Sorafenib is the first line molecular targeted therapy for patients in advanced hepatocarcinoma stage. The aim of the study was the identification of the relationship between redox and antitumoral properties of Sorafenib in liver cancer cells. Sorafenib induces mitochondrial depolarization and superoxide anion production. However, this effect was counteracted by relevant drug-related scavenging activity, determined using fluorescent and EPR approaches, which were associated with a reduced Nrf2-dependent Thioredoxin 1 (Trx1) signaling. The downregulation of Trx1 was associated with NOS3-denitrosylation, low nitric oxide generation and reduction of caspase-8 activity in HepG2. The reduction of S-nitrosylation of Cys199 and Cys304 residues in CD95 was related to low caspase-8 activation in Sorafenib-treated HepG2 cells. Different overexpression and interfering in vitro designs showed that Trx1 regulated S-transnitrosylation between NOS3 and CD95, caspase-8 activation, EGFR tyrosine phosphorylation and cell proliferation. The two in vivo models, thioacetamide-induced HCC and the subcutaneous HepG2-implantation in nude mice, showed that the antitumoral properties of Sorafenib were related to reduced Trx1 expression, CD95 S-nitrosylation and caspase-8 activity in tumors.

Background Many centers implement everolimus-based immunosuppression in liver transplant patients with hepatocellular carcinoma. We aimed to explore the potential impact of early initiated everolimus on tumor recurrence after liver transplantation. Methods This study included 192 patients with hepatocellular carcinoma undergoing liver transplantation among who 64 individuals were prospectively enrolled (2012-2015) and received early initiated everolimus (ie, started between postoperative day 15 to 21), whereas the remaining 128 patients acted as historical controls without everolimus. Propensity score matching was performed to ensure comparability. Multivariate Cox regression and competing risks analysis were used to control for potential confounders. Results Patients with and without everolimus were comparable in terms of number of nodules (P = 0.37), total tumor diameter (P = 0.44), Milan criteria fulfillment (P = 0.56), and histological differentiation (P = 0.61), but there were increased microvascular invasion rates in the everolimus group (26.5% vs 13.3%; P = 0.026). Tumor recurrence rates were similar with and without everolimus (10.9% vs 9.9% at 36 months respectively; P = 0.18). After controlling for microvascular invasion among other potential confounders, everolimus had no significant impact on tumor recurrence, neither in the multivariate Cox regression (relative risk = 3.23; P = 0.09), nor in the competing risks analysis for tumor recurrence-death (relative risk = 1.02; P = 0.94). Patients receiving everolimus had reduced tacrolimus trough concentrations and lower serum creatinine within the first 18 months postliver transplantation. Conclusion Everolimus may not be universally prescribed to prevent tumor recurrence in liver transplant patients with hepatocellular carcinoma. Future randomized trials should be focused on patients with histological features of increased tumor aggressiveness, in whom the potential benefit would be higher.

The elevation of insulin-like growth factor 1 (IGF-1) and adipokine retinol-binding protein 4 (RBP-4) is known to be associated with the risk of many cancers. The aim of this study was to evaluate the serum concentrations of IGF-1 and RBP-4 in patients with PDAC and chronic pancreatitis (CP).The study included 43 patients with PDAC, 39 patients with CP and 10 controls. The concentrations of IGF-1 and RBP-4 were obtained using the ELISA method (Corgenix UK Ltd R&D Systems). The study protocol was approved by the Bioethics Committee at the Medical University of Lodz.In PDAC patients the serum IGF-1 level was significantly higher than in patients with CP (107.79 ± 66.40 ng/ml vs 89.91 ± 74.06 ng/ml; P < 0.05). Patients with both CP and diabetes mellitus (DM) were noted to have a significantly lower level of IGF-1 compared with those who only had CP (51.33 ± 24.30 ng/ml vs 108.42 ± 82.39 ng/ml; P = 0.01). The same result was obtained for men with and without DM (58.05 ± 32.44 ng/ml vs 98.79 ± 79.47 ng/ml, P = 0.05). As regards the serum level of RBP-4, the PDAC and CP groups were not significantly different from each other.Diabetes accompanying PDAC does not influence the level of IGF-1 as opposed to diabetes in the course of CP. The IGF-1 level can be useful for early diagnosis of PDAC. High concentration of RBP-4 is not specific to pancreatic cancer, so it does not appear to be a useful biomarker for PDAC.

Objective To determine the efficacy of coenzyme Q 10 ( CoQ10 ) in preventing renal injury in patients with lithiasis undergoing extracorporeal shockwave lithotripsy ( ESWL ). Patients and Methods Prospective, randomised, double‐blind, placebo‐controlled clinical trial of 100 patients with renal lithiasis who were treated with ESWL . The patients were distributed randomly into two groups receiving either placebo or CoQ10 (200 mg/day), a powerful antioxidant with vasoactive properties, orally administered during the week before ESWL and for 1 week after. Renal dysfunction markers, vasoactive hormones, oxidative stress, plasma levels of several interleukins and vascular resistance index ( VRI ) using D oppler ultrasound were evaluated the week before ESWL , 2 h before ESWL and at 2 h, 24 h and 7 days after ESWL . Results There was a significant increase in glomerular filtration ( P = 0.013), as well as a decrease in the albumin/creatinine ratio and the β 2 ‐microglobulin level ( P = 0.02) after 1 week of treatment in the CoQ10 group. These changes were maintained at the follow‐up after ESWL . The administration of CoQ10 was associated with improvement in vasoactive hormone parameters, VRI and interleukin levels. These improvements were maintained until the end of the follow‐up period. However, the administration of CoQ10 was not associated with significant changes in the oxidative stress parameters. Conclusion Our results indicate that CoQ10 administration improves renal function and vasoactive and inflammation parameter values, allowing for preconditioning before the tissue insult caused by ESWL .

Coagulation monitoring during liver transplantation (LT) is, even today, fundamental to reduce blood loss during surgery. Thromboelastometry (TEM) is a proven technique for controlling the various parameters that influence coagulation. However, there are no studies linking "intra operating room" TEM (orTEM) with LT outcomes. We describe a case-control study in 303 liver graft recipients analyzing variables associated with operative complications and long-term LT outcomes. The results showed that orTEM reduced the use of blood products in patients with Model for End-Stage Liver Disease scores of >= 21, retransplantation, and high surgical difficulty and important intraoperative bleeding. In addition, results in survival and postoperative complications were better when orTEM was used. In conclusion, we confirm that use of orTEM is associated with less use of blood products and a lower rate of complications after LT.

INTRODUCTION:The use of grafts from donors older than 70 years of age is increasing due to the decrease in the number of donors and the increase in waiting list patients.MATERIAL AND METHODS:We undertook a univariate and multivariate analysis of 980 adult recipients of whole liver grafts, 129 of them from donors aged 70 years or older.RESULTS:No differences were found in patient survival compared with recipients of younger grafts. There were no higher rates of rejection, vascular or biliary complications, postoperative bleeding, or infections, but older grafts were associated with graft dysfunction (P = .01) and a higher frequency of postoperative refractory ascites (P = .007), but without a greater need for retransplantation. As graft-associated factors, the joint presence in the donor of diabetes (P = .00; confidence interval [CI] = 0.04-0.117), hypertension (P = .00; CI = 0.22-0.39), and weight of more than 90 kg (P = .031; CI = 0.05-0.104) were suggestive of poor prognostic factors in recipient survival. Survival in hepatitis C virus (HCV) recipients or recipients aged older than 60 years was worse with donors aged older than 70 years, although not significantly so. With grafts from donors aged older than 80 years (n = 15), although patient survival rate was good (70% at 10 years), there was a higher rate of retransplantation (20%) and the early mortality rate was 13.3%.CONCLUSIONS:Use of grafts from donors aged older than 70 years is safe, with similar survival to patients with younger grafts. The appearance of initial dysfunction with prolonged ascites may be due to a delay in reaching a correct functionality, but was not associated with increased mortality, complications, or need for retransplantation. It should also be avoided in recipients older than 60 years or with HCV. Grafts older than 80 years were associated with a good long-term patient survival but at the expense of a higher rate of retransplantation. However, it helps to reduce the time on the waiting list and, thus, mortality. We noted decreased survival associated with donor hypertension, diabetes, and obesity, so these donors should be selected more rigorously.

The purpose of the study was to analyze the incidence of intra-abdominal infectious complications after the application of a fibrinogen sealant to the duodenojejunal anastomosis in simultaneous pancreas–kidney transplants (SPK) with enteric drainage.

Introduction. Among patients with type I diabetes mellitus and end-stage renal disease, simultaneous pancreas-kidney (SPK) transplantation is associated with increased survival compared with solitary kidney transplants or dialysis.Methods. A retrospective, descriptive study was performed on 101 consecutive SPK transplantation performed in our center over the last 20 years. We excluded six pancreas alone, eight pancreas after kidney, and four retransplantations. We analyzed demographic characteristics and patient and graft survivals. We also compared patient and pancreatic graft survivals between three periods: 1989 to 1999, 2000 to 2003, and 2004 to 2007. In the first period, bladder drainage was performed in all patients. In the second and third periods, it was replaced by enteric drainage.Results. Overall patient survival was 83.2%. Kidney graft loss occurred in 12 (11.8%) patients and pancreas graft loss in 21 (20.7%) patients. Overall pancreatic graft survival was 79.2% with a 1-year value of 87.1%. By periods, pancreatic graft survival was 75% during the bladder drainage era; 76.9% in the second period; and 85.7% in the third period (P = .88).Conclusion. SPK transplantations in diabetic patients with end-stage renal disease were associated with improving pancreas graft survival throughout the study period.

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 mg/m(2) mg/m(2)) protocol with monthly cycles of cisplatin (60) and adriamycin (30 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 G 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.

Prognosis after liver transplantation depends on a combination of recipient and donor variables. The purpose of this study is to define an allocation system of steatotic donor livers relative to recipient model for end‐stage liver disease (MELD) score. We reviewed 500 consecutive OLT, computing the MELD score for each recipient. Fatty infiltration in grafts was categorized in no steatosis, 10–30%, 30–60% and ≥60% steatosis. MELD score did not affect preservation injury and graft dysfunction, which were increased with fat content. Recipient and graft survivals lowered when increasing MELD score. Outcome in low‐risk recipients (MELD ≤9) was not altered with steatosis, except those with ≥60%. Survival functions in moderate‐risk recipients (MELD 10–19) were moderately affected with 10–30% steatosis and severely with those with >30. Exactly 30–60% steatotic grafts work poorly in high‐risk recipients (MELD ≥20), and very poorly with ≥60% steatosis. Prognosis of candidates is optimally influenced when divergence of recipient–donor risks is presented.

La tasa de mortalidad en la lista de espera de trasplante hepático se sitúa en España en torno al 10%. Sin embargo, este porcentaje puede aumentar en un 5-10% más si se añaden las exclusiones de esta lista por gravedad extrema y muy baja probabilidad de sobrevivir al trasplante, y los pacientes con hepatocarcinoma (CHC) que progresan y rebasan los límites de extensión aceptados. No existe un consenso bien definido sobre los criterios de distribución de órganos, es decir, sobre la gestión de la lista de espera, que pasa a ser un factor determinante de la tasa de mortalidad pretrasplante. Frente al modelo de priorizar a los pacientes más graves, que reduciría la mortalidad pretrasplante, se propone la selección de los candidatos con mayores probabilidades de supervivencia. La defensa de cualquiera de estas estrategias introduce sesgos de índole ética de difícil evaluación. No hay en definitiva un modelo universalmente aceptado para la distribución de donantes, de tal modo que algunos centros optan por seguir un criterio cronológico en el que, respetando el grupo sanguíneo, los pacientes son trasplantados de acuerdo con el orden de inclusión.

Tumour necrosis factor-alpha (TNF-alpha) mediates hepatocyte cell death by D-galactosamine (D-GalN) and its protection by prostaglandin El (PGE(1)). The activation of immune system plays an important role in the development of liver injury. TNF-a and PGE(1) regulate the activity and cytokine release of different inflammatory cells. The present study was undertaken to determine if the noxious or hepatic protective properties of TNF-alpha during D-GalN-induced liver injury was related to an alteration by PGE(1) of the immunoregulatory activity of TNF-a. The role of TNF-alpha was assessed by anti-TNF-alpha antibodies to D-GalN-treated rats in the presence or absence of PGE(1). D-GalN enhanced the percentage of monocytes and T lymphocytes in the total peripheral blood mononuclear cells (PBMCS). D-GaIN enhanced the activation degree of monocytes, but reduced that of T lymphocytes. D-GaIN also enhanced TNF-alpha, IL-1alpha, IL-6 and IFN-gamma concentrations in blood. Anti-TNF-alpha antibodies abolished all immunological changes and greatly reduced liver damage induced by D-GalN. The protection by PGE(1) against D-GalN liver injury was associated with an increase in TNF-alpha concentration and a reduction of IL-1alpha and IL-6. These changes were associated with a reduction of monocyte activation degree and a recovery of that of T lymphocytes. Although anti-TNF-alpha antibodies abolished the protection by PGE(1) against D-GalN-liver injury, they did not essentially counteract the effect of the prostanoid in all immunological parameters studied. The present study showed that the protection against D-GalN liver damage by PGE(1) or anti-TNF-alpha was associated with similar effects on the inflammatory parameters studied. Nevertheless, the abolishment of liver protection by PGE(1) with anti-TNF-alpha in D-GalN-treated rats in the presence of a protective cytokine profile suggests that the release of TNF-alpha induced by PGE(1) pre-administration was exerting a direct protective effect on hepatocytes against D-GalN injury. Consequently, the effect of PGE(1) on inflammatory parameters studied during liver injury was unrelated to TNF-alpha. (C) 2002 Elsevier Science B.V. All rights reserved.

PURPOSE:The purpose of this study was to assess the accumulated effects of marginal donor quality factors on liver preservation injury (LPI). METHODS:The most recent 400 consecutive liver transplantations at our institution were reviewed. Marginal liver donor criteria included the following: older than 60 years, an intensive care unit stay under ventilatory support for more than 4 days, a cold ischemia time more than 14 hr, high inotropic drug use, prolonged hypotensive episodes for more than 1 hr and less than 60 mm Hg, a peak serum sodium more than 155 mEq/L, and high levels of bilirubin, alanine transferase, or amino transferase. The type of steatosis (macrovesicular or microvesicular) was quantified in four categories: no steatosis, mild (<30%), moderate (30-60%), and severe (> 60%). LPI was stratified histologically in four levels: no damage, mild, moderate, and severe injury. These variables were included in a logistic regression analysis for prediction of the probability of the appearance of LPI. RESULTS:Five variables showed an independent influence on LPI: high inotropic drug use (odds ratio [OR]=1.56), donor age (OR=1.017 per year), moderate to severe macrovesicular steatosis (OR=3.63), cold ischemia time (OR=1,109 per hour), and prolonged stay in an intensive care unit (OR=1.79). Severe LPI was present in 32.7% of the grafts from donors without any factor of the model; in 46.8% from donors with one factor (P =0.09); in 66.2% from donors with two factors (P =0.006); and in 78.3% from donors with at last three factors (P =0.002) (global P=0.0001; chi2 =21.8). CONCLUSIONS:LPI can be potentially predicted based on donor and graft conditions. Accumulation of factors is correlated with an increased effect on LPI.

BACKGROUND:Prostaglandin E1 (PGE1) reduces cell death in experimental and clinical liver dysfunction.OBJECTIVES:Whether PGE1 protects against D-galactosamine (D-GalN)-associated hepatocyte cell death by the regulation of tumour necrosis factor-alpha (TNF-alpha) and/or nitric oxide (NO) in hepatocytes or cocultured Kupffer cells was examined.METHODS:Anti-TNF-alpha antibodies were used to evaluate the role of TNF-alpha during D-GalN cytotoxicity and its protection by PGE1 in cocultured hepatocytes and Kupffer cells. Cell apoptosis and necrosis were assessed by DNA fragmentation and lactate dehydrogenase release, respectively. Nitrite+nitrate (NOx), as NO end products, and TNF-alpha concentrations were measured in the culture medium. The role of NO was determined by measuring inducible NO synthase (iNOS) expression and the effect of its inhibition during d-GalN cytotoxicity and its protection by PGE1.RESULTS:D-GalN enhanced hepatocyte cell death associated with high TNF-alpha and NOx levels in a culture medium. Anti-TNF-alpha and iNOS inhibition suggested that TNF-alpha was mediating apoptosis, but not necrosis, through the stimulation of NO production. The antiapoptotic activity of PGE1 was associated with a reduction of NO production, but was blocked by iNOS inhibition. This apparent contradiction was explained by the ability of PGE1 to enhance iNOS expression shortly after its administration and inhibit it later during d-GalN treatment. Anti-TNF-alpha antibodies did not reduce the exacerbation of d-GalN-associated cell death in hepatocytes by cocultured Kupffer cells.CONCLUSION:TNF-alpha mediates D-GalN-induced apoptosis via NO production in cultured hepatocytes. The protective effect of PGE1 against D-GalN-induced apoptosis is probably through the induction of low iNOS expression that was followed by a reduction of iNOS expression and NO production induced by the hepatotoxin. The exacerbation of hepatocyte cell death by Kupffer cells was not related to TNF-alpha and NO.

IN OUR SECTIONS, diabetic nephropathy as a result of diabetes mellitus type I is the etiology of terminal renal insufficiency in 6% of patients on a dialysis program and in 8.7% of kidney transplant patients. This group of patients can benefit from a combined pancreas-kidney transplant (PKT), rather than an isolated kidney transplant (KT). This type of transplant eliminates the need for dialysis and therapy with insulin, as well as stabilizes retinopathy, neuropathy, and diabetic nephropathy. The aim of this article is to compare the results of PKT with those of isolated KT in patients with terminal renal insufficiency secondary to mellitus diabetes type I, assessing the number of rejections, kidney graft function, kidney and pancreas graft survival and patient survival during the first 2 posttransplant years.

Objective To investigate myocardial function in patients with obstructive jaundice before and after internal biliary drainage.Summary Background Data Increased plasma levels of atrial natriuretic peptide (ANP) have been found in patients with biliary obstruction.Methods Thirteen patients with newly diagnosed obstructive jaundice and no previous heart, lung, or renal disease were studied using a Swan-Ganz catheter. Hemodynamic measurements were taken before and 4 days after internal biliary drainage. Levels of ANP and brain natriuretic peptide (BNP) were obtained and liver function tests were also determined.Results Plasma levels of ANP and BNP were increased twofold to fourfold in the basal state and declined after biliary drainage. Independent variables predicting left ventricular systolic work were total bilirubin concentrations, duration of jaundice, and BNP. In addition, bilirubin concentrations correlated with pulmonary vascular resistance, mean arterial pulmonary pressure, and right ventricular systolic work. Internal biliary drainage resulted in an improvement in left ventricular systolic work. A correlation was found between decreasing ANP concentrations and increasing cardiac output.Conclusions Increased plasma levels of natriuretic peptides in patients with obstructive jaundice may reflect a subclinical myocardial dysfunction correlating with the degree of jaundice. After internal biliary drainage, there is a measurable improvement of cardiac function.