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Glycogen phosphorylase (GP) is the rate-determining enzyme in glycogenolysis, and its druggability has been extensively studied over the years for the development of therapeutics against type 2 diabetes (T2D) and, more recently, cancer. However, the conservation of binding sites between the liver and muscle isoforms makes the inhibitor selectivity challenging. Using a combination of kinetic, crystallographic, modeling, and cellular studies, we have probed the binding of dietary flavonoids epigallocatechin gallate (EGCG) and epigallocatechin (EGC) to GP isoforms. The structures of rmGPb-EGCG and rmGPb-EGC complexes were determined by X-ray crystallography, showing binding at the quercetin binding site (QBS) in agreement with kinetic studies that revealed both compounds as noncompetitive inhibitors of GP, with EGCG also causing a significant reduction in cell viability and migration of U87-MG glioblastoma cells. Interestingly, EGCG exhibits different binding modes to GP isoforms, revealing QBS as a promising site for GP targeting, offering new opportunities for the design of liver-selective GP inhibitors.

Background & Aims: Sarcopenia has significant burden in cirrhosis and has been shown to worsen short-term post-liver transplantation (LT). This study aims to evaluate the long-term change in sarcopenia post-LT along with its associations and predictors., Methods: A retrospective study of adult patients who underwent LT at a tertiary centre between 1/1/2009 and 12/31/2018. Relevant demographic and clinical data were collected. Skeletal muscle index (SMI) was calculated using standard of care computerised tomography (CT) scans pre- and post-LT. Sarcopenia was defined using previously established cut-points. The primary outcome was SMI change post-LT and secondary outcome was post-LT mortality., Results: Out of 1165 patients, 401 met inclusion criteria (1,205 CT scans reviewed). The average age at transplant was 57 years; 63% were male. The average BMI was 28 kg/m 2 . Thirteen percent of females and 32% of males had sarcopenia pre-LT. Post-LT SMI declined by 4.7 cm 2 /m 2 in the first year then by 0.39 cm 2 /m 2 per year thereafter. Females had greater rate of decline in SMI after the first year compared with males (0.87 cm 2 /m 2 per year vs. 0.17 cm 2 /m 2 per year, respectively, p  = 0.02). Post-LT physical rehabilitation, infection, and readmissions were not associated with SMI trajectory. At 3 years post-LT, 31% of females and 48% of males had sarcopenia. Baseline sarcopenia was the only predictor of long-term post-LT sarcopenia on multivariable analysis, but it was not associated with mortality., Conclusions: Sarcopenia does not appear to resolve post-LT and likely worsens leading to nearly doubling its prevalence in those with long-term follow-up. Immediate post-LT physical rehabilitation was not associated with SMI trajectory in our cohort., Impact and Implications: The prevalence of sarcopenia is high among patients with cirrhosis; however, data are mixed on the impact of sarcopenia on post-liver transplant (LT) course and there have been no studies evaluating the long-term evolution of sarcopenia post-LT beyond 1 year. In this study, we analysed changes in muscle mass up to 3 years after transplant in 401 patients and found that sarcopenia did not resolve in most liver transplant recipients and skeletal muscle mass tended to worsen after transplant with the greatest decline in muscle mass in the first year post-LT. Interestingly, sarcopenia did not influence post-transplant outcomes. Future prospective studies are needed to further understand the natural course of sarcopenia post-LT to guide interventions aiming at reversing post-LT sarcopenia., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Purpose: To evaluate whether same-day discharge increased the incidence of 30-day readmission (30dR) after conventional transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) at a single institution., Materials and Methods: In this retrospective study, 253 patients with HCC underwent 521 transarterial chemoembolization procedures between 2013 and 2020. TACE was performed with 50-mg doxorubicin/10-mg mitomycin C/5-10-mL ethiodized oil/particles. Patients not requiring intravenous pain medications were discharged after a 3-hour observation, and 30dR was tracked. The primary objective was to determine the incidence of 30dR in same-day discharge patients versus patients admitted for observation using the chi-square test. Secondary objectives assessed factors associated with overnight admission and factors predictive of 30dR using generalized estimated equation calculations and logistic regression., Results: In the cohort, 24 readmissions occurred within 30 days (4.6%). Same-day discharge was completed after 331 TACE procedures with sixteen 30dRs (4.8%). Patients admitted overnight were readmitted 8 times after 190 TACE procedures (4.2%). This difference was not statistically significant (P = .4). Factors predicting overnight admission included female sex (58/190 [30.5%] vs 58/331 [17.5%], P < .001) and tumor size of ≥3.8 cm (104/190 [55%] vs 85/190 [45%]). Factors predicting 30dR included female sex (10/116 [8.6%] vs 14/405 [0.2%]) and younger age (median [interquartile range], 63 years [55-65 years] vs 65 years [59-71 years]). At regression, factors predictive of 30dR were Child-Pugh Class B/C (odds ratio [OR], 2.1; P = .04) and female sex (OR, 2.9; P = .004)., Conclusions: Same-day discharge after conventional TACE is a safe and effective strategy with 30dR rate of <5%, similar to overnight observation., (Copyright © 2022 SIR. Published by Elsevier Inc. All rights reserved.)

Background: Severe renal dysfunction is common among liver transplant (LT) candidates and often prompts simultaneous liver-kidney transplantation (SLKT) consideration. In view of 2017 United Network of Organ Sharing (UNOS) criteria for SLKT, we investigated the likelihood and predictors of renal recovery among patients who met the aforementioned criteria yet received liver transplant alone (LTA)., Methods: We retrospectively analyzed relative renal recovery (RRR; increase in eGFR to >30 ml/min) in adult LTA recipients between 1/2009 and 1/2019., Results: Of 1165 LT recipients, 54 met 2017 UNOS criteria, with 37 receiving LTA. RRR occurred in 84% of LTA recipients, none of whom had pre-LT eGFR <20 ml/min. Sustained RRR (>180 days) occurred in 43% of patients. While prolonged pre-LT severe renal impairment (eGFR <30 ml/min) predicted failure to have sustained RRR (HR .19 per 90-day, CI .04-.87, p < .005), having an eGFR measurement of >30 ml/min within 90 days pre-LT (HR 5.52, CI 1.23-24.79, p .01) associated with achieving sustained RRR. Sustained RRR was protective against the composite outcome of renal replacement therapy, kidney transplant, and death (HR .21, p .01)., Conclusion: LT candidates who meet 2017 UNOS criteria for SLKT yet undergo LTA can still have relative renal recovery post-LT, exceeding 80% on short-term follow-up and 40% on long-term follow-up. eGFR trends within 90 days pre-LT can predict sustained renal recovery, which appears protective of adverse outcomes. These recovery rates advocate for applying the more restrictive criteria for SLKT outlined in this article and increasing utilization of the safety net (SN) policy for those who do not meet the proposed criteria., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cardiovascular disease (CVD) significantly contributes to morbidity and mortality after liver transplantation (LT). Cirrhotic cardiomyopathy (CCM) is a risk factor for CVD after transplant. CCM criteria were originally introduced in 2005 with a revision proposed in 2020 reflecting echocardiographic technology advancements. This study assesses the two criteria sets in predicting major adverse cardiac events (MACE) after transplant. This single-center retrospective study reviewed adult LT recipients between January 1, 2009, and December 31, 2018. Patients with insufficient pre-LT echocardiographic data, prior ischemic heart disease, portopulmonary hypertension, or longitudinal care elsewhere were excluded. The primary composite outcome was MACE (arrhythmia, heart failure, cardiac arrest, and/or cardiac death) after transplant. Of 1165 patients, 210 met the eligibility criteria. CCM was present in 162 patients (77%) per the original criteria and 64 patients (30%) per the revised criteria. There were 44 MACE and 31 deaths in the study period. Of the deaths, 38.7% occurred secondary to CVD. CCM defined by the original criteria was not associated with MACE after LT (p = 0.21), but the revised definition was significantly associated with MACE (hazard ratio [HR], 1.93; 95% confidence interval, 1.05-3.56; p = 0.04) on multivariable analysis. Echocardiographic variable analysis demonstrated low septal e' as the most predictive variable for MACE after LT (HR, 3.45; p < 0.001). CCM, only when defined by the revised criteria, was associated with increased risk for MACE after LT, validating the recently revised CCM definition. Abnormal septal e', reflecting impaired relaxation, appears to be the most predictive echocardiographic criterion for MACE after LT., (© 2022 American Association for the Study of Liver Diseases.)

Competing Interests: The authors have no conflicts of interest pertinent to this study. Please refer to the accompanying ICMJE disclosure forms for further details.

Anthocyanins (ACNs) are dietary phytochemicals with an acknowledged therapeutic significance. Pomegranate juice (PJ) is a rich source of ACNs with potential applications in nutraceutical development. Glycogen phosphorylase (GP) catalyzes the first step of glycogenolysis and is a molecular target for the development of antihyperglycemics. The inhibitory potential of the ACN fraction of PJ is assessed through a combination of in vitro assays, ex vivo investigation in hepatic cells, and X-ray crystallography studies. The ACN extract potently inhibits muscle and liver isoforms of GP. Affinity crystallography reveals the structural basis of inhibition through the binding of pelargonidin-3- O -glucoside at the GP inhibitor site. The glucopyranose moiety is revealed as a major determinant of potency as it promotes a structural binding mode different from that observed for other flavonoids. This inhibitory effect of the ACN scaffold and its binding mode at the GP inhibitor binding site may have significant implications for future structure-based drug design endeavors.

Database linkage is a common strategy to expand analytic possibilities. Our group recently completed a linkage between the SRTR and PHIS databases for pediatric heart transplant recipients. The aim of this project was to expand the linkage between SRTR and PHIS to include liver, kidney, lung, heart-lung, and small bowel transplants. All patients (<21 years) who underwent liver, kidney, lung, heart-lung, or small bowel transplant were identified from the PHIS database using APR-DRG codes (2002-2018). Linkage was performed in a stepwise approach using indirect identifiers. Hospital costs were estimated based on hospital charges and cost-to-charge ratios, inflated to 2018 dollars and described by transplant type. A total of 14 061 patients overlapped between databases. Of these, 13 388 (95.2%) were uniquely linked. Linkage success ranged from 92.6% to 97.8% by organ system. A total of 12 940 (92%) patients had complete cost data. Hospitalization costs were greatest for patients undergoing small bowel transplantation with a median cost of $734 454 (IQR $336 174 - $1 504 167), followed by heart $565 386 (IQR $352 813 - $999 216), heart-lung $471 573 (IQR $328 523 - 992 438), lung $303 536 (IQR $215 383 - $612 749), liver $200 448 (IQR $130 880 - $357 897), and kidney transplant $94 796 (IQR $73 157 -$131 040). We report a robust linkage between the SRTR and PHIS databases, providing an invaluable tool to assess resource utilization in solid organ transplant recipients. Our analysis provides contemporary cost data for pediatric solid organ transplantation from the largest US sample reported to date. It also provides a platform for expanded analyses in the pediatric transplant population., (© 2019 Wiley Periodicals, Inc.)

Importance: Some infants with biliary atresia are treated with primary liver transplant (pLT), but most are initially treated with biliary-enteric drainage (BED) with a subsequent salvage liver transplant. Given the improvements in liver transplant outcomes, it is important to determine whether BED treatment remains the optimal surgical algorithm for patients with biliary atresia., Objective: To compare the survival of patients with biliary atresia initially treated with BED with patients who underwent pLT., Design, Setting, and Participants: This cohort study used deidentified records from the California Office of Statewide Health Planning and Development database to identify patients with biliary atresia (n = 1252) between January 1, 1990, through December 31, 2015. Patients were categorized into 1 of 2 cohorts: those who received BED treatment and those who underwent pLT. Excluded from the study were those born before January 1, 1995, and those without any documented operative intervention by age 5 years. Data analysis was performed from January 1, 1990, to December 31, 2015., Main Outcomes and Measures: Overall survival was compared between the BED and pLT cohorts using the Kaplan-Meier method. The treatment's association with treatment era was examined by comparing survival before 2002 and on or after January 1, 2002., Results: In total, 1252 patients with biliary atresia were identified. After exclusions, 626 remained; of these patients, 351 (56.1%) were female and 275 (43.9%) were male with a median (interquartile range) age at intervention for initial BED treatment of 65 (48-81) days. Among the 626 patients studied, initial BED treatment was performed in 313 patients (50.0%), and pLT was performed in 313 patients (50.0%). Although patients who underwent pLT had a higher mortality rate within the first 3 months after the procedure, they had a reduced risk of long-term mortality compared with patients initially managed with BED treatment (hazard ratio [HR] ≥6 months after the initial procedure, 0.19; 95% CI, 0.08-0.42; P = .01). Patients requiring salvage liver transplant had a substantially higher risk of mortality than patients who received pLT (HR, 0.43; 95% CI 0.25-0.76; P = .003). Those who underwent pLT had superior survival compared with BED treatment recipients on or after 2002 (HR, 0.16; 95% CI, 0.05-0.54; P < .001), and that persisted when censoring patients who underwent salvage liver transplant (HR, 0.23; 95% CI, 0.07-0.82; P = .01)., Conclusions and Relevance: Patients who underwent pLT experienced superior long-term survival compared with patients who underwent BED treatment. Multi-institutional trials are needed to determine which initial treatment is most advantageous to patients with biliary atresia.

Background: Organ donor shortages continue to persist, especially in regions of the United States where competition is highest and recipients frequently attain a Model for End-Stage Liver Disease (MELD) score of 40 or higher before transplantation. The benefits of Share 35 in highly competitive regions may be underestimated when examining the collective national experience. The purpose of this study was to examine the outcomes of liver transplantation in recipients with a MELD of 40 or higher after implementation of Share 35 in a single center located in region 5., Methods: The method used in this study was single-center retrospective analysis of 207 liver transplant recipients who achieved MELD score of 40 or higher from April 21, 2002, to May 15, 2015., Results: Multivariable analysis identified implementation of Share 35 as the strongest predictor of graft survival in MELD of 40 or higher liver transplantation. The post-Share 35, 1-year graft survival was 94% compared with 75% pre-Share 35 (P = 0.002). Post-Share 35 recipients waited significantly less time until transplantation (10 vs 16 days, P = 0.015), and fewer were hospitalized for more than 28 days before their transplant (6% vs 18%, P = 0.05). Multivariable analysis identified recipients with diabetes at the time of listing as the strongest predictor of posttransplant patient mortality., Conclusions: Implementation of the Share 35 allocation policy has a significant effect on outcomes by improving organ access and minimizing candidate waiting times. Recipients achieving a MELD of 40 or higher at our center post-Share 35 had an improved 1-year graft survival. However, nearly 40% remained hospitalized for more than 4 weeks posttransplant, and 20% were discharged to an acute care facility.

Background: Aging has been associated with increasing common bile duct (CBD) diameter and reported as independently predictive of the likelihood of choledocolithiasis. These associations are controversial with uncertain diagnostic utility in patients presenting with symptomatic disease. The current study examined the relationship between age, CBD size, and the diagnostic probability of choledocolithiasis., Methods: Symptomatic patients undergoing evaluation for suspected choledocolithiasis from January 2008 to February 2011 were reviewed. In the cohort without choledocolithiasis, the relationship between aging and CBD size was examined as a continuous variable and by comparing mean CBD size across stratified age groups. Multivariate analysis examined the relationship between increasing age and diagnostic probability of choledocolithiasis in all patients., Results: Choledocolithasis was diagnosed by MR cholangiopancreatography (MRCP) or endoscopic retrograde (ERCP) in 496 of 1,000 patients reviewed. Mean CBD was 6.0 mm (±2.8 mm) in the 504 of 1,000 patients without choledocolithiasis on ERCP/MRCP. Increasing age had no correlation with CBD size as a continuous variable (r2 = 0.011, p = 0.811). No difference occurred across age groups (Kruskal-Wallis, p = 0.157). Age had no association with diagnostic likelihood of choledocolithiasis (AOR [95% CI] 0.99 [0.98-1.01], adjusted-p = 0.335)., Conclusion: In a large population undergoing investigation for biliary disease, increasing age was neither associated with increasing CBD diameter nor predictive of the likelihood of choledocolithiasis., (© 2017 S. Karger AG, Basel.)

In certain regions of the United States in which organ donor shortages are persistent and competition is high, recipients wait longer and are critically ill with Model for End-Stage Liver Disease (MELD) scores ≥40 when they undergo liver transplantation. Recent implementation of Share 35 has increased the percentage of recipients transplanted at these higher MELD scores. The purpose of our study was to examine national data of liver transplant recipients with MELD scores ≥40 and to identify risk factors that affect graft and recipient survival. During the 12-year study period, 5002 adult recipients underwent deceased donor whole-liver transplantation. The 1-, 3-, 5- and 10-year graft survival rates were 77%, 69%, 64% and 50%, respectively. The 1-, 3-, 5- and 10-year patient survival rates were 80%, 72%, 67% and 53%, respectively. Multivariable analysis identified previous transplant, ventilator dependence, diabetes, hepatitis C virus, age >60 years and prolonged hospitalization prior to transplant as recipient factors increasing the risk of graft failure and death. Donor age >30 years was associated with an incrementally increased risk of graft failure and death. Recipients after implementation of Share 35 had shorter waiting times and higher graft and patient survival compared with pre-Share 35 recipients, demonstrating that some risk factors can be mitigated by policy changes that increase organ accessibility., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Advent of hepatitis B immunoglobulin (HBIG) as the mainstay of prophylaxis against hepatitis B recurrence after liver transplantation with antiviral drugs has resulted in excellent outcomes for liver transplantation in hepatitis B virus (HBV)-related cirrhosis in the last two decades. However, there is no consensus on a gold standard prophylaxis protocol and several controversies over the duration, dose, and route of administration of HBIG with or without different antivirals exist among liver transplantation centers. We present this review of different prophylaxis regimens including HBIG and antiviral monotherapy, combination of HBIG with antivirals, and withdrawal of HBIG and whole prophylaxis. HBIG monotherapy in either the intramuscular or the subcutaneous form is an accepted choice for prevention of HBV re-infection after liver transplantation in low risk patients. Withdrawal of HBIG monotherapy may be considered but should only occur after transitioning to an oral antiviral therapy such as adefovir, tenofovir, or entecavir. Lamivudine monotherapy may be associated with a higher recurrence rate compared to more potent antivirals. In high risk patients, intramuscular or subcutaneous HBIG in combination with an antiviral, most commonly lamivudine, is currently considered the standard of care. Complete discontinuation of all preventative therapy cannot be recommended at this time and should only be performed in the setting of a clinical trial.

An eight-yr-old female with a history of multifocal lymphangioendotheliomatosis and thrombocytopenia presented for MVT. The patient had multiple vascular lesions in the skin and stomach in infancy. Although her cutaneous lesions resolved with vincristine and methylprednisolone, her gastric lesions persisted. Eight yr later, she was diagnosed with portal hypertension and decompensating liver function despite therapy with bevacizumab, propranolol, furosemide, and spironolactone. Upon presentation, she was found to have a Kasabach-Merritt-like coagulopathy in association with multiple lesions in her GI tract and persistent gastric lesions. Although treatment with methylprednisolone and sirolimus normalized her coagulation factors and d-dimer levels, she never developed sustained improvement in her thrombocytopenia. Her liver function continued to deteriorate and she developed hepatorenal syndrome. Given better outcomes after OLT in comparison with MVT, she underwent OLT, with the plan to manage her GI lesions with APC post-transplant. Post-transplant, her liver function and coagulopathy normalized, and GI tract lesions disappeared upon screening with capsule endoscopy. The patient is doing well, without recurrence of either GI lesions or thrombocytopenia, at 18 months after transplantation., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hispanic race and low socioeconomic status are established predictors of disparity in access to kidney transplantation. This single-center retrospective review was undertaken to determine whether Hispanic race predicted kidney transplant outcomes. A total of 720 patients underwent kidney transplantation from January 1, 2004 to December 31, 2013, including 398 Hispanic patients and 322 non-Hispanic patients. Hispanic patients were significantly younger (p < 0.0001), on hemodialysis for longer (p = 0.0018), had a greater percentage with public insurance (p < 0.0001), more commonly had diabetes as the cause of end-stage renal disease (p = 0.0167), and had a lower percentage of living donors (p = 0.0013) compared to non-Hispanic patients. There was no difference in one-, five-, and 10-yr graft (97%, 81%, and 61% vs. 95%, 76%, and 42% p = 0.18) or patient survival (98%, 90%, and 84% vs. 97%, 87%, and 69% p = 0.11) between the Hispanic and non-Hispanic recipients. Multivariate analysis identified increased recipient age and kidney donor profile index to be predictive of lower graft survival and increasing recipient age to be predictive of lower patient survival. In the largest single-center study on kidney transplantation outcomes in Hispanic patients, there is no difference in graft and recipient survival between Hispanic and non-Hispanic kidney transplant patients, and in multivariate analysis, Hispanic race is not a risk factor for graft or patient survival., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The diagnosis of side-branch intraductal papillary mucinous neoplasms (IMPNs) is increasingly more common, but their appropriate management is still evolving. We recently began performing laparoscopic hand-assisted enucleation or duodenal-sparing pancreatic head resection for these lesions with vigilant postoperative imaging., Materials and Methods: Seventeen patients with pancreatic cystic lesions were included in this single-center retrospective review from January 1, 2008 to March 30, 2013. Indication for surgical intervention was growth in size of the cyst, symptoms, cyst size >3 cm, and/or presence of a mural nodule. Twelve patients underwent laparoscopic hand-assisted enucleation, and 5 patients underwent laparoscopic hand-assisted pancreatic head resection., Results: The mean age of patients was 64 years old. The most common presenting symptom was abdominal pain. The indication for surgical intervention was growth in the cyst or symptoms in the majority of patients. Fourteen lesions were in the head/uncinate, two were in the pancreatic body, and one was in the tail. Final pathology was consistent with side-branch IPMN in 13 patients (1 with focal adenocarcinoma). Three patients had serous cysts, and 1 had a mucinous cyst. Three patients developed pancreatic leaks, which were controlled with intraoperative placed drains, whereas 1 patient required additional drain placement. Median time from surgery to latest follow-up imaging is over 2 years. No patients have developed recurrent cysts or adenocarcinoma., Conclusions: Duodenal-sparing pancreatic head resection or pancreatic enucleation for patients with presumed side-branch IPMN is a safe and efficacious option, in terms of both operative outcomes and postoperative recurrence risk.

Background: No guidelines exist for the management of cardiophrenic lymph nodes in patients with hepatocellular carcinoma (HCC) being evaluated for liver transplantation., Methods: One hundred and seventy-eight patients with HCC listed for liver transplant received both pre-transplant computed tomography (CT) and follow-up CT scans. Enlarged cardiophrenic lymph nodes on CT were characterized and followed on subsequent scans; lymph node outcomes were assigned to "reduced" and "not reduced" categories. Tumor and patient characteristics were also recorded., Results: Seventy-one of one hundred and seventy-eight patients (39.9%) had at least one cardiophrenic lymph node larger than 8 mm in diameter on pre-transplant CT. One hundred and sixty-six total lymph nodes were characterized. Six lymph nodes (3.6%) in two patients increased in size on follow-up imaging; all six cardiophrenic lymph nodes were presumed to represent metastases. There was a statistically significant reduction in lymph node size in patients who were transplanted vs. those who were not transplanted. Furthermore, a statistically significant association was found between increasing Model for End-Stage Liver Disease score and lymph node size reduction. There were no significant differences in post-transplant survival between patients with different lymph node outcomes., Conclusion: In the absence of metastatic disease in other sites, these lymph nodes are probably reactive; further workup is likely not necessary., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HPS is a significant complication of portal hypertension in children with chronic liver disease and is an established indication for LT. It is characterized clinically by the triad of pulmonary vascular dilatation causing hypoxemia in the setting of advanced liver disease. NRH, a cause of non-cirrhotic portal hypertension, is characterized by diffuse benign transformation of the hepatic parenchyma into small regenerative nodules with minimal or no fibrosis. Development of NRH and HPS in pediatric LT recipients has not been reported, although occasional cases have been reported in adult LT recipients. In this report, we discuss a case of a three-yr-old male who developed HPS, two yr after LT. Pulmonary and cardiac causes for hypoxemia were ruled out by appropriate investigations including a chest X ray, echocardiogram, cardiac catheterization, and a CT angiographic study. The diagnosis of HPS was confirmed via bubble echocardiogram that demonstrated intrapulmonary shunting. Open liver biopsy revealed marked NRH. The patient underwent liver retransplantation that resulted in complete reversal of his pulmonary symptoms and normal oxygen saturations within three months after LT., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Many centers perform aggressive liver resection for patients with cholangiocarcinoma, because improved survival has been reported after resection with negative margins. Patients with extensive tumor burden sometimes require trisectionectomy for clearance of disease with increased risk of liver insufficiency and postoperative complications. A retrospective review was conducted examining records for 62 patients who were taken to the operating room for cholangiocarcinoma from January 1, 2000, to March 31, 2010. Thirty-eight patients underwent surgical resection: 17 patients underwent trisectionectomy and 21 patients underwent liver resections. No statistically significant differences were found between patients who underwent liver resection compared with those who underwent trisectionectomy with regard to demographics or complications. Pathology was rereviewed by a single pathologist, and no statistically significant differences were found between the two groups in any of the recorded pathology results. No significant differences in survival were found between the two groups. The median survival for liver resection patients was 2.9 years and for trisegmentectomy patients was 2.8 years. Complete resection with negative margins remains the current surgical goal in the treatment for cholangiocarcinoma. Performing trisectionectomy in an effort to clear all disease is safe with comparable outcomes to patients needing less extensive liver resections.

Purpose: Ocular melanoma is a rare disease with a strong predilection for the liver. Systemic and locoregional treatments for metastatic ocular melanoma have had disappointing results, with an average survival of 5-7 months. Resection and/or radiofrequency ablation (RFA) of liver lesions were attempted to improve the patient outcomes., Methods: Eight patients with liver metastasis from ocular melanoma underwent surgery and/or RFA at the University of Southern California, University Hospital from 1 January 2001 to 31 December 2009. Their charts were retrospectively reviewed., Results: All patients had undergone eye enucleation as the primary treatment. Four patients had all metastatic liver lesions addressed: one patient underwent left lateral segmentectomy and three patients had combinations of left lateral segmentectomies, wedge resections and RFA of two to four lesions. Two patients underwent surgical biopsies for diagnosis, one patient was unresectable and one patient underwent RFA of a dominant lesion. The median survival was 36 months. The median survival of patients who underwent surgery alone or in conjunction with RFA to address all liver lesions was 46 months., Conclusions: There are few reports of RFA for metastatic ocular melanoma. RFA of liver lesions in addition to resection can perhaps lead to improved survival and may play a critical role in the future management of this disease.

Background: Patients with Model for End-Stage Liver Disease (MELD) scores of 40 or higher are at high risk for liver transplantation. In some regions, the organ donor shortage has resulted in a substantial increase in the number of patients who underwent transplantation with MELD scores of 40 or higher. The objective of this study was to characterize the outcomes of liver transplantation in these patients., Methods: A single-center retrospective study evaluating the outcome of liver transplantation in 38 consecutive patients achieving a MELD score of 40 or higher from January 1, 2006, to November 30, 2010, was conducted. Patient and graft survivals and independent risk factors for postoperative death or graft loss were determined., Results: Kaplan-Meier-based 1-, 2-, and 3-year patient survival rates were 89%, 82%, and 77% with 1-, 2-, and 3-year graft survival rates of 84%, 75%, and 70.3%, respectively. One of three recipients was on a vasopressor before transplantation, and 13% were mechanically ventilated. Renal replacement therapy was used before operation in 90% of the recipients. Postoperative length of stay averaged 38 days. There was a 42% incidence of postoperative bacteremia and an 18% incidence of bile duct stricture within 6 months. Univariate analysis identified admission-to-transplantation time and recipient diabetes as risk factors for graft failure and patient death. Multivariate analysis confirmed recipient diabetes as a risk factor for patient survival and admission-to-transplantation time of more than 15 days as a risk factor for graft survival., Conclusions: Acceptable outcomes are achievable after liver transplantation in patients with MELD scores of 40 or higher but come at high pretransplantation and posttransplantation resource utilization.

Human Cytomegalovirus is a commonly identified herpesvirus that establishes a state of latent infection in the majority of the population by adulthood. A coordinated immune response involving both the innate and adaptive immune system prevents active viral replication and disease. Cellular immunity appears particularly important to control of viremia requiring both a CMV-specific CD4+ and CD8+ T cell response. Solid organ transplant recipients are particularly susceptible to CMV related disease due to the immunosuppression necessary to prevent organ rejection, with patients receiving T cell depleting therapies being at highest risk. The deleterious outcomes of CMV in organ transplant recipients result from both direct cytopathic and indirect immune-modulatory effects of CMV viral replication. The recognition of the negative effects of CMV in solid organ transplantation has resulted in the routine prophylaxis of organ recipients with antiviral nucleoside analogues. The appropriate duration of therapy is still controversial although guidelines do exist. The ability to assay an individual immune response to CMV should allow for tailored duration of therapy in the future.

Background: Children with small capacity, defunctionalized urinary bladders present unique operative challenges. Thus, traditional practice has included pretransplant bladder augmentation, but this has several adverse consequences., Methods: A single-institutional, retrospective review from January 1, 2004 to December 31, 2008 was conducted. Twelve pediatric patients, whom had not undergone pretransplant bladder augmentation, did not have neurogenic bladders or require preoperative catheterization, and a small capacity defunctionalized bladders were included. All were managed by the same surgeon with a previously described ureteral implantation, and a 7F ureteral stent attached to a large diameter suprapubic catheter was removed in a joint manner without cystoscopy at 2 weeks. Data were collected on patient and graft survival, rejection episodes, urinary tract infection (UTI) requiring antibiotics, grade of vesicoureteral reflux, and posttransplant bladder capacity., Results: One-year patient and graft survival rates were 100%. One patient experienced a clinical rejection episode, which was successfully treated. Five patients (41.7%) had a UTI requiring abx treatment within the first postoperative year, but at 1 year, all patients had sterile urinary tracts. After removal of suprapubic catheters and ureteral stents, all patients were able to void spontaneously. Seven patients had no posttransplant ureteral reflux, three had grade 1 reflux, and two had grade 3 reflux (both successfully treated). The average age estimated pretransplant bladder and 1 year posttransplant bladder capacity was 14.5% and 84% of expected, respectively., Conclusions: In pediatric end-stage renal disease patients with a small capacity defunctionalized bladder, it is reasonable to proceed with kidney transplantation without pretransplant bladder augmentation, thus avoiding an unnecessary surgery.

T cell Ig mucin (Tim) molecules modulate CD4(+) T cell responses. In keeping with the view that Tim-1 generates a stimulatory signal for CD4(+) T cell activation, we hypothesized that an agonist Tim-1-specific mAb would intensify the CD4(+) T cell-dependant allograft response. Unexpectedly, we determined that a particular Tim-1-specific mAb exerted reciprocal effects upon the commitment of alloactivated T cells to regulatory and effector phenotypes. Commitment to the Th1 and Th17 phenotypes was fostered, whereas commitment to the Treg phenotype was hindered. Moreover, ligation of Tim-1 in vitro effectively deprogrammed Tregs and thus produced Tregs unable to control T cell responses. Overall, the effects of the agonist Tim-1-specific mAb on the allograft response stemmed from enhanced expansion and survival of T effector cells; a capacity to deprogram natural Tregs; and inhibition of the conversion of naive CD4(+) T cells into Tregs. The reciprocal effects of agonist Tim-1-specific mAbs upon effector T cells and Tregs serve to prevent allogeneic transplant tolerance.

Allograft(dagger) transplant outcome, rejection or tolerance, depends upon striking a balance between the pertinent cytopathic and regulatory T cells. The drug cyclosporine is a widely used immunosuppressive agent among transplant recipients. Previous studies have demonstrated that cyclosporine blocks apoptosis of activated T cells and the ability of costimulation blockade based regimens to create peripheral transplant tolerance. We now test the hypothesis that the mechanism by which cyclosporine blocks tolerance induction is IL-2 dependent, and linked to a detrimental effect upon T(reg) function. Our study demonstrates that cyclosporine blocks IL-2 gene expression and activation induced cell death (AICD) of alloreactive T effector cells. We also show that cyclosporine abolishes the beneficial effects of a donor specific transfusion (DST) plus anti-CD154 monoclonal antibody (alpha CD154) regimen on enhanced T(regs) function and allograft tolerance induction. Interestingly, provision of IL-2/Fc, a long-lived form of IL-2, completely reverses the detrimental effects of this adjunctive cyclosporine treatment on AICD of alloreactive T effectors, T(regs) function and tolerance induction. Furthermore, in a MHC mismatched islet allograft model, the combination of cyclosporine with IL-2/Fc permitted long-term allograft survival and induced alloantigen specific allograft tolerance. The combination of IL-2/Fc and cyclosporine treatment may provide a new clinical strategy to promote transplant tolerance.

While both direct and indirect allorecognition are involved in allograft rejection, evidence to date suggests that tolerance is primarily dependent on indirect pathway-triggered CD4+CD25+ T cell-mediated immunoregulation. However, the precise influence of these two pathways on CD4+CD25+ T-cell function has not been addressed. In the current study, we have utilized an adoptive transfer model to assess selectively how the absence of either direct or indirect allorecognition affects CD4+CD25+ T-cell function. The effects of the loss of the direct pathway were assessed by transplanting skin grafts from minor histocompatibility mismatched B10.D2 (H-2d) donors onto Balb/c (H-2d) recipients, or by placing bone marrow chimeric DBA/2 (H-2d/H-2b) allografts onto C57BL/6 (H-2b) hosts. The requirement for indirect allorecognition was tested by grafting DBA/2 skin allografts onto either C57BL/6- or MHC-II-deficient C57BL/6 recipients. We report here that although CD4+CD25+ regulatory T cells can suppress both directly and indirectly generated alloresponses, immunoregulation is favored when indirect presentation is the sole mechanism of allorecognition. Hence, in the absence of indirect presentation, net CD4+CD25+ T cell-dependent immunoregulation is weak, and high ratios of CD4+CD25+ to CD4+CD25 T cells are required to ensure graft survival.

PNF following liver transplantation (LT) is an infrequent but life-threatening complication. Liver allocation under MELD is based upon recipient severity of illness, a known risk factor for the occurrence of PNF. The incidence of PNF since the application of MELD has not previously been reported. The SRTR database was studied since inception of MELD until September 2004 for all adult recipients of deceased donor LT. PNF was defined as graft loss or death within 14 days of LT secondary to PNF or without defined cause. A total of 10545 transplants met inclusion criteria and PNF occurred in 613 (5.81%) of recipients. Univariate analysis demonstrated donor age, serum creatinine >1.5 mg/mL, hypertension and CVA as risk factors for PNF. Recipient factors included life support, mechanical ventilation, use of inotropes, hemodialysis, initial status 1 and use of a shared transplant. In the multivariate model only donor age and recipient serum creatinine, bilirubin, on life support and status 1 at transplant were significant risk factors for PNF. In this analysis of PNF in the MELD era the incidence of PNF does not appear to have increased from prior reports. Risk factors for PNF are related to donor age and severity of recipient illness.

Background: The goal of this study is to determine the effects of ex vivo hyperbaric pressure administration of AS-ICAM-1 ODN and systemic anti-LFA-1 mAb treatment on reperfusion injury in the rat cardiac allograft model., Methods: A PVG to ACI functional heterotopic rat heart model was used. Donor hearts were treated with either saline or AS-ICAM-1 ODN and 5 atm of hyperbaric pressure for 45 minutes. Anti-LFA-1 mAb was administered systemically prior to reperfusion of the allograft. Allografts were procured 24 hours after transplantation for assessment of reperfusion injury or 72 hours to determine ICAM-1 protein expression., Results: Ex vivo administration of AS-ICAM-1 ODN led to decreases in percentage wet weight (77.1+/-0.83% vs 78.7+/-1.0%, p < 0.05), myeloperoxidase activity (3.14+/-0.72 vs 4.07+/-0.59, p < 0.05), contraction band necrosis (6.4+/-6.47% vs 21.1+/-7.43%, p < 0.01), and ICAM-1 protein expression determined by immunohistochemistry compared to saline controls. Treatment with anti-LFA-1 mAb resulted in decreases in wet weight ratio (76.7+/-0.63%, p < 0.05 vs saline), myeloperoxidase activity (3.58+/-0.39, p < 0.05 vs saline) and contraction band necrosis (11.8+/-3.56%, p < 0.05 vs saline). Combination of pressure administration of AS-ICAM-1 ODN and anti-LFA-1 mAb decreased wet weight ratios (77.1+/-0.93%, p < 0.05 vs saline), myeloperoxidase activity (2.88+/-0.44, p < 0.01 vs saline), and contraction band necrosis (6.75+/-5.67%, p < 0.05 vs saline)., Conclusions: Ex vivo pressure mediated delivery of AS-ICAM-1 ODN decreases ICAM-1 protein expression, reduces reperfusion injury in rodent cardiac allografts, and is more effective than anti-LFA-1 mAb treatment alone.

The mechanisms underlying the cardiovascular benefits of Mediterranean-style diets are not fully understood. The high content of monounsaturated fatty acids in Mediterranean-style diets derived from oleate-rich olive oil may be beneficial in reducing low density lipoprotein (LDL) oxidation and its subsequent development of atherogenic properties. This study sought to assess the proinflammatory potential of LDL isolated from subjects consuming a diet naturally rich in olive oil. LDL was isolated from 18 Greek, 18 American, and 11 Greek-Americans subjects, all of whom were living in the United States. Fatty acid composition and vitamin E levels of LDL were determined, as was the extent of copper-mediated LDL oxidation. LDL was also mildly oxidized by exposure to fibroblasts overexpressing 15-lipoxygenase and tested in vitro for bioactivity by determining its ability to stimulate monocyte chemotaxis and adhesion to endothelial cells. To confirm that dietary fatty acids influence the proinflammatory properties of mildly oxidized LDL, LDL was also isolated from 13 healthy American subjects after consumption of an 8-week liquid diet supplemented with either oleic (n=6) or linoleic (n=7) acid and tested for bioactivity in a similar fashion. There were no differences in the baseline lipid profiles among the Greeks, Americans, or Greek-Americans. Oleic acid content in LDL was 20% higher in the Greek compared with the American or Greek-American subjects (P<0.001). The extent of in vitro LDL oxidation, measured by conjugated diene formation, was lower in the Greek subjects (P<0.02), but there was no difference in the lag time. Induction of monocyte chemotaxis and adhesion by mildly oxidized LDL was decreased by 42% in the Greek group compared with the American subjects (P<0.001). There was an inverse correlation between the oleic acid content of LDL and stimulation of monocyte chemotaxis (r=-0.64, P<0.001) and a positive correlation between the polyunsaturated fatty acid content of LDL (total linoleate and arachidonic acids levels in LDL) and stimulation of monocyte chemotaxis (r=0.51, P<0.01) in the entire cohort. There were no differences in LDL vitamin E content between the groups. In the liquid-diet groups, the oleic acid-supplemented group had a 113% higher oleic acid content in LDL and a 46% lower linoleic acid content in LDL than the linoleate-supplemented group (P<0.001), whereas the vitamin E content in LDL was equal in both groups. When exposed to oxidative stress, the LDL enriched in oleic acid promoted less monocyte chemotaxis (52% lower) and reduced monocyte adhesion by 77% in comparison with linoleate-enriched LDL (P<0.001). There was a strong, negative correlation between oleic acid LDL content and monocyte adhesion (r=-0.73, P<0.001) and a strong, positive correlation between polyunsaturated fatty acid LDL content and monocyte adhesion (r=0.87, P<0.001). This study demonstrates that dietary enrichment of LDL with oleic acid is realistic and readily achieved by using diets currently in use in Mediterranean countries. In addition, these data suggest that LDL enriched with oleic acid and reduced in polyunsaturated fatty acids may be less easily converted to a proinflammatory, minimally modified LDL.

Event-related potentials (ERPs) were elicited in 30, non-consecutive, non-demented individuals, complaining of short-term memory disturbances. Fifteen of them had a moderate diffuse cerebral atrophy on their brain CT and the other 15 had a negative brain CT. ERPs were also elicited in 15 age-matched controls with no reported memory disturbances and negative brain CTs. The statistical analysis showed that the group of individuals with cerebral atrophy had a significantly prolonged P300 (P3) latency and a decreased P3 amplitude compared to controls. It is concluded that among persons complaining of short-term memory disturbances, the individuals who show cerebral atrophy, taken as a group, have a P3 latency prolongation and/or low P3 amplitude a finding which reflects an impaired information processing.