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Background An accelerated course of hepatic fibrosis may occur in liver transplantation (LT) patients despite normal or slightly abnormal liver blood tests. Aim To identify screening tools based on blood biomarkers to predict late allograft dysfunction in LT recipients. Methods 174 LT recipients were enrolled. Liver biopsy, liver functional tests, cytokine quantitation in serum, as well as soluble MHC class I polypeptide-related sequence A and B (sMICA/sMICB) and soluble UL16 binding protein 2 (sULBP2) were performed. Results Patients with late graft dysfunction had a significantly higher donor age, lower albumin level, higher alanine (ALT) and aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), total bilirubin and alkaline phosphatase (ALP), higher sMICA, sULBP2, higher interleukin (IL) 6, interferon γ and lower IL10 in serum as compared to recipients without allograft dysfunction. In order to provide a better statistical accuracy for discriminating 5-year allograft dysfunction from other less progressive subtype of allograft injury, we established a predictive model, based on 7 parameters (serum ALP, ALT, AST, GGT, sMICA, IL6 and albumin) which provided an Area Under the Receiver Operating Characteristics (AUROC) curve of 0.905. Conclusions Blood-based biomarkers can significantly improve prediction of late liver allograft outcome in LT patients. The new developed score comprising serum parameters, with an excellent AUROC, can be reliably used for diagnosing late allograft dysfunction in transplanted patients.

Background With regard to quality of life and organ shortage, follow-up after liver transplantation (LT) should consider risk factors for allograft failure in order to avoid the need for re-LT and to improve the long-term outcome of recipients. Therefore, the aim of this study was to explore potential risk factors for allograft failure after LT. Material and methods A total of 489 consecutive LT recipients who received follow-up care at the University Hospital of Muenster were included in this study. Database research was performed, and patient data were retrospectively reviewed. Risk factors related to donor and recipient characteristics potentially leading to allograft failure were statistically investigated using binary logistic regression analysis. Graft failure was determined as graft cirrhosis, need for re-LT because of graft dysfunction, and/or allograft-associated death. Results The mean age of recipients at the time of LT was 50.3 ± 12.4 years, and 64.0 % were male. The mean age of donors was 48.7 ± 15.5 years. Multivariable statistical analysis revealed male recipient gender (p = 0.04), hepatitis C virus infection (HCV) (p = 0.014), hepatocellular carcinoma (HCC) (p = 0.03), biliary complications after LT (p Conclusion Male recipients, patients who received LT for HCV or HCC, those with pretransplant diabetes mellitus, and LT recipients with biliary complications are at high risk for allograft failure and thus should be monitored closely.

The significance of humoral immune response for allograft survival after liver transplantation (LT) is still a matter of debate. The aim of this cross-sectional study was to assess immunological and clinical factors associated with advanced fibrosis (F3-F4) and chronic graft failure in LT recipients.Serum samples from 174 patients prospectively enrolled and followed up for 12 months were tested for anti-HLA antibodies and compared against donor HLA types. Immunohistochemical C4d staining was performed on formalin-fixed, paraffin-embedded liver tissue.Mean time period from LT to enrollment was 66.9 ± 51.9 months. Independent predictive factors for graft failure included donor-positive cytomegalovirus serostatus (P = 0.02), donor-specific antibodies (DSA) against HLA class II (P = 0.03), donor age (P = 0.01), hepatitis C virus allograft reinfection (P = 0.0008), and biliary complications (P = 0.003). HLA class II DSA and HLA class I antibody positivity, hepatitis C virus reinfection, and mycophenolate mofetil-free regimens were significant risk factors for advanced fibrosis after LT. There was a significant association between C4d deposition on allograft endothelial cells and presence of class II DSA (P0.0001). Patients with C4d deposits had a 4.3 times higher risk of graft failure than those with negative staining and a significantly lower median time to graft failure (94.6 months [range, 3.6-158.9 months] vs 176.4 months [range, 9.4-217.8 months], P0.0001).Screening for HLA DSA might be useful for early identification of LT recipients at increased risk of graft failure who could benefit from closer surveillance and tailored immunosuppressive regimens.

This report describes how donor- and recipient-derived immunity was influenced by immunosuppressive treatment of ABO incompatibility (rituximab and immunoadsorption/plasmaphereses) in the long-term. We present an 8-year course of Hepatitis B virus (HBV) immunity, isohemagglutinins and B cell numbers. Whereas cellular HBV immunity was transferred from the HBV vaccinated donor (blood group A1) to the HBV naïve recipient (blood group 0), humoral HBV specific immune transfer was lacking. Starting at month 17 after transplantation, the recipient was vaccinated six times against HBV. Anti-HBs did not appear until the sixth vaccination at month 44. Immunoadsorption prior to transplantation reduced anti-A1 IgG titers from 256 to 2. Titers after transplantation remained low (⩽64). B cell numbers were below standard values up to month 26, then normalized and exceeded normal values from year 7 to 8 post transplantation. In conclusion, donor-derived B cell immunity was lost but recipient-derived immunity persisted after ABO incompatible transplantation.

We report on a small bowel transplant patient, donor/recipient seropositive (D+/R+) for cytomegalovirus (CMV), with a clinical course complicated by CMV disease. Anti-CMV prophylaxis was given for 100 days. Immunosuppression consisted of alemtuzumab, tacrolimus, mycophenolate mofetil and prednisolone. Five months posttransplant, CMV tissue invasive disease of the upper gastrointestinal tract was evident without the presence of viremia, tested by quantitative polymerase chain reaction (PCR). Complete viral load suppression was achieved with intravenous ganciclovir, followed by valganciclovir for secondary prophylaxis. Mycophenolate mofetil and prednisolone were discontinued. Shortly thereafter the patient presented with recurrent CMV and candida esophagitis. While on ganciclovir and caspofungin, the patient developed CMV tissue invasive disease of the ileal graft, with persistent absence of viremia. Foscarnet and CMV immunoglobulin were added. Viral load declined to undetectable levels; however, clinical improvement did not occur due to occurrence of graft rejection. Despite infliximab and high dose prednisolone, graft rejection was progressive, requiring surgical explantation of the graft. This case highlights the importance of additional diagnostic tools such as endoscopy including PCR analysis of tissue samples. Extension of primary antiviral prophylaxis interval up to 6 months and prolonged retreatment for recurrent CMV disease may be useful to avoid severe CMV-related complications.

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.

BACKGROUND Subcutaneous self-administration of hepatitis B immunoglobulin (HBIg) prophylaxis is preferred by patients, but compliance with the assigned regimen in routine practice is undocumented. MATERIAL AND METHODS A prospective, observational, 18-week, open-label, single-arm, multicenter study assessed compliance and tolerability in maintenance liver transplant patients self-administering subcutaneous HBIg at home according to local practice. RESULTS Sixty-one patients were analyzed (median follow-up 18 weeks, range 14.0-27.9 weeks), with 961/1006 injections (95.5%) administered at home during the study. Other than in 4 patients, HBIg was prescribed for weekly administration (500 IU/L, n=39; 1000 IU/L, n=18) at study entry. Eighteen patients (29.5%) were assigned a dose lower than recommended in the Summary of Product Characteristics. The primary variable of compliance failure, defined as ≥ 1 hepatitis B surface antibody (anti-HBs) serum trough level

Background International data on training, work, and lifestyle of transplant physicians and surgeons are scarce. Such data might help in development of uniform education paths and provide insights for young clinicians interested in this field. This study aimed at the evaluation of these data in all transplant-associated medical disciplines. Methods A survey on professional and academic training, workload, and lifestyle was generated. The questionnaire was distributed to all members of the German Transplant Association (DTG), utilizing the tool SurveyMonkey(®) . Results A total of 127 members of the DTG responded (male/female 66.1%/33.9%, 45.8±10.3 years). The majority had been working in transplant medicine for more than 10 years (61.9%). Fifteen respondents (11.8%) obtained an official European certification (European Union of Medical Specialists). A total of 57 (48.3%) respondents worked full time on research during training. The research focus was clinical for most respondents (n=72, 61.5%). An average working time of 62±1.5 h/wk was reported. Fifty-eight percent of all respondents complained of inadequate remuneration and 50% reported inadequate acknowledgment of their professional performance. Conclusion This is the first study reporting characteristics of training, work, and lifestyle in an interdisciplinary cohort of German transplant physicians and surgeons. Enormous efforts in clinical and research work were reported, associated with high rates of professional and financial dissatisfaction.

The calcineurin inhibitor (CNI) tacrolimus (Tac) is an effective immunosuppressant used after liver transplantation (LTx), but is often associated with CNI nephrotoxicity. Currently, there is no simple clinical predictor for CNI nephrotoxicity after LTx. We hypothesized that the Tac metabolism rate - defined as the blood concentration normalized by its daily dose (the C/D ratio) - is associated with post-LTx renal impairment.We analyzed the relationship between the C/D ratio and post-transplant renal function in 179 patients who underwent LTx between 2000 and 2012 and were initially immunosuppressed with Tac, mycophenolate mofetil, and prednisolone. Six months after LTx, 115 patients were categorized into 1 of 2 groups based on their Tac C/D ratio (1.09 or ≥1.09): fast (n=58) or slow (n=57) metabolizers. The renal function was determined 36 months after LTx using the estimated glomerular filtration rate (eGFR) as described by Cockcroft and Gault.At the time of LTx there was no statistically significant difference between the eGFR of fast and slow metabolizers. Six months (P=0.016), 12 months (P=0.001), and 36 months (P=0.018) after LTx, fast Tac metabolizers had significantly more impaired renal function than slow metabolizers. Because of a presumption of CNI nephrotoxicity, 32.8% of fast metabolizers and 14.0% of slow metabolizers were switched from Tac to other immunosuppressants (P=0.027).In this study, the Tac metabolism rate appears to influence renal function after LTx, suggesting that a C/D ratio of1.09 is associated with increased CNI nephrotoxicity in LTx recipients.

BACKGROUND Preoperative imaging and donor selection are cardinal components of adult-to-adult live donor liver transplantation (ALDLT). The purpose of this study was to evaluate our three-dimensional (3D) computed tomography image-derived computer-assisted surgical planning (3D CASP) in ALDLT. METHODS Eighty-three consecutive ALDLTs (71 right and 12 left) were planned with 3D CASP. Graft, remnant, and total liver volume compliance were calculated and compared with actual intraoperative values. Computed risk analysis encompassing territorial liver mapping, functional (safely drained) volumes, and outflow congestion volumes in grafts and remnants allowed for the individualized management of the middle hepatic vein (MHV). RESULTS Graft volume compliance was 13.5%±4.4%. Three small-for-size (SFS) grafts with lethal SFS syndrome (SFSS) had nonsignificant volume compliance with maximal graft volume-body weight ratios of less than 0.83. Seven SFS grafts with reversible or absent SFSS showed maximal graft volume-body weight ratios of 0.9 to 1.16. Significant differences were identified for (a) virtual graft and remnant congestion volumes of risky versus nonrisky MHV types (49%±6% and 34%±7% vs. 29%±8% and 33%±12%, P

SUMMARY 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. Copyright © 2012 John Wiley & Sons, Ltd.

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.

The Bismuth-Corlette (BC) classification is the current preoperative standard to assess hilar cholangiocarcinomas (HC). The aim of this study is to evaluate the accuracy, sensitivity, and prognostic value of the BC classification. Data of patients undergoing resection for HC were analyzed. Endoscopic retrograde cholangiography and standard computed tomography were undertaken in all cases. Additional 3D-CT-reconstructions, magnetic resonance imaging, and percutaneous transhepatic cholangiography were obtained in selected patients. A systematic review and meta-analysis of the literature was performed. Ninety patients underwent resection of the hilar bile duct confluence, with right or left hemihepatectomy in 68 instances. The overall accuracy of the BC classification was 48 per cent. Rates of BC under- and over-estimation were 29 per cent and 23 per cent, respectively. The addition of MRI, 3D-CT-reconstructions, or percutaneous transhepatic cholangiography improved the accuracy to 49 per cent ( P = 1.0), 53 per cent ( P = 0.074), and 64 per cent ( P < 0.001), respectively. Lowest sensitivity rates were for BC Type IIIA/IIIB tumors. Meta-analysis of published BC data corresponding to 540 patients did not reach significance. The BC classification has low accuracy and no prognostic value in cases of HC undergoing resection.

Amphiregulin (AREG) is a ligand of the epidermal growth factor (EGF) receptor and may play a role in the development of cirrhosis and hepatocellular carcinoma in patients infected with hepatitis C virus (HCV). AREG showed an enhanced expression in HCV-infected human hepatoma cells according to gene array analysis. Therefore, we addressed the question about the role of AREG in HCV infection. AREG expression level was elevated in hepatoma cells containing a subgenomic HCV replicon or infected by HCV. Using a reporter assay, AREG promoter activity was found to be upregulated upon HCV infection. The enhanced AREG expression in hepatoma cells was partly caused by dsRNAs, HCV NS3 protein and autocrine stimulation. AREG was able to activate cellular signalling pathways including ERK, Akt and p38, promote cell proliferation, and protect cells from HCV-induced cell death. Further, knockdown of AREG expression increased the efficiency of HCV entry, as proven by HCV pseudoparticles reporter assay. However, the formation and release of infectious HCV particles were reduced by AREG silencing with a concomitant accumulation of intracellular HCV RNA pool, indicating that the assembly and release of HCV progeny may require AREG expression. Blocking the MAPK–ERK pathway by U0126 in Huh7.5.1 cells had a similar effect on HCV replication. In conclusion, HCV infection leads to an increase in AREG expression in hepatocytes. AREG expression is essential for efficient HCV assembly and virion release. Due to the activation of the cellular survival pathways, AREG may counteract HCV-induced apoptosis of infected hepatocytes and facilitate the development of liver cirrhosis and hepatocellular carcinoma.

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

Summary Hepatitis B re-infection prophylaxis is crucial for graft and recipient survival for transplanted patients and is administered routinely after liver transplantation for hepatitis B. Aim of the current study was the investigation of efficacy, safety and feasibility of home-treatment of a novel human hepatitis B immunoglobulin BT088 (Zutectra®) after weekly subcutaneous application in liver-transplanted patients. A total of 23 patients (5 female, 18 male, median age 51 years) were enrolled and switched from monthly IV to weekly SC hepatitis B immunoglobulin administration. During a period of 18 weeks (optional 24 weeks) anti-HBs levels, signs of re-infection, adverse events and feasibility of self-administration were studied. After 8 weeks of training patients showing good compliance and stable antibody titres were allowed to start self-administration at home. All patients maintained a safety level of >100 U/l anti-HBs. No failure was noted, no re-infection occurred. A total of 10 treatment-emergent events were assessed as related to study drug application (injection-site haematoma, headache, abdominal pain, fatigue and haematuria). High numbers of self-administration (287 vs. 122 by staff) demonstrated general feasibility of SC administration. Weekly subcutaneous administration of BT088 (Zutectra®– registered trade mark in the EU) is effective, safe and presents an easy-to-apply treatment option for combined hepatitis B virus re-infection prophylaxis in liver transplant patients (Eudra CT Number: 2005-003737-40).

Cirrhotic cardiomyopathy may appear following liver transplantation. Brain-natriuretic peptide (BNP) values exceeding 391 pg/ml or 567 pg/ml may partially reflect ventricular stress because of cardiac dysfunction or indicate cirrhotic cardiomyopathy, respectively. The aim of the study was to assess cardiac dysfunction in liver transplant patients and its correlation with BNP as a biomarker. From 1/2008 to 7/2009, 157 adult liver transplant recipients with proven cirrhosis were recruited for the study. BNP and liver enzymes were recorded upon admission, on the first postoperative day (POD) and 1 week after transplantation. Patients with ischemic heart attacks were excluded from the study. We identified two groups of patients. Group 1 was characterized by a BNP 391 pg/ml. Group 2 had a significantly higher model of end-stage liver disease score than Group 1 (median 30, range 10-40 versus median 22, range 10-40, respectively; P = 0.003), required significantly more dialysis treatments and had a significantly higher mortality rate. Postoperative echocardiography in patients with a BNP >391 pg/ml indicated diastolic dysfunction in all of the patients and systolic dysfunction in 10 of the patients. Increased serum-BNP was associated with an overall higher mortality rate.

Interferon-alpha (IFN-alpha) is widely used for the treatment of malignant and viral diseases. Conflicting results of IFN-alpha-mediated effects on dendritic cell (DC) homeostasis have been reported and its impact on human blood DC is largely unknown. We investigated the phenotypic, migratory, and allostimulatory activities of plasmacytoid DCs (PDCs) and myeloid DCs (MDCs) upon in vitro exposure to IFN-alpha without the addition of exogenous DC growth factors. IFN-alpha-exposed PDCs exhibited an increase in viability but showed an immature phenotype and a diminished allostimulatory potential. Furthermore, IFN-alpha-treated PDCs displayed a dramatically augmented expression of CD54 and CD62L as well as an increased migratory response to CC chemokine ligand (CCL)19, CXC chemokine ligand (CXCL)11, and CXCL12, suggesting an enhanced ability to migrate into peripheral lymph nodes through high endothelial venules. Myeloid DCs exposed to IFN-alpha exhibited a matured phenotype with an increased propensity to migrate toward lymph node chemokines, yet without gaining an enhanced allostimulatory capacity. Our results provide new insights into the differential immunomodulatory action of IFN-alpha on distinct human blood DC subsets and thus, may present translational significance.

Die autoimmunen Lebererkrankungen stellen im Endstadium der Leberzirrhose eine Indikation zur Lebertransplantation dar. Die Dringlichkeit der Organallokation wird in den zu Eurotransplant gehorenden Landern seit Dezember 2006 nach dem MELD-System („model for end-stage liver disease“) bestimmt. Der Lab-MELD-Score wird errechnet anhand von Serumkreatinin, Serumbilirubin und Prothrombinzeit, wobei letztere als International Normalized Ratio (INR) angegeben wird. Bei Patienten mit primar sklerosierender Cholangitis konnen bei bestimmten Komplikationen, wie z. B. biliarer Sepsis, zusatzlich Match-MELD-Standardkriterien hinzu gezogen werden, um eine Erhohung der Dringlichkeit fur die Spenderorganallokation zu bewirken. Aufgrund der guten Ergebnisse im Kurzzeitverlauf nach Lebertransplantation hat sich die Aufmerksamkeit zunehmend auf die Verbesserung der Langzeitprognose gerichtet. Hierbei nimmt die Behandlung der Rezidiverkrankungen einen wichtigen Stellenwert ein. Die Diagnose eines Rezidivs ist bei transplantierten Patienten mit einer Autoimmunhepatitis oder einer cholestatischen Lebererkrankung schwieriger als bei nichttransplantierten Patienten. Obwohl die zur Verfugung stehenden therapeutischen Optionen bei Auftreten eines Rezidivs der autoimmunen Lebererkrankung nach Transplantation limitiert sind, wird das Langzeituberleben der Patienten nicht signifikant dadurch beeintrachtigt.

The ultimate goal of treatment is suppression of viral replication to undetectable HBV-DNA levels prior to and after liver transplantation (LT) to prevent infection of the newly transplanted liver. Most published data are available from therapy with lamivudine (LAM) in pre- and post-transplant HBV patients. Add-on therapy with adefovir dipivoxil (ADV) in pre-transplant LAM-resistant patients has been shown to represent an effective antiviral strategy leading to hepatic recompensation in many cases and, eventually, removal from the waiting list. Newer nucleos(t)ide analogues such as entecavir, tenofovir and telbivudine have shown lower resistance rates than LAM and more antiviral potency in studies in the non-transplant setting. Combined hepatitis B immune globulin (HBIG) and nucleos(t)ide analogue therapy have been widely adopted as the most effective treatment strategy against recurrent HBV disease after LT. Many programs have evaluated lower doses or a shorter duration of HBIG and intramuscular versus intravenous routes of administration. Active immunisation using recombinant HBV vaccines, including the S, pre-S1 and pre-S2 regions, and those with immunostimulatory adjuvants, seem to be more immunogenic than the currently available vaccines and have been used in studies to replace HBIG. Furthermore, it has been shown that immune memory against HBV can be adoptively transferred from organ donors to transplant recipients. Nucleos(t)ide analogue combination therapies might provide an alternative to the current treatment paradigm with costly HBIG; however, experience with this new treatment regimen is very limited and controlled clinical studies are urgently warranted to investigate its safety and efficacy and to determine which nucleos(t)ide analogue combinations will be the most promising in the long term after LT. Copyright © 2008 John Wiley & Sons, Ltd.

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.

Introduction The aim of this study was to analyze vascular and biliary variants at the hilar and sectorial level in right graft adult living donor liver transplantation. Methods From January 2003 to June 2007, 139 consecutive live liver donors underwent three-dimensional computed tomography (3-D CT) reconstructions and virtual 3-D liver partitioning. We evaluated the portal (PV), arterial (HA), and biliary (BD) anatomy. Results The hilar and sectorial biliary/vascular anatomy was predominantly normal (70%–85% and 67%–78%, respectively). BD and HA showed an equal incidence (30%) of hilar anomalies. BD and PV had a nearly identical incidence of sectorial abnormalities (64.7% and 66.2%, respectively). The most frequent “single” anomaly was seen centrally in HA (21%) and distally in BD (18%). A “double” anomaly involved BD/HA (7.2%) in the hilum, and HA/PV and BD/PV (6.5% each) sectorially. A “triple” anomaly involving all systems was found at the hilum in 1.4% of cases, and at the sectorial level in 9.4% of instances. Simultanous central and distal abnormalities were rare. In this study, 13.7% of all donor candidates showed normal hilar and sectorial anatomy involving all 3 systems. A simultaneous central and distal “triple” abnormality was not encountered. A combination of “triple” hilar anomaly with “triple” sectorial normality was observed in 2 cases (1.4%). A central “triple” normality associated with a distal “triple” abnormality occurred in 7 livers (5%). Conclusions Our data showed a variety of “horizontal” (hilar or sectorial) and “vertical” (hilar and sectorial) vascular and biliary branching patterns, providing comprehensive assistance for surgical decision-making prior to right graft hepatectomy.

Summary Background Calcineurin inhibitor (CNI)-related nephrotoxicity significantly contributes to chronic renal failure after liver transplantation. Methods In this prospective study, liver transplantation patients with renal dysfunction were randomized either to receive mycophenolate mofetil (MMF) followed by stepwise reduction of CNI with defined minimal CNI-trough levels (MMF group), or to continue their maintenance CNI dose (control group). Immune monitoring was performed in a subgroup of the patients. Results In the MMF group (n = 50), renal function assessed by serum creatinine improved >10% in 62% of patients, was stable in 36% and deteriorated >10% in 2% after 12 months compared with baseline values. Mean serum creatinine levels (± s.d.) significantly decreased from 1.90 ± 0.44 mg/dL to 1.61 ± 0.39 mg/dL and the corresponding calculated glomerular filtration rate significantly increased from 38.8 ± 9.6 mL/min/1.73 m2 to 47.0 ± 11.8 mL/min/1.73 m2 over a 12-month follow-up period. Blood pressure and levels of liver enzymes significantly decreased. In the control group (n = 25), there were no significant changes with respect to the investigated parameters. The MMF group had significantly lower numbers of circulating cytotoxic T cells compared with the controls; whereas regulatory T cells significantly increased. Conclusion Combined MMF and minimal dose CNI therapy after liver transplantation is nephroprotective and may promote allograft tolerance.

Peptide receptor radionuclide therapy is a new therapeutic modality for patients with nonresectable neuroendocrine tumors. The technique is based on the unique ability of these tumors to express cell membrane-specific peptide receptors that can be targeted with radiolabeled somatostatin analogues. A high level of uptake on somatostatin receptor scintigraphy is a prerequisite for effective treatment. The efficacy of this method has been proven in several clinical trials. In a substantial number of patients, an improvement of life quality has been achieved in addition to a marked morphologic and biochemical tumor response. Serious side effects are rarely observed. Attention must be paid to kidney protection during the treatment. The present review summarizes the clinical experience with the treatment of advanced neuroendocrine tumors with radiolabeled somatostatin analogues and focuses on patient selection and the appropriate timing of the therapy. Finally, it emphasizes treatment-related issues that deserve attention in the future.

Renal dysfunction often occurs in liver transplant (LT) recipients receiving calcineurin inhibitor (CNI)-based immunosuppressive regimens, increasing morbidity and mortality rates. Replacement of CNIs by mTOR inhibitor-based immunosuppressive protocols may prevent renal impairment in LT recipients.Outcomes in patients who underwent LT between 1996 and 2010 at our center and who were switched from CNI-based to mTOR inhibitor-based immunosuppression were retrospectively analyzed. Renal course, hyperlipidemia, and graft rejection were assessed in patients maintained on this CNI-free regimen for at least 24 months.Of the 85 patients switched from CNI-based to mTOR inhibitor-based, CNI-free immunosuppression, 78 met the inclusion criteria. Within the first 6 weeks after switching, the covariable adjusted estimated glomerular filtration rate (eGFR) increased 5.6 mL/min [95% confidence interval 2.6-8.7 mL/min, p0.001], but there were no further statistically noticeable changes in eGFR. Concentrations of cholesterol and triglycerides increased statistically, noticeable within the first 12 months after drug conversion. Histologically proven graft rejection was observed in 4 patients (5.1%) after conversion.Conversion from CNI-based to CNI-free, mTOR inhibitor-based immunosuppression after LT is safe and can result in significant renal recovery. CNI-free, mTOR inhibitor-based immunosuppression is a potential option for patients with contraindications for CNIs and for LT recipients with rapid reduction in kidney function due to CNIs.

Immunosuppression, denervation of biliary tract, and presence of biliary strictures favor colonization of bile with microorganisms after liver transplantation. Little is known about spectrum and antibiotic susceptibility of this colonization.Bile and feces were collected prospectively from 38 patients who underwent endoscopic retrograde cholangiopancreaticography after liver transplantation. Samples were analyzed for colonization and antibiotic susceptibility.From the 38 tested bile samples, 86.6% tested positive. Of those, 26 (78.8%) were polymicrobial. Of isolated bile samples, 52 (64.2%) were gram-positive, 22.2% were gram-negative, and 13.6% revealed Candida albicans. Most detectable gram-positive bacteria were Enterococcus faecium. Most detectable gram-negative bacteria were E. coli and Klebsiella pneumonia. Our analyses revealed high resistance rates of the isolates. Only 55.6% of isolates were sensitive to ciprofloxacin, 54% were sensitive to piperacillin/tazobactam, and 60.3% were sensitive to imipenem. High susceptibility rates were found for linezolid and vancomycin (72.9% and 72.6%, respectively). We found a high correlation between microorganisms found in bile and those isolated from stool.Bile of liver transplant recipients is frequently colonized with microorganisms. The starting point of this colonization is usually the intestine. Systematic analysis of bile colonization during endoscopic interventions on biliary tracts of liver transplant recipients might help to select effective prophylactic antibiotic regimes as well as to facilitate the choice of suitable antimicrobial therapy in case of septic complications.

Die Prognose lebertransplantierter Patienten wird im Langzeitverlauf durch die Nebenwirkungen der immunsuppressiven Therapie, die Entwicklung von De-novo-Malignomen, aber auch durch die Rekurrenz der Grunderkrankung determiniert. Die Behandlung mit Interferon-α und Ribavirin stellt bei den lebertransplantierten Patienten mit Hepatitis C unter Voraussetzung einer sorgfaltigen Selektion und Uberwachung ein sicheres, aber weniger effizientes Therapiekonzept als im Nichttransplantbereich dar. Bei der Hepatitis B konnte die Reinfektionsrate durch eine postoperative Kombinationstherapie aus Hepatitis-B-Hyperimmunglobulin und einem Nukleos(t)idanalogon erfolgreich auf < 10% gesenkt werden. Neue molekularbiologische Techniken wie auch die Genotypisierung des hepatozellularen Karzinoms gewinnen zur Einschatzung des rezidivfreien Uberlebens zunehmend an Bedeutung. Die Diagnosestellung eines Rezidivs einer cholestatischen Lebererkrankung und der Autoimmunhepatitis ist schwieriger als bei nicht transplantierten Patienten, und die zur Verfugung stehenden therapeutischen Optionen sind limitiert. Eine psychiatrische Evaluation und die sorgfaltige Beurteilung der Compliance sind zur Einschatzung des Rezidivrisikos bei Patienten mit alkoholbedingter Lebererkrankung erforderlich. Im Langzeitverlauf versterben bis zur Halfte der Patienten an transplantationsspezifischen Komplikationen; dabei sind 30–70% dieser Falle auf ein Rezidiv der Grunderkrankung zuruckzufuhren. Vor diesem Hintergrund sind strategische Verbesserungen in der Pravention und Behandlung rekurrenter Grunderkrankungen nach Lebertransplantation zur Steigerung des Langzeituberlebens notwendig.

As liver transplantation (LT) is now being performed with excellent 1-year graft survival rates of 85% to 90%, attention has been shifted to reducing long-term complications of calcineurin inhibitors (CNI). We randomized LT patients (2:1) who displayed renal dysfunction under CNI treatment to either mycophenolate mofetil (MMF) (1000 mg twice a day) followed by stepwise reduction of CNI (n = 21; Tac trough levels

In mice as well as humans, cytotoxic T lymphocytes (CTL) specific for wild-type-sequence (wt) p53 peptides have been shown to react against a wide range of tumors, but not normal cells. As such, they are attractive candidates for developing broadly applicable cancer vaccines. Of particular interest is the potential of using p53-based vaccines in high-risk individuals to prevent cancer. Methylcholanthrene, an immunosuppressive polycyclic hydrocarbon carcinogen implicated as a causative agent in human cancers, has long been used to induce murine tumors with a high incidence of genetic alterations and sensitivity to wt p53-specific CTL. To analyze the potential of p53-based vaccines on primary tumors, we evaluated the efficacy of DNA and dendritic cell vaccines targeting wt p53 peptides given to methylcholanthrene-treated mice in the protection or therapy settings. The results indicate that the efficacy of these vaccines relative to reducing tumor incidence were severely compromised by vaccine-induced tumor escape. As compared to tumors induced in non-immunized mice, a higher incidence of epitope-loss tumors was detected in tumors from the immunized mice. The increase in tumor escape arose as a consequence of either increased frequencies of mutations within/flanking p53 epitope-coding regions or downregulation of expression of the major histocompatibility complex Class I molecules that present these epitopes for T cell recognition These findings are consistent with current views of immunoselection occurring in patients receiving tumor peptide-based immunotherapy, and impact on the design and implementation of p53-based vaccines, in particular, those aimed at treating individuals at high risk for developing cancer.

Chronic viral hepatitis is the leading indication for orthotopic liver transplantation worldwide. Hepatitis B immunoglobulin and lamivudine (LAM) have been widely adopted as an effective treatment strategy against recurrent hepatitis B virus (HBV) infection in posttransplant patients. However, immunosuppression and the anti-hepatitis B surface (anti-HBs)–mediated immune pressure on HBV may culminate in the emergence and/or selection of immune escape HBV mutants. The emergence of mutations in the tyrosine methionine, aspartate, aspartate motif of the DNA polymerase represents a significant problem of long-term LAM therapy. Newer nucleoside analogs, such as adefovir dipivoxil (ADV) and entecavir, may provide a rescue therapy for LAM-resistant strains to avoid potential aggressive courses of HBV graft reinfection in liver transplant recipients. Previously, the selection of novel ADV-resistant mutations has been described in approximately 2% of patients over a 2-year treatment period. Five-year resistance surveillance programs are currently ongoing to monitor the emergence of ADV-resistant mutants in the long-term. Because of significant advances in detection, monitoring, and treatment options of hepatitis B, patient and graft survival have become excellent over the last years.

OBJECTIVE: To present an institutional experience with the use of right liver grafts in adult patients and to assess the practicability and efficacy of this procedure by analyzing the results. SUMMARY BACKGROUND DATA: Living donor liver transplantation (LDLT) for the pediatric population has gained worldwide acceptance. In the past few years, LDLT has also become feasible for adult patients due to technical evolution in hepatobiliary surgery and increased experience with reduced-size and split-liver transplants. Nevertheless, some graft losses remain unexplained and are possibly due to unrecognized venous outflow problems. METHODS: From April 1998 to September 2002, we performed 74 right LDLTs (segments 5-8). The 74 donors were selected from 474 candidates according to standard protocol. The median age of the donors was 35 years (range 18-58 years) and 51 years (range 18-64 years) in recipients. Standard and extended indications for transplantation were considered. Over the period reported, technical modifications in the bile duct anastomosis (duct-to-duct, end-to-end, or end-to-side) and a new graft implantation technique that provides maximized venous outflow, leading to outcome improvement, were developed. RESULTS: 64.9% of patients had liver cirrhosis and 35.1% had malignancy. While 44 donors (59.5%) presented an uneventful postoperative course, 27% minor (pleural effusion, pneumonia, venous thrombosis, wound infection, incisional hernia) and 13.5% major (biliary leakage, death of a donor due to unrecognized hereditary liver disease, and consecutive liver insufficiency) complications were documented. In recipients, 23% biliary complications and 6.8% hepatic artery thrombosis occurred. The overall patient and graft survival rate after 1 year was 79.4% and 75.3%, respectively. In cases with extended indication, the patient survival rate was 74% and the graft survival rate 68% at 12 months. Using technical modifications in the last 10 recipients, including 2 critically decompensated cirrhotics, the survival rate was 100% at a median follow-up of 3.5 months. CONCLUSIONS: In our transplant program, living donor liver transplantation has become a standard option in the adult patient population. The critical issue of this procedure is donor morbidity. Technical improvements in the harvesting and implantation of right grafts can also offer hope to patients with challenging forms of end-stage liver disease or malignant liver tumors.

Resistance to lamivudine and hyperimmune globulin (HBIG) may cause severe graft reinfection with progression to fulminant hepatic failure in liver transplant recipients. In this report, we describe the clinical course of a patient with perinatally acquired chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma who developed severe fibrosing cholestatic hepatitis after living donor liver transplantation because of the emergence of lamivudine and HBIG-resistant chronic hepatitis B. Immunohistochemistry demonstrated that more than 30% of hepatocytes stained positively for hepatitis B core antigen. Hepatitis B virus sequence analysis revealed several mutations in the polymerase gene (L528M, M552I, M552V) as well as in the surface gene region encoding the immunogenic major hydrophilic loop of the small surface protein (G130N, M133T, D144G). The amino acid exchange at codon 144 has already been described to escape neutralization by HBIG. Combined treatment with lamivudine and adefovir dipivoxil (ADV) was associated with a dramatic biochemical, virological and clinical response with resolution of jaundice, ascites, peripheral edema and pleural effusions. Serum bilirubin normalized, HBV DNA levels significantly decreased and liver biopsy was remarkable for the absence of viral protein. These results indicate that ADV may provide a sustained rescue treatment for aggressive courses of HBV graft reinfection in liver transplant recipients.

Key points 1. Adult-to-adult living donor liver transplantation has been established as a means of overcoming the cadaveric organ shortage. 2. The anatomic situation of right-liver grafts and additional factors, i.e., underlying liver disease of the recipient, are responsible for different results in pediatric and adult recipients. 3. In transplant recipients, small-for-size grafts, vascular problems, and biliary tract complications contribute to surgical morbidity. 4. Management of biliary leakages needs additional attention to achieve better overall survival rates.

Hepatocellular carcinoma (HCC) accounts for most primary malignancies of the liver. The most important risk factor is liver cirrhosis. HCC can be traced by the tumor marker alpha-fetoprotein. Patients with a known liver cirrhosis should regularly be screened, including sonography and alpha-fetoprotein evaluation. Surgical therapy - either partial liver resection or liver transplantation - is the only treatment that can potentially achieve long-term survival. The presence of liver cirrhosis is likely to induce postoperative liver insufficiency and is associated with higher local tumor recurrence rate. Patients without liver cirrhosis or Child-Pugh A patients with tumors smaller than 5 cm may be considered as the ideal target group for resection. For more advanced stages of cirrhosis and tumors of less than 5 cm up to 7 cm in size, liver transplantation offers a better prognosis. Long waiting time for a suitable organ negatively influences liver transplantation outcome. Living donor liver transplantation is a novel therapeutic option that improves posttransplant survival and extends the indication for transplantation in hepatocellular carcinoma.

AIM: To investigate middle hepatic vein (MHV) management in adult living donor liver transplantation and safer remnant volumes (RV). METHODS: There were 59 grafts with and 12 grafts without MHV (including 4 with MHV-5/8 reconstructions). All donors underwent our five-step protocol evaluation containing a preoperative protocol liver biopsy Congestive vs non-congestive RV, remnant-volume-body-weight ratios (RVBWR) and postoperative outcomes were evaluated in 71 right graft living donors. Dominant vs non-dominant MHV anatomy in total liver volume (d-MHV/TLV vs nd-MHV/TLV) was constellated with large/small congestion volumes (CV-index). Small for size (SFS) and non-SFS remnant considerations were based on standard cut-off- RVBWR and RV/TLV. Non-congestive RVBWR was based on non-congestive RV. RESULTS: MHV and non-MHV remnants showed no significant differences in RV, RV/TLV, RVBWR, total bilirubin, or INR. SFS-remnants with RV/TLV < 30% and non-SFS-remnants with RV/TLV ≥ 30% showed no significant differences either. RV and RVBWR for non-MHV (n = 59) and MHV-containing (n = 12) remnants were 550 ± 95 mL and 0.79 ± 0.1 mL vs 568 ± 97 mL and 0.79 ± 0.13, respectively (P = 0.423 and P = 0.919. Mean left RV/TLV was 35.8% ± 3.9%. Non-MHV (n = 59) and MHV-containing (n = 12) remnants (34.1% ± 3% vs 36% ± 4% respectively, P = 0.148. Eight SFS-remnants with RVBWR < 0.65 had a significantly smaller RV/TLV than 63 non-SFS-remnants with RVBWR ≥ 0.65 [SFS: RV/TLV 32.4% (range: 28%-35.7%) vs non-SFS: RV/TLV 36.2% (range: 26.1%-45.5%), P < 0.009. Six SFS-remnants with RV/TLV < 30% had significantly smaller RVBWR than 65 non-SFS-remnants with RV/TLV ≥ 30% (0.65 (range: 0.6-0.7) vs 0.8 (range: 0.6-1.27), P < 0.01. Two (2.8%) donors developed reversible liver failure. RVBWR and RV/TLV were concordant in 25%-33% of SFS and in 92%-94% of non-SFS remnants. MHV management options including complete MHV vs MHV-4A selective retention were necessary in n = 12 vs n = 2 remnants based on particularly risky congestive and non-congestive volume constellations. CONCLUSION: MHV procurement should consider individual remnant congestive- and non-congestive volume components and anatomy characteristics, RVBWR-RV/TLV constellation enables the identification of marginally small remnants.

Dendritic cells (DCs) induce and regulate T-cell-mediated immune responses. Circulating precursor (p)DC1 and pDC2 from patients with chronic hepatitis B virus (HBV) infection were quantified by flow cytometry. To assess their function, DC1 were cultured from patients and compared to those of healthy volunteers. HBV patients exhibited a significant decrease in the proportion of freshly isolated pDC1 to pDC2. DC1 propagated from patients showed lower expression of costimulatory molecules and impaired allostimulatory capacity in comparison to controls. After exposure to proinflammatory cytokines, expression of costimulatory molecules, secretion of interleukin-12 (IL-12) and allostimulatory properties increased, but capacity for T-cell stimulation and IL-12 production remained inferior to that of control DCs. HBV-DNA was amplified by polymerase chain reaction in DC1 cultured from all patients. Viral particles were visible in DC1 by electron microscopy. These results suggest that intracellular presence of HBV impairs DC1 functional maturation and subsequent deficits in T-lymphocyte activation may contribute to viral persistence.

Background and study aims Biliary tract complications after liver transplantation are usually treated by endoscopic retrograde cholangiopancreatography. When biliary tract intervention is indicated, endoscopic sphincterotomy is often required. However, data regarding complication rates after endoscopic sphincterotomy in liver transplant recipients are limited. This study therefore investigated complication rates during the first 15 days after endoscopic sphincterotomy in liver transplant recipients. Patients and methods This study retrospectively reviewed 157 consecutive liver transplant recipients who underwent endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy between January 1998 and August 2013 at the University Hospital of Munster, Germany. Complications that occurred within the first 15 days after the procedure were recorded, and complication rates were compared between patients who underwent conventional and precut endoscopic sphincterotomy. Results A total of 24 complications (15.2%) were recorded, including 9 cases (5.7%) of pancreatitis, 6 cases (3.8%) of bleeding, and 1 case (0.6%) of perforation. There were no procedure-related deaths. There were no significant differences in complication rates between the two sphincterotomy techniques. The rate of post-procedural pancreatitis decreased over time. Conclusion Endoscopic sphincterotomy is a safe procedure in liver transplant recipients. The procedure-related complication rate is reasonable and most complications can be managed conservatively.

AIM: To outline the feasibility, safety, adverse events and early results of endoscopic ultrasound (EUS)-radiofrequency ablation (RFA) in pancreatic neoplasms using a novel probe. METHODS: This is a multi-center, pilot safety feasibility study. The intervention described was radiofrequency ablation (RF) which was applied with an innovative monopolar RF probe (1.2 mm Habib EUS-RFA catheter) placed through a 19 or 22 gauge fine needle aspiration (FNA) needle once FNA was performed in patients with a tumor in the head of the pancreas. The Habib™ EUS-RFA is a 1 Fr wire (0.33 mm, 0.013”) with a working length of 190 cm, which can be inserted through the biopsy channel of an echoendoscope. RF power is applied to the electrode at the end of the wire to coagulate tissue in the liver and pancreas. RESULTS: Eight patients [median age of 65 (range 27-82) years; 7 female and 1 male] were recruited in a prospective multicenter trial. Six had a pancreatic cystic neoplasm (four a mucinous cyst, one had intraductal papillary mucinous neoplasm and one a microcystic adenoma) and two had a neuroendocrine tumors (NET) in the head of pancreas. The mean size of the cystic neoplasm and NET were 36.5 mm (SD ± 17.9 mm) and 27.5 mm (SD ± 17.7 mm) respectively. The EUS-RFA was successfully completed in all cases. Among the 6 patients with a cystic neoplasm, post procedure imaging in 3-6 mo showed complete resolution of the cysts in 2 cases, whilst in three more there was a 48.4% reduction [mean pre RF 38.8 mm (SD ± 21.7 mm) vs mean post RF 20 mm (SD ± 17.1 mm)] in size. In regards to the NET patients, there was a change in vascularity and central necrosis after EUS-RFA. No major complications were observed within 48 h of the procedure. Two patients had mild abdominal pain that resolved within 3 d. CONCLUSION: EUS-RFA of pancreatic neoplasms with a novel monopolar RF probe was well tolerated in all cases. Our preliminary data suggest that the procedure is straightforward and safe. The response ranged from complete resolution to a 50% reduction in size.

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. 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. 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. EUS can complement ERCP to improve diagnosis of biliary complications after LT and help guide treatment strategies to address these complications.

Enhanced green fluorescent protein (EGFP) is a novel marker gene product, which is readily detectable using techniques of fluorescence microscopy, flow cytometry, or macroscopic imaging. In the present studies, we have examined the immunogenicity of EGFP in murine models. A stable transfectant of the transplantable CMS4 sarcoma of BALB/c origin expressing EGFP, CMS4-EGFP-Zeo, was generated. Splenocytes harvested from mice immunized with a recombinant adenovirus expressing EGFP (Ad-EGFP) were restimulated in vitro with CMS4-EGFP-Zeo. Effector lymphocytes displayed strong cytotoxicity against CMS4-EGFP-Zeo, but not against mock-transfected CMS4-Zeo tumor cells. A number of candidate H2-Kd-binding peptides derived from the EGFP protein were chosen according to an epitope prediction program and synthesized. These peptides were tested for their ability to bind to H2-Kd molecules and stimulate IFNgamma-production by splenocytes harvested from Ad-EGFP-immunized mice. Using this methodology, the peptide, HYLSTQSAL (corresponding to EGFP200-208) which strongly binds to H2-Kd molecules, was identified as a naturally occurring epitope of EGFP. These results should facilitate the use of EGFP as a model tumor antigen in BALB/c mice.

Objective The peripheral intrahepatic biliary anatomy, especially at the sectorial level on the right side, has not been adequately described. The purpose of our study was to systematically describe this complex anatomy in clinically applicable fashion. Patients and Methods We analyzed three-dimensional computed tomography (CT) imaging reconstructions of 139 potential living liver donors evaluated at our institution between January 2003 and June 2007. Results Eighty-nine (64%) donors had a normal right bile duct sectorial anatomy. In the other 50/139 (36%) cases, we observed abnormal sectorial branching patterns, with 45/50 abnormalities as trifurcations, whereas the remaining ones were quadrifurcations. In 22/50 (44%) abnormalities, a linear branching pattern (types B1/C1) and an early segmental origin off the right hepatic duct (types B3/C3) were present, a finding of particular danger when performing a right graft hepatectomy. In 2 cases, we noted a mixed type (B6/C6) of a rare complex anatomy. Conclusions Our proposed classification of the right sectorial bile duct system clearly displays the “area at risk” encountered when performing right graft adult live donor liver transplantation and tumor resections involving the right lobe of the liver.