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S-Nitrosated human serum albumin (SNO-HSA) is useful in preventing liver ischemia/reperfusion injury, and SNO-HSA should thus be able to prevent cell injury during liver transplantation. However, the potential protective effect of SNO-HSA on a combination of cold and warm ischemia, which is obligatory when performing liver transplantation, has not been examined. Therefore, we evaluated the protective effect of SNO-HSA added to University of Wisconsin (UW) solution during cold or/and warm ischemia in situ and in vitro. First, we observed that apoptotic and necrotic cell death were increased during cold and warm ischemia, respectively. SNO-HSA, which possesses anti-apoptosis activity at low NO concentrations, can inhibit cold ischemia injury both in situ and in vitro. In contrast, SNO-HSA had no significant effect on warm liver ischemia injury which, however, can be reduced by UW solution. We also demonstrated that the cellular uptake of NO from SNO-HSA can occur during cold ischemia resulting in induction of heme oxygenase-1 within 3h of cold ischemia. Our results indicate that treatment with SNO-HSA or UW solution alone is not sufficient to inhibit liver injury during a period of both cold and warm ischemia. However, a combination of SNO-HSA and UW solution can be used to prevent the two types of ischemia. SNO-HSA-added UW solution could be very useful in transplantation, because the previously imposed constraints on preservation time can be removed. This is a great advantage in a situation as the present one with increased utilization of scarce donor organs for more recipients.
Copyright © 2013 Elsevier Inc. All rights reserved.
Although data support adverse prognosis of overlap subtype of chronic grant-versus-host disease (GVHD), the importance of site of gastrointestinal (GI) and type of hepatic involvement is not known. Using data from the Chronic GVHD Consortium observational cohort study (N = 567, total of 2115 visits), we examined whether the site of GI (esophageal, upper GI, or lower GI) and type of hepatic (bilirubin, alkaline phosphatase, alanine aminotransferase) involvement are associated with overall survival (OS) and nonrelapse mortality (NRM), symptoms, quality of life (QOL) and functional status measures. In multivariate analysis utilizing data from enrollment visits only, lower GI involvement (HR, 1.67; P = .05) and elevated bilirubin (HR, 2.46; P = .001) were associated with OS; both were also associated with NRM. In multivariable analysis using all visits (time-dependent covariates), GI score greater than zero (HR, 1.69; P = .02) and elevated bilirubin (HR, 3.73; P < .001) were associated with OS; results were similar for NRM. Any esophageal involvement and GI score greater than zero were associated with both symptoms and QOL, whereas elevated bilirubin was associated with QOL. We found no consistent evidence that upper GI involvement, alkaline phosphatase, alanine aminotransferase, or NIH liver score add prognostic value for survival, overall symptom burden, or QOL. These data support important differences in patient-reported outcomes according to GI and hepatic involvement among chronic GVHD-affected patients and identify those with elevated bilirubin or higher GI score at any time, or lower GI involvement at cohort enrollment, as patients at greater risk for mortality under current treatment approaches.
Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated.
METHODS - We analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health-AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided.
RESULTS - Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users.
CONCLUSIONS - Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.
PURPOSE - To report the incidence of liver function test (LFT) toxicities after radioembolization with yttrium-90 ((90)Y) SIR-Spheres and review potential risk factors.
MATERIALS AND METHODS - Patients receiving (90)Y for radioembolization of primary or metastatic liver tumors had follow-up LFTs 29-571 days after treatment. The incidence and duration of bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) toxicities were documented using common terminology criteria. Factors that were assessed included previous intra-arterial (IA) therapy, systemic chemotherapy, low tumor-to-normal liver tissue ratio at mapping angiography, vascular stasis, and higher prescribed (90)Y doses.
RESULTS - There were 81 patients who underwent 122 infusions and had follow-up LFTs. Of 122 infusions, 71 (58%) were associated with toxicity. One patient died with radiation-induced liver disease. Grade 3 or greater toxicities occurred in seven (7%) patients after nine procedures. The median durations of laboratory elevations for bilirubin, AST, and ALT were 29 days, 29 days, and 20 days. Toxicity developed after 51 (71%) of 72 infusions with previous IA therapy versus 20 (40%) of 50 infusions in treatment-naïve areas (P = .0006). Absence of previous systemic therapy was associated with greater risk of toxicity versus previous chemotherapy (47% vs 66%, P = .03). Other factors were not associated with increased toxicity.
CONCLUSIONS - Mild hepatotoxicity developed frequently after infusion of SIR-Spheres using the body surface area method, with normalization of LFTs in most patients. Grade 3 or greater toxicities were seen in < 10% of infusions. Toxicity was strongly associated with previous IA therapy.
Copyright © 2011 SIR. Published by Elsevier Inc. All rights reserved.
The incidence of soft tissue deformation has been well documented in neurosurgical procedures and is known to compromise the spatial accuracy of image-guided surgery systems.Within the context of image-guided liver surgery (IGLS), no detailed method to study and analyze the observed organ shape change between preoperative imaging and the intra-operative presentation has been developed. Contrary to the studies of deformation in neurosurgical procedures, the majority of deformation in IGLS is imposed prior to resection and due to laparotomy and mobilization. As such, methods of analyzing the organ shape change must be developed to use the intra-operative data (e.g. laser range scan (LRS) surfaces) acquired with the organ in its fully deformed shape. To achieve this end we use a signed closest point distance deformation metric computed after rigid alignment of the intra-operative LRS data with organ surfaces generated from the preoperative tomograms. The rigid alignment between the intra-operative LRS surfaces and pre-operative image data was computed with a feature weighted surface registration algorithm. In order to compare the deformation metrics across patients, an inter-patient non-rigid registration of the pre-operative CT images was performed. Given the inter-patient liver registrations, an analysis was performed to determine the potential similarities in the distribution of measured deformation between patients for which similar procedures had been performed. The results of the deformation measurement and analysis indicates the potential for soft tissue deformation to compromise surgical guidance information and suggests a similarity in imposed deformation among similar procedure types.
OBJECTIVE - Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults.
DESIGN - We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated severe (grade III/IV) cutaneous and/or hepatic adverse events within 8 weeks of initiating nevirapine. Controls did not experience adverse events during more than 18 weeks of nevirapine therapy.
METHODS - Cases and controls were matched 1: 2 on baseline CD4 T-cell count, sex, and race. Individuals with 150 or less CD4 T cells/μl at baseline were excluded. We characterized 123 human leukocyte antigen (HLA) alleles and 2744 single-nucleotide polymorphisms in major histocompatibility complex (MHC) and drug metabolism and transport genes.
RESULTS - We studied 276 evaluable cases (175 cutaneous adverse events, 101 hepatic adverse events) and 587 controls. Cutaneous adverse events were associated with CYP2B6 516G→T (OR 1.66, all), HLA-Cw*04 (OR 2.51, all), and HLA-B*35 (OR 3.47, Asians; 5.65, Thais). Risk for cutaneous adverse events was particularly high among Blacks with CYP2B6 516TT and HLA-Cw*04 (OR 18.90) and Asians with HLA-B*35 and HLA-Cw*04 (OR 18.34). Hepatic adverse events were associated with HLA-DRB*01 (OR 3.02, Whites), but not CYP2B6 genotypes. Associations differed by population, at least in part reflecting allele frequencies.
CONCLUSION - Among patients with at least 150 CD4 T cells/μl, polymorphisms in drug metabolism and immune response pathways were associated with greater likelihood of risk for nevirapine-related adverse events. Results suggest fundamentally different mechanisms of adverse events: cutaneous, most likely MHC class I-mediated, influenced by nevirapine CYP2B6 metabolism; hepatic, most likely MHC class II-mediated and unaffected by such metabolism. These risk variants are insensitive for routine clinical screening.
Absence of bile ducts (BDs) in >50% of portal tracts is currently the most widely accepted criterion for the diagnosis of ductopenia. In this study, we describe an alternative method for the quantitative assessment of BDs based on the percentage of portal tracts containing unpaired hepatic arteries (HAs). Diagnostic criteria for ductopenia were defined as follows: 1. presence of at least 1 unpaired HA in >10% of all portal tracts; 2. at least 2 unpaired HAs present in different portal tracts in a given sample. In liver biopsies from patients with primary biliary cirrhosis and suspected chronic allograft rejection (n = 32), loss of BD was detected in 59.4% of patients using the unpaired HA method compared with 43.7% (P = 0.31), 21.9% (P = 0.005), and 12.5% (P = 0.001) by the traditional method, depending on specific adequacy criteria used (no adequacy criteria, >10 portal tracts, or >5 complete portal tracts per biopsy, respectively). The percentage of portal tracts containing BD(s) was significantly affected by the degree of portal inflammation, fibrosis stage, percentage of complete portal tracts, and biopsy width, whereas none of these factors influenced the prevalence of unpaired arteries. The unpaired HA method showed higher sensitivity for the detection of mild degrees of loss of BD compared with the traditional method, and was not influenced by factors that affected the percentage of portal tracts containing BDs.
Although minimally invasive hepatic resection surgery has shown decreased morbidity in select patients, conventional laparoscopic liver resection has inherent limitations with reduced freedom of movement within the abdominal cavity and 2-dimensional view of the operative field. Robotic liver surgery allows surgeons to perform advanced procedures with a potential for improved precision and ergonomics as well as a 3-dimensional view of the surgical site. However, use of the robot entails a steep learning curve and additional equipment. The purpose of this article is to summarize the emerging field of robotic liver surgery and include the authors' early experience with these operations.
Copyright 2010 Elsevier Inc. All rights reserved.
Loss of polycystin-2 (PC2) in mice (Pkd2(-/-)) results in total body edema, focal hemorrhage, structural cardiac defects, abnormal left-right axis, hepatorenal and pancreatic cysts, and embryonic lethality. The molecular mechanisms by which loss of PC2 leads to these phenotypes remain unknown. We generated a model to allow targeted Pkd2 inactivation using the Cre-loxP system. Global inactivation of Pkd2 produced a phenotype identical to Pkd2(-/-) mice with undetectable PC2 protein and perinatal lethality. Using various Cre mouse lines, we found that kidney, pancreas, or time-specific deletion of Pkd2 led to cyst formation. In addition, we developed an immortalized renal collecting duct cell line with inactive Pkd2; these cells had aberrant cell-cell contact, ciliogenesis, and tubulomorphogenesis. They also significantly upregulated beta-catenin, axin2, and cMyc. Our results suggest that loss of PC2 disrupts normal behavior of renal epithelial cells through dysregulation of beta-catenin-dependent signaling, revealing a potential role for this signaling pathway in PC2-associated ADPKD.