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Background We studied the determinants of hemodynamics and analyzed the incidence, risk factors, and clinical impact of pulmonary homograft dysfunction following Ross surgery, after a 20-year follow-up at our referral center. Methods From 1997 to 2017, a total of 142 patients underwent surgery using the Ross procedure. The development of moderate-severe stenosis (peak transhomograft pressure gradient 36 mm Hg or greater) and surgical or percutaneous Ross homograft reinterventions were evaluated by echocardiography in the immediate postoperative period and at annual intervals. Results After 20 years of follow-up, 31% of patients had moderate-severe homograft stenosis, and 9.1% had had to undergo one or two reinterventions, of which, six were valve replacements and seven were percutaneous interventions. At 1, 5, and 20 years, 89.4%, 74.6%, and 69% of these patients, respectively, were free from moderate-severe stenosis; and 99.3%, 95.7%, and 90.9%, respectively, had freedom from homograft reintervention. The pediatric group had a higher risk factor for homograft stenosis (hazard ratio 3.70; 95% confidence interval, 1.56 to 7.20, P = .002), whereas donor age behaved as a protective factor (hazard ratio 0.98; 95% confidence interval, 0.95 to 0.99; P = .044). Pulmonary homograft stenosis tended to appear in the first year (10.6%) or at 5 years (25.4%). Conclusions Pulmonary homografts implanted in the Ross procedure offer satisfactory long-term results, but the level of homograft dysfunction is not negligible. Young recipient and donor age were associated with a higher rate of homograft stenosis during follow-up. Moreover, homograft dysfunction usually occurred during the first few years of follow-up, and may have been related to immune responses.

Resumen Introduccion El objetivo de este estudio consistio en identificar los factores asociados a la recurrencia y supervivencia del liposarcoma retroperitoneal primario. Metodos Se analizo retrospectivamente una base de datos prospectiva de 35 pacientes con liposarcoma retroperitoneal primario tratados quirurgicamente entre 2004-2015. Los criterios de exclusion fueron tumores recurrentes y metastasicos. Se analizo la supervivencia global (SG) y la supervivencia libre de enfermedad. Los datos de los pacientes se compararon entre los pacientes con o sin recurrencia dentro de los 12 meses posteriores a la cirugia. Los factores de riesgo se determinaron mediante analisis de regresion logistica. Resultados La SG a los 5 anos fue del 61,1%. La supervivencia libre de enfermedad al ano y a los 3 anos fue del 68,6% al ano y del 17,1%respectivamente. La SG en el grupo con recurrencia precoz fue del 36,4% a los 5 anos frente al 71,3% en el grupo sin recurrencia precoz (p = 0,011). La recurrencia precoz se asocio a una disminucion de la SG (HR = 4,05; IC95%: 1,27-12,96; p = 0,018). La multifocalidad y margenes quirurgicos R1 estuvieron asociados a la recurrencia precoz. Los factores asociados a la recurrencia fueron el subtipo histologico, multifocalidad, grado histologico y margenes quirurgicos. La cirugia en bloque presento un efecto protector frente a la recurrencia precoz y estuvo asociada a una mayor supervivencia libre de enfermedad y SG. Conclusiones Este estudio pone de manifiesto la importancia del abordaje quirurgico agresivo en el tratamiento del liposarcoma retroperitoneal, especialmente en aquellos pacientes con caracteristicas histopatologicas que empobrecen el pronostico.

Introduction The aim of this study is to identify factors associated to recurrence and survival in primary retroperitoneal liposarcomas. Methods Prospective database of 35 patients with primary retroperitoneal liposarcoma treated 2004–2015 were retrospectively analyzed. Exclusion criteria were recurrent and metastatic tumors. Overall survival (OS) and disease-free survival were reviewed. Patient data were compared between patients with or without recurrence within 12 months after surgery. Risk factors were determined using logistic regression analysis. Results Five-year OS was 61.1%. One and three-year disease-free survival were 68.6% and 17.1% respectively. OS in the early recurrence group was 36.4 months compared with 43.2 months in the group without early recurrence (P=.011). Early recurrence was associated with a reduction in OS (HR=4.05; CI95%: 1.27–12.96; P=.018). Multifocality and microscopic positive margins R1 were associated with early recurrence. Histologic subtype, margin of resection, histologic grade and multifocality were factors associated with recurrence. Contiguously involved organ resection had a beneficial effect on early recurrence and was associated with an increase in disease-free survival and OS. Adjuvant treatments had no protective effect on recurrence. Conclusions This study underlines the crucial role aggressive surgical approach in retroperitoneal Liposarcoma treatment, especially in those patients with histological characteristics that adversely the prognosis.

Polyarteritis nodosa (PAN) is one of the systemic vasculitis that affects the media wall of arteries of small and medium diameter. Diagnosis proves difficult due to the unspecific symptoms that dominate the clinical profile. Liver involvement is very diverse, ranging from the development of cirrhotic liver disease to acute abdomen presentation that requires surgery because of liver rupture. The management of these patients requires an expert multidisciplinary team. There are several cases in the literature that describe a sudden liver rupture as the first manifestation of a PAN. In this paper we present the case of a 75 years old patient without any previous disease, who is subjected to major hepatic resection for spontaneous liver rupture.

Background Liver resection is a feasible treatment for multiple liver diseases. There is no evidence about the impact of age on liver regeneration. Objective To assess the effect of age on liver regeneration in an experimental in vivo animal model of 70%-partial hepatectomy. Methods Forty young (Y) and old (O) Wistar male rats ( n = 80) were distributed into four groups [controls (C), sham operated (SO), hepatectomy 6 h (H6), and 48 h (H48)]. Different morphometric and biochemical factors, oxidative and nitrosative stress, lipid peroxidation, cytokines kinetics, and histopathologic tissular parameters were determined. Results Early postoperative mortality was higher in aged rats ( P = 0.049). Morphometric determinations, liver regeneration index, and total volume weight were favorable to young rats. Serum transaminase levels were higher in aged rats. Parameters of necrosis (measured by histopathologic injury [HI: 0-I-II-III]), regeneration (measured by bromodeoxyuridine-BrdU incorporation) and apoptosis (determined by the TDT-mediated dUTP nick end labeling-TUNEL) were well-synchronized in young rats. Parameters of oxidative stress such as reduced (GSH), oxidized (GSSG) glutathione and lipid peroxidation (measured by hepatic malondialdehyde –MDA-) were lower in young animals throughout the studied period. Nitrosative stress measured by nitric oxide (NO) end-products was higher in late stages in resected old rats. Pro-inflammatory cytokines (TNF- α) reached higher and earlier levels in aged rats while pro-regenerative cytokines (IL-6) were significantly higher in early stages for young rats and in late stages for aged rats. The levels of TGF-β were higher in young rats. Conclusion Liver regeneration is delayed and reduced in aged animals submitted to liver resection.

Briceno J, Ciria R, de la Mata M, Montero JL, Rufian S, Lopez-Cillero P. Extended criteria donors in liver transplant candidates with hepatorenal syndrome. Clin Transplant 2011: 25: E257–E263. © 2011 John Wiley & Sons A/S. Abstract: Hepatorenal syndrome (HRS) is a complication of cirrhosis with a poor prognosis without transplantation. The aim of this study is to analyze the influence of extended criteria donors (ECD) on the postoperative outcome of recipients with HRS. The last 498 patients were divided according to pre-transplant type 1 or 2 HRS. Sixty-six (13.25%) recipients fulfilled HRS criteria. Three-month graft survival was 84% with at-listing recipient serum creatinine ranging from 0–0.8 mg/dL; 80% with s-creatinine = 0.9–1.5 mg/dL; 79% with s-creatinine = 1.6–2.5 mg/dL; and 58% with s-creatinine >2.6 mg/dL (log-rank = 18.039; p = 0.001). Recipients with HRS presented higher levels of pre-transplant creatinine and lower levels of sodium, more episodes of hemodialysis and ascitis, and higher model of end-stage liver disease-scores. Three-month graft survival in recipients with HRS relative to ECD-variables showed differences in univariate analysis according to graft steatosis (85% in absent steatosis = 0–10%; 78% in mild steatosis = 10–30%; 76% in moderate steatosis = 30–60%; and 49% when severe steatosis >60%; log-rank = 5.146; p = 0.023). Cox-proportional-hazard-model revealed that graft macrosteatosis per-30%-increments (p = 0.000; HR = 1.303 [1.24–1.33] per-30%-increment) and donors >65 yr (p = 0.089; HR = 1.622 [1.17–1.94]) were independent predictors of graft loss in recipients with HRS. In conclusion, the use of ECD in recipients with cirrhosis and HRS is a good option. However, grafts from moderate-to-severe steatosis and those from aged donors must be carefully allocated in candidates with HRS.

Vitamin E (alpha-tocopherol) has demonstrated antioxidant activity and gene-regulatory properties. d-Galactosamine (D-GalN)-induced cell death is mediated by nitric oxide in hepatocytes, and it is associated with hepatic steatosis. The beneficial properties of alpha-tocopherol and their relation to oxidative stress and gene regulation were assessed in D-GalN-induced cell death. Hepatocytes were isolated from human liver resections by a collagenase perfusion technique. alpha-Tocopherol (50 microM) was administered at the advanced stages (10 h) of D-GalN-induced cell death in cultured hepatocytes. Cell death, oxidative stress, alpha-tocopherol metabolism, and NF-kappaB-, pregnane X receptor (PXR)-, and peroxisome proliferator-activated receptor (PPAR-alpha)-associated gene regulation were estimated in the hepatocytes. D-GalN increased cell death and alpha-tocopherol metabolism. alpha-Tocopherol exerted a moderate beneficial effect against apoptosis and necrosis induced by D-GalN. Induction (rifampicin) or inhibition (ketoconazole) of alpha-tocopherol metabolism and overexpression of PXR showed that the increase in PXR-related CYP3A4 expression caused by alpha-tocopherol enhanced cell death in hepatocytes. Nevertheless, the reduction in NF-kappaB activation and inducible nitric oxide synthase expression and the enhancement of PPAR-alpha and carnitine palmitoyl transferase gene expression by alpha-tocopherol may be relevant for cell survival. In conclusion, the cytoprotective properties of alpha-tocopherol are mostly related to gene regulation rather than to antioxidant activity in toxin-induced cell death in hepatocytes.

Nitric oxide (NO) participates in the cell death induced by d-Galactosamine (d-GalN) in hepatocytes, and NO-derived reactive oxygen intermediates are critical contributors to protein modification and hepatocellular injury. It is anticipated that S-nitrosation of proteins will participate in the mechanisms leading to cell death in d-GalN-treated human hepatocytes. In the present study, d-GalN-induced cell death was related to augmented levels of NO production and S-nitrosothiol (SNO) content. The biotin switch assay confirmed that d-GalN increased the levels of S-nitrosated proteins in human hepatocytes. S-nitrosocysteine (CSNO) enhanced protein S-nitrosation and altered cell death parameters that were related to S-nitrosation of the executioner caspase-3. Fifteen S-nitrosated proteins participating in metabolism, antioxidative defense and cellular homeostasis were identified in human hepatocytes treated with CSNO. Among them, seven were also identified in d-GalN-treated hepatocytes. The results here reported underline the importance of the alteration of SNO homeostasis during d-GalN-induced cell death in human hepatocytes.

Orthotopic liver transplantation (OLT) is the best treatment for nonresectable hepatocellular carcinoma (HCC), but tumor recurrence reduces long-term and medium-term survival. The effectiveness of adjuvant chemotherapy to prevent tumor recurrence has not been fully established. Methods Three hundred eighty-seven consecutive patients, including 43 with HCC superimposed on liver cirrhosis, underwent OLT. Twelve patients with one or more prognostic criteria for HCC recurrence were entered into a prospective prophylaxis protocol with monthly cycles of cisplatin (60 mg/m2) and adriamycin (30 mg/m2), beginning the fourth week post-OLT for a maximum of seven sessions. Results The 5-year survival of the non-HCC patients was 65.7% and that of the HCC patients was 60.46% (P = NS). Chemotherapy was reasonably well tolerated, but the 9 patients with hepatitis C- or B-associated cirrhosis showed viral and histological recurrence of the primary disease. A high proportion of patients (7 of 12) developed tumor recurrence during the first year after OLT. Six of these patients died, all but one due to HCC relapse. Five patients remain healthy and tumor free at 58 to 130 months. Post-OLT adjuvant chemotherapy does not avoid tumor recurrence and its fatal consequences but may contribute to prolonged tumor-free survival among a significant proportion of patients with high-risk HCC. However, the uncertain implications on viral recurrence and the lack of control groups do not allow post-OLT chemotherapy to be recommended outside controlled clinical trials, which are clearly warranted.

Hepatitis C virus (HCV) is a major health problem that leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma, being the most frequent indication for liver transplantation in several countries. Unfortunately, HCV re-infects the liver graft almost invariably following reperfusion, with an accelerated history of recurrence, leading to 10%-30% of patients progressing to cirrhosis within 5 years of transplantation. In this sense, some groups have even advocated for not re-transplanting this patients, as lower patient and graft outcomes have been reported. However, the management of HCV recurrence is being optimized and several strategies to reduce post-transplant recurrence could improve outcomes, decrease the rate of re-transplantation and optimize the use of available grafts. Three moments may be the focus of potential actions in order to decrease the impact of viral recurrence: the pre-transplant moment, the transplant environment and the post-transplant management. In the pre-transplant setting, it is not well established if reducing the pre transplant viral load affects the risk for HCV progression after transplant. Obviously, antiviral treatment can render the patient HCV RNA negative post transplant but the long-term benefit has not yet been fully established to justify the cost and clinical risk. In the transplant moment, factors as donor age, cold ischemia time, graft steatosis and ischemia/reperfusion injury may lead to a higher and more aggressive viral recurrence. After the transplant, discussion about immunosuppression and the moment to start the treatment (prophylactic, pre-emptive or once-confirmed) together with new antiviral drugs are of interest. This review aims to help clinicians have a global overview of post-transplant HCV recurrence and strategies to reduce its impact on our patients.

Background The current methods available for screening and detecting hepatocellular carcinoma (HCC) have insufficient sensitivity and specificity, and only a low percentage of diagnosis of small tumours is based on these assays. Because HCC is usually asymptomatic at potentially curative stages, identification of biomarkers for the early detection of HCC is essential to improve patient survival. Aim The aim of this study was to identify candidate markers for HCC development in the plasma from hepatitis C virus (HCV)-infected cirrhotic patients. Methods We compared protein expression profiles of plasma samples from HCV-infected cirrhotic patients with and without HCC, using two-dimensional fluorescence difference gel electrophoresis (2-D DIGE) coupled with MALDI-TOF/TOF mass spectrometry. The 2-D DIGE results were analysed statistically using Decyder™ software, and verified by western blot and enzyme-linked immunosorbent assay (ELISA). Results In the plasma of HCV-infected HCC patients, we observed decreased expression of complement component 9, ficolin-3 (FCN3), serum amyloid P component (SAP), fibrinogen-gamma and immunoglobulin gamma-1 chain, and increased expression of vitronectin (VTN) and galectin-3 binding protein (G3BP) by DIGE analysis. ELISA confirmed DIGE results for VTN and G3BP but not for SAP or FCN3 in a larger patient population. Conclusions The proteins VTN and SAP are candidate biomarkers for HCC development in HCV-infected cirrhotic patients.

Background Orthotopic liver transplantation (OLT) is currently the elective treatment for advanced liver cirrhosis and acute liver failure. Ischemia/reperfusion damage may jeopardize graft function during the postoperative period. Cardiotrophin-1 (CT-1) has demonstrated cytoprotective properties in different experimental models of liver injury. There is no evidence to demonstrate its potential use in the prevention of the ischemia/reperfusion injury that occurs during OLT. The present study is the first report to show that the administration of CT-1 to donors would benefit the outcome of OLT. Materials and methods We tested the cytoprotective effect of CT-1 administered to the donor prior to OLT in an experimental pig model. Hemodynamic changes, hepatic histology, cell death parameters, activation of cell signaling pathways, oxidative and nitrosative stress, and animal survival were analyzed. Results Our data showed that CT-1 administration to donors increased animal survival, improved cardiac and respiratory functions, and reduced hepatocellular injury as well as oxidative and nitrosative stress. These beneficial effects, related to the activation of AKT, ERK, and STAT3, reduced caspase-3 activity and diminished IL-1β and TNF-α expression together with IL-6 upregulation in liver tissue. Conclusions The administration of CT-1 to donors reduced ischemia/reperfusion injury and improved survival in an experimental pig model of OLT.

Resumen Presentamos el caso clinico de una mujer de 33 anos diagnosticada de carcinoma suprarrenocortical en estadio avanzado. Describimos la forma de presentacion clinica, los metodos diagnosticos empleados y el tratamiento, especialmente en su aspecto quirurgico, que puede precisar en determinadas ocasiones conocimientos y habilidades en cirugia hepatica y vascular para intentar conseguir la reseccion completa del tumor y mejorar la supervivencia en estos pacientes, generalmente muy jovenes; asimismo, realizamos una actualizacion bibliografica diagnosticoterapeutica de esta neoplasia, rara en su frecuencia pero agresiva en su evolucion

Rifampicin has been used for the treatment of patients with jaundice and pruritus. This study evaluated the effect of rifampicin on the expression of different detoxification systems and bile acid transporters during in-vivo and in-vitro experimental models of cholestasis.Rifampicin was administered to glycochenodeoxycholic acid (GCDCA)-treated human hepatocytes and bile duct-obstructed rats. Different parameters related to cell death, and the expression of phase I and II drug metabolizing enzymes (DME) and bile acid transporters were determined.The induction of hepatocellular injury induced by cholestasis was associated with a reduction in cytochrome P4503A4 (CYP3A4), CYP7A1, and UDP-glucuronosyltransferase 2B4 (UGT2B4) expression, as well as an increase in import (Na(+)-taurocholate co-transporting polypeptide, NTCP) system expression. The beneficial properties of rifampicin were associated with an increase in DME and export bile acid systems (multidrug resistance-associated protein 4, MRP4, and bile acid export pump to bile duct, BSEP) expression, as well as a reduction in NTCP expression.The beneficial effect of rifampicin in cholestasis is associated with an increase in DME expression involved in toxic, bile acid and cholesterol metabolism, as well as a reduction in the bile acid importing system in hepatocytes.

The involvement of bone marrow hematopoietic stem cells (BMHSC) mobilization during liver regeneration from hepatectomized patients is under debate. The main aim of this study was to investigate the role of BMHSC mobilization after hepatic resection in 33 patients with liver disease.Mobilization of CD34(+) BMHSC after 72 h of surgery was found in peripheral blood of some, but not all, of the hepatectomized patients. These CD34(+) cells co-expressed other stem cells markers. The patients without BMHSC mobilization showed high levels of circulating and liver tissue BMHSC (CD34(+) cells) previous to surgery. Therefore, two types of patients: "mobilizers" and "non-mobilizers" were distinguished based on the values of CD34(+) cells before and after surgery. Changes in cytokines involved in the hepatic regeneration (HGF and TGF-β), and in BMHSC mobilization process (SCF, SDF-1, IL-12, or MMP-2), were detected in both groups. In addition, a higher activation previous to surgery of the SDF-1/CXCR4 axis in liver tissue was observed in non mobilizers patients compared to mobilizer patients.BMHSC mobilization seems to be associated with variations in the levels of cytokines and proteolytic enzymes involved in hepatic regeneration and bone marrow matrix degradation. Hepatectomy may be an insufficient stimulus for BMSHC mobilization. The pre-hepatectomy higher levels CD34(+) cells in peripheral blood and liver, associated to the activation of hepatic SDF-1/CXCR4 axis, suggest a BMHSC mobilization process previous to surgery in non mobilizer patients.

Hepatorenal syndrome (HRS) is a complication of cirrhosis with a poor prognosis without transplantation. The aim of this study is to analyze the influence of extended criteria donors (ECD) on the postoperative outcome of recipients with HRS. The last 498 patients were divided according to pre-transplant type 1 or 2 HRS. Sixty-six (13.25%) recipients fulfilled HRS criteria. Three-month graft survival was 84% with at-listing recipient serum creatinine ranging from 0-0.8 mg/dL; 80% with s-creatinine = 0.9-1.5 mg/dL; 79% with s-creatinine = 1.6-2.5 mg/dL; and 58% with s-creatinine2.6 mg/dL (log-rank = 18.039; p = 0.001). Recipients with HRS presented higher levels of pre-transplant creatinine and lower levels of sodium, more episodes of hemodialysis and ascitis, and higher model of end-stage liver disease-scores. Three-month graft survival in recipients with HRS relative to ECD-variables showed differences in univariate analysis according to graft steatosis (85% in absent steatosis = 0-10%; 78% in mild steatosis = 10-30%; 76% in moderate steatosis = 30-60%; and 49% when severe steatosis60%; log-rank = 5.146; p = 0.023). Cox-proportional-hazard-model revealed that graft macrosteatosis per-30%-increments (p = 0.000; HR = 1.303 [1.24-1.33] per-30%-increment) and donors65 yr (p = 0.089; HR = 1.622 [1.17-1.94]) were independent predictors of graft loss in recipients with HRS. In conclusion, the use of ECD in recipients with cirrhosis and HRS is a good option. However, grafts from moderate-to-severe steatosis and those from aged donors must be carefully allocated in candidates with HRS.

Background To explain the influence of recipient status combined with the accumulation of extended criteria donor (ECD) variables on the appearance of severe ischemia-reperfusion injury and graft survival in a model for end-stage liver disease (MELD)-based system, we analyzed our most recent consecutive liver transplantations (LTs), dividing them into two periods: 400 LTs (1992-2002; pre-MELD era) and 275 LTs (2002-2007; post-MELD era). Methods Primary dysfunction (PD) was defined as primary graft failure that required emergency retransplantation or as initial poor function. Donor variables were included in a regression model to assess the probability of PD. Results Donor age, macrovesicular steatosis more than 30%, and cold ischemia time were associated with allograft dysfunction. Mean probability of PD was 14.8%, 19.2%, 27.5%, and 37.4% for ECD 0, 1, 2, and more than or equal to 3, respectively (P=0.003). Distribution of no-mild, moderate, and severe ischemia-reperfusion injuries among MELD categories was 72.53%, 24.17%, and 3.30% (MELD group=12-19); 56.52%, 36.96%, and 6.5% (MELD group=20-28); and 23.91%, 54.35%, and 21.74% (MELD group >or=29), respectively (P=0.043). The development of PD according to ECD variables was 18.8%, 18.1%, 28.0%, and 35.3% for ECD 0, 1, 2, and more than or equal to 3, respectively (P=0.047). These variables were independent predictors of PD (Cox proportional regression model): ECD 2 (relative risk [RR]=1.59; 95% confidence interval [CI]=1.25-1.62), ECD 3 (RR=2.74; 95% CI=2.38-3.13), MELD 21 to 30 (RR=1.89; 95% CI=1.32-2.06), and MELD more than or equal to 30 (RR=3.38; 95% CI=2.43-3.86). Graft survival decreased, whereas MELD and the number of ECD variables increased. Conclusion The combination of three or more ECD variables and an MELD more than or equal to 29 is the worst scenario for graft success after LT.

Background & Aims Reactive oxygen species (ROS) and nitric oxide (NO) exert a relevant role during bile acid-induced hepatotoxicity. Whether α-Tocopherol regulates oxidative and nitrosative stress, bile acid transporter expression and their NO-dependent post-translational modifications, and cell death were assessed in vitro and in vivo . Methods α-Tocopherol and/or NO donors (DETA-NONOate or CSNO, and V-PYRRO/NO) were administered to glycochenodeoxycholic acid (GCDCA)-treated cultured human hepatocytes or to bile duct obstructed rats. Cell injury, superoxide anion \( O 2 - \) production, as well as inducible nitric oxide synthase (NOS-2), cytochrome P4507A1 (CYP7A1), heme oxygenase-1, (HO-1) and bile acid transporter expression were determined. Cysteine S -nitrosylation and tyrosine nitration of Na + -taurocholate co-transporting polypeptide (NTCP), as well as taurocholic acid (TC) uptake were also evaluated. Results GCDCA-induced cell death was associated with increased \( O 2 - \) production, NTCP and HO-1 expression, and with a reduction of CYP7A1 and NOS-2 expression. α-Tocopherol reduced cell death, \( O 2 - \) production, CYP7A1, NTCP, and HO-1 expression, as well as increased NOS-2 expression and NO production in GCDCA-treated hepatocytes. α-Tocopherol and NO donors increased NTCP cysteine S -nitrosylation and tyrosine nitration, and reduced TC uptake in hepatocytes. α-Tocopherol and V-PYRRO/NO reduced liver injury and NTCP expression in obstructed rats. Conclusions The regulation of CYP7A1, NTCP, and HO-1 expression may be relevant for the cytoprotective properties of α-Tocopherol and NO against mitochondrial dysfunction, oxidative stress and cell death in GCDCA-treated hepatocytes. The regulation of NO-dependent post-translational modifications of NTCP by α-Tocopherol and NO donors reduces the uptake of toxic bile acids by hepatocytes.

Objective To analyze the primary factors that influence the development and consolidation of a pediatric liver transplantation program. Patients and Methods This was a retrospective study of 100 liver transplantation procedures performed in 84 pediatric patients between May 1990 and November 2007. The male-female ratio was 40:60. Mean (SD) age was 5 years (40 patients were younger than 2 years); cold ischemia time was 7.10 (3.1) hours; surgery time was 5.2 (2.2) hours; and time on the waiting list for transplantation was 75 (range, 1–1012) days. Indications for transplantation included cholestatic disease (43%), acute hepatic failure (AHF; 34%), metabolic disorders (14%), and cirrhosis (9%). Transplanted organs included 3 split grafts, 29 partial grafts, and 8 living-donor grafts. Results Mean graft survival was 70.4%, 59.2%, and 58.1% at 1, 3, and 5 years, respectively. Factors that influenced graft outcome were age younger than 2 years; surgery time more than 6 hours; and AHF vs cholestatic disease, metabolic disorders, and cirrhosis. There were no significant differences in long-term (51% vs 59%) and short-term (71% vs 70%) graft survival between procedures performed in 1990–1998 compared with those performed in 1999–2007; however, there was a higher percentage (P = .005) of recipients at high risk (age younger than 2 years or with AHF) in the later period. All data were consistent with those of the European Liver Transplant Registry 2007. Conclusions A pediatric liver transplantation program can be established by a group experienced in liver transplantation.

12 páginas, 7 figuras, 1 tabla.-- et al., D-Galactosamine (D-GalN) induces reactive oxygen species (ROS) generation and cell death in cultured hepatocytes. The aim of the study was to evaluate the cytoprotective properties of N-acetylcysteine (NAC), coenzyme Q(10) (Q(10)) and the superoxide dismutase (SOD) mimetic against the mitochondrial dysfunction and cell death in D-GalN-treated hepatocytes. Hepatocytes were isolated from liver resections. NAC (0.5 mM), Q(10) (30 microM) or MnTBAP (Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (1mg/mL) were co-administered with D-GalN (40 mM) in hepatocytes. Cell death, oxidative stress, mitochondrial transmembrane potential (MTP), ATP, mitochondrial oxidized/reduced glutathione (GSH) and Q(10) ratios, electronic transport chain (ETC) activity, and nuclear- and mitochondria-encoded expression of complex I subunits were determined in hepatocytes. d-GalN induced a transient increase of mitochondrial hyperpolarization and oxidative stress, followed by an increase of oxidized/reduced GSH and Q(10) ratios, mitochondrial dysfunction and cell death in hepatocytes. The cytoprotective properties of NAC supplementation were related to a reduction of ROS generation and oxidized/reduced GSH and Q(10) ratios, and a recovery of mitochondrial complexes I+III and II+III activities and cellular ATP content. The co-administration of Q(10) or MnTBAP recovered oxidized/reduced GSH ratio, and reduced ROS generation, ETC dysfunction and cell death induced by D-GalN. The cytoprotective properties of studied antioxidants were related to an increase of the protein expression of nuclear- and mitochondrial-encoded subunits of complex I. In conclusion, the co-administration of NAC, Q(10) and MnTBAP enhanced the expression of complex I subunits, and reduced ROS production, oxidized/reduced GSH ratio, mitochondrial dysfunction and cell death induced by D-GalN in cultured hepatocytes., This study has been supported by the Instituto de Salud Carlos III (FIS 02/0181, FIS 05/0703) and the Consejería de Salud (SAS 50/03). CIBERehd is funded by the Instituto de Salud Carlos III.

The aim of this study was to determine the influence of donor graft steatosis on overall outcome, viral recurrence, and fibrosis progression in orthotopic liver transplantation (OLT) for hepatitis C virus (HCV) cirrhosis. One hundred twenty patients who underwent OLT for HCV cirrhosis between 1995 and 2005 were included in the study. Donor steatosis was categorized as absent (0%-10%; n = 40), mild (10%-30%; n = 32), moderate (30%-60%; n = 29), or severe (60%; n = 19). A Cox multivariate analysis for marginal donor variables and a Model for End-Stage Liver Disease index were performed. Fibrosis evolution was analyzed in liver biopsies (fibrosis2 oror =2) 3, 6, and 12 months post-OLT and in the late post-OLT period. Fifty-six grafts were lost (46%). The survival of the grafts was inversely proportional to donor liver steatosis: 82%, 72%, and 72% at 1, 2, and 3 years post-OLT in the absence of steatosis; 73%, 63%, and 58% with mild steatosis; 74%, 62%, and 43% with moderate steatosis; and 62%, 49%, and 42% with severe steatosis (P = 0.012). HCV recurrence was earlier and more frequent in recipients with steatosis30% (46% versus 32% at 3 months, P = 0.017; 58% versus 43% at 6 months, P = 0.020; 70% versus 56% at 12 months, P = 0.058; and 95% versus 69% at 3 years post-OLT, P = 0.0001). Graft survival was lower in alcoholic liver disease recipients versus HCV recipients when steatosis was30% at 3, 6, and 12 months post-OLT (P = 0.042) but not when steatosis was30% (P = 0.53). A higher fibrosis score was obtained 3 months post-OLT (P = 0.033), 6 months post-OLT (P = 0.306), 12 months post-OLT (P = 0.035), and in the late post-OLT period (P = 0.009). In conclusion, donor graft steatosis influences the outcome of OLT for HCV cirrhosis. HCV recurrence is more frequent and earlier in recipients of moderately and severely steatotic livers. Fibrosis evolution is higher when graft steatosis is30%. OLT with30% steatotic donor livers should be precluded in HCV recipients.

The liver is one organ clearly influenced by nitric oxide (NO), and acute and chronic exposure to this substance has been associated with distinct patterns of liver disease. Disruption or deregulation of S-nitrosothiol (SNO) signalling leads to impairment of cellular function and disease, and this study was aimed to identify potential targets for protein S-nitrosation during alteration of SNO homeostasis in human hepatocytes. Cells were treated with S-nitroso-L-cysteine (CSNO), an effective physiological nitrosothiol for delivering NO bioactivity to cells. Treatment with CSNO augmented the levels of S-nitrosoproteins detected both by chemiluminescence and the biotin switch method. CSNO treatment also increased S-nitrosoglutathione reductase (GSNOR) activity that returned SNO content to basal levels. This increased enzymatic activity was related to augmented levels of ADH-5 mRNA, the gene encoding for GSNOR in humans. In addition, the treatment with the SNO also increased cell death. Twenty S-nitrosoproteins were identified in CSNO-treated hepatocytes, including mitochondrial aldehyde dehydrogenase, protein disulphide isomerase, Hsp60, GRP75 and Raf kinase inhibitor protein. The identification in the S-nitrosatable proteome of proteins involved in metabolism, maintenance of cellular homeostasis and signalling points to the relevance of protein S-nitrosation to the physiology and pathophysiology of human hepatocytes.

Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers in the world, with limited options for treatment unless timely diagnosed. Chronic hepatitis C virus (HCV) infection and persistent heavy alcohol consumption are independent risk factors for HCC development, which may induce a specific protein expression pattern different from those caused separately. The aim of the study was to identify protein biomarkers for the detection of HCC in HCV-infected alcoholic patients with cirrhosis in order to improve survival. We compared protein expression profiles of plasma samples from 52 HCV-infected alcoholic patients with and without HCC, using 2-D DIGE coupled with MALDI-TOF/TOF mass spectrometry. The 2-D DIGE results were analyzed statistically using Decyder software, and verified by western-blot and ELISA. In plasma samples from HCV-infected alcoholic patients, we found significantly differential expression profiles of carboxypeptidase-N, ceruloplasmin (CP), complement component 4a (C4a), fibrinogen-alpha (FGA), immunoglobulin mu chain C region, serum albumin, and serum paraoxonase/arylesterase 1 (PON1). Deregulation of plasma/serum levels of the identified proteins was associated to HCV, ethanol consumption, and/or HCC progression. In the validation through ELISA, C4a serum concentration was increased in HCC patients (2.4±1 ng/mg vs 1.8±0.6 ng/mg; p = 0.029), being the only independent predictor of HCC in the multivariate analysis (OR = 2.15; p = 0.015), with an AUROC = 0.70. The combination of C4a, FGA, CP and PON1 improved slightly the predictive ability of C4a alone (AUROC 0.81). In conclusion, we identified proteins related to acute-phase response, oxidative stress, or immune response, whose differential expression in plasma may be attributed to the presence of HCC. Among them, C4a, and its combination with CP, FGA and PON1, could be considered as potentially reliable biomarkers for the detection of HCC in HCV-infected alcoholic patients.

Objective: the goal of this research has been to evaluate the survival, in long and short term, of the patient receiving liver transplant for hepatocellular carcinoma (HCC), the risk of posttransplant tumor relapse and factors related to this complication. Design: retrospective study of a consecutive series of patients having had liver transplant for HCC. Patients and methodology: transplant patients for HCC from 1989 to November 2003. Patients were selected due to general limitations of nodule size and quantity, which were subsequently published as Milan criteria. Also, criteria agreed in the Conference of Barcelona were followed in the pre-transplant diagnosis. Results: the survival of this 81 patients group was of the 80, 61 and 52% for 1, 5 and 10 years respectively. In the 32% of the cases the HCC was an incidental finding in the explant. In the 12.3%, the tumor relapse was verified. The multivariate research identified the size of the nodule (OR = 1,7944) (IC 95% = 1,1332-2,8413) and the vascular invasion (OR = 6,6346) (IC 95% = 1,4624-30,1003) as risk factors of relapse. Conclusions: the liver transplant in selected patients with HCC has good results in medium and long term. The risk of post-transplant tumor relapse becomes notably reduced and is associated with the size of the nodule and the microscopic vascular invasion.

The pre-administration of PGE1 reduced inducible nitric oxide synthase (NOS-2) expression and cell death induced by d -galactosamine ( d -GalN) in cultured rat hepatocytes. The present study evaluated the role of nitric oxide (NO) during PGE1 treatment in fully established d -GalN-induced cytotoxicity in cultured human hepatocytes. Human hepatocytes were isolated from liver resections by classic collagenase perfusion. PGE1 (1 μM) was administered at 2 h before d -GalN (40 mM), or 2 or 10 h after d -GalN in cultured hepatocytes. The production of NO was inhibited by N-ω-nitroso- l -arginine methyl ester ( l -NAME) (0.5 mM). Various parameters related to oxidative and nitrosative stress, mitochondrial dysfunction, NF-κB activation, NOS-2 expression and cell death were evaluated in hepatocytes. NO mediated mitochondrial disturbances, nitrosative stress and cell death in d -GalN-treated hepatocytes. The administration of PGE1 10 h after d -GalN enhanced NF-κB activation, NOS-2 expression and nitrosative stress. Although PGE1 administered at 2 h before or 2 h after d -GalN reduced apoptosis and necrosis, its administration 10 h after d -GalN had no beneficial effect on cell death. In conclusion, the administration of PGE1 during advanced d -GalN cytotoxicity induced nitrosative stress and lost its cytoprotective properties in cultured human hepatocytes.

AIM: To report our experience with long-term outcomes after multimodal management therapy. METHODS: An observational retrospective study was performed containing seven patients with hepatoblastoma (Hbl) treated in our institution, a tertiary referral center, from 2003 to 2011. Demographic, preoperative, surgical, and outcome variables were collected. A survival analysis and a review of the current literature related to combination neoadjuvant chemotherapy and surgical resection on Hbl were performed. RESULTS: The median age at surgery was 14.4 mo, with a male to female ratio of 4:3. Pretext staging at diagnosis was as follows: stage I, 4 cases; stage II, 2 patients; and stage III, 1 case. Mean pretreatment tumor volume was 735 cm3. Five out of seven patients received neoadjuvant chemotherapy according to SIOPEL-3 or SIOPEL-6 protocols. Tumor volume and alpha-fetoprotein levels significantly dropped after neoadjuvant therapy. Surgical procedures performed included hemihepatectomies, segmentectomies and atypical resection. All patients received chemotherapy after surgery. Median postoperative hospital stay was 8 d. All patients were alive and disease-free after a median follow-up period of 23 mo. With regards to the literature review, seventeen articles were found that were related to our search. CONCLUSION: Our series shows how multimodal management of Hbl, exhaustive control and a meticulous surgical approach leads to almost 100% complete resection with optimal postoperative results.

Orthotopic liver transplantation (OLT) offers the only chance to eliminate both tumor and liver disease in patients with hepatocellular carcinoma (HCC) and cirrhosis. However, tumor progression while on the waiting list and recurrence after OLT are frequent. We undertook a large multicenter study to assess survival and related factors of recurrence after OLT. This retrospective study analyses data from 307 consecutive patients with HCC and cirrhosis treated with OLT between 1990 and 1997 in eight centers in Spain. OLT was indicated only for small (

Objective To examine the effectiveness of fibrin sealants as supportive treatment to improve hemostasis and decrease the incidence of bile leakage and intra-abdominal collections. Design Prospective, controlled, quasiexperimental study. Setting Tertiary referral center, University Hospital Reina Sofia. Patients A total of 115 patients (58 in the control group and 57 in the collagen sponge group) scheduled for conventional hepatectomies. Interventions Patients were distributed into groups for major and minor hepatectomies with or without application of a carrier-bound collagen sponge on the raw surface of the liver. Main Outcome Measures The main outcome measures were postoperative mortality, incidence and severity of postoperative surgical complications, and length of hospital stay. The secondary outcome measures were postoperative drainage output volume, transfusion requirements, and changes in biochemical parameters (hemoglobin, bilirubin, alanine aminotransferase, and platelet levels). Results The fibrin sealant after major liver resection was effective for decreasing drainage volume (mean [SD] volume, 1124.7 [842.8] mL in the control group and 691.2 [499.5] mL in the collagen sponge group; P = .007) with a higher volume of output by drain each postoperative day in the control patients ( P = .003); postoperative blood transfusion requirements (18.9% vs 7.0%, respectively; P = .04); moderate to severe postoperative complications (21% vs 8%, respectively; P = .03); and mean (SD) hospital stay (12.6 [6.7] vs 9.6 [5.1] days, respectively; P = .03). Conclusion The use of a new carrier-bound collagen sponge after major liver resection may be recommended because of its clinical and cost-savings effectiveness.

We report an unusual pathological entity of a pseudoaneurysm of the right hepatic artery, which developed two years after the resection of a type II hilar cholangiocarcinoma and secondary to an excessive skeletonization for regional lymphadenectomy and neoadjuvant external-beam radiotherapy. After a sudden and massive hematemesis, a multidetector computed tomographic angiography (MDCTA) showed a hepatic artery pseudoaneurysm. Angiography with embolization of the pseudoaneurysm was attempted using microcoils with adequate patency of the hepatic artery and the occlusion of the pseudoaneurysm. A new episode of hematemesis 3 wk later revealed a partial revascularization of the pseudoaneurysm. A definitive interventional radiological treatment consisting of transarterial embolization (TAE) of the right hepatic artery with stainless steel coils and polyvinyl alcohol particles was effective and well-tolerated with normal liver function tests and without signs of liver infarction.