Meta-analysis and Meta-regression of Survival After Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma.

OBJECTIVE: To systematically review studies reporting survival data following neoadjuvant chemoradiation and orthotopic liver transplantation (NCR-OLT) for unresectable perihilar cholangiocarcinoma (pCC). BACKGROUND: Despite survival improvements for other cancers, the prognosis of pCC remains dismal. Since publication of the Mayo protocol in 2000, increasing numbers of series globally are reporting outcomes after NCR-OLT. METHODS: MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from January 2000 to February 2019. A meta-analysis of proportions was conducted, pooling 1, 3-, and 5-year overall survival and recurrence rates following NCR-OLT across centers. Per protocol and intention to treat data were interrogated. Meta-regression was used to evaluate PSC as a confounder affecting survival. RESULTS: Twenty studies comprising 428 patients were eligible for analysis. No RCTs were retrieved; the majority of studies were noncomparative cohort studies. The pooled 1, 3-, and 5-year overall survival rates following OLT without neoadjuvant therapy were 71.2% (95% CI 62.2%-79.4%), 48.0% (95% CI 35.0%-60.9%), and 31.6% (95% CI 23.1%-40.7%). These improved to 82.8% (95% CI 73.0%-90.8%), 65.5% (95% CI 48.7%-80.5%), and 65.1% (95% CI 55.1%-74.5%) if neoadjuvant chemoradiation was completed. Pooled recurrence after 3 years was 24.1% (95% CI 17.9%-30.9%) with neoadjuvant chemoradiation, 51.7% (95% CI 33.8%-69.4%) without. CONCLUSIONS: In unresectable pCC, NCR-OLT confers long-term survival in highly selected patients able to complete neoadjuvant chemoradiation followed by transplantation. PSC patients appear to have the most favorable outcomes. A high recurrence rate is of concern when considering extending national graft selection policy to pCC.

Infections and associated behaviors among deceased organ donors: Informing the assessment of risk.

BACKGROUND: For infectious disease risk assessment among deceased organ donors, pre-donation clinical, microbiological, and behavioral information are reviewed; however, uncertainty may arise due to false negative screening results of recently acquired infections. METHOD: The burden of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV), and residual risks (RR) of undetected virus was estimated, with the impact of more sensitive screening. RESULTS: For United Kingdom potential deceased organ donors between 2010 and 2014, prevalence of HBsAg was 0.1%, HIV 0.06% and HCV 0.9%, increasing to 25.7% in people who injected drugs (PWID). Incidence, derived from new blood donors, was multiplied by duration of screening assay window periods to give RR per 100 000 donors as 0.43 (95% confidence interval [CI] 0.03-3.99) for HBV, 0.08 (95% CI 0.02-0.21) for HIV, and 5.96 (95% CI 0.82-37.89) for HCV. For PWID, HCV RR was 163.3 (95% CI 22.8-1107.8) compared to 2.76 (95% CI 0.35-17.36) for non-PWID. RR decreased significantly with nucleic acid testing (NAT), and, for HCV, antigen testing had a similar impact. CONCLUSION: While the burden of HCV risk lies within PWID, these are in small numbers therefore few HCV antigen or NAT tests would be needed to more accurately assess risk.

Pushing the boundaries in liver graft utilisation in transplantation: Case report of a donor with previous bile duct injury repair.

INTRODUCTION: Liver transplantation is a recognised treatment for extensive bile duct injuries with secondary biliary cirrhosis or recurring sepsis. However, there have been no reports of successful liver transplantation from a donor who sustained a previous bile duct injury. PRESENTATION OF CASE: Here we discuss the case of a liver transplant from a 51-year-old brain dead donor who had suffered a Strasberg E1 bile duct injury and had undergone a Roux-en-Y hepaticojejunostomy 24 years prior to donation. The liver was successfully recovered and transplanted into a 56-year-old male recipient with end stage liver disease consequent to alpha 1 antitrypsin deficiency. The graft continues to function well 36 months post-transplant, with normal liver function tests and imaging revealing a patent hepaticojejunostomy. DISCUSSION: The potential associated vascular injuries should be identified during bench preparation whilst the management of biliary reconstruction at the time of transplant should follow the principles of biliary reconstruction in cases with biliary injuries, extending the hilar opening into the left duct. CONCLUSION: This case highlights the successful utilisation of a post bile duct injury repair liver, employing an experienced procurement team and careful bench assessment and reconstruction.

Timing of enteral nutrition in acute pancreatitis: meta-analysis of individuals using a single-arm of randomised trials.

INTRODUCTION: In acute pancreatitis, enteral nutrition (EN) reduces the rate of complications, such as infected pancreatic necrosis, organ failure, and mortality, as compared to parenteral nutrition (PN). Starting EN within 24 h of admission might further reduce complications. METHODS: A literature search for trials of EN in acute pancreatitis was performed. Authors of eligible trials were requested to provide the data of all patients in the EN-arm of their trials. A meta-analysis of individual patient data was performed. The cohort of patients with EN was divided into patients receiving EN within 24 h or after 24 h of admission. Multivariable logistic regression, adjusting for predicted disease severity and trial, was used to study the effect of timing of EN on a composite endpoint of infected pancreatic necrosis, organ failure, or mortality. RESULTS: Observational data from 165 individuals from 8 randomised trials were obtained; 100 patients with EN within 24 h and 65 patients with EN after 24 h of admission. In the multivariable model, EN started within 24 h of admission compared to EN started after 24 h of admission, reduced the composite endpoint from 45% to 19% (adjusted odds ratio [OR] of 0.44; 95% confidence interval [CI] 0.20-0.96). Within the composite endpoint, organ failure was reduced from 42% to 16% (adjusted OR 0.42; 95% CI 0.19-0.94). CONCLUSIONS: In this meta-analysis of observational data from individuals with acute pancreatitis, starting EN within 24 h after hospital admission, compared with after 24 h, was associated with a reduction in complications.

Outcomes of transplantation of livers from donation after circulatory death donors in the UK: a cohort study.

OBJECTIVES: Outcomes of liver transplantations from donation after circulatory death (DCD) donors may be inferior to those achieved with donation after brain death (DBD) donors. The impact of using DCD donors is likely to depend on specific national practices. We compared risk-adjusted graft loss and recipient mortality after transplantation of DCD and DBD livers in the UK. DESIGN: Prospective cohort study. Multivariable Cox regression and propensity score matching were used to estimate risk-adjusted HR. SETTING: 7 liver transplant centres in the National Health Service (NHS) hospitals in England and Scotland. PARTICIPANTS: Adults who received a first elective liver transplant between January 2005 and December 2010 who were identified in the UK Liver Transplant Audit. INTERVENTIONS: Transplantation of DCD and DBD livers. OUTCOMES: Graft loss and recipient mortality. RESULTS: In total, 2572 liver transplants were identified with 352 (14%) from DCD donors. 3-year graft loss (95% CI) was higher with DCD livers (27.3%, 21.8% to 33.9%) than with DBD livers (18.2%, 16.4% to 20.2%). After adjustment with regression, HR for graft loss was 2.3 (1.7 to 3.0). Similarly, 3-year mortality was higher with DCD livers (19.4%, 14.5% to 25.6%) than with DBD livers (14.1%, 12.5% to 16.0%) with an adjusted HR of 2.0 (1.4 to 2.8). Propensity score matching gave similar results. Centre-specific adjusted HRs for graft loss and recipient mortality seemed to differ among transplant centres, although statistical evidence is weak (p value for interaction 0.08 and 0.24, respectively). CONCLUSIONS: Graft loss and recipient mortality were about twice as high with DCD livers as with DBD livers in the UK. Outcomes after DCD liver transplantation may vary between centres. These results should inform policies for the use of DCD livers.

Meta-analysis of intermittent Pringle manoeuvre versus no Pringle manoeuvre in elective liver surgery.

BACKGROUND AND OBJECTIVES: Intermittent Pringle manoeuvre (IPM) is frequently used during liver surgery. This meta-analysis aimed to review the impact on blood loss, operating time and morbidity and mortality with and without use of IPM. METHODS: An electronic search was performed of the MEDLINE, EMBASE, PubMed databases using both subject headings (MeSH) and truncated word searches to identify all articles published that related to this topic. Pooled risk ratios were calculated for categorical outcomes, and mean differences (MDs) for secondary continuous outcomes, using the fixed-effects and random-effects models for meta-analysis. RESULTS: Four randomized controlled trials encompassing 392 patients were analysed to achieve a summated outcome. Pooled data analysis showed the use of IPM resulted in reduced transection time/cm(2) (MD -0.53 (-0.88, -0.18) min/cm(2) (P = 0.003)) but with comparable blood loss (mL/cm(2)) (MD -1.67 (-4.41, 1.08) mL/cm(2), P = 0.23), overall blood loss (MD -20.42 (-89.42, 48.58) mL), blood transfusion requirements (risk ratio 0.78 (0.40, 1.52, P = 0.47)) and morbidity and mortality compared to no Pringle manoeuvre. In addition, there was no significant difference in the post-operative hospital stay (MD 0.37 (-0.60, 1.34) days). CONCLUSIONS: There is no evidence that the routine use of IPM improves perioperative and post-operative outcomes compared to no Pringle manoeuvre and its routine may not be recommended.

The value of immunophenotyping hepatocellular adenomas: consecutive resections at one UK centre.

AIMS: To determine the utility of immunophenotyping for classification of hepatocellular adenomas resected at one Scottish centre. METHODS AND RESULTS: This study comprised a retrospective review and immunophenotyping of consecutive resected benign hepatocellular tumours. Fifty-five patients (seven men) had 64 adenomas and 26 focal nodular hyperplasias (FNHs) resected. Map-like glutamine synthetase (GS) staining was specific for FNH. Immunophenotyping changed the morphological typing for three adenomas and resolved 16 of 18 unclassified or equivocal cases, revealing GS positivity in these (seven) and four others. Steatotic/liver fatty acid binding protein-deficient adenomas were the commonest type in women (12/29 women, 41%) but were absent from men. Where one of multiple adenomas was morphologically unclassified, there was still a shared immunophenotype. Diffuse CD34 positivity correlated with GS positivity or unclassified status (P < 0.0001). Supervised cluster analysis identified morphological discriminants for FNH and predictors of adenoma type and their insensitivity in predicting GS status. Forty per cent of men and 7% of women with adenomas had a specific adenoma risk, including danazol and portal venopathies. Inflammatory adenomas were associated with metabolic syndrome, steatosis, or alcohol (P = 0.053). Four patients showed carcinoma ex-adenoma. CONCLUSIONS: The distribution of adenoma types in this population matches that in others, and immunoprofiling is required for accurate typing. Carcinoma ex-adenoma is uncommon and fits the published risk profile (large size and GS-positive).

Multimodal therapy for hepatocellular carcinoma: a complementary approach to liver transplantation.

OBJECTIVE: To evaluate the survival benefit of multimodal therapy for the treatment of HCC. BACKGROUND: Orthotopic liver transplantation (OLT) is considered the treatment of choice for selected patients with hepatocellular carcinoma (HCC). However, donor organ shortages and patients whose HCCs exceed OLT criteria require consideration of alternate therapeutic options such as hepatic resection, radiofrequency ablation (RFA), ethanol injection (EI), transarterial chemoembolization (TACE), and chemotherapy (CTX). This study was performed to evaluate the survival benefit of multimodal therapy for treatment of HCC as complementary therapy to OLT. METHODS: A retrospective review was conducted of HCC patients undergoing therapy following multidisciplinary review at our institution from 1996 . 2006 with a minimum of a 2 year patient follow-up. Data were available on 247/252 patients evaluated. Relevant factors at time of diagnosis included symptoms, hepatitis B (HBV) and C (HCV) status, antiviral therapy, Child-Pugh classification, portal vein patency, and TNM staging. Patients underwent primary treatment by hepatic resection, RFA, EI, TACE, CTX, or were observed (best medical management). Patients with persistent or recurrent disease following initial therapy were assessed for salvage therapy. Survival curves and pairwise multiple comparisons were calculated using standard statistical methods. RESULTS: Mean overall survival was 76.8 months. Pairwise comparisons revealed significant mean survival benefits with hepatic resection (93.2 months), RFA (66.2 months), and EI (81.1 months), compared with TACE (47.4 months), CTX (24.9 months), or observation (31.4 months). Shorter survival was associated with symptoms, portal vein thrombus, or Child-Pugh class B or C. HCV infection was associated with significantly shorter survival compared with HBV infection. Antiviral therapy was associated with significantly improved survival in chronic HBV and HCV patients only with earlier stage disease. CONCLUSION: Multimodal therapy is effective therapy for HCC and may be used as complementary treatment to OLT.

Long-term outcome following liver transplantation for paracetamol overdose.

Paracetamol overdose (POD) is a major cause of acute liver failure (ALF) requiring liver transplantation in the United Kingdom. To characterize the early and late outcome after orthotopic liver transplantation (OLT) for POD in the Scottish Liver Transplant Unit over a 14-year period (1992-2006). Data were obtained from a prospective database combined with case-note review. Of 127 liver transplants performed for ALF, 44 were for POD. The median age was 30 (range 18-51). In 18 patients (63.7%), POD was associated with alcohol/other drugs, nine (20.5%) had a staggered overdose and four patients (9.1%) accidentally overdosed. Nineteen patients (43.2%) had a history of previous overdose/psychiatric illness. Post-transplant mortality during the index admission was 30% (13 patients), whilst five patients died during follow-up. The actuarial 5-year patient survival was 54.5%, whilst graft survival was 49.5%. Some 23% of the patients were re-transplanted: primary nonfunction (1), hepatic artery thrombosis (3) and chronic rejection (2). Three patients had a subsequent transplant; three patients had two further transplants. Nine patients (35%) continue to have social/psychiatric issues. OLT for POD is associated with significant early and late morbidity and mortality. A multidisciplinary approach is required to identify the suitable candidates, in whom transplantation should be pursued promptly.

Fatal hepatitis C associated fibrosing cholestatic hepatitis as a complication of cyclophosphamide and corticosteroid treatment of active glomerulonephritis.

Fibrosing cholestatic hepatitis (FCH) is an aggressive and usually fatal form of viral hepatitis in immunocompromised patients. It is characterized by progressive cholestasis leading to hepatic failure, and a characteristic histopathological features including: periportal fibrosis, ballooning degeneration of hepatocytes, cholestasis, with minimal inflammation. FCH has been reported almost exclusively in heavily immunosuppressed organ transplant recipients or patients with AIDS. This case report describes a previously immunocompetent patient with previously stable chronic hepatitis C who developed fibrosing cholestatic hepatitis after receiving cyclophosphamide and corticosteroids for active glomerulonephritis.

Acute lower gastrointestinal bleeding from a dieulafoy lesion proximal to the anorectal junction post-orthotopic liver transplant.

A 67-year-old woman underwent an orthotopic liver transplantation for end stage liver disease secondary to chronic autoimmune hepatitis. She developed sudden massive hematochezia on post-operative day 23 with hemodynamic compromise. The source of hemorrhage was found at colonoscopy after careful irrigation and inspection to be a dieulafoy lesion situated just proximal to the anorectal junction. Hemostasis was achieved with epinephrine injection and thermal coagulation.

The effects of macrophage migratory inhibitory factor on acute-phase protein production in primary human hepatocytes.

Macrophage inhibitory factor (MIF) is a pituitary peptide released during the physiological stress response, a T-cell product secreted during the antigen-specific response and a pro-inflammatory macrophage cytokine secreted after LPS stimulation. It has become apparent that MIF is central to the regulation of the inflammatory response and is implicated in the pathogenesis of a variety of acute and chronic inflammatory conditions. This is, at least in part, due to the apparent counter-regulation of the anti-inflammatory actions of glucocorticoids, including the reversal of glucocorticoid-mediated IL-6 release inhibition. This study examines the effect of recombinant MIF on regulation of the acute phase response in isolated human hepatocytes. MIF alone increased C-reactive protein (CRP) release in a dose-dependent manner < or = 0.1 ng/ml after which the effects of MIF were attenuated. In combination with IL-6 both CRP and and alpha-1-antichymotrypsin (ACT) release were increased above levels found with either IL-6 or MIF treatment alone. Dexamethasone attenuated the effects of MIF upon CRP production but increased the MIF stimulated release of ACT. The study demonstrates that the effects of MIF upon the acute phase response are complex and can differentially modulate the production of acute phase proteins depending on the presence of other factors.

Subcutaneous administration of hepatitis B immune globulin in combination with lamivudine following orthotopic liver transplantation: effective prophylaxis against recurrence.

Prophylaxis against recurrent hepatitis B virus (HBV) infection with hepatitis B immune globulin (HBIG), in combination with antiviral agents such as lamivudine, has allowed transplantation for this condition to become feasible and accepted. Current protocols allow for HBIG administration either intravenously or intramuscularly. To date, there has been no reported experience with the subcutaneous route of post-transplant HBIG delivery. We report our experience of a 60-yr-old man for whom liver transplantation was performed for chronic HBV. HBIG was administered intramuscularly during the anhepatic phase of surgery. The finding of a portal vein thrombosis requiring repeated thrombectomy necessitated chronic anticoagulation. Post-operatively, HBIG was administered subcutaneously, in four separate injections, for a daily dose of 2170 IU along with continued lamivudine dosing. Hepatitis B surface antibody (anti-HBs) titres reached a serum concentration of >500 IU/L by seven d post-transplant and approximately 1000 IU/L by nine d post-transplant. Five months post-transplant, with continued combination of subcutaneous HBIG and lamivudine, there has been no recurrent HBV infection and anti-HBs titres have been at target levels. Our experience suggests that subcutaneous delivery of HBIG may be a feasible consideration when intramuscular/intravenous dosing is not possible.

Eicosapentaenoic acid perturbs signalling via the NFkappaB transcriptional pathway in pancreatic tumour cells.

In addition to various roles in membrane structure and metabolism, polyunsaturated fatty acids have effects on signal transduction and on the regulation of gene expression. Eicosapentaenoic acid (EPA) is an omega-3 fatty acid which is known to induce cell cycle arrest and apoptosis in pancreatic tumour cells. NFkappaB is a key transcription factor regulating genes involved in the immune response and has been implicated in apoptotic pathways. In this study we investigated the effect of eicosapentanoic acid on the NFkappaB pathway in pancreatic tumour cells. The pancreatic cell line MIA PaCa2 was incubated in the presence of the fatty acids EPA (n-3), arachidonic acid (AA, n-6) or oleic acid (OA, n-9) before pulsing with TNF to provide a kinetic assessment of NFkappaB activation and IkappaBalpha degradation. Pre-incubation of pancreatic cells with EPA or AA for 2 h before pulsing with TNF preserved IkappaBalpha but did not prevent NFkappaB activation. Indeed, NFkappaB activation was prolonged after exposure to EPA. N-acetyl-L-cysteine did not influence the effect of EPA on TNF-stimulated IkappaBalpha degradation. These results suggest that the omega-3 fatty acid EPA perturbs the NFkappaB pathway by a novel mechanism. This mechanism may be important in delineating alternative pathways to NFkappaB activation.

Diagnosis and early management of acute pancreatitis.

Acute pancreatitis is a common emergency with the potential for significant complications. Despite advances in the understanding of the pathogenetic mechanisms of acute pancreatitis and the completion of a number of randomized trials studying specific therapies, the early management of patients remains supportive.