Transarterial embolization is an acceptable bridging therapy to hepatocellular carcinoma prior to liver transplantation.

BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that requires liver transplantation (LT). Despite patients with HCC being prioritized by most organ allocation systems worldwide, they still have to wait for long periods. Locoregional therapies (LRTs) are employed as bridging therapies in patients with HCC awaiting LT. Although largely used in the past, transarterial embolization (TAE) has been replaced by transarterial chemoembolization (TACE). However, the superiority of TACE over TAE has not been consistently shown in the literature. AIM: To compare the outcomes of TACE and TAE in patients with HCC awaiting LT. METHODS: All consecutive patients with HCC awaiting LT between 2011 and 2020 at a single center were included. All patients underwent LRT with either TACE or TAE. Some patients also underwent percutaneous ethanol injection (PEI), concomitantly or in different treatment sessions. The choice of LRT for each HCC nodule was determined by a multidisciplinary consensus. The primary outcome was waitlist dropout due to tumor progression, and the secondary outcome was the occurrence of adverse events. In the subset of patients who underwent LT, complete pathological response and post-transplant recurrence-free survival were also assessed. RESULTS: Twelve (18.5%) patients in the TACE group (only TACE and TACE + PEI; n = 65) and 3 (7.9%) patients in the TAE group (only TAE and TAE + PEI; n = 38) dropped out of the waitlist due to tumor progression (P log-rank test = 0.29). Adverse events occurred in 8 (12.3%) and 2 (5.3%) patients in the TACE and TAE groups, respectively (P = 0.316). Forty-eight (73.8%) of the 65 patients in the TACE group and 29 (76.3%) of the 38 patients in the TAE group underwent LT (P = 0.818). Among these patients, complete pathological response was detected in 7 (14.6%) and 9 (31%) patients in the TACE and TAE groups, respectively (P = 0.145). Post-LT, HCC recurred in 9 (18.8%) and 4 (13.8%) patients in the TACE and TAE groups, respectively (P = 0.756). Posttransplant recurrence-free survival was similar between the groups (P log-rank test = 0.71). CONCLUSION: Dropout rates and posttransplant recurrence-free survival of TAE were similar to those of TACE in patients with HCC. Our study reinforces the hypothesis that TACE is not superior to TAE as a bridging therapy to LT in patients with HCC.

Probing Mastoparan-like Antimicrobial Peptides Interaction with Model Membrane Through Energy Landscape Analysis.

Antimicrobial Peptides (AMPs) have emerged as promising alternatives to conventional antibiotics due to their capacity to disrupt the lipid packing of bacterial cell membranes. This mechanism of action may prevent the development of resistance by bacteria. Understanding their role in lipid packing disruption and their structural properties upon interaction with bacterial membranes is highly desirable. In this study, we employed Molecular Dynamics simulations and the Energy Landscape Visualization Method (ELViM) to characterize and compare the conformational ensembles of mastoparan-like Polybia-MP1 and its analogous H-MP1, in which histidines replace lysine residues. Two situations were analyzed: (i) the peptides in their free state in an aqueous solution containing water and ions and (ii) the peptides spontaneously adsorbing onto an anionic lipid bilayer, used as a bacteria membrane mimetic. ELViM was used to project a single effective conformational phase space for both peptides, providing a comparative analysis. This projection enabled us to map the conformational ensembles of each peptide in an aqueous solution and assess the structural effects of substituting lysines with histidines in H-MP1. Furthermore, a single conformational phase space analysis was employed to describe structural changes during the adsorption process using the same framework. We show that ELViM provides a comprehensive analysis, able to identify discrepancies in the conformational ensembles of these peptides that may affect their affinity to the membrane and adsorption kinetics.

Low hepatic artery resistive index on Doppler ultrasound performed on the first post-liver transplant day is associated both with hepatic artery thrombosis and decreased graft survival.

PURPOSE: Although liver transplantation (LT) outcomes have improved significantly over the last decades, early vascular complications are still associated with elevated risks of graft failure. Doppler ultrasound (DUS) enables detection of vascular complications, provides hepatic artery Resistive Index (RI). The aim of our study was to evaluate the association of the RI parameters of DUS performed in the first post-transplant week with post-transplant outcomes. METHODS: All consecutive patients undergoing a first LT between 2001 and 2019 at a single center were included. Patients were divided into two groups: RI < 0.55 and RI ≥ 0.55. Patients were also divided according to the presence or absence of hepatic artery thrombosis (HAT). Graft survival was compared between groups. RESULTS: Overall, 338 patients were included. HAT occurred in 23 patients (6.8%), of which 7 were partial and 16, complete. Biliary complications were more common in patients with HAT (10 [43.5%]) vs. 38 [12.1%] [p < 0.001]). Graft survival was lower for patients with HAT (p = 0.047). Also, RI < 0.55 was associated with increased incidence of HAT (p < 0.001). Additionally, patients with RI < 0.55 on post-operative day 1 had decreased graft survival as compared to patients with RI > 0.55 (p = 0.041). RI on post-operative day 3 and 5 was not predictive of inferior graft outcomes. CONCLUSIONS: Intensive use of DUS in the early post-LT period offers the possibility of early diagnosis of vascular complications, guiding medical and surgical management of HAT. Additionally, according to our data, low RI (< 0.55) on the first postoperative day also is a predictor of HAT and decreased graft-survival.

Percutaneous ethanol injection is an acceptable bridging therapy to hepatocellular carcinoma prior to liver transplantation.

PURPOSE: Locoregional therapies (LRT) are employed for bridging patients with hepatocellular carcinoma (HCC) awaiting orthotopic liver transplantation (OLT). Although the main LRT options include transarterial chemoembolization (TACE) and radiofrequency ablation (RFA), percutaneous ethanol injection (PEI) is an alternative with considerably lower costs. This study is a pioneering evaluation of the natural history of PEI bridging to OLT as compared to TACE. METHODS: All consecutive cirrhotic patients with HCC enlisted for OLT (2011-2020) at a single center were analyzed. Patients were divided into three LRT modality groups: PEI, TACE, and PEI+TACE. The primary study outcome was waitlist dropout due to tumor progression beyond Milan criteria. A comparison of post-transplant outcomes of patients as stratified by LRT modality also was performed. RESULTS: One hundred twenty-nine patients were included (PEI=56, TACE=43, PEI+TACE=30). The dropout rate due to tumor progression was not different among the three groups: PEI=8.9%, TACE=14%, PEI+TACE=16.7% (p=0.54). Thirteen (76.4%) patients underwent OLT after successful downstaging (3 [75%] in the PEI group, 5 [83.3%] in the TACE group, and 5 [71.4%] in the PEI+TACE group). For the 96 patients undergoing OLT, 5-year post-transplant recurrence-free survival was PEI=55.6% vs. TACE=55.1% vs. PEI+TACE=71.4% (p=0.42). Complete/near-complete pathological response rate was similar among groups (p=0.82). CONCLUSION: Dropout rates and post-transplant recurrence-free survivals related to PEI were comparable to those of TACE. This study supports the use of PEI alone or in combination with TACE for HCC patients awaiting OLT whenever RFA is not an option.

The effect of acidic pH on the adsorption and lytic activity of the peptides Polybia-MP1 and its histidine-containing analog in anionic lipid membrane: a biophysical study by molecular dynamics and spectroscopy.

Antimicrobial peptides (AMPs) are part of the innate immune system of many species. AMPs are short sequences rich in charged and non-polar residues. They act on the lipid phase of the plasma membrane without requiring membrane receptors. Polybia-MP1 (MP1), extracted from a native wasp, is a broad-spectrum bactericide, an inhibitor of cancer cell proliferation being non-hemolytic and non-cytotoxic. MP1 mechanism of action and its adsorption mode is not yet completely known. Its adsorption to lipid bilayer and lytic activity is most likely dependent on the ionization state of its two acidic and three basic residues and consequently on the bulk pH. Here we investigated the effect of bulk acidic (pH 5.5) and neutral pH (7.4) solution on the adsorption, insertion, and lytic activity of MP1 and its analog H-MP1 to anionic (7POPC:3POPG) model membrane. H-MP1 is a synthetic analog of MP1 with lysines replaced by histidines. Bulk pH changes could modulate this peptide efficiency. The combination of different experimental techniques and molecular dynamics (MD) simulations showed that the adsorption, insertion, and lytic activity of H-MP1 are highly sensitive to bulk pH in opposition to MP1. The atomistic details, provided by MD simulations, showed peptides contact their N-termini to the bilayer before the insertion and then lay parallel to the bilayer. Their hydrophobic faces inserted into the acyl chain phase disturb the lipid-packing.

Transient Elastography in HIV Infected Patients with Liver Steatosis Identifies a High-Risk Group for Non-Alcoholic Steatohepatitis.

OBJECTIVE: The study aimed to assess the role of TE in HIV-infected patients with NAFLD. METHODS: HIV-infected patients undergoing ART were enrolled between August 2016 and February 2017, following the inclusion criteria: ≥18 years with undetectable HIV viral load. Exclusion criteria included pregnancy, alcohol intake ≥20g/day and co-infection with hepatitis B or C. Patients underwent an abdominal US to diagnose liver steatosis. Significant fibrosis (≥F2) was considered when APRI>1.0, FIB4>3 and liver stiffness ≥7.1kPa. Subjects with TE ≥7.1kPa were prescribed a liver biopsy and the NAFLD Scoring System ≥3 was considered as a diagnosis of NASH. The poisson regression model was used to identify factors associated with liver steatosis. RESULTS: 98 patients were included. The mean age of the subjects was 49±11 years and 53 (54.1%) were males. Liver steatosis was diagnosed in 31 patients (31.6%) and was independently associated with male sex (PR= 2.18) and higher BMI (PR=1.08). Among the 31 patients with NAFLD, 26 showed results for TE, APRI and FIB4. The prevalence of significant fibrosis assessed by TE, APRI and FIB4 was 26.9%, 6.4% and 3.2%, respectively. Seven patients (26.9%) had a TE result ≥7.1kPa, which was associated with higher triglyceride levels, FIB4 score and CAP values. Liver biopsy was perfomed on six of those with TE ≥7.1kPa and NASH was found in 5 (83.3%) and liver fibrosis without NASH in one. CONCLUSION: NAFLD prevalence in HIV-infected patients is higher than the general population. TE ≥7.1kPa was not able to diagnose significant fibrosis but accurately detect a subgroup of patients at a high risk for NASH among HIV monoinfected individuals with steatosis.

Impact of intraoperative blood salvage and autologous transfusion during liver transplantation for hepatocellular carcinoma.

PURPOSE: Intraoperative blood salvage (IBS) with autologous blood transfusion is controversial in liver transplantation (LT) for hepatocellular carcinoma (HCC). This study evaluated the role of IBS usage in LT for HCC. METHODS: In a retrospective cohort study at a single center from 2002 to 2018, the outcomes of LT surgery for HCC were analyzed. Overall survival and disease-free survival of patients who received IBS were compared with those who did not receive IBS. Cancer recurrence, length of hospital stay, post-transplant complications, and blood loss also were evaluated. The primary aim of this study was to evaluate overall mid-term and long-term survival (4 and 6 years, respectively). RESULTS: Of the total 163 patients who underwent LT for HCC in the study period, 156 had complete demographic and clinical data and were included in the study. IBS was used in 122 and not used in 34 patients. Ninety-five (60.9%) patients were men, and the mean patient age was 58.5 ± 7.6 years. The overall 1-year, 5-year, and 7-year survival in the IBS group was 84.2%, 67.7%, and 56.8% vs. 85.3%, 67.5%, and 67.5% in the non-IBS group (p = 0.77). The 1-year, 5-year, and 7-year disease-free survival in the IBS group was 81.6%, 66.5%, and 55.4% vs. 85.3%, 64.1%, and 64.1% in the non-IBS group (p = 0.74). For patients without complete HCC necrosis (n = 121), the 1-year, 5-year, and 7-year overall survival rates for those who received IBS (n = 95) were 86.2%, 67.7%, and 49.6% vs. 84.6%, 70.0%, and 70.0% for 26 patients without IBS (p = 0.857). For the same patients, the 1-year, 5-year, and 7-year disease-free survival in the IBS group was 84.0%, 66.8%, and 64.0% vs. 88.0%, 72.8%, and 72.8% in the non-IBS group (p = 0.690). CONCLUSION: IBS does not appear to be associated with worse outcomes in patients undergoing LT for HCC, even in the presence of viable HCC in the explant. There seems to be no reason to contraindicate the use of IBS in LT for HCC.

Sinusoidal obstruction syndrome secondary the intake of Senecio brasiliensis: A case report.

Hepatic sinusoidal obstruction syndrome (HSOS) is a hepatic vascular disease histologically characterized by edema, necrosis, detachment of endothelial cells in small sinusoidal hepatic and interlobular veins and intrahepatic congestion, which leads to portal hypertension and liver dysfunction. In the Western world, most HSOS cases are associated with myeloablative pretreatment in a hematopoietic stem cell transplantation setting. Here we report a case of a 54 years old female patient, otherwise healthy, with no history of alcoholic ingestion, who presented with jaundice and signs of portal hypertension, including ascites and bilateral pleural effusion. She had no history of liver disease and denied any other risk factor for liver injury, except Senecio brasiliensis ingestion as a tea, prescribed as a therapy for menopause. Acute viral hepatitis and thrombosis of the portal system were excluded in complementary investigation, as well as sepsis, metastatic malignancy and other liver diseases, setting a RUCAM score of 6. Computed tomography demonstrated a diffuse liver parenchymal heterogeneity (in mosaic) and an extensive portosystemic collateral venous circulation, in the absence of any noticeable venous obstruction. HSOS diagnosis was confirmed through a liver biopsy. During the following-up period, patient developed refractory pleural effusion, requiring hemodialysis. Right before starting anticoagulation, she presented with abdominal pain and distention, with findings compatible of mesenteric ischemia by computed tomography. A laparotomy was performed, showing an 80cm segment of small bowel ischemia, and resection was done. She died one day after as a result from a septic shock refractory to treatment. The presented case was related to oral intake of S. brasiliensis, a plant containing pyrrolidine alkaloids, which are one of the main causes of HSOS in the East, highlighting the risk of liver injury with herbs intake.

Hepatic steatosis among people living with HIV in Southern Brazil: prevalence and risk factors.

Chronic liver disease is an important cause of morbidity and mortality among people living with human immunodeficiency virus (HIV) and is frequently related to non-alcoholic fatty liver disease (NAFLD). The objective is to estimate the prevalence and risk factors of hepatic steatosis among consecutive patients with stable HIV infection on antiretroviral therapy (ART). Also, the use of transient elastography (TE) as a mean to identify a subgroup at risk for non-alcoholic steatohepatitis (NASH) and/or liver fibrosis. HIV infected patients were enrolled between August2016 and February2017. Inclusion criteria: ≥18 years with undetectable HIV viral load. Exclusion criteria: pregnancy; alcohol intake ≥20 g/day and co-infection B or C viruses. Patients underwent ultrasound (US) to diagnose liver steatosis. Significant fibrosis (≥F2) was estimated if at least one of the following were present: APRI > 1.0, FIB4 > 3 and/or liver stiffness ≥7.1kPa. Subjects with TE ≥ 7.1kPa were proposed a liver biopsy and NAFLD Scoring System (NAS) ≥ 3 was considered as diagnosis of NASH. A total of 98 patients were included. Liver steatosis was diagnosed in 31 patients (31.6%) and was independently associated with male gender, BMI, ALT and total bilirubin levels. The prevalence of significant fibrosis assessed by TE, APRI and FIB4 was 26.9%, 6.4% and 3.2%, respectively. Seven patients had a TE result ≥7.1kPa. NASH was found in 5 (83.3%). Among HIV infected patients undergoing ART, almost one third have NAFLD. Neither TE, APRI or FIB4 were able to act as surrogates for significant liver fibrosis. Nevertheless, TE ≥ 7.1kPa was able to accurately select a subgroup of patients at risk for NASH.

Disease Progression in Patients With Hepatitis C Virus Infection Treated With Direct-Acting Antiviral Agents.

BACKGROUND & AIMS: Little is known about how a sustained virologic response (SVR) to treatment of hepatitis C virus infection with direct-acting antivirals (DAAs) affects patient mortality and development of new liver-related events. We aimed to evaluate the incidence of disease progression in patients treated with DAAs. METHODS: We performed a prospective multicenter cohort study of 1760 patients who received DAA treatment at 23 hospitals in Latin America, from May 1, 2016, through November 21, 2019. We excluded patients with a history of liver decompensation, hepatocellular carcinoma (HCC), or solid-organ transplantation. Disease progression after initiation of DAA therapy included any of the following new events: liver decompensation, HCC, liver transplantation, or death. Evaluation of variables associated with the primary outcome was conducted using a time-dependent Cox proportional hazards models. RESULTS: During a median follow-up period of 26.2 months (interquartile range, 15.3-37.5 mo), the overall cumulative incidence of disease progression was 4.1% (95% CI, 3.2%-5.1%), and after SVR assessment was 3.6% (95% CI, 2.7%-4.7%). Baseline variables associated with disease progression were advanced liver fibrosis (hazard ratio [HR], 3.4; 95% CI, 1.2-9.6), clinically significant portal hypertension (HR, 2.1; 95% CI, 1.2-3.8), and level of albumin less than 3.5 mg/dL (HR, 4.1; 95% CI, 2.3-7.6), adjusted for SVR achievement as a time covariable. Attaining an SVR reduced the risk of liver decompensation (HR, 0.3; 95% CI, 0.1-0.8; P = .016) and de novo HCC (HR, 0.2; 95% CI, 0.1%-0.8%; P = .02) in the overall cohort. CONCLUSIONS: Treatment of hepatitis C virus infection with DAAs significantly reduces the risk of new liver-related complications and should be offered to all patients, regardless of disease stage. Clinicaltrials.gov: NCT03775798.

B.A.R.C.O.S. (Brazilian Argentine Hepatitis C Collaborative Observational Study): Effectiveness and clinical outcomes of HCV treatment with daclatasvir and sofosbuvir with or without ribavirin.

Real-world data evaluating the effectiveness of direct-acting antivirals (DAAs) in hepatitis C virus (HCV) treatment have been reported from different regions. Our aim was to evaluate the effectiveness and clinical outcomes of daclatasvir (DCV) and sofosbuvir (SOF) ± ribavirin (RBV) in a prospective multicentre cohort study including patients from Argentina and Brazil who received DCV/SOF ± RBV for 12 or 24 weeks from 2015 to 2018. Multivariable logistic regression models were carried out to identify factors associated with failure to achieve sustained virologic response (SVR) as a primary end point, and to death, decompensation, hepatocellular carcinoma (HCC) or liver transplantation (LT) as a composite secondary end point. From a total of 1517 patients treated with DCV/SOF, 906 completed 12 weeks post-treatment evaluation and were included in the analysis. Overall SVR12 rate was 96.1% (95% CI: 94.6%-97.2%), and 95% (95% CI: 92.8%-96.6%) in patients with cirrhosis. LT recipients and presence of cirrhosis were independently associated with failure to achieve SVR. During post-SVR12 follow-up, cumulative incidence of the secondary end point was 2.4% (95% CI: 1.5%-3.6%); two patients died from nonliver-related causes and two from HCC, five underwent LT, 12 developed HCC and 17 patients developed hepatic decompensation. Independent variables associated with these composite secondary end points were prior to HCV treatment and presence of cirrhosis. In conclusion, although the high pangenotypic effectiveness of DCV/SOF ± RBV was confirmed in our real-life cohort, patients with compensated and decompensated cirrhosis showed higher risk of non-SVR and complication appearance during treatment or after achieving SVR.

Pre-transplant ALBI Grade 3 Is Associated with Increased Mortality After Liver Transplantation.

BACKGROUND: Although MELD score is a reliable tool for estimating mortality in the waiting list, criteria for preoperative prediction of survival after liver transplantation (LT) are lacking. ALBI score was validated as a prognostic marker for hepatocellular carcinoma patients undergoing transarterial chemoembolization, hepatic resection, and sorafenib treatment but not for LT outcomes yet. This study aimed to evaluate ALBI score as a prognostic factor in LT. METHODS: This is a single-center analysis of patients undergoing LT between October 2001 and June 2017. Primary endpoint was overall post-LT mortality. Secondary endpoint was 90-day mortality. RESULTS: Of all 301 patients included in this study, 185 (61.5%) were males. The median age was 54.1 ± 11.3 years. Univariate and multivariate analysis revealed that ALBI grade 3 (HR 1.836, 95% CI 1.154-2.921, p = 0.010), low serum albumin (HR 0.628, 95% CI 0.441-0.893, p = 0.010), black race (HR 2.431, 95% CI 1.160-5.092, p = 0.019), and elevated body mass index (HR 1.061, 95% CI 1.022-1.102, p = 0.002) all were associated with decreased overall survival following LT. Patients with both ALBI grade 3 (n = 25) and calculated MELD score ≥ 25 had the lowest overall survival (p < 0.001). DISCUSSION: ALBI grade 3 was related to lower post-LT survival and can be utilized as a tool for risk stratification in LT.

Treatment with direct-acting antivirals for HCV decreases but does not eliminate the risk of hepatocellular carcinoma.

BACKGROUND & AIMS: Data from Europe and North America have been published regarding the risk of developing hepatocellular carcinoma (HCC) after treatment with direct antiviral agents (DAA). We proposed to evaluate cumulative incidence and associated risk factors for de novo HCC. METHODS: This was a prospective multicentre cohort study from Latin America including 1400 F1-F4-treated patients with DAAs (F3-F4 n = 1017). Cox proportional regression models (hazard ratios, HR and 95% CI) were used to evaluate independent associated variables with HCC. Further adjustment with competing risk regression and propensity score matching was carried out. RESULTS: During a median follow-up of 16 months (IQR 8.9-23.4 months) since DAAs initiation, overall cumulative incidence of HCC was 0.02 (CI 0.01; 0.03) at 12 months and 0.04 (CI 0.03; 0.06) at 24 months. Cumulative incidence of HCC in cirrhotic patients (n = 784) was 0.03 (CI 0.02-0.05) at 12 months and 0.06 (CI 0.04-0.08) at 24 months of follow-up. Failure to achieve SVR was independently associated with de novo HCC with a HR of 4.9 (CI 1.44; 17.32), after adjusting for diabetes mellitus, previous interferon non-responder, Child-Pugh and clinically significant portal hypertension. SVR presented an overall relative risk reduction for de novo HCC of 73% (CI 15%-91%), 17 patients were needed to be treated to prevent one case of de novo HCC in this cohort. CONCLUSIONS: Achieving SVR with DAA regimens was associated with a significant risk reduction in HCC. However, this risk remained high in patients with advanced fibrosis, thus demanding continuous surveillance strategies in this population.

Molecular Aspects of the Dengue Virus Infection Process: A Review.

BACKGROUND: At the present time, dengue is one of the most important arboviruses affecting man, becoming a serious global public health problem, especially in subtropical and tropical countries, where environmental conditions favor the development and proliferation of the mosquito Aedes aegypti. Dengue is caused by a type of flavivírus, which is an enveloped virus of spherical geometry. Nowadays, it is one of the diseases with the highest incidence in Brazil, reaching the population of all states, regardless of social class. Several papers address the molecular aspects of infection of human cell by the viruses, which are reviewed in this work. CONCLUSION: Analyzing the three-dimensional structures of the fusion peptide of dengue virus protein E, we observed that the fusion peptide presents a region rich in hydrophobic residues and a "collar" of charged, polar residues. Probably, this hydrophilic collar plays an important role in the fusion process between the dengue virus and the cell membrane. In order for this disease to cease being a serious global public health problem, we must deepen our knowledge about the fusion process between the dengue virus and the cell membrane through further experimental and, especially, computational studies to find ways to inhibit the mechanism of virus infection.

Bosentan Inducing Autoimmune Hepatitis in a Patient with Idiopathic Pulmonary Arterial Hypertension.

A 41-year-old woman diagnosed with idiopathic pulmonary hypertension presented symptoms despite the use of vasodilators, requiring treatment with bosentan. Previously, the patient had no signs of autoimmunity and had normal liver function. After three years of bosentan use, aminotransferase levels increased, without improvement after bosentan suspension, leading to complementary investigation. The diagnosis of autoimmune hepatitis was confirmed by biopsy, already in the stage of cirrhosis. In conclusion, in case of aminotransferase levels that remain persistently elevated, despite the reduction in doses and/or suspension of bosentan, autoimmune hepatitis must be investigated and treated urgently due to possibly rapid progression to cirrhosis..

Transarterial Embolization and Percutaneous Ethanol Injection as an Effective Bridge Therapy before Liver Transplantation for Hepatitis C-Related Hepatocellular Carcinoma.

Background. Transarterial chemoembolization alone or in association with radiofrequency ablation is an effective bridging strategy for patients with hepatocellular carcinoma awaiting for a liver transplant. However, cost of this therapy may limit its utilization. This study was designed to evaluate the outcomes of a protocol involving transarterial embolization, percutaneous ethanol injection, or both methods for bridging hepatocellular carcinomas prior to liver transplantation. Methods. Retrospective review of all consecutive adult patients who underwent a first liver transplant as a treatment to hepatitis C-related hepatocellular carcinoma at our institution between 2002 and 2012. Primary endpoint was patient survival. Secondary endpoint was complete tumor necrosis. Results. Forty patients were analyzed, age 58 ± 7 years. There were 23 males (57.5%). Thirty-six (90%) out of the total 40 patients were within Milan criteria. Complete necrosis was achieved in 19 patients (47.5%). One-, 3-, and 5-year patient survival were, respectively, 87.5%, 75%, and 69.4%. Univariate analysis did not reveal any variable to impact on overall patient survival. Conclusions. Transarterial embolization, ethanol injection, or the association of both methods followed by liver transplantation comprises effective treatment strategy for hepatitis C-related hepatocellular carcinoma. This strategy should be adopted whenever transarterial chemoembolization and/or radiofrequency ablation are not available options.

Low serum factor V level: early predictor of allograft failure and death following liver transplantation.

PURPOSE: According to the current criteria, the diagnosis of early allograft dysfunction usually cannot be established before the end of the first week after liver transplantation. Thus, early predictive tests for detecting allograft dysfunction are still warranted to prevent allograft failure. This study was undertaken to assess the role of low serum factor V activity as an early prognostic factor (postoperative day 2) after liver transplantation. METHODS: A retrospective review of all consecutive adult patients who underwent first orthotopic whole-graft liver transplant at our institution between March 2002 and June 2011 was undertaken. Primary endpoint was graft failure within 90 days after transplantation. RESULTS: Of all 105 patients analyzed in this study, 39 (37.1 %) were female and 66 (62.9 %) were male. Mean age was 52.7 ± 11.7 years, and median follow-up period was 2474 ± 164 days. There were overall 33 (31.4 %) deaths, 13 of those occurring on the first 90 post-transplant days. Multivariate analysis demonstrated that serum factor V lower than 41.5 % and female gender had a negative impact not only on allograft failure/death within 90 days after transplantation (RR = 5.30, CI = 1.40-20.2, p = 0.015 and RR = 5.23, CI = 1.53-21.33, p = 0.008) but also on overall mortality. For prediction of allograft failure/death occurring during the first 3 months, serum factor V level of 41.5 % or lower exhibited a specificity of 87.9 %, a sensitivity of 42.9 %, an accuracy of 81.9 %, a positive predictive value of 35.3 %, and a negative predictive value of 90.9 %. CONCLUSIONS: Assessment of serum factor V levels on postoperative day 2 might be a promising prognostic tool for early prediction of inferior outcomes after liver transplantation.

Synthesis, cytotoxicity and in vitro antileishmanial activity of naphthothiazoles.

The leishmaniasis is a spectral disease caused by the protozoan Leishmania spp., which threatens millions of people worldwide. Current treatments exhibit high toxicity, and there is no vaccine available. The need for new lead compounds with leishmanicidal activity is urgent. Considering that many lead leishmanicidal compounds contain a quinoidal scaffold and the thiazole heterocyclic ring is found in a number of antimicrobial drugs, we proposed a hybridization approach to generate a diverse set of semi-synthetic heterocycles with antileishmanial activity. We found that almost all synthesized compounds demonstrated potent activity against promastigotes of Leishmania (Viannia) braziliensis and reduced the survival index of Leishmania amastigotes in mammalian macrophages. Furthermore, the compounds were not cytotoxic to macrophages at fivefold higher concentrations than the EC50 for promastigotes. All molecules fulfilled Lipinski's Rule of Five, which predicts efficient orally absorption and permeation through biological membranes, the in silico pharmacokinetic profile confirmed these characteristics. The potent and selective activity of semi-synthetic naphthothiazoles against promastigotes and amastigotes reveals that the 2-amino-naphthothiazole ring may represent a scaffold for the design of compounds with leishmanicidal properties and encourage the development of drug formulation and new compounds for further studies in vivo.

Structural modeling of high-affinity thyroid receptor-ligand complexes.

Understanding the molecular basis of the binding modes of natural and synthetic ligands to nuclear receptors is fundamental to our comprehension of the activation mechanism of this important class of hormone regulated transcription factors and to the development of new ligands. Thyroid hormone receptors (TR) are particularly important targets for pharmaceuticals development because TRs are associated with the regulation of metabolic rates, body weight, and circulating levels of cholesterol and triglycerides in humans. While several high-affinity ligands are known, structural information is only partially available. In this work we obtain structural models of several TR-ligand complexes with unknown structure by docking high affinity ligands to the receptors' ligand binding domain with subsequent relaxation by molecular dynamics simulations. The binding modes of these ligands are discussed providing novel insights into the development of TR ligands. The experimental binding free energies are reasonably well-reproduced from the proposed models using a simple linear interaction energy free-energy calculation scheme.