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Myocardial injury, defined as an elevation of cardiac troponin (cTn) resulting from ischemia, is associated with substantial mortality in surgical patients, and its incidence, risk factors, and impact on patients undergoing liver transplantation (LT) are poorly understood. In this study, adult patients who experienced perioperative hemodynamic derangements and had cTn measurements within 30 days after LT between 2006 and 2013 were studied. Of 502 patients, 203 (40.4%) met the diagnostic criteria (cTn I ≥0.1 ng/mL) of myocardial injury. The majority of myocardial injury occurred within the first three postoperative days and presented without clinical signs or symptoms of myocardial infarction. Thirty-day mortality in patients with myocardial injury was 11.4%, significantly higher compared with that in patients without myocardial injury (3.4%, P<.01). Cox analysis indicated the peak cTn was significantly associated with 30-day mortality. Multivariable logistic analysis identified three independent risk factors: requirement of ventilation before transplant (odds ratios (OR) 1.6, P=.006), RBC≥15 units (OR 1.7, P=.006), and the presence of PRS (OR 2.0, P=.028). We concluded that post-LT myocardial injury in this high-risk population was common and associated with mortality. Our findings may be used in pretransplant stratification. Further studies to investigate this postoperative cardiac complication in all LT patients are warranted., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Heat shock transcription factor 1 (HSF1) has been implicated in the differential regulation of cell stress and disease states. β-catenin activation is essential for immune homeostasis. However, little is known about the role of macrophage HSF1-β-catenin signaling in the regulation of NLRP3 inflammasome activation during ischemia/reperfusion (I/R) injury (IRI) in the liver. This study investigated the functions and molecular mechanisms by which HSF1-β-catenin signaling influenced NLRP3-mediated innate immune response in vivo and in vitro. Using a mouse model of IR-induced liver inflammatory injury, we found that mice with a myeloid-specific HSF1 knockout (HSF1 M-KO ) displayed exacerbated liver damage based on their increased serum alanine aminotransferase levels, intrahepatic macrophage/neutrophil trafficking, and proinflammatory interleukin (IL)-1β levels compared to the HSF1-proficient (HSF1 FL/FL ) controls. Disruption of myeloid HSF1 markedly increased transcription factor X-box-binding protein (XBP1), NLR family, pyrin domain-containing 3 (NLRP3), and cleaved caspase-1 expression, which was accompanied by reduced β-catenin activity. Knockdown of XBP1 in HSF1-deficient livers using a XBP1 small interfering RNA ameliorated hepatocellular functions and reduced NLRP3/cleaved caspase-1 and IL-1β protein levels. In parallel in vitro studies, HSF1 overexpression increased β-catenin (Ser552) phosphorylation and decreased reactive oxygen species (ROS) production in bone-marrow-derived macrophages. However, myeloid HSF1 ablation inhibited β-catenin, but promoted XBP1. Furthermore, myeloid β-catenin deletion increased XBP1 messenger RNA splicing, whereas a CRISPR/CRISPR-associated protein 9-mediated XBP1 knockout diminished NLRP3/caspase-1., Conclusion: The myeloid HSF1-β-catenin axis controlled NLRP3 activation by modulating the XBP1 signaling pathway. HSF1 activation promoted β-catenin, which, in turn, inhibited XBP1, leading to NLRP3 inactivation and reduced I/R-induced liver injury. These findings demonstrated that HSF1/β-catenin signaling is a novel regulator of innate immunity in liver inflammatory injury and implied the therapeutic potential for management of sterile liver inflammation in transplant recipients. (Hepatology 2016;64:1683-1698)., (© 2016 by the American Association for the Study of Liver Diseases.)

Objectives: We report single-institution clinical efficacy and safety outcomes for patients with unresectable locally advanced cholangiocarcinoma who were treated with stereotactic body radiation therapy (SBRT) and a subset of patients who received neoadjuvant SBRT and chemotherapy as part of an orthotopic liver transplantation (OLT) protocol., Methods and Materials: From October 2008 to June 2015, 31 consecutive patients with unresectable extrahepatic (n = 25) or intrahepatic (n = 6) cholangiocarcinoma were treated with SBRT and retrospectively analyzed. Four patients underwent liver transplantation, and 1 underwent resection. SBRT was delivered in 5 fractions with a median dose of 40 Gy. Toxicity was scored using the Common Terminology Criteria for Adverse Events Version 4.0. Overall survival (OS), time to progression, and local control were estimated using the Kaplan-Meier method., Results: The median follow-up time was 11.5 months. The 1- and 2-year OS rates were 59% and 33%, respectively, with a median survival of 15.7 months. The 1- and 2-year freedom from progression was 67% and 34%, respectively. Median time to progression was 16.8 months. Nine patients had local failure. The actuarial 1- and 2-year local control rates were 78% and 47%, respectively. Among patients who also had OLT, the median OS was 31.3 months. Twenty-four patients (77%) experienced some form of acute grade 1-2 toxicity, most commonly fatigue or pain. Five patients (16%) experienced grade ≥3 toxicity., Conclusions: SBRT is a promising option for patients with unresectable or recurrent cholangiocarcinoma either as a component of neoadjuvant therapy prior to OLT or as part of definitive therapy for patients who are unresectable and not eligible for transplantation.

Unlabelled: The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that "very early" iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with "very early" iCCA and those with "advanced" disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the "very early" iCCA group and 33/48 (69%) the "advanced" group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the "advanced" group (3.1 [2.5-4.4] versus 1.6 [1.5-1.8]). After a median follow-up of 35 (13.5-76.4) months, the 1-year, 3-year, and 5-year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1-year, 3-year, and 5-year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02., Conclusion: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178-1188)., (© 2016 by the American Association for the Study of Liver Diseases.)

Background: Despite widespread use of transjugular intrahepatic portosystemic shunt (TIPS) for treatment of portal hypertension, a paucity of nationwide data exists on predictors of the economic impact related to TIPS., Aims: Using the National Inpatient Sample (NIS) database from 2001 to 2012, we aimed to evaluate factors contributing to hospital cost of patients admitted to US hospitals for TIPS., Methods: Using the NIS, we identified a discharge-weighted national estimate of 61,004 TIPS procedures from 2001 to 2012. Through independent sample analysis, we determined profile factors related to increases in hospital costs., Results: Of all TIPS cases, the mean charge adjusted for inflation to the year 2012 is $125,044 ± $160,115. The mean hospital cost adjusted for inflation is $44,901 ± $54,565. Comparing pre- and post-2005, mean charges and cost have increased considerably ($98,154 vs. $142,652, p < 0.001 and $41,656 vs. $46,453, p < 0.001, respectively). Patients transferred from a different hospital, weekend admissions, Asian/Pacific Islander patients, and hospitals in the Northeastern and Western region had higher cost. Number of diagnoses and number of procedures show positive correlations with hospital cost, with number of procedures exhibiting stronger relationships (Pearson 0.613). Comorbidity measures with highest increases in cost were pulmonary circulation disorders ($32,157 increase, p < 0.001)., Conclusion: The cost of the TIPS procedure is gradually rising for hospitals. Alongside recent healthcare reform through the Affordable Care Act, measures to reduce the economic burden of TIPS are of increasing importance. Data from this study are intended to aid physicians and hospitals in identifying improvements that could reduce hospital costs.

Recent technological advances have enabled real-time near-infrared fluorescence cholangiography (NIRFC) with indocyanine green (ICG). Whereas several studies have shown its feasibility, dosing and timing for practical use have not been optimized. We undertook a prospective study with systematic variation of dosing and timing from injection of ICG to visualization. Adult patients undergoing laparoscopic biliary and hepatic operations were enrolled. Intravenous ICG (0.02-0.25 mg/kg) was administered at times ranging from 10 to 180 minutes prior to planned visualization. The porta hepatis was examined using a dedicated laparoscopic system equipped to detect NIRFC. Quantitative analysis of intraoperative fluorescence was performed using a scoring system to identify biliary structures. A total of 37 patients were enrolled. Visualization of the extrahepatic biliary tract improved with increasing doses of ICG, with qualitative scores improving from 1.9 ± 1.2 (out of 5) with a 0.02-mg/kg dose to 3.4 ± 1.3 with a 0.25-mg/kg dose (P < .05 for 0.02 vs 0.25 mg/kg). Visualization was also significantly better with increased time after ICG administration (1.1 ± 0.3 for 10 minutes vs 3.4 ± 1.1 for 45 minutes, P < .01). Similarly, quantitative measures also improved with both dose and time. There were no complications from the administration of ICG. These results suggest that a dose of 0.25 mg/kg administered at least 45 minutes prior to visualization facilitates intraoperative anatomical identification. The dosage and timing of administration of ICG prior to intraoperative visualization are within a range where it can be administered in a practical, safe, and effective manner to allow intraoperative identification of extrahepatic biliary anatomy using NIRFC., (© The Author(s) 2016.)

Aim: To evaluate and validate the national trends and predictors of in-patient mortality of transjugular intrahepatic portosystemic shunt (TIPS) in 15 years., Methods: Using the National Inpatient Sample which is a part of Health Cost and Utilization Project, we identified a discharge-weighted national estimate of 83884 TIPS procedures performed in the United States from 1998 to 2012 using international classification of diseases-9 procedural code 39.1. The demographic, hospital and co-morbility data were analyzed using a multivariant analysis. Using multi-nominal logistic regression analysis, we determined predictive factors related to increases in-hospital mortality. Comorbidity measures are in accordance to the Comorbidity Software designed by the Agency for Healthcare Research and Quality., Results: Overall, 12.3% of patients died during hospitalization with downward trend in-hospital mortality with the mean length of stay of 10.8 ± 13.1 d. Notable, African American patients (OR = 1.809 vs Caucasian patients, P < 0.001), transferred patients (OR = 1.347 vs non-transferred, P < 0.001), emergency admissions (OR = 3.032 vs elective cases, P < 0.001), patients in the Northeast region (OR = 1.449 vs West, P < 0.001) had significantly higher odds of in-hospital mortality. Number of diagnoses and number of procedures showed positive correlations with in-hospital death (OR = 1.249 per one increase in number of procedures). Patients diagnosed with acute respiratory failure (OR = 8.246), acute kidney failure (OR = 4.359), hepatic encephalopathy (OR = 2.217) and esophageal variceal bleeding (OR = 2.187) were at considerably higher odds of in-hospital death compared with ascites (OR = 0.136, P < 0.001). Comorbidity measures with the highest odds of in-hospital death were fluid and electrolyte disorders (OR = 2.823), coagulopathy (OR = 2.016), and lymphoma (OR = 1.842)., Conclusion: The overall mortality of the TIPS procedure is steadily decreasing, though the length of stay has remained relatively constant. Specific patient ethnicity, location, transfer status, primary diagnosis and comorbidities correlate with increased odds of TIPS in-hospital death.

Aim: To evaluate whether intra-procedural cone-beam computed tomography (CBCT) performed during modified balloon-occluded retrograde transvenous obliteration (mBRTO) can accurately determine technical success of complete variceal obliteration., Methods: From June 2012 to December 2014, 15 patients who received CBCT during mBRTO for treatment of portal hypertensive gastric variceal bleeding were retrospectively evaluated. Three-dimensional (3D) CBCT images were performed and evaluated prior to the end of the procedure, and these were further analyzed and compared to the pre-procedure contrast-enhanced computed tomography to determine the technical success of mBRTO including: Complete occlusion/obliteration of: (1) gastrorenal shunt (GRS); (2) gastric varices; and (3) afferent feeding veins. Post-mBRTO contrast-enhanced CT was used to confirm the accuracy and diagnostic value of CBCT within 2-3 d., Results: Intra-procedural 3D-CBCT images were 100% accurate in determining the technical success of mBRTO in all 15 cases. CBCT demonstrated complete occlusion/obliteration of GRS, gastric varices, collaterals and afferent feeding veins during mBRTO, which was confirmed with post-mBRTO CT. Two patients showed incomplete obliteration of gastric varices and feeding veins on CBCT, which therefore required additional gelfoam injections to complete the procedure. No patient required additional procedures or other interventions during their follow-up period (684 ± 279 d)., Conclusion: CBCT during mBRTO appears to accurately and immediately determine the technical success of mBRTO. This may improve the technical and clinical success/outcome of mBRTO and reduce additional procedure time in the future.

Background and Aims: All-oral interferon-free antivirals are highly effective in treating recurrent hepatitis C (HCV) infection in liver transplant (LT) recipients. The aim of the study was to assess immunosuppression needs after achieving a sustained viral response (SVR)., Methods: We compared immunosuppression needs before and after achieving a SVR in adult LT recipients treated for recurrent HCV infection with all-oral direct acting agents., Results: We identified 52 liver LT treated recipients who achieved a SVR. The median (25th and 75th percentile interquartile range [IQR]) age was 62 years (57.75, 65). Most recipients received tacrolimus (TAC) for their immunosuppressant regimen. After achieving SVR, there was no statistically significant difference in daily dose of TAC unadjusted per weight (p > 0.05). However, there was a statistically significant decrease in daily dose of TAC adjusted per weight, serum levels of TAC, and the product of glomerular filtration rate and TAC. No statistically significant differences in cyclosporine unadjusted/adjusted per weight daily dose or serum levels were noted., Conclusions: Immunosuppression needs were increased for those patients treated with TAC but not cyclosporine. LT recipients prescribed TAC require close monitoring after treatment completion to avoid potential risk of acute rejection.

Endoplasmic reticulum (ER) stress plays critical roles in the pathogenesis of liver ischemia-reperfusion injury (IRI). As ER stress triggers an adaptive cellular response, the question of what determines its functional outcome in liver IRI remains to be defined. In a murine liver partial warm ischemia model, we studied how transient (30 minutes) or prolonged (90 minutes) liver ischemia regulated local ER stress response and autophagy activities and their relationship with liver IRI. Effects of chemical chaperon 4-phenylbutyrate (4-PBA) or autophagy inhibitor 3-methyladenine (3-MA) were evaluated. Our results showed that although the activating transcription factor 6 branch of ER stress response was induced in livers by both types of ischemia, liver autophagy was activated by transient, but inhibited by prolonged, ischemia. Although 3-MA had no effects on liver IRI after prolonged ischemia, it significantly increased liver IRI after transient ischemia. The 4-PBA treatment protected livers from IRI after prolonged ischemia by restoring autophagy flux, and the adjunctive 3-MA treatment abrogated its liver protective effect. The same 4-PBA treatment, however, increased liver IRI and disrupted autophagy flux after transient ischemia. Although both types of ischemia activated 5' adenosine monophosphate-activated protein kinase and inactivated protein kinase B (Akt), prolonged ischemia also resulted in downregulations of autophagy-related gene 3 and autophagy-related gene 5 in ischemic livers. These results indicate a functional dichotomy of ER stress response in liver IRI via its regulation of autophagy. Transient ischemia activates autophagy to protect livers from IRI, whereas prolonged ischemia inhibits autophagy to promote the development of liver IRI.

Purpose: Acute respiratory distress syndrome (ARDS) is a devastating complication with substantial mortality. The aims of this study were to identify the incidence, preoperative and intraoperative risk factors, and impact of ARDS on outcomes in patients after orthotopic liver transplantation (OLT)., Materials and Methods: Adult OLT patients between January 2004 and October 2013 at our center were included. Postoperative ARDS was determined using the criteria proposed by the Berlin Definition. Multivariate logistic models were used to identify preoperative and intraoperative risk factors for ARDS., Results: Of 1726 patients during the study period, 71 (4.1%) developed ARDS. In the preoperative model, encephalopathy (odds ratio [OR], 2.22; P = .022), preoperative requirement of intubation (OR, 2.06; P = .020), and total bilirubin (OR, 1.02; P = .003) were independent risk factors. In the intraoperative model, large pressor bolus was the sole risk factor for ARDS (OR, 2.69; P = .001). Postoperatively, patients with ARDS had a 2-fold increase in 1-year mortality, mechanical ventilation time, and length of hospital stay., Conclusions: Acute respiratory distress syndrome occurred at a rate of 4.1% following OLT in adult patients and was associated with preoperative encephalopathy, requirement of intubation, and total bilirubin and intraoperative large boluses of pressors. Acute respiratory distress syndrome was associated with increased mortality, longer ventilation time, and hospital stay., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The utility of Aspergillus galactomannan (GM) and β-D-glucan (BG) in liver transplant recipients remains uncertain., Methods: As part of a randomized, double-blind trial of antifungal prophylaxis in liver transplant recipients at risk for invasive fungal infections (IFIs), GM and BG were assessed in 199 patients at baseline (enrollment) and weekly thereafter for the duration of study drug. Receiver operating characteristic (ROC) analysis was used to evaluate the accuracy of these for the diagnosis of IFIs., Results: Overall, 46.4% of the patients at baseline had positive GM (index ≥ 0.5) and 89.6% had BG of 80 pg/mL or greater with BG level of 500 pg/mL or greater in 31.8%. Patients with invasive aspergillosis (IA) (3/3) had positive GM at baseline as did 45.5% of those without IA (P = 0.098); the area under the ROC curve for the diagnosis of IA was 0.77 (fair test, ie, good sensitivity but poor specificity). Using BG cutoff of 80 pg/mL or higher, 100% (12/12) of the patients with IFI had positive baseline BG and as did 88.9% (160/180) of those without IFI (P = 0.618); the area under the ROC curve for predicting IFIs was 0.56 (poor test). In multivariate analyses, GM positivity was associated with study site (P = 0.041), and BG positivity with renal replacement therapy (P = 0.05) and study site (P = 0.01). The GM and BG levels declined over time; positivity at subsequent time points was lower in comparison with baseline (P < 0.001)., Conclusions: The GM and BG tests had significant center variability and limited accuracy for the diagnosis of IFIs in high-risk liver transplant recipients.

Background & Aims: Hepatitis C is the most common indication for liver transplantation (LT). Recurrent infection is universal and can lead to progressive liver disease. Widespread use of interferon-based therapy has been limited by intolerability and adverse effects., Methods: We retrospectively evaluated the safety, tolerability, and efficacy of sofosbuvir and simeprevir in the treatment of recurrent hepatitis C in adult (age >18) LT recipients., Results: Seventy-six percent of the recipients were male and the mean age [±standard deviation (SD)] was 61 (±6.0) years. The mean time (±SD) from LT to treatment initiation was 71.8 (±77.1) months. Of the 26 patients with viral levels measured 4 weeks after starting antiviral therapy, 58% were undetectable. At the end of therapy, viral load was undetectable in all transplant recipients. The 12 week sustained viral response (SVR) was 93%. All recipients were able to complete therapy and no patients required growth factors of blood product transfusion during treatment. No patient required drug interruption of their immunosuppressant therapy., Conclusion: The use of sofosbuvir and simeprevir is efficacious, safe, and tolerable and should be considered in LT recipients with recurrent HCV who are candidates for antiviral therapy., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Importance: Damage control (DC) with intra-abdominal packing and delayed reconstruction is an accepted strategy in trauma and acute care surgery but has not been evaluated in liver transplant., Objective: To evaluate the incidence, effect on survival, and predictors of the need for DC using intra-abdominal packing and delayed biliary reconstruction in patients with coagulopathy or hemodynamic instability after liver allograft reperfusion., Design, Setting, and Participants: We performed a retrospective analysis of adults undergoing liver transplant at a large transplant center from February 1, 2002, through July 31, 2012., Main Outcomes and Measures: Predictors of DC, effects on graft, and patient survival., Results: Of 1813 patients, 150 (8.3%) underwent DC during liver transplant, with 84 (56.0%) requiring a single additional operation for biliary reconstruction and abdominal closure and 57 (38.0%) requiring multiple additional operations. Compared with recipients without DC, patients requiring DC had greater Model for End-stage Liver Disease scores (33 vs 27; P < .001); more frequent pretransplant hospitalization (72.0% vs 47.9%; P < .001), intubation (33.3% vs 19.9%; P < .001), vasopressors (23.2% vs 10.9%; P < .001), renal replacement therapy (49.6% vs 30.3%; P < .001), and prior major abdominal operations (48.3% vs 21.9%; P < .001), including prior liver transplant (29.3% vs 8.9%; P < .001); greater operative transfusion requirements (37 vs 13 units of packed red blood cells; P < .001); worse intraoperative base deficit (10.3 vs 8.4; P = .03); more frequent postreperfusion syndrome (56.2% vs 27.3%; P < .001); and longer cold (430 vs 404 minutes; P = .04) and warm (46 vs 41 minutes; P < .001) ischemia times. Patients who underwent DC followed by a single additional operation for biliary reconstruction and abdominal closure had similar 1-, 3-, and 5-year graft survival (71%, 62%, and 62% vs 81%, 71%, and 67%; P = .26) and patient survival (72%, 64%, and 64% vs 84%, 75%, and 70%; P = .15) compared with recipients not requiring DC. Multivariate predictors of DC included prior liver transplant or major abdominal operation, longer pretransplant recipient and donor length of stay, greater Model for End-stage Liver Disease score, and longer warm and cold ischemia times (C statistic, 0.75)., Conclusions and Relevance: To our knowledge, this study represents the first large report of DC as a viable strategy for liver transplant recipients with coagulopathy or hemodynamic instability after allograft reperfusion. In DC recipients not requiring additional operations, outcomes are excellent and comparable to 1-stage liver transplant.

Hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide, is difficult to treat and highly lethal. Since HCC is predominantly diagnosed in patients with cirrhosis, treatment planning must consider both the severity of liver disease and tumor burden. To minimize the impact to the patient while treating the tumor, techniques have been developed to target HCC. Anatomical targeting by surgical resection or locoregional therapies is generally reserved for patients with preserved liver function and minimal to moderate tumor burden. Patients with decompensated cirrhosis and small tumors are optimal candidates for liver transplantation, which offers the best chance of long-term survival. Yet, only 20%-30% of patients have disease amenable to anatomical targeting. For the majority of patients with advanced HCC, chemotherapy is used to target the tumor biology. Despite these treatment options, the five-year survival of patients in the United States with HCC is only 16%. In this review we provide a comprehensive overview of current approaches to target HCC. We also discuss emerging diagnostic and prognostic biomarkers, novel therapeutic targets identified by recent genomic profiling studies, and potential applications of immunotherapy in the treatment of HCC.

In the last 30 years, operative, technical and medical advances have made liver transplantation (LT) a life-saving therapy that is used worldwide today. Global industrialization has been a contributor to morbid obesity and this has brought about the metabolic syndrome along with many downstream complications of such. Non-alcoholic steatohepatitis (NASH) has become a recognized hepatic manifestation of the metabolic syndrome and NASH cirrhosis is predicted to be the primary indication for LT in the United States by 2025. Several case series and database reviews have begun analyzing the efficacy of weight reduction surgery in the LT recipient. These data have reasonably demonstrated that weight reduction surgery in the LT recipient is a feasible endeavor. However, several questions have been raised regarding the type of weight reduction surgery, timing of surgery in relation to LT, patient and allograft survival and post-LT maintenance of weight loss to name a few. We look forward to a time when weight reduction surgery will work to improve the technical conduct of LT, improve perioperative benchmarks such as blood transfusions, intensive care unit length of stay and help to prevent recurrence of NASH cirrhosis in the medically complicated obese patient. In the meantime, well-designed prospective clinical trials that focus on the issues highlighted will help guide us in the care of these complicated patients who will soon account for the majority of the patients in our clinics.

Hepatic ischemia and reperfusion injury (IRI) is an inflammatory condition and a significant cause of morbidity and mortality after surgery. Matrix metalloproteinases (MMPs) have been widely implicated in the pathogenesis of inflammatory diseases. Among the different MMPs, gelatinases (MMP-2 and MMP-9) are within the most prominent MMPs detected during liver IRI. While the role of MMP-9 in liver damage has been fairly documented, direct evidence of the role for MMP-2 activity in hepatic IRI remains to be established. Due to the lack of suitable inhibitors to target individual MMPs in vivo, gene manipulation is as an essential tool to assess MMP direct contribution to liver injury. Hence, we used MMP-2-/- deficient mice and MMP-2+/+ wild-type littermates to examine the function of MMP-2 activity in hepatic IRI. MMP-2 expression was detected along the sinusoids of wild-type livers before and after surgery and in a small population of leukocytes post-IRI. Compared to MMP-2+/+ mice, MMP-2 null (MMP-2-/-) mice showed exacerbated liver damage at 6, 24, and 48 hours post-reperfusion, which was fatal in some cases. MMP-2 deficiency resulted in upregulation of MMP-9 activity, spontaneous leukocyte infiltration in naïve livers, and amplified MMP-9-dependent transmigration of leukocytes in vitro and after hepatic IRI. Moreover, complete loss of MMP-2 activity impaired the degradation of poly (ADP-ribose) polymerase (PARP-1) in extensively damaged livers post-reperfusion. However, the administration of a PARP-1 inhibitor to MMP-2 null mice restored liver preservation to almost comparable levels of MMP-2+/+ mice post-IRI. Deficient PARP-1 degradation in MMP-2-null sinusoidal endothelial cells correlated with their increased cytotoxicity, evaluated by the measurement of LDH efflux in the medium. In conclusion, our results show for the first time that MMP-2 gene deletion exacerbates liver IRI. Moreover, they offer new insights into the MMP-2 modulation of inflammatory responses, which could be relevant for the design of new pharmacological MMP-targeted agents to treat hepatic IRI.

Objectives: To evaluate the rate, effect, and predictive factors of a complete pathologic response (cPR) in patients with hepatocellular carcinoma (HCC) undergoing locoregional therapy (LRT) before liver transplantation (LT)., Background: Eligible patients with HCC receive equal model for end-stage liver disease prioritization, despite variable risks of tumor progression, waitlist dropout, and posttransplant recurrence. Pretransplant LRT mitigates these risks by inducing tumor necrosis., Methods: Comparisons were made among HCC recipients with cPR (n = 126) and without cPR (n = 375) receiving pre-LT LRT (1994-2013). Multivariable predictors of cPR were identified., Results: Of 501 patients, 272, 148, and 81 received 1, 2, and 3 or more LRT treatments. The overall, recurrence-free, and disease-specific survival at 1-, 3-, and 5 years was 86%, 71%, 63%; 84%, 67%, 60%; and 97%, 90%, 87%. Compared with recipients without cPR, cPR patients had significantly lower laboratory model for end-stage liver disease scores, pretransplant alpha fetoprotein, and cumulative tumor diameters; were more likely to have 1 lesion, tumors within Milan/University of California, San Francisco (UCSF) criteria, LRT that included ablation, and a favorable tumor response to LRT; and had superior 1-, 3-, and 5-year recurrence-free survival (92%, 79%, and 73% vs 81%, 63%, and 56%; P = 0.006) and disease-specific survival (100%, 100%, and 99% vs 96%, 89%, and 86%; P < 0.001) with only 1 cancer-specific death and fewer recurrences (2.4% vs 15.2%; P < 0.001). Multivariate predictors of cPR included a favorable post-LRT radiologic/alpha fetoprotein tumor response, longer time interval from LRT to LT, and lower model for end-stage liver disease score and maximum tumor diameter (C-statistic 0.75)., Conclusions: Achieving cPR in patients with HCC receiving LRT strongly predicts tumor-free survival. Factors predicting cPR are identified, allowing for differential prioritization of HCC recipients based on their variable risks of post-LT recurrence. Improving LRT strategies to maximize cPR would enhance posttransplant cancer outcomes.

Background: Fibrosing cholestatic hepatitis (FCH) is an uncommon but potentially fatal complication of recurrent hepatitis C (HCV) in liver transplant recipients., Methods: We matched the treatment outcomes of 10 liver transplant recipients who developed FCH with those of 10 recipients with recurrent HCV without FCH treated with sofosbuvir and ribavirin., Results: Baseline mean alanine transaminase, aspartate transaminase, alkaline phosphatase, and total bilirubin were 186 U/L, 197 U/L, 243 U/L, and 6.7 mg/dL, respectively, in the FCH recipients and 82 U/L, 60 U/L, 110 U/L, and 0.99 mg/dL, respectively, in non-FCH recipients. The sustained viral response in FCH and non-FCH recipients was 40% and 80%, respectively. One-yr patient and graft survival rates were 90% and 80%, respectively, in FCH recipients, and 100% in non-FCH recipients. Seven FCH and six non-FCH recipients were treated for anemia with blood transfusion and/or erythropoietin growth factors., Conclusion: Our results suggest that the use of sofosbuvir and ribavirin is effective and tolerable in liver transplant recipients treated for recurrent FCH. There is a trend of lower sustained viral response, patient survival, and graft survival in the FCH recipients., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The role of donor-specific HLA antibodies (DSA) after pediatric liver transplantation (LTx) is not clearly established. We completed a cross-sectional study to characterize DSA in long-term survivors of pediatric LTx and assess the impact of C1q-binding DSA on allograft outcomes., Methods: Serum samples were collected at routine clinic visits from 50 pediatric LTx recipients classified into 3 clinical phenotypes: nontolerant (n = 18) with de novo autoimmune hepatitis (DAIH) and/or late acute cellular rejection (ACR); stable (n = 25) on maintenance tacrolimus; operationally tolerant (n = 7). Samples were blinded, and antibody detection was performed using Luminex single antigen class I and II beads. Patients with positive DSA were tested for C1q-binding DSA., Results: DSA were detected in 54% (n = 27) of the patients, with the majority directed at HLA class II antigens (DR, 41%; DQ, 53%). Patients with DSA were younger at the time of LTx (P = 0.016) and time of study (P = 0.024). Mean aspartate aminotransferase, alanine aminotransferase, total bilirubin, and gamma glutamyl transferase were higher in DSA-positive patients, though did not reach statistical significance. Nontolerant patients were significantly more likely to have DQ DSA (61%) compared to stable (20%) and tolerant (29%) patients (P = 0.021). The nontolerant phenotype was associated with DSA and C1q-binding DSA, with odds ratios of 13 (P = 0.015) and 8.6 (P = 0.006), respectively. The presence of DQ DSA was associated with DAIH and late ACR, with odds ratios of 12.5 (P = 0.004) and 10.8 (P = 0.006), respectively., Conclusions: Allograft dysfunction is not always evident in patients with DSA, but DQ DSA are strongly associated with DAIH, late ACR, and chronic rejection., Competing Interests: : The authors of this manuscript have no conflicts of interest to disclose other than the funding sources included above.

Aim: To perform a systematic review and meta-analysis of the effectiveness and complications of BRTO for gastric varices., Materials and Methods: A systematic review was performed to identify relevant articles. Inclusion criteria were applied to select studies with at least ten patients with acute bleeding or at-risk gastric varices treated with BRTO. Meta-analysis with random effects model was performed to calculate data for immediate technical success, clinical success, and complications., Results: A total of 1,016 Patients from 24 studies met inclusion criteria. Technical success rate for BRTO was 96.4 % (95 % CI 93.7, 98.3 %; Q = 3,269.26, p < 0.01, I (2) = 99.39 %). Clinical success (defined as no recurrence or rebleed of gastric varices, or complete obliteration of varices on subsequent imaging) rate was 97.3 % (95 % CI 95.2, 98.8 %; Q = 3,105.91, p < 0.01, I (2) = 99.29 %). Major complication rate was 2.6 % (95 % CI 1.1, 4.6 %; Q = 3,348.98, p < 0.01, I (2) = 99.34 %). Esophageal variceal recurrence rate was 33.3 % (95 % CI 24.6, 42.6 %; Q = 7,291.75, p < 0.01, I (2) = 99.74 %)., Conclusion: BRTO is safe and efficacious for gastric varices, and current best evidence suggests that BRTO could be considered as therapy for patients with gastric varices.

Hepatocellular carcinoma (HCC) remains a common and lethal malignancy worldwide and arises in the setting of a host of diseases. The incidence continues to increase despite multiple vaccines and therapies for viruses such as the hepatitis B and C viruses. In addition, due to the growing incidence of obesity in Western society, there is anticipation that there will be a growing population with HCC due to non-alcoholic fatty liver disease. Due to the growing frequency of this disease, screening is recommended using ultrasound with further imaging using magnetic resonance imaging and multi-detector computed tomography used for further characterization of masses. Great advances have been made to help with the early diagnosis of small lesions leading to potential curative resection or transplantation. Resection and transplantation maybe used in a variety of patients that are carefully selected based on underlying liver disease. Using certain guidelines and clinical acumen patients may have good outcomes with either resection or transplantation however many patients are inoperable at time of presentation. Fortunately, the use of new locoregional therapies has made down staging patients a potential option making them potential surgical candidates. Despite a growing population with HCC, new advances in viral therapies, chemotherapeutics, and an expanding population of surgical and transplant candidates might all contribute to improved long-term survival of these patients.

Ischemia-reperfusion injury (IRI), an innate immunity-driven local inflammation, remains the major problem in clinical organ transplantation. T cell immunoglobulin and mucin domain (TIM-3)-Galectin-9 (Gal-9) signaling regulates CD4+ Th1 immune responses. Here, we explored TIM-3-Gal-9 function in a clinically relevant murine model of hepatic cold storage and orthotopic liver transplantation (OLT). C57BL/6 livers, preserved for 20 h at 4°C in UW solution, were transplanted to syngeneic mouse recipients. Up-regulation of TIM-3 on OLT-infiltrating activated CD4+ T cells was observed in the early IRI phase (1 h). By 6 h of reperfusion, OLTs in recipients treated with a blocking anti-TIM-3 Ab were characterized by: (1) enhanced hepatocellular damage (sALT levels, liver Suzuki's histological score); (2) polarized cell infiltrate towards Th1/Th17-type phenotype; (3) depressed T cell exhaustion markers (PD-1, LAG3); and (4) elevated neutrophil and macrophage infiltration/activation. In parallel studies, adoptive transfer of CD4+ T cells from naïve WT, but not from TIM-3 Tg donors, readily recreated OLT damage in otherwise IR-resistant RAG(-/-) test recipients. Furthermore, pre-treatment of mice with rGal-9 promoted hepatoprotection against preservation-association liver damage, accompanied by enhanced TIM-3 expression in OLTs. Thus, CD4+ T cell-dependent "negative" TIM-3 costimulation is essential for hepatic homeostasis and resistance against IR stress in OLTs., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Although radiologic size criteria (Milan/University of California, San Francisco [UCSF]) have led to improved outcomes after liver transplantation (LT) for hepatocellular carcinoma (HCC), recurrence remains a significant challenge. We analyzed our 30-year experience with LT for HCC to identify predictors of recurrence., Study Design: A novel clinicopathologic risk score and prognostic nomogram predicting post-transplant HCC recurrence was developed from a multivariate competing-risk Cox regression analysis of 865 LT recipients with HCC between 1984 and 2013., Results: Overall patient and recurrence-free survivals were 83%, 68%, 60% and 79%, 63%, and 56% at 1-, 3-, and 5-years, respectively. Hepatocellular carcinoma recurred in 117 recipients, with a median time to recurrence of 15 months, involving the lungs (59%), abdomen/pelvis (38%), liver (35%), bone (28%), pleura/mediastinum (12%), and brain (5%). Multivariate predictors of recurrence included tumor grade/differentiation (G4/poor diff hazard ratio [HR] 8.86; G2-3/mod-poor diff HR 2.56), macrovascular (HR 7.82) and microvascular (HR 2.42) invasion, nondownstaged tumors outside Milan criteria (HR 3.02), nonincidental tumors with radiographic maximum diameter ≥ 5 cm (HR 2.71) and <5 cm (HR 1.55), and pretransplant neutrophil-to-lymphocyte ratio (HR 1.77 per log unit), maximum alpha fetoprotein (HR 1.21 per log unit), and total cholesterol (HR 1.14 per SD). A pretransplantation model incorporating only known radiographic and laboratory parameters had improved accuracy in predicting HCC recurrence (C statistic 0.79) compared with both Milan (C statistic 0.64) and UCSF (C statistic 0.64) criteria alone. A novel clinicopathologic prognostic nomogram included explant pathology and had an excellent ability to predict post-transplant recurrence (C statistic 0.85)., Conclusions: In the largest single-institution experience with LT for HCC, excellent long-term survival was achieved. Incorporation of routine pretransplantation biomarkers to existing radiographic size criteria significantly improves the ability to predict post-transplant recurrence, and should be considered in recipient selection. A novel clinicopathologic prognostic nomogram accurately predicts HCC recurrence after LT and may guide frequency of post-transplantation surveillance and adjuvant therapy., (Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Transabdominal intrapericardial control of the suprahepatic inferior vena cava (SIVC) is a rather uncommon procedure occasionally required in conjunction with complicated liver transplantation (LT) and hepatobiliary surgery. Experience with this technique is limited. Here we report 6 cases of LT in which transabdominal intrapericardial control of the SIVC was necessary. After institutional review board approval was obtained, a single-center, retrospective review was conducted from January 1991 to December 2013 to identify adult cases (age > 18 years) of LT in which transabdominal intrapericardial isolation of the SIVC was necessary. Among 4102 adult LT cases in the study period, 6 such cases were identified. To gain access to the pericardial space, a 6- to 9-cm vertical incision was made above the SIVC. After reperfusion, the diaphragmatic incision was partially closed and selectively drained. Pericardial tamponade developed in 1 patient, and it necessitated emergent reoperation and widespread drainage. In conclusion, transabdominal intrapericardial isolation of the SIVC is easily achieved without the need for a separate thoracic incision. However, to be effective, the pericardial incision should be only partially closed, and the pericardial sac should be drained liberally. Such patients should be carefully monitored for signs and symptoms of pericardial tamponade, the development of which should prompt an immediate return to the operating room for emergent decompression and widespread drainage., (© 2015 American Association for the Study of Liver Diseases.)

Background & Aims: By binding to T cell immunoglobulin mucin-3 (TIM-3) on activated Th1 cells, galectin-9 (Gal-9) negatively regulates Th1-type alloimmunity. Although T cells contribute to hepatic ischemia-reperfusion injury (IRI), it is unknown whether negative T cell-dependent TIM-3 co-stimulation may rescue IR-stressed orthotopic liver transplants from innate immunity-driven inflammation., Methods: We used wild type (WT) and TIM-3 transgenic (Tg) mice (C57BL/6) as liver donors and recipients in a clinically-relevant model of hepatic cold storage (20 h at 4°C in UW solution) and syngeneic orthotopic liver transplantation (OLT)., Results: Orthotopic liver transplants in WT or TIM-3Tg→TIM-3Tg groups were resistant against IR-stress, evidenced by preserved hepatocellular function (serum ALT levels) and liver architecture (Suzuki's score). In contrast, orthotopic liver transplants in WT or TIM-3Tg→WT groups were susceptible to IRI. TIM-3 induction in circulating CD4+ T cells of the recipient: (1) depressed T-bet/IFN-γ, while amplifying GATA3 and IL-4/IL-10 expression in orthotopic liver transplants; (2) promoted T cell exhaustion (PD-1, LAG-3) phenotype; and (3) depressed neutrophil and macrophage infiltration/function in orthotopic liver transplants. In parallel studies, we documented for the first time that Gal-9, a natural TIM-3 ligand, was produced primarily by and released from IR-stressed hepatocytes, both in vivo and in vitro. Moreover, exogenous recombinant Gal-9 (rGal-9) potentiated liver resistance against IRI by depressing T cell activation and promoting apoptosis of CD4+ T cells., Conclusions: Harnessing TIM-3/Gal-9 signalling at the T cell-hepatocyte interface facilitates homeostasis in IR-stressed orthotopic liver transplants. Enhancing anti-oxidant hepatocyte Gal-9 potentiates liver IR-resistance. Negative regulation by recipient TIM-3+CD4+ cells provides evidence for cytoprotective functions of a discrete T cell subset, which should be spared when applying T cell-targeted immunosuppression in transplant recipients., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Importance: The field of transplantation has made tremendous progress since the first successful kidney transplant in 1954., Objective: To determine the survival benefit of solid-organ transplant as recorded during a 25-year study period in the United Network for Organ Sharing (UNOS) database and the Social Security Administration Death Master File., Design, Setting, and Participants: In this retrospective analysis of UNOS data for solid-organ transplant during a 25-year period (September 1, 1987, through December 31, 2012), we reviewed the records of 1,112,835 patients: 533,329 recipients who underwent a transplant and 579 506 patients who were placed on the waiting list but did not undergo a transplant., Main Outcomes and Measures: The primary outcome was patient death while on the waiting list or after transplant. Kaplan-Meier survival functions were used for time-to-event analysis., Results: We found that 2,270,859 life-years (2,150,200 life-years from the matched analysis) were saved to date during the 25 years of solid-organ transplant. A mean of 4.3 life-years were saved (observed to date) per solid-organ transplant recipient. Kidney transplant saved 1,372,969 life-years; liver transplant, 465,296 life-years; heart transplant, 269,715 life-years; lung transplant, 64,575 life-years; pancreas-kidney transplant, 79,198 life-years; pancreas transplant, 14,903 life-years; and intestine transplant, 4402 life-years., Conclusions and Relevance: Our analysis demonstrated that more than 2 million life-years were saved to date by solid-organ transplants during a 25-year study period. Transplants should be supported and organ donation encouraged.

Postoperative atrial fibrillation (POAF) is common after major surgeries and is associated with increased morbidity and mortality. POAF after liver transplantation (LT) has not been reported. This study was undertaken to investigate the incidence, impact, and risk factors of POAF in LT patients. After IRB approval, LT between January 2006 and August 2013 at our center were retrospectively reviewed. POAF that occurred within 30 days after LT was included. Patients with and without POAF were compared and independent risk factors were identified by logistic regression. Of 1387 adults LT patients, 102 (7.4%) developed POAF during the study period. POAF was associated with significantly increased mortality, graft failure, acute kidney injury and prolonged hospital stay. Independent risk factors included age, body weight, MELD score, presence of previous history of AF, the vasopressors use prior to LT and pulmonary artery diastolic pressure at the end of LT surgery (odds ratios 2.0-7.2, all p < 0.05). A risk index of POAF was developed and patients with the high-risk index had more than 60% chance of developing POAF. These findings may be used to stratify patients and to guide prophylaxis for POAF in the posttransplant period., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Importance: Autologous islet transplantation is an elegant and effective method for preserving euglycemia in patients undergoing near-total or total pancreatectomy for severe chronic pancreatitis. However, few centers worldwide perform this complex procedure, which requires interdisciplinary coordination and access to a sophisticated Food and Drug Administration-licensed islet-isolating facility., Objective: To investigate outcomes from a single institutional case series of near-total or total pancreatectomy and autologous islet transplantation using remote islet isolation., Design, Setting, and Participants: Retrospective cohort study between March 1, 2007, and December 31, 2013, at tertiary academic referral centers among 9 patients (age range, 13-47 years) with chronic pancreatitis and reduced quality of life after failed medical management., Interventions: Pancreas resection, followed by transport to a remote facility for islet isolation using a modified Ricordi technique, with immediate transplantation via portal vein infusion., Main Outcomes and Measures: Islet yield, pain assessment, insulin requirement, costs, and transport time., Results: Eight of nine patients had successful islet isolation after near-total or total pancreatectomy. Four of six patients with total pancreatectomy had islet yields exceeding 5000 islet equivalents per kilogram of body weight. At 2 months after surgery, all 9 patients had significantly reduced pain or were pain free. Of these patients, 2 did not require insulin, and 1 required low doses. The mean transport cost was $16,527, and the mean transport time was 3½ hours., Conclusions and Relevance: Pancreatic resection with autologous islet transplantation for severe chronic pancreatitis is a safe and effective final alternative to ameliorate debilitating pain and to help prevent the development of surgical diabetes. Because many centers lack access to an islet-isolating facility, we describe our experience using a regional 2-center collaboration as a successful model to remotely isolate cells, with outcomes similar to those of larger case series.

Background: There has been increasing interest in using protease inhibitors with pegylated interferon and ribavirin to treat recurrent hepatitis C (HCV) disease in liver transplant recipients., Methods: We retrospectively evaluated the safety and efficacy in liver transplant recipients treated for recurrent hepatitis C genotype 1 with the combination of peginterferon, ribavirin and boceprevir., Results: Twenty liver transplant recipients were treated for recurrent hepatitis C. Baseline alanine aminotransferase, total bilirubin and HCV RNA values (± SD) were 67.5 (±50.9) mg/dl, 1.78 (±1.99) U/L, and 16 955 510 (±21 620 675) IU/ml. Anaemia was a common adverse event requiring epoetin in 16 of 20 recipients and ribavirin dose reductions in 17 of 20 recipients. One-third of recipients required a blood transfusion. Filgrastim was used in 11 of 20 patients (55%) and eltrombopag in two of 20 recipients (10%) over the course of treatment. Serum creatinine level increased significantly from a baseline value of 1.33 mg/dl to 1.59 mg/dl at week 20 of boceprevir (P < 0.005). The overall sustained viral response (SVR) was 50%. Of the 14 patients who had a viral load less than 1000 IU/ml at week 4 of boceprevir, the SVR was 71%. The SVR was 83% of the 11 patients who had undetectable viral levels at week 4 of boceprevir., Conclusions: Antiviral therapy utilizing boceprevir in liver transplant recipients requires close monitoring. Anaemia and neutropenia were common requiring growth factors in most recipients. On-treatment viral responses appear promising but long-term data are needed., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Although rapamycin (RPM) have been studied extensively in ischemia models, its functional mechanisms remains to be defined., Methods: We determined how RPM impacted the pathogenesis of ischemia-reperfusion injury (IRI) in a murine liver partial warm ischemia model, with emphasis on its regulation of hepatocyte death., Results: Rapamycin protected livers from IRI in the presence of fully developed liver inflammatory immune response. Rapamycin enhanced liver autophagy induction at the reperfusion stage. Dual mammalian (mechanistic) target of rapamycin (mTOR)1/2 inhibitor Torin 1, despite its ability to induced autophagy, failed to protect livers from IRI. The treatment with RPM, but not Torin 1, resulted in the enhanced activation of the mTORC2-Akt signaling pathway activation in livers after reperfusion. Inactivation of Akt by Triciribine abolished the liver protective effect of RPM. The differential cytoprotective effect of RPM and Torin 1 was confirmed in vitro in hepatocyte cultures. Rapamycin, but not Trin 1, protected hepatocytes from stress and tumor necrosis factor-α induced cell death; and inhibition of autophagy by chloroquine or Akt by Triciribine abolished RPM-mediated cytoprotection., Conclusion: Rapamycin protected livers from IRI by both autophagy and mTORC2-Akt activation mechanisms.

Introduction: The use of direct-acting antiviral (DAA) agents against chronic hepatitis C virus (HCV) infections can result in the successful treatment of nearly all patients. Effective antiviral treatments can prevent the progression to cirrhosis and hepatocellular malignancy, and decrease liver-related morbidity and mortality., Areas Covered: Paritaprevir-ritonavir-ombitasvir and dasabuvir (PrOD), with or without ribavirin, is an all-oral regimen approved for the treatment of HCV genotype 1 infections, including patients with compensated cirrhosis. Phase 2 and 3 clinical trials demonstrated the safety and efficacy of this regimen in HCV genotype 1-infected patients who are treatment-naïve and those who have failed peginterferon/ribavirin therapy. Additional studies evaluated the use of PrOD with or without ribavirin among special populations, including patients co-infected with human immunodeficiency virus-1 and HCV, liver transplant recipients with HCV recurrence, and patients with severe renal impairment. Additionally, the combination of paritaprevir-ritonavir-ombitasvir plus ribavirin is found to be highly efficacious, and is now approved in the US, for the treatment of HCV genotype 4 infections., Expert Opinion: The availability and use of interferon-free DAA combination regimens has resulted in a major paradigm shift in the treatment of HCV. PrOD, with or without ribavirin, is an effective, safe and tolerable treatment option.

Objective: To investigate major gastroesophageal and hemorrhagic complications that may be related to intraoperative transesophageal echocardiography (TEE) in liver transplant (LT) patients with high model for end-stage liver disease (MELD) score 25 or higher., Design: Retrospective., Setting: Single institution university setting., Participants: Of 906 transplant recipients, 656 who had MELD score 25 or higher were included for analysis., Interventions: Patient demographics, pre- and intraoperative characteristics, and major gastroesophageal and hemorrhagic complications were compared between patients with and without TEE., Measurements and Main Results: Sixty-six percent (433 patients) had intraoperative TEE and 34% (223 patients) did not. One patient in the TEE group had a major gastroesophageal complication (Mallory-Weiss tear). Eleven patients required postoperative gastrointestinal consultation. These patients were distributed evenly between the TEE and non-TEE groups. Eighteen (2.8%) had major hemorrhagic complication (defined as bloody nasogastric output>500 mL in 24 hours postoperatively). Multivariate analysis showed alcoholic cirrhosis had 5.3 higher odds of post-transplant gastroesophageal hemorrhage compared with other indications for transplant (95% confidence interval 1.8-15.8, p<0.001). TEE was not associated with an increased likelihood of major hemorrhagic complication after LT., Conclusions: The authors demonstrated that the incidence of major gastroesophageal and hemorrhagic complications following intraoperative TEE in LT patients with MELD score 25 or higher was low., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Invasive fungal infections (IFIs) are a common complication in liver transplant recipients. There are no previous randomized trials of an echinocandin for the prevention of IFIs in solid organ transplant recipients. In a randomized, double-blind trial conducted at University-affiliated transplant centers, 200 high-risk liver transplant recipients (100 patients per group) received either anidulafungin or fluconazole for antifungal prophylaxis. Randomization was stratified by Model for End-Stage Liver Disease score ≥30 and receipt of a pretransplant antifungal agent. The primary end point was IFI in a modified intent-to-treat analysis. The overall incidence of IFI was similar for the anidulafungin (5.1%) and the fluconazole groups (8.0%) (OR 0.61, 95% CI 0.19-1.94, p = 0.40). However, anidulafungin prophylaxis was associated with less Aspergillus colonization or infection (3% vs. 9%, p = 0.08), lower breakthrough IFIs among patients who had received pretransplant fluconazole (0% vs. 27%, p = 0.07), and fewer cases of antifungal resistance (no cases vs. 5 cases). Both drugs were well-tolerated. Graft rejection, fungal-free survival, and mortality were similar for both groups. Thus, anidulafungin and fluconazole have similar efficacy for antifungal prophylaxis in most liver transplant recipients. Anidulafungin may be beneficial if the patient has an increased risk for Aspergillus infection or received fluconazole before transplantation., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Unlabelled: Hepatic ischemia-reperfusion injury (IRI), an innate immunity-driven inflammation response, occurs in multiple clinical settings including liver resection, transplantation, trauma, and shock. T-cell immunoglobulin and mucin (TIM)-4, the only TIM protein not expressed on T cells, is found on macrophages and dendritic cells. The regulatory function of macrophage TIM-4 in the engulfment of apoptotic/necrotic bodies in innate immunity-mediated disease states remains unknown. This study focuses on the putative role of TIM-4 signaling in a model of liver warm ischemia (90 minutes) and reperfusion. The ischemia insult triggered TIM-4 expression by stressed hepatocellular phosphatidylserine (PS) presentation, peaking at 6 hours of reperfusion, and coinciding with the maximal hepatocellular damage. TIM-4-deficient or wild-type WT mice treated with antagonistic TIM-4 monoclonal antibody (mAb) were resistant against liver IRI, evidenced by diminished serum alanine aminotransferase (sALT) levels and well-preserved hepatic architecture. Liver hepatoprotection rendered by TIM-4 deficiency was accompanied by diminished macrophage infiltration/chemoattraction, phagocytosis, and activation of Toll-like receptor (TLR)2/4/9-dependent signaling. Correlating with in vivo kinetics, the peak of TIM-4 induction in lipopolysaccharide (LPS)-activated bone marrow derived-macrophages (BMM) was detected in 6-hour cultures. To mimic liver IRI, we employed hydrogen peroxide-necrotic hepatocytes, which readily present PS. Indeed, necrotic hepatocytes were efficiently captured/engulfed by WT (TIM-4+) but not by TIM-4-deficient BMM. Finally, in a newly established model of liver IRI, adoptive transfer of WT but not TIM-4-deficient BMM readily recreated local inflammation response/hepatocellular damage in the CD11b-DTR mouse system., Conclusion: These findings document the importance of macrophage-specific TIM-4 activation in the mechanism of hepatic IRI. Macrophage TIM-4 may represent a therapeutic target to minimize innate inflammatory responses in IR-stressed organs., (© 2014 by the American Association for the Study of Liver Diseases.)

Background: Data on complications requiring reoperation after orthotopic liver transplantation (OLT) are limited. We sought to describe the spectrum of reoperative complications after OLT, evaluate the associations with graft and patient survival, and identify predictors of need for reoperation., Study Design: We retrospectively studied adult patients who underwent primary OLT at our institution from February 2002 to July 2012. The primary outcomes included occurrence of a reoperative complication. Secondary outcomes were graft and patient survival. Multivariable logistic regression analysis was used to model the associations of recipient, donor, and operative variables with reoperation., Results: Of 1,620 patients, 470 (29%) had complications requiring reoperation. The most common reoperative complication was bleeding (17.3%). Compared with patients not requiring reoperation, patients with reoperative complications had greater Model for End-Stage Liver Disease scores and need for pretransplantation hospitalization, mechanical ventilation, vasopressors, and renal replacement therapy; considerably longer cold and warm ischemia times and greater intraoperative blood transfusion requirements; and substantially worse 1-, 3-, and 5-year graft and patient survival rates. In multivariable analysis, predictors of reoperative complications included intraoperative transfusion of packed RBCs (odds ratio [OR] = 2.21; 95% CI, 1.91-2.56), donor length of hospitalization >8 days (OR = 1.87; 95% CI, 1.28-2.73), recipient pretransplantation mechanical ventilation (OR = 1.65; 95% CI, 1.21-2.24), cold ischemia time >9 hours (OR = 1.63; 95% CI, 1.23-2.17), warm ischemia time >55 minutes (OR = 1.58; 95% CI, 1.02-2.44), earlier major abdominal surgery (OR = 1.41; 95% CI, 1.03-1.92), and elevated donor serum sodium (OR = 1.17; 95% CI, 1.03-1.31)., Conclusions: Patients who require reoperation for complications after OLT have high pretransplantation acuity and inferior post-transplantation survival. We identified factors associated with reoperative complications to guide perioperative donor-recipient matching and improve outcomes., (Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant host defense, maintains the cellular redox homeostasis., Methods: This study was designed to investigate the role and molecular mechanisms by which Nrf2 regulates toll-like receptor (TLR)4-driven inflammation response in a mouse model of hepatic warm ischemia (90 min) and reperfusion (6 hr) injury (IRI)., Results: Activation of Nrf2 after preconditioning of wild-type mouse recipients with cobalt protoporphyrin ameliorated liver IRI, evidenced by improved hepatocellular function (serum alanine aminotransferase levels), and preserved tissue architecture (histology Suzuki's score). In marked contrast, ablation of Nrf2 signaling exacerbated IR-induced liver inflammation and damage in Nrf2 knockout hosts irrespective of adjunctive cobalt protoporphyrin treatment. The Nrf2 activation reduced macrophage and neutrophil trafficking, proinflammatory cytokine programs, and hepatocellular necrosis or apoptosis while increasing antiapoptotic functions in IR-stressed livers. At the molecular level, Nrf2 activation augmented heme oxygenase-1 expression and Stat3 phosphorylation and promoted PI3K-Akt while suppressing forkhead box O (Foxo)1 signaling. In contrast, Nrf2 deficiency diminished PI3K-Akt and enhanced Foxo1 expression in the ischemic livers. In parallel in vitro studies, Nrf2 knockdown in lipopolysaccharide-stimulated bone marrow-stimulated bone marrow-derived macrophages (BMMs) decreased heme oxygenase-1 and PI3K-Akt yet increased Foxo1 transcription, leading to enhanced expression of TLR4 proinflammatory mediators. Moreover, pretreatment of bone marrow-derived macrophages with PI3K inhibitor (LY294002) activated Foxo1 signaling, which in turn enhanced TLR4-driven innate responses in vitro., Conclusion: Activation of Nrf2 promoted PI3K-Akt, and inhibited Foxo1 activity in IR-triggered local inflammation response. By identifying a novel integrated Nrf2-Akt-Foxo1 signaling network in PI3K-dependent regulation of TLR4-driven innate immune activation, this study provides the rationale for refined therapeutic approaches to manage liver inflammation and IRI in transplant recipients.

Macrophages are instrumental in the pathophysiology of liver ischemia/reperfusion injury (IRI). Although Nrf2 regulates macrophage-specific heme oxygenase-1 (HO-1) antioxidant defense, it remains unknown whether HO-1 induction might rescue macrophage Nrf2-dependent antiinflammatory functions. This study explores the mechanisms by which the Nrf2-HO-1 axis regulates sterile hepatic inflammation responses after adoptive transfer of ex vivo modified HO-1 overexpressing bone marrow-derived macrophages (BMMs). Livers in Nrf2-deficient mice preconditioned with Ad-HO-1 BMMs, but not Ad-β-Gal-BMMs, ameliorated liver IRI (at 6 h of reperfusion after 90 min of warm ischemia), evidenced by improved hepatocellular function (serum alanine aminotransferase [sALT] levels) and preserved hepatic architecture (Suzuki histological score). Treatment with Ad-HO-1 BMMs decreased neutrophil accumulation, proinflammatory mediators and hepatocellular necrosis/apoptosis in ischemic livers. Moreover, Ad-HO-1 transfection of Nrf2-deficient BMMs suppressed M1 (Nos2(+)) while promoting the M2 (Mrc-1/Arg-1(+)) phenotype. Unlike in controls, Ad-HO-1 BMMs increased the expression of Notch1, Hes1, phosphorylation of Stat3 and Akt in IR-stressed Nrf2-deficient livers as well as in lipopolysaccharide (LPS)-stimulated BMMs. Thus, adoptive transfer of ex vivo generated Ad-HO-1 BMMs rescued Nrf2-dependent antiinflammatory phenotype by promoting Notch1/Hes1/Stat3 signaling and reprogramming macrophages toward the M2 phenotype. These findings provide the rationale for a novel clinically attractive strategy to manage IR liver inflammation/damage.

Background: Although it is the only curative treatment for polycystic liver disease (PLD), orthotopic liver transplantation (OLT) has been reserved for severely symptomatic, malnourished, or refractory patients who are not candidates for palliative disease-directed interventions (DDI). Data on the effect of previous DDIs on post-transplant morbidity and mortality are scarce. We analyzed the outcomes after OLT for PLD recipients, and determined the effects of previous palliative surgical intervention on post-transplantation morbidity and mortality., Study Design: We performed a retrospective analysis of factors affecting perioperative outcomes after OLT for PLD between 1992 and 2013, including comparisons of recipients with previous major open DDIs (Open DDI, n = 12) with recipients with minimally invasive or no previous DDIs (minimal DDI, n = 16)., Results: Over the 20-year period, 28 recipients underwent OLT for PLD, with overall 30-day, 1-, and 5-year graft and patient survivals of 96%, 89%, 75%, and 96%, 93%, 79%, respectively. Compared with the minimal DDI group, open DDI recipients accounted for all 5 deaths, had inferior 90-day and 1- and 5-year survivals (83%, 83%, and 48% vs 100%, 100%, 100%; p = 0.009), and greater intraoperative (42% vs 0%; p = 0.003), total (58% vs 19%; p = 0.031), and Clavien grade IV or greater (50% vs 6%; p = 0.007) postoperative complications, more unplanned reoperations (50% vs 13%; p = 0.003), and longer total hospital (27 days vs 17 days; p = 0.035) and ICU (10 days vs 4 days; p = 0.045) stays., Conclusions: In one of the largest single-institution experiences of OLT for PLD, we report excellent long-term graft and patient survival. Previous open DDIs are associated with increased risks of perioperative morbidity and mortality. Improved identification of PLD patients bound for OLT may mitigate perioperative complications and potentially improve post-transplantation outcomes., (Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Donation after cardiac death (DCD) is an important source for expanding the donor pool for liver transplantation (LT). Although the long-term outcomes of LT using DCD grafts have been extensively studied, perioperative complications related to DCD grafts are rarely reported. The aim of this study was to determine whether DCD grafts were associated with a higher incidence of postreperfusion complications and worse outcomes in adult LT patients. After institutional review board approval, the medical records of all adult patients who underwent LT at our medical center between 2004 and 2011 were reviewed. Postreperfusion complications and posttransplant outcomes were compared between patients receiving DCD grafts and patients receiving donation after brain death (DBD) grafts. In all, 74 patients received DCD grafts during the study period, and 1369 patients received DBD grafts. An initial comparison showed that many preoperative, prereperfusion, and donor variables in the DCD group differed significantly from those in the DBD group. Propensity matching was chosen so that adjustments could be made for the differences. A postmatching analysis showed that the preoperative, prereperfusion, and donor variables no longer differed between the 2 groups. The postreperfusion requirements for blood products and vasopressors, the posttransplant ventilation times, the incidence of posttransplant acute renal injury, and the 30-day and 1-year patient and graft survival rates were comparable between the 2 groups. However, patients receiving DCD grafts experienced significantly higher rates of hyperkalemia (33.8% versus 18.9%, P < 0.05) and postreperfusion syndrome (PRS; 25.7% versus 12.3%, P < 0.05). In conclusion, after adjustments for preoperative and prereperfusion risks via propensity matching, DCD grafts remained a risk factor for postreperfusion hyperkalemia and PRS. A prophylactic regimen aimed at decreasing postreperfusion hyperkalemia and PRS is recommended for the management of LT using DCD grafts., (© 2014 American Association for the Study of Liver Diseases.)

Objective: To identify medical predictors of futility in recipients with laboratory Model of End-Stage Liver Disease (MELD) scores of 40 or more at the time of orthotopic liver transplantation (OLT)., Background: Although the survival benefit for transplant patients with the highest MELD scores is indisputable, the medical and economic effort to bring these highest acuity recipients through OLT presents a major challenge for every transplant center., Methods: This study was undertaken to analyze outcomes in patients with MELD scores of 40 or more undergoing OLT during the period February 2002 to December 2010. The analysis was focused on futile outcome (3-month or in-hospital mortality) and long-term posttransplant outcome. Independent predictors of futility and failure-free survival were identified and a futility risk model was created., Results: During the study period, 1522 adult cadaveric OLTs were performed, and 169 patients (13%) had a MELD score of 40 or more. The overall 1, 3, 5, and 8-year patient survivals were 72%, 64%, 60%, and 56%. Futile outcome occurred in 37 patients (22%). MELD score, pretransplant septic shock, cardiac risk, and comorbidities were independent predictors of futile outcome. Using all 4 factors, the futility risk model had a good discriminatory ability (c-statistic 0.75). Recipient age per year, life-threatening postoperative complications, hepatitis C, and metabolic syndrome were independent predictors for long-term survival in nonfutile patients (Harrels c-statistic 0.72)., Conclusions: Short- and long-term outcomes of recipients with MELD scores of 40 or more are primarily determined by disease-specific factors. Cardiac risk, pretransplant septic shock, and comorbidities are the most important predictors and can be used for risk stratification in these highest acuity recipients.

Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in regulating cell proliferation is well established, its function in immune responses remains to be fully appreciated. In the current study, we analyzed myeloid-specific PTEN function in regulating tissue inflammatory immune response in a murine liver partial warm ischemia model. Myeloid-specific PTEN knockout (KO) resulted in liver protection from ischemia reperfusion injury (IRI) by deviating the local innate immune response against ischemia reperfusion toward the regulatory type: expression of proinflammatory genes was selectively decreased and anti-inflammatory IL-10 was simultaneously increased in ischemia reperfusion livers of PTEN KO mice compared with those of wild-type (WT) mice. PI3K inhibitor and IL-10-neutralizing Abs, but not exogenous LPS, recreated liver IRI in these KO mice. At the cellular level, Kupffer cells and peritoneal macrophages isolated from KO mice expressed higher levels of M2 markers and produced lower TNF-α and higher IL-10 in response to TLR ligands than did their WT counterparts. They had enhanced Stat3- and Stat6-signaling pathway activation, but diminished Stat1-signaling pathway activation, in response to TLR4 stimulation. Inactivation of Kupffer cells by gadolinium chloride enhanced proinflammatory immune activation and increased IRI in livers of myeloid PTEN KO mice. Thus, myeloid PTEN deficiency protects livers from IRI by facilitating M2 macrophage differentiation., (Copyright © 2014 by The American Association of Immunologists, Inc.)