Background & Aims Primary sclerosing cholangitis (PSC) is characterised by fibro-stenosing strictures involving extrahepatic and/or large intrahepatic bile ducts. Mechanisms leading to bile duct ...injury are poorly understood. We aimed to study the biliary tree stem cell compartment located in peribiliary glands of extrahepatic and large intrahepatic bile ducts and its role in the pathogenesis of biliary fibrosis in PSC. Methods Specimens containing extrahepatic or large intrahepatic bile ducts were obtained from normal liver (n = 6), liver explants from patients with PSC (n = 11), and primary biliary cirrhosis (n = 6). Specimens were processed for histology, immunohistochemistry and immunofluorescence. Results In PSC samples, progressive hyperplasia and mucinous metaplasia of peribiliary glands were observed in large ducts with fibrosis, but not in inflamed ducts without fibrosis. Peribiliary gland hyperplasia was associated with progressive biliary fibrosis and the occurrence of dysplastic lesions. Hyperplasia of peribiliary glands was determined by the expansion of biliary tree stem cells, which sprouted towards the surface epithelium. In PSC, peribiliary glands and myofibroblasts displayed enhanced expression of Hedgehog pathway components. Peribiliary glands in ducts with onion skin-like fibrosis expressed epithelial-to-mesenchymal transition traits associated with components of Hedgehog pathway, markers of senescence and autophagy. Conclusions The biliary tree stem cell compartment is activated in PSC, its activation contributes to biliary fibrosis, and is sustained by the Hedgehog pathway. Our findings suggest a key role for peribiliary glands in the progression of bile duct lesions in PSC and could explain the associated high risk of cholangiocarcinoma.
To implement split liver transplantation (SLT) a mandatory‐split policy has been adopted in Italy since August 2015: donors aged 18‐50 years at standard risk are offered for SLT, resulting in a ...left‐lateral segment (LLS) graft for children and an extended‐right graft (ERG) for adults. We aim to analyze the impact of the new mandatory‐split policy on liver transplantation (LT)‐waiting list and SLT outcomes, compared to old allocation policy. Between August 2015 and December 2016 out of 413 potentially “splittable” donors, 252 (61%) were proposed for SLT, of whom 53 (21%) donors were accepted for SLT whereas 101 (40.1%) were excluded because of donor characteristics and 98 (38.9%) for absence of suitable pediatric recipients. The SLT rate augmented from 6% to 8.4%. Children undergoing SLT increased from 49.3% to 65.8% (P = .009) and the pediatric LT‐waiting list time dropped (229 10‐2121 vs 80 12‐2503 days P = .045). The pediatric (4.5% vs 2.5% P = .398) and adult (9.7% to 5.2% P < .001) LT‐waiting list mortality reduced; SLT outcomes remained stable. Retransplantation (HR = 2.641, P = .035) and recipient weight >20 kg (HR = 5.113, P = .048) in LLS, and ischemic time >8 hours (HR = 2.475, P = .048) in ERG were identified as predictors of graft failure. A national mandatory‐split policy maximizes the SLT donor resources, whose selection criteria can be safely expanded, providing favorable impact on the pediatric LT‐waiting list and priority for adult sick LT candidates.
The introduction of a mandatory split policy in the Italian liver allocation system significantly increases the split liver transplantation rate, providing a favorable impact on the pediatric liver transplantation waiting list without harming the adult liver transplantation waiting list.
Multipotent stem/progenitors are present in peribiliary glands of extrahepatic biliary trees from humans of all ages and in high numbers in hepato‐pancreatic common duct, cystic duct, and hilum. They ...express endodermal transcription factors (e.g., Sox9, SOX17, FOXA2, PDX1, HES1, NGN3, PROX1) intranuclearly, stem/progenitor surface markers (EpCAM, NCAM, CD133, CXCR4), and sometimes weakly adult liver, bile duct, and pancreatic genes (albumin, cystic fibrosis transmembrane conductance regulator CFTR, and insulin). They clonogenically expand on plastic and in serum‐free medium, tailored for endodermal progenitors, remaining phenotypically stable as undifferentiated cells for months with a cell division initially every ≈36 hours and slowing to one every 2‐3 days. Transfer into distinct culture conditions, each comprised of a specific mix of hormones and matrix components, yields either cords of hepatocytes (express albumin, CYP3A4, and transferrin), branching ducts of cholangiocytes (expressing anion exchanger‐2‐AE2 and CFTR), or regulatable C‐peptide secreting neoislet‐like clusters (expressing glucagon, insulin) and accompanied by changes in gene expression correlating with the adult fate. Transplantation into quiescent livers of immunocompromised mice results in functional human hepatocytes and cholangiocytes, whereas if into fat pads of streptozocin‐induced diabetic mice, results in functional islets secreting glucose‐regulatable human C‐peptide. Conclusion: The phenotypes and availability from all age donors suggest that these stem/progenitors have considerable potential for regenerative therapies of liver, bile duct, and pancreatic diseases including diabetes. (HEPATOLOGY2011;)
Stem/progenitors have been identified intrahepatically in the canals of Hering and extrahepatically in glands of the biliary tree. Glands of the biliary tree (peribiliary glands) are tubulo‐alveolar ...glands with mucinous and serous acini, located deep within intrahepatic and extrahepatic bile ducts. We have shown that biliary tree stem/progenitors (BTSCs) are multipotent, giving rise in vitro and in vivo to hepatocytes, cholangiocytes or pancreatic islets. Cells with the phenotype of BTSCs are located at the bottom of the peribiliary glands near the fibromuscular layer. They are phenotypically heterogeneous, expressing transcription factors as well as surface and cytoplasmic markers for stem/progenitors of liver (e.g. SOX9/17), pancreas (e.g. PDX1) and endoderm (e.g. SOX17, EpCAM, NCAM, CXCR4, Lgr5, OCT4) but not for mature markers (e.g. albumin, secretin receptor or insulin). Subpopulations co‐expressing liver and pancreatic markers (e.g. PDX1+/SOX17+) are EpCAM+/−, and are assumed to be the most primitive of the BTSC subpopulations. Their descendants undergo a maturational lineage process from the interior to the surface of ducts and vary in the mature cells generated: pancreatic cells in hepatopancreatic ducts, liver cells in large intrahepatic bile ducts, and bile duct cells along most of the biliary tree. We hypothesize that there is ongoing organogenesis throughout life, with BTSCs giving rise to hepatic stem cells in the canals of Hering and to committed progenitors within the pancreas. The BTSCs are likely to be central to normal tissue turnover and injury repair and to be key elements in the pathophysiology of liver, pancreas and biliary tree diseases, including oncogenesis.
To perform a systematic review and meta-analysis on donor-to-recipient gender mismatch as a risk factor for post-transplant graft loss.
A systematic literature search was performed using PubMed, ...Cochrane Library database and EMBASE. The primary outcome was graft loss after liver transplantation. Odds ratios and 95% confidence intervals were calculated to compare the pooled data between groups with different donor-to-recipient gender matches. Three analyses were done considering (1) gender mismatches (F-M and M-F)
matches (M-M and F-F); (2) Female-to-Male mismatch
other matches; and (3) Male-to-Female mismatch
other matches.
A total of 7 articles were analysed. Gender mismatch (M-F and F-M) was associated with a significant increase of graft loss respect to match (M-M and F-F) (OR: 1.30; 95%CI: 1.13-1.50;
< 0.001). When F-M mismatch was specifically investigated, it confirmed its detrimental role in terms of graft survival (OR: 1.83; 95%CI: 1.20-2.80;
= 0.005). M-F mismatch failed to present a significant role (OR: 1.09; 95%CI: 0.73-1.62;
= 0.68).
Gender mismatch is a risk factor for poor graft survival after liver transplantation. Female-to-male mismatch represents the worst combination. More studies are needed with the intent to better clarify the reasons for these results.
A library of platinum (II) complexes of general formula (O,O′-β-diketonate)PtLX (L = dimethylsulfoxide, pyridine, triphenylphosphine; X = chloride, γ-acetylacetonate) has been prepared, using ...synthetic methodologies available in the literature. The library has been supplemented with a novel platinum (II) complex bearing a triazenido N-oxide ligand. The complexes have been characterized and tested as precatalysts for the photoactivated curing of silicone resins. Correlations have been established between the nature of the employed ligands, the ultraviolet-visible (UV-Vis) absorption spectrum of the complexes and their catalytic performance, which enable the tailored preparation of complexes with improved performance in view of possible technological applications.
Background
Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) represents a new surgical technique for the resection of advanced hepatic malignancies with predicted ...insufficient future liver remnant. In some patients, ALPPS can be associated with an increased risk of poor outcomes. Minimally invasive surgery (MIS) has been proposed in combination with ALPPS with the intent to minimize this risk. We systematically evaluated the outcomes of MIS-ALPPS cases to compare the relative outcomes of open ALPPS versus MIS-ALPPS.
Methods
A systematic review was done in accordance with the PRISMA guidelines. Search terms utilized included the following: (“ALPPS”Title/Abstract OR “associating liver partition and portal vein ligation for staged hepatectomy”Title/Abstract OR “in situ split”Title/Abstract) AND (“minimally invasive”Title/Abstract OR “laparoscopic”Title/Abstract OR “robotic”Title/Abstract).
Results
Fifteen articles were identified, with a total of 27 patients reported. Colorectal metastatic disease was the most commonly observed indication for MIS-ALPPS (66.7%), followed by hepatocellular carcinoma (25.9%). Time passed from the first to the second stage ranged 7–30 days. MIS-ALPPS patients did not experience procedure failures between the first and second stages. Only four (15.4%) subjects had a grade IIIb complication. No perioperative mortality after the first or second stage was reported. Compared with open ALPPS, MIS-ALPPS demonstrated better results. Hospital stay duration ranged 8–33 days with a follow-up ranging 1–20 months.
Conclusions
MIS-ALPPS appears to be safe, with potentially lower morbidities and mortalities relative to open patients. The present results should be considered with caution. A limited number of articles exist on this topic. Furthermore, selection biases exist when comparing open versus MIS-ALPPS data. Registry studies are needed to better define the outcomes of patients undergoing MIS-ALPPS.
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