Hepatic artery reconstruction in pediatric liver transplantation: Experience from a single group.

BACKGROUND: The reconstruction of hepatic artery is a challenging part of the pediatric liver transplantation procedure. Hepatic artery thrombosis (HAT) and stenosis are complications which may result in ischemic biliary injury, causing early graft lost and even death. METHODS: Two hundred and fifty-nine patients underwent liver transplantation in 2017 in a single liver transplantation group. Among them, 225 patients were living donor liver transplantation (LDLT) and 34 deceased donor liver transplantation (DDLT). RESULTS: In LDLT all reconstructions of hepatic artery were microsurgical, while in DDLT either microsurgical reconstruction or traditional continuous suture technique was done depending on different conditions. There were five (1.9%) HATs: four (4/34, 11.8%) in DDLT (all whole liver grafts) and one (1/225, 0.4%) in LDLT (P = 0.001). Four HATs were managed conservatively using anticoagulation, and 1 accepted salvage surgery with re-anastomosis. Until now, 3 HAT patients remain in good condition, whereas two developed biliary complications. One of them needed to be re-transplanted, and the other patient died due to biliary complications. CONCLUSIONS: Microsurgical technique significantly improves the reconstruction of hepatic artery in pediatric liver transplantation. The risk for arterial complications is higher in DDLT. Conservative therapy can achieve good outcome in selected HAT cases.

Pediatric living donor liver transplantation decade progress in Shanghai: Characteristics and risks factors of mortality.

BACKGROUND: Pediatric living donor liver transplantation (LDLT) has become the gold standard for patients with end-stage liver disease. With improvements in organ preservation, immunosuppression, surgical and anesthesia techniques, the survival rates and long-term outcomes of patients after LDLT have significantly improved worldwide. However, data on anesthetic management and postoperative survival rate of pediatric LDLT in China are rare. AIM: To review the status of pediatric LDLT in Shanghai and investigate the factors related to anesthetic management and survival rate in pediatric LDLT. METHODS: We conducted a retrospective observational study to investigate the status of pediatric LDLT in Shanghai by reviewing 544 records of patients who underwent pediatric LDLT since the first operation on October 21, 2006 until August 10, 2016 at Renji Hospital and Huashan Hospital. RESULTS: The 30-d, 90-d, 1-year, and 2-year survival rates were 95.22%, 93.38%, 91.36%, and 89.34%, respectively. The 2-year patient survival rate after January 1, 2011 significantly improved compared with the previous period (74.47% vs 90.74%; hazard ratio: 2.92; 95% confidence interval (CI): 2.16-14.14; P = 0.0004). Median duration of mechanical ventilation in the intensive care unit (ICU) was 18 h [interquartile range (IQR), 15.25-20.25], median ICU length of stay was 6 d (IQR: 4.80-9.00), and median postoperative length of stay was 24 d (IQR: 18.00-34.00). Forty-seven (8.60%) of 544 patients did not receive red blood cell transfusion during the operation. CONCLUSION: Pediatric end-stage liver disease (PELD) score, anesthesia duration, operation duration, intraoperative blood loss, and ICU length of stay were independent predictive factors of in-hospital patient survival. Pediatric end-stage liver disease score, operation duration, and ICU length of stay were independent predictive factors of 1-year and 3-year patient survival.

Living-donor liver transplantation for children with tyrosinemia type I.

OBJECTIVE: To evaluate the efficacy of living-donor liver transplantation (LDLT) in children with tyrosinemia type I. METHODS: Altogether 10 patients diagnosed with tyrosinemia type I underwent LDLT between June 2013 and April 2019. Cirrhosis was the indication for LDLT in all 10 patients, and hepatocellular carcinoma (HCC) was suspected in nine. Patients' outcomes, including liver function, restoration of metabolism, quality of life and physical development, were analyzed after LDLT. RESULTS: All recipients were alive with a normal liver function after a median follow-up period of 49 months. Pathological examinations detected HCC in one patient, dysplasia in five and cirrhosis in all. Nine patients were found to have elevated alpha-fetoprotein level, and their median alpha-fetoprotein level dropped from 2520 ng/mL to a normal level after LDLT, with no recurrence of HCC detected during the follow-up. Tyrosine metabolism was restored to its normal level with normalized plasma tyrosine and succinylacetone concentrations. Moreover, urinary succinylacetone excretion decreased significantly during the follow up. LDLT improved patients' renal tubular function, as evidenced by the normalized plasma phosphate concentration and improved glomerular filtration rate. Severe rickets symptoms, including spontaneous fractures and bone pain, were also ameliorated. Improved motor function was reported by all patients' parents during the follow-up. Dietary restriction was no longer required, which was associated with a favorable catch-up in growth and improved quality of life. Complete resolution of hypertrophic cardiomyopathy was observed one year after LDLT in one patient. CONCLUSION: LDLT is an effective treatment for patients with end-stage liver disease resulting from tyrosinemia type I.

Isolation of cancer-associated fibroblasts and its promotion to the progression of intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma is a highly fatal tumor characterized by an abundant stromal environment. Cancer-associated fibroblasts play key roles in tumor growth and invasiveness and have been regarded as a potential therapeutic target. This study was designed to isolate human primary cancer-associated fibroblasts of intrahepatic cholangiocarcinoma to study tumor-stroma interactions and to analyze the clinical relevance of alpha-smooth muscle actin -positive cancer-associated fibroblasts in patients with intrahepatic cholangiocarcinoma. The isolated cancer-associated fibroblasts were positive for alpha-smooth actin, fibroblast-specific protein-1, fibroblast activation protein, and PDGFR-ß. In addition, cancer-associated fibroblasts were found to increase proliferation, migration, and invasion of cholangiocarcinoma cells in vitro and promote tumor growth of mice in vivo. Moreover, alpha-smooth muscle actin-positive expression of cancer-associated fibroblasts predicted unfavorable prognosis in patients with intrahepatic cholangiocarcinoma and showed correlation with presence of lymph node metastasis. This study may provide a useful tool to investigate further effect of cancer-associated fibroblasts on the molecular mechanism of cholangiocarcinoma cells as well as contribution of cancer-associated fibroblasts in lymphangiogenesis and lymph node metastasis.

A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma.

Merlin, which is encoded by the tumour suppressor gene Nf2, plays a crucial role in tumorigenesis and metastasis. However, little is known about the functional importance of Merlin splicing forms. In this study, we show that Merlin is present at low levels in human hepatocellular carcinoma (HCC), particularly in metastatic tumours, where it is associated with a poor prognosis. Surprisingly, a splicing variant of Merlin that lacks exons 2, 3 and 4 ((Δ2-4)Merlin) is amplified in HCC and portal vein tumour thrombus (PVTT) specimens and in the CSQT2 cell line derived from PVTT. Our studies show that (Δ2-4)Merlin interferes with the capacity of wild-type Merlin to bind ß-catenin and ERM, and it is expressed in the cytoplasm rather than at the cell surface. Furthermore, (Δ2-4)Merlin overexpression increases the expression levels of ß-catenin and stemness-related genes, induces the epithelium-mesenchymal-transition phenotype promoting cell migration in vitro and the formation of lung metastasis in vivo. Our results indicate that the (Δ2-4)Merlin variant disrupts the normal function of Merlin and promotes tumour metastasis.

Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats.

BACKGROUND & AIMS: Due to its anatomic connection, the liver is constantly exposed to gut-derived bacterial products or metabolites. Disruption of gut homeostasis is associated with many human diseases. The aim of this study was to determine the role of gut homeostasis in initiation and progression of hepatocellular carcinoma (HCC). METHODS: Disruption of intestinal homeostasis by penicillin or dextran sulfate sodium (DSS) and its restoration by probiotics were applied in a diethylnitrosamine (DEN) model of rat hepatocarcinogenesis. RESULTS: Patients with liver cirrhosis and HCC had significantly increased serum endotoxin levels. Chronic DEN treatment of rats was associated with an imbalance of subpopulations of the gut microflora including a significant suppression of Lactobacillus species, Bifidobacterium species and Enterococcus species as well as intestinal inflammation. Induction of enteric dysbacteriosis or intestinal inflammation by penicillin or DSS, respectively, significantly promoted tumor formation. Administration of probiotics dramatically mitigated enteric dysbacteriosis, ameliorated intestinal inflammation, and most importantly, decreased liver tumor growth and multiplicity. Interestingly, probiotics not only inhibited the translocation of endotoxin, which bears pathogen-associated molecular patterns (PAMPs) but also the activation of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1). As a result, the production of pro- and anti-inflammatory cytokines was skewed in favor of a reduced tumorigenic inflammation in the liver. CONCLUSIONS: The data highlights the importance of gut homeostasis in the pathogenesis of HCC. Modulation of the gut microbiota by probiotics may represent a new avenue for therapeutic intervention to treat or prevent HCC development.