate analysis showed that PVTT, tumor-node-metastasis (TNM) stage, Edmondson-Steiner grade and preoperative serum alpha-fetoprotein (AFP) level were associated with the overall and disease-free survival, whereas tumor size only influenced the overall survival. In multivariate Cox regression tests, Edmondson-Steiner grade and TNM stage were independent prognostic markers for both overall and disease-free survival. In addition, the Chi-square test showed that AFP level and Edmondson-Steiner grade were correlated with PVTT. Among them, only Edmondson-Steiner grade was shown to be of independent significance for PVTT in multi-variate logistic regression analysis. Additionally, AFP, the sole preoperative factor for PVTT, was not adequately sensitive and specific.
CONCLUSIONS: Factors relating to post-surgical prognosis and PVTT in SHCC are all tumor-related. Of these, Edmondson-Steiner grade and TNM stage might be of particular importance in survival analysis. In addition, accurate prediction of PVTT by clinicopathological parameters before surgery remains difficult.

BACKGROUND: The human telomerase reverse transcriptase (hTERT) gene encodes the catalytic subunit of telomerase, which mediates pleiotropic effects, including the regulation of senescence and proliferation and plays an important role in carcinogenesis. This study attempts to clarify the genetic predisposition to hepatocellular carcinoma (HCC), focusing on the hTERT gene rs2736098 polymorphism.
METHOD: Four hundred patients with HCC and 400 non-cancer controls were genotyped to elucidate the potential association between hTERT rs2736098 polymorphism and HCC risks.
RESULTS: Compared with the controls, the patients with HCC had a lower frequency of G/G genotype (33.3% vs 44.3%, P=0.001) and a higher frequency of G/A (51.5% vs 39.5%, P=0.001). Allele genotypic frequencies in the patients differed from those of the controls (P=0.040). The data of this study rs2736098[A] allele contributed significantly to HCC risk in female patients (OR=1.78, 95% CI, 1.17-2.72, P=0.007), patients with HCV infection (OR=2.89, 95% CI, 1.08-7.70, P=0.031), non-drinker patients (OR=1.32, 95% CI, 1.06-1.65, P=0.015), and patients not affected by HBV (OR=1.77, 95% CI, 1.30-2.40, P<0.001).
CONCLUSIONS: rs2736098[A] may be an independent here-ditary parameter in HCC, but some risk factors would cover up the association by more powerful hepatocarcinogenesis. These results are important guidance for further studies in detecting HCC-associated single nucleotide polymorphisms.

BACKGROUND: Increasing evidence suggests that the inactiva-tion of cathepsin B attenuates hepatocyte apoptosis and liver damage. This study aimed to investigate the protective effects of a cathepsin B inhibitor (CA-074me) on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute hepatic failure (AHF) in mice.
METHODS: Mice were intraperitoneally injected with a combination of LPS/D-GalN to induce AHF with or without CA-074me pretreatment. The cumulative survival rates were calculated 48 hours after the induction of AHF. As well as changes in biochemical indicators and liver histology, hepatocyte apoptosis was assessed using a TUNEL method. Serum tumor necrosis factor-α (TNF-α) production, caspase-3, caspase-8, and caspase-9 activity was evaluated. Cytosolic cytochrome c and Bcl-2 expression were measured by Western blotting.
RESULTS: The marked elevation in serum aminotransferase activity and prothrombin time found in LPS/D-GalN-treated mice was significantly improved by pretreatment with CA-074me. The efficacy of CA-074me was also confirmed by histological analysis and TUNEL assay. The survival rate significantly improved in LPS/D-GalN-induced mice given CA-074me compared with untreated mice. LPS/D-GalN-induced caspase-3 and caspase-9 activation was remarkably suppressed by CA-074me. However, the increased levels of serum TNF-α and elevated caspase-8 activity in AHF mice were not significantly reduced by CA-074me. Moreover, CA-074me sharply reduced the increased expression of cytosolic cytochrome c and markedly augmented Bcl-2 expression.
CONCLUSION: These results suggest that CA-074me has a protective effect in acute hepatic failure induced by LPS/D-GalN.

BACKGROUND: Despite a number of studies show the superiority of early over delayed cholecystectomy in the treatment of acute cholecystitis, there is still controversy over the time for intervention. This study aimed to assess the use of early versus delayed cholecystectomy for the treatment of acute cholecystitis in terms of complications, conversion to open surgery and mean hospital stay.
METHOD: We collected patients with acute cholecystitis treated at a referral center for a year, and retrospectively analyzed the chosen therapeutic approach, the percentage of conversion of early cholecystectomy to open surgery, appearance of surgical complications, and mean hospital stay.
RESULTS: The study included 117 patients, 44 women and 73 men, who had a mean age of 67.36±15.74 years. Early cholecystectomy was chosen in 31 (26.5%) and delayed cholecystectomy in 74 patients (63.2%). Of the 74 patients, 28 (37.8%) required emergency performance of delayed cholecystectomy, and 19 (25.7%) had not undergone surgery by the end of the study. While no differences were observed between early and delayed cholecystectomy in terms of surgical complications and conversion to open surgery, mean hospital stay was nevertheless significantly shorter in the early versus the delayed cholecystectomy group (8.32±4.98 vs 15.96±8.89 days).
CONCLUSION: Under the routine working conditions of a hospital that is neither specially dedicated to the surgical treatment of acute cholecystitis nor provided with specific management guidelines, early cholecystectomy can reduce the hospital stay without increase of the conversion rate or complications.

BACKGROUND: The death ligand, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), induces apoptosis and non-apoptotic signaling in some tumor cells. The purpose of this study was to investigate the roles of the pro-apoptotic TRAIL receptors, TRAIL-R1 and TRAIL-R2, as well as Bcl-xL and TRAF2 in TRAIL-induced expression of the pro-inflammatory cytokine IL-8 and the invasion-promoting protein urokinase (uPA) in pancreatic ductal adenocarcinoma (PDAC) cells.
METHODS: Colo357wt, Colo357/TRAF2, Colo357/Bcl-xL, Panc89 and PancTuI cells were stimulated with TRAIL and uPA and IL-8 expression was detected using real-time PCR. Antagonistic, receptor-specific antibodies were used to investigate the effects of TRAIL-R1 or TRAIL-R2 inhibition.
RESULTS: Dose-dependent increases in uPA and IL-8 expression were detected following TRAIL stimulation in PDAC cells. These effects were inhibited when TRAIL-R1 but not TRAIL-R2 was blocked. Overexpression of TRAF2 or Bcl-xL strongly increased TRAIL-mediated upregulation of uPA and IL-8.
CONCLUSIONS: In PDAC cells, TRAIL strongly induced uPA and IL-8 via TRAIL-R1. This response was further enhanced in cells overexpressing TRAF2 and Bcl-xL. Therefore, inhibition of the non-apoptotic "side-effects" of TRAIL treatments by inactivation of TRAF2 and Bcl-xL might represent additional relevant strategies for the treatment of pancreatic cancer.

Abdominal drainage was previously recommended as a post-hepatectomy procedure for patients with cirrhosis. This report introduces a simple technique that prevents leakage of ascitic fluid after cirrhotic hepatectomy complicated by blockage of the abdominal drain. In 59 patients who had had cirrhotic hepatectomy complicated by leakage of ascites in the drain site after drainage removal between January 2001 and April 2011, 31 underwent suture ligation (sutured group) and 28 were given urostomy bag at the abdominal drainage site (drainage group). The mean length of postoperative hospital stay in the drainage group was shorter than in the sutured group (16.11±2.61 vs 34.23±4.86 days, P=0.000). Meanwhile, the drainage group showed decreased postoperative complications, including leakage of ascites, wound infection, and collection of ascites. Drainage by urostomy bag can prevent prolonged leakage of ascitic fluid after the blockage of abdominal drains in patients undergoing cirrhotic hepatectomy.

On December 8, 2012, the 2nd editorial committee meeting of Hepatobiliary & Pancreatic Diseases International (HBPD INT) was held at Sheraton Hangzhou Wetland Park Resort, Hangzhou, China. Participants include Prof. Holger Kalthoff from University Clinic Schleswig-Holstein (UKSH), Germany, Prof. Moulay Aloui-Jamali from McGill University, Canada, and Prof. Cheuck-Seen Lai from the Pedder Clinic, Hong Kong, China. A total of 57 members attended this meeting. Prof. Shou-Chu Qian, managing editor, presided over the meeting.
At the meeting, Prof. Shu-Sen Zheng, Chief editor, briefly introduced the current status of HBPD INT and outlined the contribution of the editorial members in the past 11 years. Indexed in SCI and other databases, HBPD INT has an impact factor of 1.082 (2011 Journal Citation Reports). With current advantages, HBPD INT will integrate more resources for further development. Prof. Hongqun Liu, past-Managing Editor of Liver International, introduced their experience in running a journal and pointed out that efficient and in time decision work of the editorial office can improve the average decision date. Mr. Wen-Yang Han from Elsevier, Beijing office, in the publisher angel, introduced how to run a journal and how to improve the quality of the journal.
In discussion, Prof. Cheuck-Seen Lai, Prof. Holger Kalthoff, Prof. Moulay Alaoui-Jamali, Prof. Yue Zhu, Prof. Yong-Feng Liu, Prof. Ran Tao, Prof. Qun-Hua Zhang, Prof. Hui Cao, Prof. Qi-Fa Ye and others made concrete suggestions for the development of HBPD INT. HBPD INT will consider these suggestions and take action.
HBPD INT now in adolescence will serve as a platform for the scholars in the field of hepatobiliary and pancreatic diseases around the world.

BACKGROUND: Hepatic portal venous gas (HPVG) is a rare entity commonly associated with intestinal necrosis and fatal outcome, and various underlying diseases have been reported. Pancreatic solitary metastasis without local extension is also rare in esophageal squamous cell carcinoma.
METHODS: This report describes an interesting and unusual case of HPVG arising from pancreatic tumor. Autopsy revealed pathogenesis of HPVG and synchronous tumors of the esophagus and pancreas.
RESULTS: A 73-year-old man developed synchronous double tumor in the esophagus and pancreas several months before acute abdomen and his death, which were generated by HPVG. Autopsy revealed that HPVG was caused by gastric wall infarction owing to expansion of an isolated pancreatic metastasis from esophageal squamous cell carcinoma.
CONCLUSIONS: This is the first case of HPVG that was derived from pancreatic tumor infiltration. If he had been diagnosed with solitary pancreatic metastasis from esophageal squamous cell carcinoma in the first time, he might have an option for chemotherapy, which could let him live longer.

BACKGROUND: The most common tumors in the ampulla of Vater are adenocarcinomas. Although malignant melanoma usually occurs on the skin, it can also arise in the gastrointestinal and biliary tract.
METHOD: We present a case of a 52-year-old, previously healthy man who presented with painless jaundice.
RESULTS: Clinical examination revealed dilated intrahepatic and extrahepatic bile ducts and pancreatic duct due to the obstructive mass in the ampulla of Vater. The patient underwent pancreaticoduodenectomy and histopathological diagnosis of the resected tumor mass was malignant melanoma. Thorough clinical examination was preformed, but no other primary or metastatic site of melanoma could be found. In the next few months, the patient developed multiple liver metastases and died.
CONCLUSION: An isolated amelanotic lesion in the ampulla of Vater can be a potential diagnostic pitfall, especially in patients who have had melanoma.