Publications by authors named "Bruno Gridelli"

166 Publications

Improved Survival in Liver Transplant Patients Receiving Prolonged-release Tacrolimus-based Immunosuppression in the European Liver Transplant Registry (ELTR): An Extension Study.

Transplantation 2019 09;103(9):1844-1862

Department of Hepatology and Gastroenterology, University Hospital of Henri-Mondor, Creteil, France.

Background: We compared, through the European Liver Transplant Registry, long-term liver transplantation outcomes with prolonged-release tacrolimus (PR-T) versus immediate-release tacrolimus (IR-T)-based immunosuppression. This retrospective analysis comprises up to 8-year data collected between 2008 and 2016, in an extension of our previously published study.

Methods: Patients with <1 month follow-up were excluded; patients were propensity score matched for baseline characteristics. Efficacy measures included: univariate/multivariate analyses of risk factors influencing graft/patient survival up to 8 years posttransplantation, and graft/patient survival up to 4 years with PR-T versus IR-T. Overall, 13 088 patients were included from 44 European centers; propensity score-matched analyses comprised 3006 patients (PR-T: n = 1002; IR-T: n = 2004).

Results: In multivariate analyses, IR-T-based immunosuppression was associated with reduced graft survival (risk ratio, 1.49; P = 0.0038) and patient survival (risk ratio, 1.40; P = 0.0215). There was improvement with PR-T versus IR-T in graft survival (83% versus 77% at 4 y, respectively; P = 0.005) and patient survival (85% versus 80%; P = 0.017). Patients converted from IR-T to PR-T after 1 month had a higher graft survival rate than patients receiving IR-T at last follow-up (P < 0.001), or started and maintained on PR-T (P = 0.019). One graft loss in 4 years was avoided for every 14.3 patients treated with PR-T versus IR-T.

Conclusions: PR-T-based immunosuppression might improve long-term outcomes in liver transplant recipients than IR-T-based immunosuppression.
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http://dx.doi.org/10.1097/TP.0000000000002700DOI Listing
September 2019

Epidemiology and successful containment of a carbapenem-resistant Enterobacteriaceae outbreak in a Southern Italian Transplant Institute.

Transpl Infect Dis 2019 Aug 11;21(4):e13119. Epub 2019 Jun 11.

IRCCS-ISMETT, Palermo, Italy.

Introduction: Carbapenem-resistant enterobacteriaceae (CRE) infections are difficult to treat and pose a serious threat to solid organ transplant (SOT) recipients. At our institute we observed an infection burden in 2012.

Methods: In order to contain the spread of CRE infections, we established a taskforce to implement guidelines suggested by the Centers for Disease Control and Prevention (CDC) for this type of outbreak. Here, we describe the epidemiology of the outbreak in our SOT population, and the effectiveness of such interventions, by comparing levels of CRE hospital-acquired infection (HAI) pre- and post-task force intervention (from January 2009 to December 2012, and from September 2013 to December 2016, respectively) through a linear regression model.

Results: In this study, we included 933 patients who underwent a total of 1017 SOT procedures, 286 of whom had a CRE-positive culture (28.8%), of which 65 (22.7% of CRE positive) developed infection. One-year mortality post-SOT was significantly higher in patients with CRE infection. After the taskforce intervention, the CRE HAI rate in SOT showed a significant inverse trend (event rate: -1.28, CI -1.70 to 0.86; P < 0.01).

Conclusion: In the paucity of treatment options, the application of CDC measures in our SOT institute contributed significantly to containing CRE infections.
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http://dx.doi.org/10.1111/tid.13119DOI Listing
August 2019

Effects of Delta-Like Noncanonical Notch Ligand 1 Expression of Human Fetal Liver Hepatoblasts on Hematopoietic Progenitors.

Stem Cells Int 2019 18;2019:7916275. Epub 2019 Mar 18.

Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15203, USA.

Although the hepatic and hematopoietic progenitors of the liver are well characterized, the interactions between these two lineages remain mostly elusive. Hepatoblasts express delta-like noncanonical Notch ligand 1 (Dlk1), whose cleaved extracellular domain can become a soluble protein. We assessed the effects of DLK1 gene expression knockdown in cultures of total fetal liver cells. Furthermore, we separated Dlk1 hepatoblasts from the total liver cell fraction and investigated effects of direct cell contact. Dlk1 cells were cultured either without Dlk1 hepatoblasts, in direct contact with hepatoblasts, or separated from hepatoblasts by a porous membrane in inserts to inhibit cell contact but allow free exchange of molecules. Expression of the hepatic and hematopoietic genes, colony forming unit potential of various hematopoietic progenitors, and cell numbers and types were investigated. We found that DLK1 knockdown in total fetal liver cell cultures decreased total cell numbers. The expression of hepatic progenitor genes and mature hematopoietic genes was affected. Hematopoietic BFU-E and CFU-GM colony numbers were reduced significantly. The depletion of Dlk1 hepatoblasts in culture decreased the potential of all hematopoietic progenitors to form colonies of all types and reduced the percentage of mature hematopoietic cells. The addition of hepatoblasts in inserts to Dlk1 cells further decreased the potential to form the CFU-GM and CFU-GEMM colonies and the percentage of mature hematopoietic cells but increased total cell numbers. Conclusively, direct contact of Dlk1 supports hematopoietic progenitor expansion and functionality that cannot be reconstituted in coculture without direct cell contact.
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http://dx.doi.org/10.1155/2019/7916275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442310PMC
March 2019

Digital liver biopsy: Bio-imaging of fatty liver for translational and clinical research.

World J Hepatol 2018 Feb;10(2):231-245

Institute of Biostructure and Bioimaging, National Research Council, Naples 80145, Italy.

The rapidly growing field of functional, molecular and structural bio-imaging is providing an extraordinary new opportunity to overcome the limits of invasive liver biopsy and introduce a "digital biopsy" for study of liver pathophysiology. To foster the application of bio-imaging in clinical and translational research, there is a need to standardize the methods of both acquisition and the storage of the bio-images of the liver. It can be hoped that the combination of digital, liquid and histologic liver biopsies will provide an innovative synergistic tri-dimensional approach to identifying new aetiologies, diagnostic and prognostic biomarkers and therapeutic targets for the optimization of personalized therapy of liver diseases and liver cancer. A group of experts of different disciplines (Special Interest Group for Personalized Hepatology of the Italian Association for the Study of the Liver, Institute for Biostructures and Bio-imaging of the National Research Council and Bio-banking and Biomolecular Resources Research Infrastructure) discussed criteria, methods and guidelines for facilitating the requisite application of data collection. This manuscript provides a multi-Author review of the issue with special focus on fatty liver.
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http://dx.doi.org/10.4254/wjh.v10.i2.231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838442PMC
February 2018

Autoantibodies against CYP-2C19: A Novel Serum Marker in Pediatric De Novo Autoimmune Hepatitis?

Biomed Res Int 2017 27;2017:3563278. Epub 2017 Nov 27.

Pediatrics, Department of Medicine, Surgery, and Dentistry "Schola Medica Salernitana", University of Salerno, Baronissi, Salerno, Italy.

Diagnosis of de novo autoimmune hepatitis (AIH) after orthotopic liver transplantation (OLT) is challenging especially in the absence of hyper--globulinemia. Circulating autoantibodies are not sensitive nor specific in de novo AIH but when positive increase the diagnostic probability. We report the discovery of novel liver microsomal (LM) autoantibodies against CYP-2C19 in a 9-year-old boy with "de novo" AIH developed 7 years after OLT. Graft dysfunction presented with hypertransaminasemia (up to 400 IU/L), while serum -globulins remained within the normal range for age. Liver histology and response to high dose prednisone (2 mg/kg/day) with the addition of azathioprine therapy further supported the diagnosis of de novo AIH. Autoantibodies investigation by indirect immunofluorescence (IF) on rodent tissues showed a novel staining pattern involving the pericentral liver zone and sparing the renal tissue. Human but not rat liver proteins immunoblotting allowed us to characterize the novel LM antibodies and to identify CYP-2C19 as human antigen. The finding offers insights into the controversial discussion about autoimmunity versus alloreactivity with regard to the pathogenesis of de novo AIH. Correct information on human versus rat tissue antigens tested by methods other than IF for antibodies detection may have significant implications for the correct diagnosis and management of patients followed up after OLT.
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http://dx.doi.org/10.1155/2017/3563278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723963PMC
July 2018

Epithelial cell adhesion molecule fragments and signaling in primary human liver cells.

J Cell Physiol 2018 06 26;233(6):4841-4851. Epub 2017 Dec 26.

Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.

Epithelial Cell Adhesion Molecule (EpCAM), or CD326, is a trans-membrane glycoprotein expressed by multiple normal epithelia as well as carcinoma. Human hepatic stem cells and bile duct epithelium of the liver are EpCAM positive. In tumor cell lines, its intracellular domain can be released after cleavage of the extracellular domain. Within the cell nucleus, it induces cell proliferation, but cleavage depends on cell contact. Fragments of various lengths have been described in tumor cells. Despite its described important role in proliferation in tumor cells, there is not much known about the expression and role of EpCAM fragments in primary human liver cells. Here, we demonstrate that EpCAM protein fragments and function are considerable different between tumor cells, normal fetal and adult liver cells. Contrary to previously reported findings in tumor cells, gene knockdown or treatment with an inhibitor of the cleavage enzyme ADAM17 (TACE) rather increased cell numbers in primary human fetal liver-derived EpCAM-positive cells. EpCAM fragment sizes were not affected by treatment with inhibitor. Knockdown of EPCAM gene expression by siRNA in sorted cells did not significantly affect proliferation-associated genes or cell numbers. The intracellular domain could not be detected within cell nuclei of fetal and adult liver cells. In conclusion, signaling through the intracellular domain of EpCAM appears to be a mechanism that induces proliferation specifically in tumorigenic cells but not in normal primary EpCAM-positive liver cells.
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http://dx.doi.org/10.1002/jcp.26286DOI Listing
June 2018

Response of Human Fetal Liver Progenitor Cell Types to Temperature and pH Stresses In Vitro.

Rejuvenation Res 2018 Jun 23;21(3):257-269. Epub 2017 Oct 23.

1 Department of Surgery, McGowan Institute for Regenerative Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania.

Prolonged physiological stresses, including abnormal pH and temperature, are deleterious. However, human hepatic progenitors have been shown to be quite tolerant of temporary temperature stress such as in cold ischemia. We aimed at identifying how various stresses affect liver progenitors, and at determining whether distinct effects exist on different progenitor cells of the human liver. Total fetal liver cells were exposed to low (25°C), normal (37°C), or high (40°C) temperatures, or low (6.76), normal (7.35), or high (7.88) pH in vitro. Culture at 25°C increased cell numbers and percentages of proliferation marker Ki67 total cells. In total cell cultures, percentages of CD326 hepatic progenitors co-expressing DLK1 (delta-like 1 homolog), SSEA4, or CD90 increased, as well as proliferation of SSEA4 and CD235a progenitors. Analyses of presorted hepatic progenitors revealed that culture at 25°C increased cell numbers of CD326 hepatic stem/progenitor cells but not DLK hepatoblasts. The expression of several mesenchymal genes was reduced, and distinct hepatic stem/progenitor cell colonies emerged. At 40°C, numbers of adherent hepatic cells decreased but those of hematopoietic nonadherent cells increased. High pH did not cause major effects. Acidic pH resulted in decreased total cell numbers and affected hematopoietic cells. Percentages of DLK1 hepatoblasts were increased, but those of hematopoietic mature CD45 cells were decreased. In particular, proliferation of adherent hepatic CD326, SSEA4 progenitors, and hematopoietic CD45 cells and CD235a erythroblasts was reduced. Conclusively, our data indicate that low-temperature stress stimulates hepatic progenitor and erythroblast proliferation, whereas acidic pH promotes hepatic maturation and reduces hematopoietic cells.
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http://dx.doi.org/10.1089/rej.2016.1890DOI Listing
June 2018

HCV replication in gastrointestinal mucosa: Potential extra-hepatic viral reservoir and possible role in HCV infection recurrence after liver transplantation.

PLoS One 2017 27;12(7):e0181683. Epub 2017 Jul 27.

Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo, Italy.

Purpose: Hepatitis C virus (HCV) predominantly infects hepatocytes, although it is known that receptors for viral entry are distributed on a wide array of target cells. Chronic HCV infection is indeed characterized by multiple non-liver manifestations, suggesting a more complex HCV tropism extended to extrahepatic tissues and remains to be fully elucidated. In this study, we investigated the gastrointestinal mucosa (GIM) as a potential extrahepatic viral replication site and its contribution to HCV recurrence.

Methods: We analyzed GIM biopsies from a cohort of 76 patients, 11 of which were HCV-negative and 65 HCV-positive. Of these, 54 biopsies were from liver-transplanted patients. In 29 cases, we were able to investigate gastrointestinal biopsies from the same patient before and after transplant. To evaluate the presence of HCV, we looked for viral antigens and genome RNA, whilst to assess viral replicative activity, we searched for the replicative intermediate minus-strand RNA. We studied the genetic diversity and the phylogenetic relationship of HCV quasispecies from plasma, liver and gastrointestinal mucosa of HCV-liver-transplanted patients in order to assess HCV compartmentalization and possible contribution of gastrointestinal variants to liver re-infection after transplantation.

Results: Here we show that HCV infects and replicates in the cells of the GIM and that the favorite hosts were mostly enteroendocrine cells. Interestingly, we observed compartmentalization of the HCV quasispecies present in the gastrointestinal mucosa compared to other tissues of the same patient. Moreover, the phylogenetic analysis revealed a high similarity between HCV variants detected in gastrointestinal mucosa and those present in the re-infected graft.

Conclusions: Our results demonstrated that the gastrointestinal mucosa might be considered as an extrahepatic reservoir of HCV and that could contribute to viral recurrence. Moreover, the finding that HCV infects and replicates in neuroendocrine cells opens new perspectives on the role of these cells in the natural history of HCV infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181683PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531480PMC
September 2017

A matched pair analysis of multicenter longterm follow-up after split-liver transplantation with extended right grafts.

Liver Transpl 2017 11;23(11):1384-1395

Division of Abdominal Transplantation and Hepatobiliopancreatic Surgery, Bambino Gesù, Children's Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.

Split-liver transplantation has been proposed as an alternative to whole liver (WL) transplantation to expand the donor pool, but studies comparing adult longterm outcomes between the 2 methods are conflicting and limited. This is the first Italian multicenter study that retrospectively analyzed 119 matched-pair recipients of whole and extended right grafts (ERGs) for longterm survival outcomes. In the overall population, WL recipients showed higher patient survival at 1 (93% versus 73%), 5 (87% versus 65%), and 10 years (83% versus 60%) after transplantation compared with split-liver recipients (P < 0.001); graft survivals of WL recipients were also superior at 1 (90% versus 76%), 5 (84% versus 57%), and 10 years (81% versus 52%) posttransplant (P < 0.001). However, among the 81 matched pairs that survived the first posttransplant year, 5- and 10-year patient survivals were 90% and 81% for split recipients and 99% and 96% for whole recipients, respectively (P = 0.34). The 5- and 10-year graft survivals were also comparable: 87% and 77% for split recipients, and 86% and 82% for whole recipients (P = 0.86). Cox regression analysis identified donor age >50, donor-to-recipient weight ratio < 1, retransplantation status, and United Network for Organ Sharing I-IIA status as risk factors for partial graft use. There were no significant differences in 5-year outcomes based on center volume. In conclusion, we demonstrate that adult liver transplantation with ERGs can achieve longterm success comparable with that of whole grafts in appropriate patients but should be selectively used in patients with risk factors. Liver Transplantation 23 1384-1395 2017 AASLD.
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http://dx.doi.org/10.1002/lt.24808DOI Listing
November 2017

Pharmacokinetics of prolonged-release tacrolimus versus immediate-release tacrolimus in de novo liver transplantation: A randomized phase III substudy.

Clin Transplant 2017 06 27;31(6). Epub 2017 Apr 27.

Medical affairs, Astellas Pharma Europe Ltd, Chertsey, UK.

Background: With the same dose of tacrolimus, lower systemic exposure on the first day of dosing has been reported for prolonged-release tacrolimus compared with immediate-release tacrolimus, prompting investigation of differing initial doses.

Methods: This substudy of a double-blind, randomized, phase III trial in de novo liver transplant recipients compared the pharmacokinetics of once-daily prolonged-release tacrolimus (initial dose: 0.2 mg/kg/day) versus twice-daily immediate-release tacrolimus (initial dose: 0.1 mg/kg/day) during the first 2 weeks post-transplant.

Results: Pharmacokinetic data were analyzed from patients receiving prolonged-release tacrolimus (n=13) and immediate-release tacrolimus (n=12). Mean systemic exposure (AUC ) was higher with prolonged-release versus immediate-release tacrolimus. Dose-normalized AUC (normalized to 0.1 mg/kg/day) showed generally lower exposure with prolonged-release tacrolimus versus immediate-release tacrolimus. There was good correlation between AUC and concentration at 24 hours after the morning dose (r=.96 and r=.86, respectively), and the slope of the line of best fit was similar for both formulations.

Conclusions: Doubling the initial starting dose of prolonged-release tacrolimus compared with immediate-release tacrolimus overcompensated for lower exposure on Day 1. A 50% higher starting dose of prolonged-release tacrolimus than immediate-release tacrolimus may be required for similar systemic exposure. However, doses of both formulations can be optimized using the same trough-level monitoring system. (ClinicalTrials.gov number: NCT00189826).
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http://dx.doi.org/10.1111/ctr.12958DOI Listing
June 2017

Transplantation of hepatocytes from genetically engineered pigs into baboons.

Xenotransplantation 2017 03 28;24(2). Epub 2017 Jan 28.

Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy.

Background: Some patients with acute or acute-on-chronic hepatic failure die before a suitable human liver allograft becomes available. Encouraging results have been achieved in such patients by the transplantation of human hepatocyte progenitor cells from fetal liver tissue. The aim of the study was to explore survival of hepatocytes from genetically engineered pigs after direct injection into the spleen and other selected sites in immunosuppressed baboons to monitor the immune response and the metabolic function and survival of the transplanted hepatocytes.

Methods: Baboons (n=3) were recipients of GTKO/hCD46 pig hepatocytes. All three baboons received anti-thymocyte globulin (ATG) induction and tapering methylprednisolone. Baboon 1 received maintenance immunosuppressive therapy with tacrolimus and rapamycin. Baboons 2 and 3 received an anti-CD40mAb/rapamycin-based regimen that prevents sensitization to pig solid organ grafts. The baboons were euthanized 4 or 5 weeks after hepatocyte transplantation. The baboon immune response was monitored by the measurement of anti-non-Gal IgM and IgG antibodies (by flow cytometry) and CFSE-mixed lymphocyte reaction. Monitoring for hepatocyte survival and function was by (i) real-time PCR detection of porcine DNA, (ii) real-time PCR for porcine gene expression, and (iii) pig serum albumin levels (by ELISA). The sites of hepatocyte injection were examined microscopically.

Results: Detection of porcine DNA and porcine gene expression was minimal at all sites of hepatocyte injection. Serum levels of porcine albumen were very low-500-1000-fold lower than in baboons with orthotopic pig liver grafts, and approximately 5000-fold lower than in healthy pigs. No hepatocytes or infiltrating immune cells were seen at any of the injection sites. Two baboons (Baboons 1 and 3) demonstrated a significant increase in anti-pig IgM and an even greater increase in IgG, indicating sensitization to pig antigens.

Discussion And Conclusions: As a result of this disappointing experience, the following points need to be considered. (i) Were the isolated pig hepatocytes functionally viable? (ii) Are pig hepatocytes more immunogenic than pig hearts, kidneys, artery patch grafts, or islets? (iii) Does injection of pig cells (antigens) into the spleen and/or lymph nodes stimulate a greater immune response than when pig tissues are grafted at other sites? (iv) Did the presence of the recipient's intact liver prevent survival and proliferation of pig hepatocytes? (v) Is pig CD47-primate SIRP-α compatibility essential? In conclusion, the transplantation of genetically engineered pig hepatocytes into multiple sites in immunosuppressed baboons was associated with very early graft failure. Considerable further study is required before clinical trials should be undertaken.
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http://dx.doi.org/10.1111/xen.12289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397320PMC
March 2017

Donor safety in living donor liver donation: An Italian multicenter survey.

Liver Transpl 2017 02 30;23(2):184-193. Epub 2016 Dec 30.

Transplant Center, Division of General Surgery and Abdominal Transplantation, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Major concerns about donor morbidity and mortality still limit the use of living donor liver transplantation (LDLT) to overcome the organ shortage. The present study assessed donor safety in LDLT in Italy reporting donor postoperative outcomes in 246 living donation procedures performed by 7 transplant centers. Outcomes were evaluated over 2 time periods using the validated Clavien 5-tier grading system, and several clinical variables were analyzed to determine the risk factors for donor morbidity. Different grafts were obtained from the 246 donor procedures (220 right lobe, 10 left lobe, and 16 left lateral segments). The median follow-up after donation was 112 months. There was no donor mortality. One or more complications occurred in 82 (33.3%) donors, and 3 of them had intraoperative complications (1.2%). Regardless of graft type, the rate of major complications (grade ≥ 3) was 12.6% (31/246). The overall donor morbidity and the rate of major complications did not differ significantly over time: 26 (10.6%) donors required hospital readmission throughout the follow-up period, whereas 5 (2.0%) donors required reoperation. Prolonged operative time (>400 minutes), intraoperative hypotension (systolic < 100 mm Hg), vascular abnormalities, and intraoperative blood loss (>300 mL) were multivariate risk factors for postoperative donor complications. In conclusion, from the standpoint of living donor surgery, a meticulous and well-standardized technique that reduces operative time and prevents blood loss and intraoperative hypotension may reduce the incidence of donor complications. Transparency in reporting results after LDLT is mandatory, and we should continue to strive for zero donor mortality. Liver Transplantation 23 184-193 2017 AASLD.
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http://dx.doi.org/10.1002/lt.24651DOI Listing
February 2017

Complications and Near-Miss Events After Hepatectomy for Living-Related Liver Donation: An Italian Single Center Report of One Hundred Cases.

Ann Transplant 2016 Sep 22;21:596-601. Epub 2016 Sep 22.

Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, Abdominal Surgery and Organ Transplantation Unit, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (IRCCS-ISMETT), Palermo, Italy.

BACKGROUND In healthy individuals, such as liver living donors, potential complications may occur during surgery. Reporting such complications and near-miss events is mandatory to improve living donor management and safety. MATERIAL AND METHODS This retrospective study was performed on a prospective database with the aim of providing a brief analysis of the perioperative, medium-term, and long-term complications, and the near-miss events in a single center series of 100 consecutive liver resections for adult-to-adult living-donor liver transplantation. RESULTS Only 23.3% of potential living donors underwent surgery. No living donor mortality was reported; 29 patients (29%) experienced at least one complication. Five patients developed mild long-term dysfunction; two aborted hepatectomies, and there were two near-miss events reported. CONCLUSIONS A strategy for an accurate assessment of living donor complications and strict selection criterion cannot be overemphasized, as well as the need to continuously update center patient outcome reports.
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http://dx.doi.org/10.12659/aot.899662DOI Listing
September 2016

Response of Primary Human Bone Marrow Mesenchymal Stromal Cells and Dermal Keratinocytes to Thermal Printer Materials In Vitro.

J Med Biol Eng 2016;36:153-167. Epub 2016 Mar 30.

Department of Surgery, School of Medicine, McGowan Institute for Regenerative Medicine, University of Pittsburgh, 3025 East Carson Street, Suite 216, Pittsburgh, PA 15203 USA ; Department of Bioengineering, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pennsylvania, USA.

Advancement in thermal three-dimensional printing techniques has greatly increased the possible applications of various materials in medical applications and tissue engineering. Yet, potential toxic effects on primary human cells have been rarely investigated. Therefore, we compared four materials commonly used in thermal printing for bioengineering, namely thermally printed acrylonitrile butadiene styrene, MED610, polycarbonate, and polylactic acid, and investigated their effects on primary human adult skin epidermal keratinocytes and bone marrow mesenchymal stromal cells (BM-MSCs) in vitro. We investigated indirect effects on both cell types caused by potential liberation of soluble substances from the materials, and also analyzed BM-MSCs in direct contact with the materials. We found that even in culture without direct contact with the materials, the culture with MED610 (and to a lesser extent acrylonitrile butadiene styrene) significantly affected keratinocytes, reducing cell numbers and proliferation marker Ki67 expression, and increasing glucose consumption, lactate secretion, and expression of differentiation-associated genes. BM-MSCs had decreased metabolic activity, and exhibited increased cell death in direct culture on the materials. MED610 and acrylonitrile butadiene styrene induced the strongest expression of genes associated to differentiation and estrogen receptor activation. In conclusion, we found strong cell-type-specific effects of the materials, suggesting that materials for applications in regenerative medicine should be carefully selected not only based on their mechanical properties but also based on their cell-type-specific biological effects.
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http://dx.doi.org/10.1007/s40846-016-0118-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853461PMC
March 2016

Mini-Invasive Approach Contributes to Expand the Indication for Liver Resection for Hepatocellular Carcinoma Without Increasing the Incidence of Posthepatectomy Liver Failure and Other Perioperative Complications: A Single-Center Analysis.

J Laparoendosc Adv Surg Tech A 2016 Jun 25;26(6):439-46. Epub 2016 Apr 25.

1 Abdominal Surgery and Organ Transplantation Unit, Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione) , Palermo, Italy .

Background: Liver resection (LR) for hepatocellular carcinoma (HCC) is the best alternative option for increasing the survival of many patients with intermediate or advanced stages of the Barcelona Clinic Liver Cancer staging classification. Mini-invasive approach may play a positive role in treating a tumor rising almost exclusively in a diseased liver.

Methods: A prospectively collected database was retrospectively reviewed for 167 consecutive patients who underwent LR between 1999 and 2015.

Results: A total of 38 LRs were performed from 1999 to 2009 (Period I), and 129 between 2010 and 2015 (Period II). Laparoscopic procedures increased from 5.3% to 38.1%. Not undergoing laparoscopic LR increased length of stay, and Clavien Grade II or worse complications. Ninety-day mortality decreased from 5.2% to 0%, and morbidity did not differ significantly, despite the fact that the most complex patients were in Period II.

Conclusions: Mini-invasive approaches allow to safely expand limits of LR for HCC; in particular, laparoscopic approach favors surgical option even in more complex patients without increase the risk of posthepatic liver failure or other postsurgical complications.
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http://dx.doi.org/10.1089/lap.2016.0134DOI Listing
June 2016

Severe Acute Respiratory Failure due to Inhalation of Baby Powder and Successfully Treated with Venous-Venous Extracorporeal Membrane Oxygenation.

A A Case Rep 2015 Dec;5(12):228-30

From the *ICU Department, ISMETT-UPMC, Palermo, Italy; †Pediatric Anesthesia, ISMETT-UPMC, Palermo, Italy; ‡Department of Pneumology, ISMETT-UPMC, Palermo, Italy; §Department of Surgery, ISMETT-UPMC, Palermo, Italy; ‖Department of Cardiothoracic Surgery, ISMETT-UPMC, Palermo, Italy; and ¶Department of Anesthesia and Critical Care, ISMETT- UPMC, Palermo, Italy.

Accidental inhalation of powder is a potential problem for infants. The clinical effects of inhaling powder depend on the powder contents, degree of aspiration, and the child's underlying systemic response. We present a case of accidental inhalation of rice starch powder in a 17-month-old girl, which led to severe acute respiratory distress syndrome responsive to conventional treatment, ultimately requiring venous-venous extracorporeal membrane oxygenation.
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http://dx.doi.org/10.1213/XAA.0000000000000236DOI Listing
December 2015

Long-Term Structural and Functional Myocardial Adaptations in Healthy Living Kidney Donors: A Pilot Study.

PLoS One 2015 10;10(11):e0142103. Epub 2015 Nov 10.

Division of Cardiovascular Diseases, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy.

Background And Aims: Compensatory renal hypertrophy following unilateral nephrectomy (UNX) occurs in the remaining kidney. However, the long-term cardiac adaptive process to UNX remains poorly defined in humans. Our goal was to characterize myocardial structure and function in living kidney donors (LKDs), approximately 12 years after UNX.

Methods And Results: Cardiac function and structure in 15 Italian LKDs, at least 5 years after UNX (median time from donation = 8.4 years) was investigated and compared to those of age and sex matched U.S. citizens healthy controls (n = 15). Standard and speckle tracking echocardiography (STE) was performed in both LKDs and controls. Plasma angiotensin II, aldosterone, atrial natriuretic peptide (ANP), N terminus pro B-type natriuretic peptide (NT-proBNP), cyclic guanylyl monophosphate (cGMP), and amino-terminal peptide of procollagen III (PIIINP) were also collected. Median follow-up was 11.9 years. In LKDs, LV geometry and function by STE were similar to controls, wall thickness and volumes were within normal limits also by CMR. In LKDs, CMR was negative for myocardial fibrosis, but apical rotation and LV torsion obtained by STE were impaired as compared to controls (21.4 ± 7.8 vs 32.7 ± 8.9 degrees, p = 0.04). Serum creatinine and PIIINP levels were increased [1.1 (0.9-1.3) mg/dL, and 5.8 (5.4-7.6)] μg/L, respectively), while urinary cGMP was reduced [270 (250-355) vs 581 (437-698) pmol/mL] in LKDs. No LKD developed cardiovascular or renal events during follow-up.

Conclusions: Long-term kidney donors have no apparent structural myocardial abnormalities as assessed by contrast enhanced CMR. However, myocardial deformation of the apical segments, as well as apical rotation, and LV torsion are reduced. The concomitant increase in circulating PIIINP level is suggestive of fibrosis. Further studies, focused on US and EU patients are warranted to evaluate whether these early functional modifications will progress to a more compromised cardiac function and structure at a later time.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142103PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640880PMC
June 2016

Circulatory response to volume expansion and transjugular intrahepatic portosystemic shunt in refractory ascites: Relationship with diastolic dysfunction.

Dig Liver Dis 2015 Dec 3;47(12):1052-8. Epub 2015 Sep 3.

Liver Unit, Hospital Clínic, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.

Background: Cirrhotic cardiomyopathy may lead to heart failure in stressful circumstances, such as after transjugular intrahepatic portosystemic shunt (TIPS) placement.

Aim: To examine whether acute volume expansion predicts haemodynamic changes after TIPS and elicits signs of impending heart failure.

Methods: We prospectively evaluated refractory ascites patients (group A) and compensated cirrhotics (group B), who underwent echocardiography, NT-proBNP measurement, and heart catheterization before and after volume load; group A repeated measurements after TIPS.

Results: 15 patients in group A (80% male; 54±12.4 years) and 8 in group B (100% male; 56±6.2 years) were enrolled. Echocardiography disclosed diastolic dysfunction in 30% and 12.5%, respectively. In group A, volume load and TIPS induced a significant increase in right atrial, mean pulmonary, capillary wedge pressure and cardiac index, and a decrease in systemic vascular resistance (respectively, 4.7±2.8 vs. 9.9±3.6 mmHg; 13.3±3.5 vs. 21.9±5.9 mmHg; 8.3±3.4 vs. 15.4±4.7 mmHg; 3.7±0.7 vs. 4.6±11 t/min/m2; 961±278 vs. 767±285 dynscm(-5); and 10.1±3.3 vs. 14.2±3.4 mmHg; 17.5±4 vs. 25.2±4.2 mmHg; 12.3±4 vs. 19.3±3.4 mmHg; 3.4±0.8 vs. 4.5±0.91l t/min/m2; 779±62 vs. 596±199 dynscm(-5), p<0.001 for all pairs). At 24h, cardiopulmonary pressures returned towards baseline.

Conclusions: Acute volume expansion predicted haemodynamic changes immediately after TIPS. All patients had adequate haemodynamic adaptation to TIPS; none developed signs of heart failure.
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http://dx.doi.org/10.1016/j.dld.2015.08.014DOI Listing
December 2015

Liver Volume Restoration and Hepatic Microarchitecture in Small-for-Size Syndrome.

Ann Transplant 2015 Jul 7;20:381-9. Epub 2015 Jul 7.

Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Background: We investigated preoperative parameters that could work as markers of liver regeneration (LR), and tried to create an algorithm for therapeutic decision-making, looking at the clinical setting of post-hepatectomy liver failure (PHLF) after major liver resection for malignancies (LRM) and of the small-for-size syndrome (SFSS) after adult-to-adult living related liver transplantation (LRLT), considering PHLF and SFSS a single clinical entity.

Material And Methods: The clinical data of 2 series of 10 consecutive patients who experienced liver-specific complications after LRLT or LRM between 2008 and 2013 were analyzed. LR was evaluated by multidetector computed tomography (MDCT) and hepatic parenchymal findings with specific re-examinations of liver biopsies. The analysis was done according to demographics, tumor characteristics, and postoperative complications occurring within 90 days of surgery and codified within the Clavien classification.

Results: A total of 13 cases of SFSS occurred in 8 LRLT recipients (61.5%) and in 5 patients after LRM (38.5%). The incidence of SFSS was significantly associated with a greater spleen volume/future remnant liver volume ratio (1.08±0.5; P=0.02) and a reduced number of hepatic tumors (0.58±0.6; P=0.04). A greater degree of LR was not associated with a lesser likelihood of developing SFSS (P=0.31). SFSS incidence and re-examination of post-operative liver biopsies differed according to the evidence of focal endothelial denudation in the portal vein and centrilobular hepatocanalicular cholestasis. We found an association between SFSS incidence and the immunohistochemical overexpression of cytological proliferation marker Ki-67 (29.3±29.8%; P=0.007), which was a significant predictor of poor post-operative survival (OR=1.12, C.I.: 1.013; 1.242).

Conclusions: SFSS is a rare but dangerous clinical entity characterized by anarchic hepatic regeneration. We suggest focusing on early diagnosis in order to establish non-surgical modulation of the portal inflow, in conjunction with optimization of medical management.
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http://dx.doi.org/10.12659/AOT.894082DOI Listing
July 2015

Experimental hepatocyte xenotransplantation--a comprehensive review of the literature.

Xenotransplantation 2015 Jul-Aug;22(4):239-48. Epub 2015 May 7.

Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.

Hepatocyte transplantation (Tx) is a potential therapy for certain diseases of the liver, including hepatic failure. However, there is a limited supply of human livers as a source of cells and, after isolation, human hepatocytes can be difficult to expand in culture, limiting the number available for Tx. Hepatocytes from other species, for example, the pig, have therefore emerged as a potential alternative source. We searched the literature through the end of 2014 to assess the current status of experimental research into hepatocyte xenoTx. The literature search identified 51 reports of in vivo cross-species Tx of hepatocytes in a variety of experimental models. Most studies investigated the Tx of human (n = 23) or pig (n = 19) hepatocytes. No studies explored hepatocytes from genetically engineered pigs. The spleen was the most common site of Tx (n = 23), followed by the liver (through the portal vein [n = 6]) and peritoneal cavity (n = 19). In 47 studies (92%), there was evidence of hepatocyte engraftment and function across a species barrier. The data provided by this literature search strengthen the hypothesis that xenoTx of hepatocytes is feasible and potentially successful as a clinical therapy for certain liver diseases, including hepatic failure. By excluding vascular structures, hepatocytes isolated from genetically engineered pig livers may address some of the immunological problems of xenoTx.
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http://dx.doi.org/10.1111/xen.12170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519403PMC
May 2016

IL28B polymorphisms of both recipient and donor cooperate to influence IFN treatment response in HCV recurrence after liver transplantation, but IL28B SNPs of the recipient play a major role in IFN-induced blocking of HCV replication.

New Microbiol 2015 Apr 29;38(2):201-10. Epub 2015 Apr 29.

Regenerative Medicine and Biomedical Technologies Unit, Department of Laboratory Medicine and Advanced Biotechnologies, ISMETT, Palermo, Italy; RiMed Foundation, Palermo, Italy.

Single nucleotide polymorphisms (SNPs) of the IL28B locus are associated with a positive response to pegylated interferon-alpha and ribavirin (pegIFN-alpha/RBV) treatment of HCV-infected patients. This study evaluated the association between SNPs rs12980275, rs12979860 and rs8099917 and treatment outcome of HCV recurrent infection in HCV-positive patients who underwent liver transplant. We aimed to assess to what extent recipient and/or graft donor IL28B polymorphisms contribute to HCV clearance after transplantation influencing the response to the antiviral treatment. We found that the allele frequencies in donors were in agreement with the pattern expected in the European population. The frequency of favourable genotypes was significantly lower in recipients than in donors, reasonably because the recipients represented a group of patients affected by chronic Hepatitis C. Our study demonstrated that the positive outcome of the pegIFN-alpha/RBV treatment of HCV recurrence is associated with the co-presence of favourable genotypes of both donors and recipients. However, IL28B SNPs of the recipient seem to play a major role in this clinical setting. In particular, homozygosis of rs12979860 favourable genotype in recipients was associated with sustained virological response independently from the donor's genotype. Thus, identification of these SNPs may be useful to predict the response to IFN-based therapy of HCV recurrent infection in liver-transplanted patients.
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April 2015

ISMETT: An International Collaboration on Organ Transplantation.

Clin Transpl 2015 ;31:87-99

Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, University of Pittsburgh Medical Center, Palermo, Italy.

The Institute of the Mediterranean for Transplantation and High Specialty Therapies (ISMETT) is a multi-organ transplant and high specialty center located in Palermo, Italy and managed by the University of Pittsburgh Medical Center. Clinical transplant activity started in 1999 and, herein, we illustrate the outcomes achieved over the past 15 years. In total, ISMETT has performed 997 liver transplants (83.9% adults, 16.1% pediatrics) with a significant percentage of liver transplants from cadaver split livers (17%) and partial grafts from living donors (11.5%). Among liver transplant recipients, the overall five-year graft survival was 74.3% in the adult population and 79% in the pediatric population. ISMETT has also performed 419 kidney transplants in total: 211 from cadaveric donors (22 double), 176 from living donors, and 32 combined (19 with liver, 11 with pancreas, and 2 with heart). The 5-year renal graft survival was 82.2% (cadaveric donor) and 92.2% (living donor). More recently, in 2005, ISMETT started pancreas, lung, and heart transplant programs. In total, 16 pancreas transplants have been performed, of which 12 were simultaneous pancreas-kidney transplants, 1 was pancreas after kidney, and 3 were pancreas alone transplants. One pancreatic islet transplant was also performed in a patient who had already undergone kidney transplantation. Patient and pancreas graft survivals at 1 year were 86.7% and 73.3%, respectively, and 80% and 73.3% at five years (pancreas survival is defined as normoglycemia and insulin-independence). Lung transplant has been performed in 133 patients (116 double and 17 single lung). Eleven were pediatric (8% of all transplants). The 1-month, 1-year, and 5-year overall graft survivals were, 93.8%, 81.4%, and 75.6%, respectively. Heart transplantation has been performed in 133 adults (85% were male). Coronary artery disease and cardiomyopathy were the leading underlying heart disease diagnoses leading to transplant. Mechanical support (ventricular assist device or extracorporeal membrane oxygenation) as a bridge to transplant was used in 18% of the heart transplant cases. One-year heart graft survival was 83% and 5-year heart graft survival was 81%.
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January 2015

Role of transcription factor CCAAT/enhancer-binding protein alpha in human fetal liver cell types in vitro.

Hepatol Res 2015 Aug 9;45(8):919-32. Epub 2014 Oct 9.

Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Aim: The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) has been shown to play an important role in liver development, cell proliferation and differentiation. It is, however, largely unknown if C/EBPα regulates cell differentiation and proliferation differently in the diverse cell types of the human liver. We investigated the role of C/EBPα in primary human fetal liver cells and liver cell subpopulations in vitro using a 3-D perfusion bioreactor as an advanced in vivo-like human organ culture model.

Methods: Human fetal liver cells were investigated in vitro. C/EBPα gene expression was knocked down using siRNA or overexpressed by plasmid transfection. Cell type-specific gene expression was studied, cell populations and their proliferation were investigated, and metabolic parameters were analyzed.

Results: When C/EBPα gene expression was knocked down, we observed a significantly reduced expression of typical endothelial, hematopoietic and mesenchymal genes such as CD31, vWF, CD90, CD45 and α-smooth muscle actin in fetal cells. The intracellular expression of hepatic proteins and genes for liver-specific serum proteins α-fetoprotein and albumin were reduced, their protein secretion was increased. Fetal endothelial cell numbers were reduced and hepatoblast numbers were increased. C/EBPα overexpression in fetal cells resulted in increased endothelial numbers, but did not affect mesenchymal cell types or hepatoblasts.

Conclusion: We demonstrated that the effects of C/EBPα are specific for the different human fetal liver cell types, using an advanced 3-D perfusion bioreactor as a human in vivo-like model.
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http://dx.doi.org/10.1111/hepr.12420DOI Listing
August 2015

Phases I-II Matched Case-Control Study of Human Fetal Liver Cell Transplantation for Treatment of Chronic Liver Disease.

Cell Transplant 2015 26;24(8):1627-38. Epub 2014 Jun 26.

Hepatology Unit, Department of Medicine, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo, Italy.

Fetal hepatocytes have a high regenerative capacity. The aim of the study was to assess treatment safety and clinical efficacy of human fetal liver cell transplantation through splenic artery infusion. Patients with end-stage chronic liver disease on the waiting list for liver transplantation were enrolled. A retrospectively selected contemporary matched-pair group served as control. Nonsorted raw fetal liver cell preparations were isolated from therapeutically aborted fetuses. The end points of the study were safety and improvement of the Model for End-Stage Liver Disease (MELD) and Child-Pugh scores. Nine patients received a total of 13 intrasplenic infusions and were compared with 16 patients on standard therapy. There were no side effects related to the infusion procedure. At the end of follow-up, the MELD score (mean ± SD) in the treatment group remained stable from baseline (16.0 ± 2.9) to the last observation (15.7 ± 3.8), while it increased in the control group from 15.3 ± 2.5 to 19 ± 5.7 (p = 0.0437). The Child-Pugh score (mean ± SD) dropped from 10.1 ± 1.5 to 9.1 ± 1.4 in the treatment group and increased from 10.0 ± 1.2 to 11.1 ± 1.6 in the control group (p = 0.0076). All treated patients with history of recurrent portosystemic encephalopathy (PSE) had no further episodes during 1-year follow-up. No improvement was observed in the control group patients with PSE at study inclusion. Treatment was considered a failure in six of the nine patients (three deaths not liver related, one liver transplant, two MELD score increases) compared with 14 of the 16 patients in the control group (six deaths, five of which were caused by liver failure, four liver transplants, and four MELD score increases). Intrasplenic fetal liver cell infusion is a safe and well-tolerated procedure in patients with end-stage chronic liver disease. A positive effect on clinical scores and on encephalopathy emerged from this preliminary study.
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http://dx.doi.org/10.3727/096368914X682422DOI Listing
June 2016

Liver regeneration after liver resection: clinical aspects and correlation with infective complications.

World J Gastroenterol 2014 Jun;20(22):6953-60

Duilio Pagano, Marco Spada, Fabio Tuzzolino, Davide Cintorino, Luigi Maruzzelli, Giovanni Vizzini, Angelo Luca, Alessandra Mularoni, Paolo Grossi, Bruno Gridelli, Salvatore Gruttadauria, Istituto Mediterraneo Trapianti e Terapie ad Alta Specializzazione, University of Pittsburgh Medical Center in Italy, 90127 Palermo, Italy.

Aim: To investigate whether early liver regeneration after resection in patients with hepatic tumors might be influenced by post-operative infective complications.

Methods: A retrospective analysis of 27 liver resections for tumors performed in a single referral center from November 2004 to January 2010. Regeneration was evaluated by multidetector computed tomography at a mean follow-up of 43.85 d. The Clavien-Dindo classification was used to evaluate postoperative events in the first 6 mo after transplantation, and Centers for Disease Control and Prevention definitions were used for healthcare associated infections data. Generalized linear regression models with Gaussian family distribution and log link function were used to reveal the principal promoters of early liver regeneration.

Results: Ten of the 27 patients (37%) underwent chemotherapy prior to surgery, with a statistically significant prevalence of patients with metastasis (P = 0.007). Eight patients (30%) underwent embolization, 3 with primary tumors, and 5 with secondary tumors. Twenty patients (74%) experienced complications, with 12 (60%) experiencing Clavien-Dindo Grade 3a to 5 complications. Regeneration ≥ 100% occurred in 10 (37%) patients. The predictors were smaller future remnant liver volume (-0.002; P < 0.001), and a greater spleen volume/future remnant liver volume ratio (0.499; P = 0.01). Patients with a resection of ≥ 5 Couinaud segments experienced greater early regeneration (P = 0.04). Nine patients experienced surgical site infections, and in 7 cases Clavien-Dindo Grade 3a to 4 complications were detected (P = 0.016). There were no significant differences between patients with primary or secondary tumors, and either onset or infections or severity of surgical complications.

Conclusion: Regardless of the onset of infective complications, future remnant liver and spleen volumes may be reliable predictors of early liver regeneration after hepatic resection on an otherwise healthy liver.
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http://dx.doi.org/10.3748/wjg.v20.i22.6953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051937PMC
June 2014

Characterization of Liver-Specific Functions of Human Fetal Hepatocytes in Culture.

Cell Transplant 2015 7;24(6):1139-53. Epub 2014 Mar 7.

Fondazione Ri.MED, Regenerative Medicine and Biomedical Technologies Unit, Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT, Palermo, Italy.

This study was designed to assess liver-specific functions of human fetal liver cells proposed as a potential source for hepatocyte transplantation. Fetal liver cells were isolated from livers of different gestational ages (16-22 weeks), and the functions of cell preparations were evaluated by establishing primary cultures. We observed that 20- to 22-week-gestation fetal liver cell cultures contained a predominance of cells with hepatocytic traits that did not divide in vitro but were functionally competent. Fetal hepatocytes performed liver-specific functions at levels comparable to those of their adult counterpart. Moreover, exposure to dexamethasone in combination with oncostatin M promptly induced further maturation of the cells through the acquisition of additional functions (i.e., ability to store glycogen and uptake of indocyanine green). In some cases, particularly in cultures obtained from fetuses of earlier gestational ages (16-18 weeks gestation), cells with mature hepatocytic traits proved to be sporadic, and the primary cultures were mainly populated by clusters of proliferating cells. Consequently, the values of liver-specific functions detected in these cultures were low. We observed that a low cell density culture system rapidly prompted loss of the mature hepatocytic phenotype with downregulations of all the liver-specific functions. We found that human fetal liver cells can be cryopreserved without significant loss of viability and function and evaluated up to 1 year in storage in liquid nitrogen. They might, therefore, be suitable for cell banking and allow for the transplantation of large numbers of cells, thus improving clinical outcomes. Overall, our results indicate that fetal hepatocytes could be used as a cell source for hepatocyte transplantation. Fetal liver cells have been used so far to treat end-stage liver disease. Additional studies are needed to include these cells in cell-based therapies aimed to treat liver failure and inborn errors of metabolism.
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http://dx.doi.org/10.3727/096368914X680082DOI Listing
March 2016

A Bayesian methodology to improve prediction of early graft loss after liver transplantation derived from the liver match study.

Dig Liver Dis 2014 Apr 9;46(4):340-7. Epub 2014 Jan 9.

Digestive Disease Section, University of Milan Bicocca, Milan, Italy; Yale University Liver Centre, New Haven, USA; Italian Association for the Study of the Liver (AISF), Italian National Transplant Centre (CNT) and Italian Liver Transplant Centres, Italy.

Background: To generate a robust predictive model of Early (3 months) Graft Loss after liver transplantation, we used a Bayesian approach to combine evidence from a prospective European cohort (Liver-Match) and the United Network for Organ Sharing registry.

Methods: Liver-Match included 1480 consecutive primary liver transplants performed from 2007 to 2009 and the United Network for Organ Sharing a time-matched series of 9740 transplants. There were 173 and 706 Early Graft Loss, respectively. Multivariate analysis identified as significant predictors of Early Graft Loss: donor age, donation after cardiac death, cold ischaemia time, donor body mass index and height, recipient creatinine, bilirubin, disease aetiology, prior upper abdominal surgery and portal thrombosis.

Results: A Bayesian Cox model was fitted to Liver-Match data using the United Network for Organ Sharing findings as prior information, allowing to generate an Early Graft Loss-Donor Risk Index and an Early Graft Loss-Recipient Risk Index. A Donor-Recipient Allocation Model, obtained by adding Early Graft Loss-Donor Risk Index to Early Graft Loss-Recipient Risk Index, was then validated in a distinct United Network for Organ Sharing (year 2010) cohort including 2964 transplants. Donor-Recipient Allocation Model updating using the independent Turin Transplant Centre dataset, allowed to predict Early Graft Loss with good accuracy (c-statistic: 0.76).

Conclusion: Donor-Recipient Allocation Model allows a reliable donor and recipient-based Early Graft Loss prediction. The Bayesian approach permits to adapt the original Donor-Recipient Allocation Model by incorporating evidence from other cohorts, resulting in significantly improved predictive capability.
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http://dx.doi.org/10.1016/j.dld.2013.11.004DOI Listing
April 2014

Right hepatic lobe living donation: a 12 years single Italian center experience.

World J Gastroenterol 2013 Oct;19(38):6353-9

Salvatore Gruttadauria, Duilio Pagano, Davide Cintorino, Antonio Arcadipane, Mario Traina, Riccardo Volpes, Angelo Luca, Giovanni Vizzini, Bruno Gridelli, Marco Spada, Istituto Mediterraneo Trapianti e Terapie ad Alta Specializzazione, University of Pittsburgh Medical Center in Italy, 90127 Palermo, Italy.

Mini invasive techniques are taking over conventional open liver resections in the setting of left lateral segmentectomy for living liver donation, and hydride procedure are being implemented for the living related right hepatectomy. Our center routinely performs laparoscopic left lateral segmentectomy for pediatric recipient and has been the first in the Europe performing an entirely robotic right hepatectomy. Great emphasis is posed on living donor safety which is the first priority during the entire operation, then the most majority of our procedures are still conventional open right hepatectomy (RHLD), defined as removal of a portion of liver corresponding to Couinaud segments 5-8, in order to obtain a graft for adult to adult living related liver transplant. During this 10 years period some changes, herein highlighted, have occurred to our surgical techniques. This study reports the largest Italian experience with RHLD, focused on surgical technique evolution over a 10 years period. Donor safety must be the first priority in right-lobe living-related donation: the categorization of complications of living donors, specially, after this "highly sensitive" procedure, reflects the need for prompt and detailed reports.
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http://dx.doi.org/10.3748/wjg.v19.i38.6353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3801305PMC
October 2013

Transplantation: Partial liver grafts are safe for young children.

Authors:
Bruno Gridelli

Nat Rev Gastroenterol Hepatol 2013 Aug 9;10(8):450-1. Epub 2013 Jul 9.

Mediterranean Institute for Transplantation and Advanced Specialized Therapies, Via Ernesto Tricomi 5, Palermo 90127, Italy.

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http://dx.doi.org/10.1038/nrgastro.2013.124DOI Listing
August 2013

Diagnosis of sclerosing cholangitis in children: blinded, comparative study of magnetic resonance versus endoscopic cholangiography.

Clin Res Hepatol Gastroenterol 2013 Dec 3;37(6):596-601. Epub 2013 Jul 3.

Department of Clinical and Experimental Medicine, Pediatric Gastroenterology, University of Pisa, Pisa, Italy.

Background: Magnetic resonance cholangiography (MRC) has been validated as comparable to endoscopic retrograde cholangiography (ERC) for the diagnosis of sclerosing cholangitis (SC) in adult patients. In children, MRC is widely used based mainly on non-comparative studies.

Patients And Methods: ERCs and MRCs of seven children (median age 9, range: 7-20 years) with SC and 17 controls (median age 6, range: 2 months-20 years) with other chronic liver diseases were reviewed in a blinded, random and independent way. All patients underwent both examinations within a 6-months slot. All ERCs and 17 MRCs were performed under general anesthesia. One radiologist evaluated both ERCs and MRCs and one interventional endoscopist independently reviewed only ERCs. Reviewers did not receive any clinical information. Diagnosis of SC, established on the basis of history, laboratory data, radiological examinations and clinical course, was used as gold standard to compare ERC and MRC diagnostic accuracy.

Results: Overall image quality was graded as very good in 57% of MRC and in 71% of ERC cases; difference was not statistically significant (P=0.24) although the probability for MRC to be diagnostic increased with patient's age. Depiction of first, second and fourth-order intrahepatic bile duct was better in ERC (P=0.004, 0.02 and 0.023, respectively); depiction of the extrahepatic bile duct was comparable (P=0.052). Diagnostic accuracy of MRC and ERC was very high, without statistically significant difference (P=0.61).

Conclusion: Despite an overall better depiction of the biliary tree by ERC, MRC is comparable for the diagnosis of SC in children. These data support MRC as the first imaging approach in children with suspected SC.
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http://dx.doi.org/10.1016/j.clinre.2013.05.014DOI Listing
December 2013