Endoscopic ultrasound: valuable tool for diagnosis of biliary complications in liver transplant recipients?

BACKGROUND: Biliary complications after liver transplantation (LT) are still common and are an important cause of mortality and morbidity. Until now, endoscopic retrograde cholangiopancreatography (ERCP) has been considered the gold standard for diagnosing such complications. The aim of this study was to evaluate the diagnostic yield and therapeutic impact of endoscopic ultrasound (EUS) in the management of biliary complications after LT. METHODS: Thirty-seven liver transplant patients who presented with clinical, biochemical, sonographic, and/or histological evidence of biliary complications, and who first received EUS followed by ERCP, were enrolled into this prospective observational study. Subsequently, we evaluated the value of EUS in detecting and classifying biliary complications after LT. RESULTS: Thirty-seven biliary complications were detected in 32 patients. Endoscopic ultrasound showed an overall sensitivity and accuracy of 94.6 % each. In cases of biliary cast and ischemic cholangiopathy, EUS was found to be diagnostically superior to ERCP and has had, in these cases, a significant impact on clinical decision-making. However, EUS was less reliable when diagnosing anastomotic strictures. CONCLUSION: EUS can complement ERCP to improve diagnosis of biliary complications after LT and help guide treatment strategies to address these complications.

MicroRNA-101 inhibits human hepatocellular carcinoma progression through EZH2 downregulation and increased cytostatic drug sensitivity.

BACKGROUND & AIMS: Oncogene polycomb group protein enhancer of zeste homolog 2 (EZH2) has been proposed to be a target gene of putative tumor suppressor microRNA-101 (miR-101). The aim of our study was to investigate the functional role of both miR-101 and EZH2 in human hepatocellular carcinoma (HCC). METHODS: MiR-101 and EZH2 expressions were evaluated in tumor tissues of 99 HCC patients and 7 liver cancer cell lines by real-time PCR. Luciferase reporter assay was employed to validate whether EZH2 represents a target gene of miR-101. The effect of miR-101 on HCC growth as well as programmed cell death was studied in vitro and in vivo. RESULTS: MiR-101 expression was significantly downregulated in most of HCC tissues and all cell lines, whereas EZH2 was significantly overexpressed in most of HCC tissues and all cell lines. There was a negative correlation between expression levels of miR-101 and EZH2. Luciferase assay results confirmed EZH2 as a direct target gene of miR-101, which negatively regulates EZH2 expression in HCC. Ectopic overexpression of miR-101 dramatically repressed proliferation, invasion, colony formation as well as cell cycle progression in vitro and suppressed tumorigenicity in vivo. Furthermore, miR-101 inhibited autophagy and synergized with either doxorubicin or fluorouracil to induce apoptosis in tumor cells. CONCLUSION: Tumor suppressor miR-101 represses HCC progression through directly targeting EZH2 oncogene and sensitizes liver cancer cells to chemotherapeutic treatment. Our findings provide significant insights into molecular mechanisms of hepatocarcinogenesis and may have clinical relevance for the development of novel targeted therapies for HCC.

Hepatitis B and C in liver transplantation: new strategies to combat the enemies.

Hepatitis B immune globulin-free therapeutic regimens with a nucleos(t)ide analogue (NUC) or NUC combinations after liver transplantation (LT) are currently being investigated for their efficacy and safety as HBV re-infection prophylaxis in clinical studies. Recurrence rates differ among these studies as most of them are limited by a non-randomised study design, small sample size, lack of long-term data and varying time intervals for the switch from combined to purely virostatic prophylaxis. Post-transplant pre-emptive antiviral therapy with pegylated IFN and ribavirin is associated with low sustained virological response rates and was found to have no advantage over treatment of manifest HCV re-infection. Safety and efficacy of triple antiviral therapy including boceprevir or telaprevir in patients with manifest HCV re-infection are currently under investigation in clinical trials. Relevant drug interactions have been shown to occur during calcineurin inhibitor (CNI) and concomitant triple antiviral therapy, which vary with type of CNI and choice of HCV protease inhibitor. Newer direct-acting antivirals with lower or minimal toxicity, when used in combination with immunosuppressives, are worthy of further study in LT patients. This review focuses on hot topics in the management of hepatitis B and C patients before and after LT and offers a critical summarised selection of the corresponding relevant studies published in the current literature or presented at recent liver congresses.

Calcineurin inhibitors in liver transplantation - still champions or threatened by serious competitors?

Current strategies for immunosuppression in liver transplant (LT) recipients include the design of protocols targeting a more individualized approach to reduce risk factors such as renal failure, cardiovascular complications and malignancies. Renal injury in LT recipients may be often multifactorial and is associated with increased risk of post-transplant morbidity and mortality. The quest for low toxicity immunosuppressive regimens has been challenging and resulted in CNI minimization protocols or CNI withdrawal and conversion to mycophenolate mofetil (MMF) and/or mammalian target of rapamycin inhibitor-based immunosuppressive regimens. Use of antibody induction to delay CNI administration may be an option in particular in immunocompromized, critically ill patients with high MELD scores. Protocols including MMF introduction and concomitant CNI minimization have the potential to recover renal function even in the medium and long term after LT. We review on hot topics in the prevention and management of acute and chronic renal injury in LT patients. For this purpose, we present and critically discuss results from immunosuppressive studies published in the current literature or presented at recent LT meetings.

Strategies to prevent or reduce acute and chronic kidney injury in liver transplantation.

Acute kidney injury (AKI) has a major impact on short- and long-term survival in liver transplant (LT) patients. There is no currently accepted uniform definition of AKI, which would facilitate standardization of the care of patients with AKI and to improve and enhance collaborative research efforts. New promising biomarkers such as neutrophil gelatinase-associated lipocalin or kidney injury molecule-1 have been developed for the prevention of delayed AKI treatment. Early dialysis has been shown to be beneficial in patients with AKI stage III according to the classification of the Acute Kidney Injury Network, whereas treatment with loop diuretics or dopamine is associated with worse outcome. The mainstay for the prevention of AKI seems to be avoidance of volume depletion and maintenance of a mean arterial pressure >65 mmHg. Although the aetiology of chronic kidney disease in transplant recipients may be multifactorial, calcineurin-inhibitor (CNI)-induced nephrotoxicity significantly contributes to the development of renal dysfunction over time after LT. The delayed introduction of CNI at minimal doses has shown to be safe and effective for the preservation of kidney function. Other strategies to overcome CNI nephrotoxicity include CNI minimization protocols or CNI withdrawal and conversion to mycophenolate mofetil or the mammalian target of rapamycin inhibitor-based immunosuppressive regimens. However, CNI avoidance may bear a higher rejection risk. Thus, more results from randomized-controlled studies are urgently warranted to determine which drug combinations are the most beneficial approaches for the potential introduction of CNI-free immunosuppressive regimens.

Genetic, immunological and clinical risk factors for biliary strictures following liver transplantation.

BACKGROUND: Biliary strictures after liver transplantation (LT) are a major cause of morbidity and reduced graft survival. AIMS: The purpose of this study was to investigate genetic, immunological and clinical risk factors for the occurrence of post-LT ischaemic type biliary lesions (ITBLs) and biliary anastomotic strictures (AS). METHODS: Clinical and laboratory data, chemokine receptor (CCR) genotypes, chemotactic cytokines and anti-major-histocompatibility complex antibodies in serum were investigated in 162 LT patients. RESULTS: In the univariate analysis, older donor and recipient age, partial LT, high peak aspartate aminotransaminase (AST) levels and CC chemokine receptor 5 delta32 loss-of-function mutation (CCR5Δ32) were associated with ITBL, whereas LT for acute liver failure (ALF), ABO-compatible non-identical LT, presence of donor-specific anti-human leucocyte antigen (HLA) class II antibodies and fractalkine receptor (CX3CR1)-249II allele were associated with AS. In the multivariate analysis, CCR5Δ32 was an independent risk factor for ITBL, whereas LT for ALF, ABO-compatible non-identical LT, and CX3CR1-249II allele remained predictive for AS. Serum levels of interferon-gamma and interleukin (IL)-6 as well as IL-10 were significantly increased in patients with biliary strictures. CONCLUSION: Specific chemokine receptor polymorphisms of the recipient are associated with development of post-LT biliary strictures. Altered cytokine profile may contribute to enhanced fibrotic tissue remodelling and biliary stricture formation. Screening of anti-HLA antibodies might be useful for early identification of at-risk patients who could benefit from closer surveillance and tailored immunosuppressive regimen. Our findings may have relevance for prediction and management of post-LT biliary strictures.

Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and long-term survival.

UNLABELLED: Radioembolization has been demonstrated to allow locoregional therapy of patients with hepatocellular carcinoma not eligible for transarterial chemoembolization or other local therapies. The aim of this study was to validate evidence of the safety and efficacy of this treatment in a European sample of patients with advanced hepatocellular carcinoma (HCC). Therefore, 108 consecutive patients with advanced HCC and liver cirrhosis were included. Yttrium-90 (Y-90) microspheres were administered in a lobar fashion over the right or left branch of the hepatic artery. The response to treatment was evaluated by computed tomography (CT) imaging applying Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO) criteria with recent European Association for the Study of the Liver / National Cancer Institute (EASL/NCI) amendments. Time to progression (TTP) and overall survival were estimated by the Kaplan-Meier method. In all, 159 treatment sessions were performed ranging between one to three treatments per patient. The mean radiation dose per treatment was 120 (± 18) Gy. According to EASL criteria, complete responses were determined in 3% of patients, partial responses in 37%, stable disease 53%, and primary progression in 6% of patients. TTP was 10.0 months, whereas the median overall survival was 16.4 months. No lung or visceral toxicity was observed. The most frequently observed adverse events was a transient fatigue-syndrome. CONCLUSION: Radioembolization with Y-90 glass microspheres for patients with advanced HCC is a safe and effective treatment which can be utilized even in patients with compromised liver function. Because TTP and survival appear to be comparable to systemic therapy in selected patients with advanced HCC, randomized controlled trials in combination with systemic therapy are warranted.

Liver transplantation with donors over the expected lifespan in the model for end-staged liver disease era: is Mother Nature punishing us?

BACKGROUND: The lack of sufficient donors to satisfy the waiting list requirements has prompted many to expand the acceptance criteria. The purpose of this study was to evaluate our liver transplantation (LT) experience with donors beyond the average lifespan. PATIENTS AND METHODS: From January 2008 to December 2009, we received 75 liver offers involving donors ≥ 75 years of age. Donor and recipient data were analysed by both uni- and multivariate Cox proportional hazard model analyses. RESULTS: We performed 32 adult liver transplants (43%). Half of the patients received organs through rescue allocations. Seven recipients (22%) developed initial poor function. Two had primary graft non-function (PNF). Four recipients were re-transplanted (two PNF and two ischaemic-type bile lesions). One- and 3-year cumulative survival was 62 and 51% respectively. PNF, lab model for end-staged liver disease (MELD), post-LT haemodialysis, post-LT re-operations and post-LT sepsis were significant predictors by univariate analysis. Only PNF reached multivariate significance (P = 0.0307). Rescue offer allocation reached significance as a predictor of PNF by general linear model forward analysis. One- and 3-year 'MELD based allocation' (n = 16) vs 'rescue allocation' (n = 16) survival rates were 44 and 29% vs 82 and 76% respectively (P = 0.0197). CONCLUSIONS: Although grafts from donors ≥ 75 years allow for an expansion of the donor pool, long-term recipient survival is inferior to that encountered with younger donors. Acceptable results could be obtained by identifying 'preferred' recipients for rescue allocations.

Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice-daily tacrolimus-based regimen to once-daily tacrolimus extended-release formulation.

The aim of this study was to determine the efficacy, safety, and immunosuppressant adherence in 125 stable liver transplant (LT) patients converted from twice-daily tacrolimus (TAC BID) to once-daily TAC (TAC OD). Tacrolimus trough levels, laboratory parameters, metabolic disorders, selected patient reported outcomes, and adverse events were assessed. Mean TAC trough level concentration was 6.1 ± 2.3 ng/ml at study entry, decreased to 5.5 ± 2.1 ng/ml (P = 0.016) and 5.5 ± 2.2 ng/ml (P = 0.019) after 1 and 2 weeks, respectively, and tended to equal the baseline value during further follow-up. At week 1, TAC concentrations were lower in 62.4% of patients and higher in 36.0% when compared with baseline. Renal and cardiovascular risk factors remained stable and no rejection episodes occurred over 12 months. Adverse events were consistent with the safety profile known from previous studies with TAC BID. Nonadherence measured by the "Basel Assessment of Adherence Scale to Immunosuppressives" was evident in 66.4% at study entry and decreased to 30.9% postconversion (P < 0.0001). Prevalence of nonadherence at baseline was significantly higher in patients converted >2 years after LT and in those ≤60 years of age. Conversion to TAC OD is safe, enhances immunosuppressant adherence and should be accompanied by a close TAC level monitoring during the initial period.

Changes in staging for hepatocellular carcinoma after radiofrequency ablation prior to liver transplantation as found in the explanted liver.

BACKGROUND/AIMS: To analyze the efficacy of radiofrequency ablation (RFA) prior to liver transplantation (LT) in liver explants. METHODOLOGY: We reviewed pathological findings in the explanted livers of 13 patients with histologically proven HCC and liver cirrhosis who underwent RFA as bridging treatment prior to LT. Eight patients had solitary nodules with a median diameter of 4cm, whereas five patients had two tumors each with a median total diameter of 3.3cm prior to RFA. One session of RFA was performed by all patients. RESULTS: Tumor regression was proved in 3/13 patients whereas steady disease was observed in 5/13 patients (38%). Tumor regression was observed only in one of the five patients having two tumors prior to RFA. Pathology proved a multifocal tumor in four patients, including one patient with a radiological presumed solitary tumor. Tumor progression was observed in 5/13 patients (38%). CONCLUSIONS: Although the majority of our patients (8/13, 62%) had a solitary tumor at the beginning of treatment, tumor progression was observed in a large proportion (38%) among them. The underestimation of tumor lesions in radiology and partial necrosis of the tumor achieved in most patients limit the role of RFA as bridging treatment prior to LT.

Drainage patterns of right and accessory hepatic veins: anatomical-functional classification derived from 3-dimensional CT reconstructions.

BACKGROUND/AIMS: Inadequate knowledge of the right (RHV) and accessory (IHV) hepatic 'venous drainage' territories can lead to severe postoperative venous congestion after right graft live donor liver transplantation. The purpose of our study was to define the anatomical-functional RHV and IHV drainage territories. METHODOLOGY: One hundred and forty consecutive live liver donor candidates were evaluated by means of 3-D CT reconstructions and 3-D virtual hepatectomies. Three RHV/IHV drainage patterns were identified and 'risky' configurations for right graft resections were defined. RESULTS: Livers with 'small' IHV drainage volumes (90.1±63.2mL) had dominant type IRHV/ IHV or non-dominant type III-RHV/IHV total liver (TL) complexes. All other cases had 'large' IHV volumes (294.7±115.5mL, p<0.001) with dominant type II-RHV/IHV TL complexes. Loss of IHV drainage volume (such as with no IHV reconstruction) in these cases was associated with a 'dominance transition' from right (RHV) to middle (MHV) hepatic veins, placing the grafts at 'high risk' for venous congestion. CONCLUSIONS: Type II-RHV/IHV complexes with large IHV drainage volumes are at 'high risk' for venous congestion in live donor liver transplantation.

Role of microRNA-199a-5p and discoidin domain receptor 1 in human hepatocellular carcinoma invasion.

BACKGROUND: Micro-ribonucleic acid (miRNA)-199a-5p has been reported to be decreased in hepatocellular carcinoma (HCC) compared to normal tissue. Discoidin domain receptor-1 (DDR1) tyrosine kinase, involved in cell invasion-related signaling pathway, was predicted to be a potential target of miR-199a-5p by the use of miRNA target prediction algorithms. The aim of this study was to investigate the role of miR-199a-5p and DDR1 in HCC invasion. METHODS: Mature miR-199a-5p and DDR1 expression were evaluated in tumor and adjacent non-tumor liver tissues from 23 patients with HCC undergoing liver resection and five hepatoma cell lines by the use of real-time quantitative RT-PCR (qRT-PCR) analysis. The effect of aberrant miR-199a-5p expression on cell invasion was assessed in vitro using HepG2 and SNU-182 hepatoma cell lines. Luciferase reporter assay was employed to validate DDR1 as a putative miR-199a-5p target gene. Regulation of DDR1 expression by miR-199a-5p was assessed by the use qRT-PCR and western blotting analysis. RESULTS: A significant down-regulation of miR-199a-5p was observed in 65.2% of HCC tissues and in four of five cell lines. In contrast, DDR1 expression was significantly increased in 52.2% of HCC samples and in two of five cell lines. Increased DDR1 expression in HCC was associated with advanced tumor stage. DDR1 was shown to be a direct target of miR-199a-5p by luciferase reporter assay. Transfection of miR-199a-5p inhibited invasion of HepG2 but not SNU-182 hepatoma cells. CONCLUSIONS: Decreased expression of miR-199a-5p contributes to increased cell invasion by functional deregulation of DDR1 activity in HCC. However, the effect of miR-199a-5p on DDR1 varies among individuals and hepatoma cell lines. These findings may have significant translational relevance for development of new targeted therapies as well as prognostic prediction for patients with HCC.

Identification of a 17beta-hydroxysteroid dehydrogenase type 12 pseudogene as the source of a highly restricted BALB/c Meth A tumor rejection peptide.

Mass spectrometric analysis identified the peptide recognized by a cytotoxic T lymphocyte (CTL) specific for the chemically induced BALB/c Meth A sarcoma as derived from a 17beta-hydroxysteroid dehydrogenase type 12 (Hsd17b12) pseudogene present in the BALB/c genome, but only expressed in Meth A sarcoma. The sequence of the peptide is TYDKIKTGL and corresponds to Hsd17b12(114-122) with threonine instead of isoleucine at codon 114 and is designated Hsd17b12(114T). Immunization of mice with an Hsd17b12(114T) peptide-pulsed dendritic cell-based vaccine or a non-viral plasmid construct expressing the Hsd17b12(114T) peptide protected the mice from lethal Meth A tumor challenge in tumor rejection assays. A Hsd17b12(114-122) peptide-pulsed vaccine was ineffective in inducing resistance in mice to Meth A sarcoma. These results confirm the immunogenicity of the identified tumor peptide, as well as demonstrate the efficacies of these vaccine vehicles. These findings suggest that the role of the human homolog of Hsd17b12, HSD17B12, as a potential human tumor antigen be explored.

Diagnosis of tuberculosis infection in patients awaiting liver transplantation.

This study examined the performance of a tuberculosis (TB)-specific enzyme-linked immunospot assay in 48 patients awaiting liver transplantation. They were tested with T-SPOT.TB, tuberculin skin test (TST), and lymphocyte transformation test (LTT) using tuberculin as a stimulus. A questionnaire was used to gain information on TB exposure. Four patients were defined as positive by T-SPOT.TB, 6 by TST, and 28 by LTT. The patients displaying positive results to T-SPOT.TB were also positive in the TST and LTT. We considered them to have latent TB because they were repeatedly (two or three times) positive to the T-SPOT.TB and reported TB exposure. Active TB was excluded by negative multislice computed tomography, negative culture, and absence of symptoms. In 1 patient, T-cell reactivity toward TB peptides was lost 1 and 2 months posttransplantation. Another patient, however, tested 8 and 13 months posttransplantation, displayed measurable cellular TB immune responses. This finding suggests that the measurement of cellular TB immune responses shortly after transplantation may fail. If possible, patients with end-stage liver disease should be screened for TB prior to transplantation. Our data are the first evidence that T-SPOT.TB may be useful to diagnose latent TB in patients awaiting liver transplantation.

Phosphorylation of p70S6 kinase predicts overall survival in patients with clear margin-resected hepatocellular carcinoma.

BACKGROUND/AIMS: The mammalian target of rapamycin (mTOR) inhibitors play a key role in regulating signal transduction by blocking the mTOR pathway and combining anticancer and immunosuppressive properties. This study was undertaken to determine the prevalence and clinicopathological relevance of phospho-p70S6 (p-p70S6) kinase in hepatocellular carcinoma (HCC) and to investigate the effects of rapamycin on HCC in vitro. METHODS: A total of 196 patients with HCCs were treated either with surgical resection (n=106) or liver transplantation (n=90). Tumour tissue was investigated for p-p70S6, phospho-AKT, Ki-67, Cyclin-D1 and apoptosis, and staining results were correlated with clinicopathologically relevant parameters. RESULTS: Overall, p-p70S6 was detected in 24.5% (48/196) of HCCs. In the resection group, 26.4% (28/106) of HCC were positive and 22.2% (20/90) in the transplant group. p-p70S6 was significantly associated with elevated Cyclin-D1 immunoexpression and was correlated with decreased overall survival (P=0.011) in patients resected with a clear margin. In multivariate COX regression analysis, p-p70S6 was identified as an independent prognostic parameter in patients resected with a clear margin. Rapamycin induced apoptosis and growth inhibition by G0/G1 cell cycle arrest in vitro. However, in HCC patients p-p70S6 kinase was not associated with proliferation or apoptosis. CONCLUSIONS: Activation of p70S6 kinase indicates aggressive tumour behaviour in patients with clear margin-resected HCC. Identification of p-p70S6 kinase in HCC selects high-risk patients who may benefit from drugs targeting the mTOR pathway.

Validation of putative reference genes for gene expression studies in human hepatocellular carcinoma using real-time quantitative RT-PCR.

BACKGROUND: Reference genes, which are often referred to as housekeeping genes are frequently used to normalize mRNA levels between different samples in quantitative reverse transcription polymerase chain reaction (qRT-PCR). The selection of reference genes is critical for gene expression studies because the expression of these genes may vary among tissues or cells and may change under certain circumstances. Here, a systematic evaluation of six putative reference genes for gene expression studies in human hepatocellular carcinoma (HCC) is presented. METHODS: Six genes, beta-2-microglobulin (B2M), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), hydroxymethyl-bilane synthase (HMBS), hypoxanthine phosphoribosyl-transferase 1 (HPRT1), succinate dehydrogenase complex, subunit A (SDHA) and ubiquitin C (UBC), with distinct functional characteristics and expression patterns were evaluated by qRT-PCR. Inhibitory substances in RNA samples were quantitatively assessed and controlled using an external RNA control. The stability of selected reference genes was analyzed using both geNorm and NormFinder software. RESULTS: HMBS and GAPDH were identified as the optimal reference genes for normalizing gene expression data between paired tumoral and adjacent non-tumoral tissues derived from patients with HCC. HMBS, GAPDH and UBC were identified to be suitable for the normalization of gene expression data among tumor tissues; whereas the combination of HMBS, B2M, SDHA and GAPDH was suitable for normalizing gene expression data among five liver cancer cell lines, namely Hep3B, HepG2, HuH7, SK-HEP-1 and SNU-182. The determined gene stability was increased after exclusion of RNA samples containing relatively higher inhibitory substances. CONCLUSION: Of six genes studied, HMBS was found to be the single best reference gene for gene expression studies in HCC. The appropriate choice of combination of more than one reference gene to improve qRT-PCR accuracy depends on the kind of liver tissues or cells under investigation. Quantitative assessment and control of qRT-PCR inhibitors using an external RNA control can reduce the variation of qRT-PCR assay and facilitate the evaluation of gene stability. Our results may facilitate the choice of reference genes for expression studies in HCC.

Liver transplantation for hepatocellular carcinoma and cirrhosis in candidates with undetectable or very low alpha-fetoprotein levels: is an expansion of the listing criteria justified?

BACKGROUND: Liver transplantation (LT) is the optimal therapy for hepatocellular carcinoma (HCC) in the setting of cirrhosis. The purpose of this study was to evaluate the results after LT for HCC patients with very low alpha fetoprotein (AFP) values both in our series and in literature reports. METHODOLOGY: Data obtained prospectively on 51 transplanted patients with HCC having AFP values < 30 ng/mL preoperatively were analyzed. RESULTS: Four-year overall and recurrence-free survival was 81% and 79%, respectively (median follow up of 35 months). Twenty nine patients (57%) were within the Milan criteria. Thirteen patients (25%) demonstrated advanced tumor stages. Ablative bridging treatments were attempted in 27 instances, and were associated with significantly worse overall and recurrence-free survivals (p=0.0209 and p=0.0111, respectively). Patients with AFP values < 30 ng/mL and no bridging treatments experienced 4-year overall and recurrence-free survivals of 96% and 95%, respectively. CONCLUSIONS: HCC patients with AFP values < 30 ng/mL who undergo LT with no bridging treatments experience excellent overall and recurrence-free survival rates, even with advanced tumor stages, independent of the Milan listing criteria.

[Current concepts for prophylaxis and treatment of hepatitis B virus reinfection after liver transplantation]. / Aktuelle Konzepte zur Prophylaxe und Behandlung der Hepatitis-B-Virus-Reinfektion nach Lebertransplantation.

Pretransplant complete viral suppression and posttransplant combined hepatitis B immunglobulin (HBIG)/nucleos(t)ide analog therapy lead to successful prevention of hepatitis B virus (HBV) reinfection in approximately 95% of HBV patients. Low-dose intramuscular HBIG protocols have yielded cost reduction by > 50%. However, passive immunoprophylaxis is still expensive and requires close monitoring of the liver transplant (LT) patient. HBIG-free therapeutic regimens with new promising nucleos(t)ide analog combinations are currently being investigated for their efficacy and safety as first-line therapy in clinical studies.Third-generation HBV vaccines, including the S, pre-S1, and pre-S2 regions or combination vaccines with immunostimulatory adjuvants, seem to be more immunogenic than the currently available vaccines and may allow long-term discontinuation of HBIG in selected responders. Adoptive transfer of immunity against HBV was successful in some LT patients in clinical studies. Future investigations need to elucidate, if donor-derived immunity is a transient immunologic phenomenon or persistently controls HBV.

Acute allograft rejection in liver transplant recipients: Incidence, risk factors, treatment success, and impact on graft failure.

Objective This study was performed to identify risk factors for acute cellular rejection after liver transplantation (LT). Methods Consecutive LT recipients who underwent surgery in our institution from 2002 to 2015 were retrospectively evaluated. Results In total, 176 patients were eligible for statistical analysis. During a mean observation period of 61.1 ± 36.3 months, 43 episodes of acute rejection were evident. Of these, 34 (79.0%) were responsive to methylprednisolone, 3 (7.0%) were treated by adjusting the dosage of immunosuppressive agents, and 6 (14.0%) were methylprednisolone-resistant and treated using anti-thymocyte globulin. Biliary complications (odds ratio [OR] = 4.89, 95% confidence interval [CI] = 2.00-11.98); donor-negative, recipient-positive CMV mismatch (OR = 9.88, 95% CI = 1.18-82.36); sex mismatch (OR = 3.16, 95% CI = 1.31-8.10); and sex mismatch with a female donor (OR = 3.00, 95% CI = 1.10-7.58) were identified as significant risk factors for acute graft rejection after LT. Conclusion In patients who develop acute cellular rejection after LT, biliary complications should be evaluated as a potential cause. Most acute rejections after LT respond to bolus corticosteroid therapy.

Predictors of graft and patient survival in hepatitis C virus (HCV) recipients: model to predict HCV cirrhosis after liver transplantation.

BACKGROUND: Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is almost universal, but the natural history of recurrent HCV in the allograft is highly variable. Our study had two aims: 1) to assess the impact of different pre- and postLT factors on graft and patient survival in HCV transplant recipients and 2) to create a model which may predict the patients at risk for HCV-related graft cirrhosis at 5 years postLT. METHODS: A total of 168 LTs were considered for this study. Univariate and multivariate Cox proportional hazards regression model was used, as well as logistic regression analysis to create a model of prediction of HCV cirrhosis within 5 years after LT. RESULTS: Predictive factors for both decreased graft and patient survival included patients recently transplanted (2000-2004), induction without azathioprine, short-term therapy with mycophenolate mofetil and prednisone (< or =6 months), presence of early cholestasis, histologically proven early recurrence of hepatitis C. Recipient human leukocyte antigen DR3 positivity, presence of early cholestasis, and donor age >50 years were identified as independent predictors of graft cirrhosis within 5 years. A predictive model was established in order to calculate at 6 months a risk score for graft HCV cirrhosis within 5 years postLT using a formula that included the identified independent predictors. The area under receiver operating characteristic curve was 0.83, indicating a good ability to predict medium-term HCV allograft cirrhosis. CONCLUSION: This model may be a useful tool for better identifying high-risk HCV patients who should be selected for early initiation of antiviral therapy.