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Purpose of Review: Morphological criteria (i.e., Milan Criteria) have been considered for a long time to be the best tool for selecting patients with hepatocellular cancer (HCC) waiting for liver transplantation (LT). In the last ten years, a refinement of the selection criteria has been observed, with the introduction of biological tumor characteristics enabling to enlarge the number of potential transplant candidates and to select LT candidates with a lower risk of posttransplant recurrence., Recent Findings: Several biological tumor aspects have been explored and validated in international cohorts to expand the ability to predict patients at high risk for recurrence. Alpha-fetoprotein, radiological response to locoregional treatments, and other more recently proposed markers have been principally explored. Moreover, more complex statistical approaches (i.e., deep learning) have been advocated to explore the nonlinear intercorrelations between the investigated features., Summary: The addition of biological aspects to morphology has improved the ability to discriminate among high- and low-risk patients for recurrence. New prognostic algorithms based on the more sophisticated artificial intelligence approach are further improving the capability to select LT candidates with HCC., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Long-term survival after liver transplantation (LT) for hepatocellular cancer (HCC) continues to increase along with the modification of inclusion criteria. This study aimed at identifying risk factors for 5- and 10-year overall and HCC-specific death after LT., Methods: A total of 1,854 HCC transplant recipients from 10 European centers during the period 1987-2015 were analyzed. The population was divided in three eras, defined by landmark changes in HCC transplantability indications. Multivariable logistic regression analyses were used to evaluate the significance of independent risk factors for survival., Results: Five- and 10-year overall survival (OS) rates were 68.1% and 54.4%, respectively. Two-hundred forty-two patients (13.1%) had HCC recurrence. Five- and 10-year recurrence rates were 16.2% and 20.3%. HCC-related deaths peaked at 2 years after LT (51.1% of all HCC-related deaths) and decreased to a high 30.8% in the interval of 6 to 10 years after LT. The risk factors for 10-year OS were macrovascular invasion (OR = 2.71; P = 0.001), poor grading (OR = 1.56; P = 0.001), HCV status (OR = 1.39; P = 0.001), diameter of the target lesion (OR = 1.09; P = 0.001), AFP slope (OR = 1.63; P = 0.006), and patient age (OR = 0.99; P = 0.01). The risk factor for 10-year HCC-related death were AFP slope (OR = 4.95; P < 0.0001), microvascular (OR = 2.13; P < 0.0001) and macrovascular invasion (OR = 2.32; P = 0.01), poor tumor grading (OR = 1.95; P = 0.001), total number of neo-adjuvant therapies (OR = 1.11; P = 0.001), diameter of the target lesion (OR = 1.11; P = 0.002), and patient age (OR = 0.97; P = 0.001). When analyzing survival rates in function of LT era, a progressive improvement of the results was observed, with patients transplanted during the period 2007-2015 showing 5- and 10-year death rates of 26.8% and 38.9% (vs. 1987-1996, P < 0.0001; vs. 1997-2006, P = 0.005)., Conclusions: LT generates long-term overall and disease-free survival rates superior to all other oncologic treatments of HCC. The role of LT in the modern treatment of HCC becomes even more valued when the follow-up period reaches at least 10 years. The results of LT continue to improve even when prudently widening the inclusion criteria for transplantation. Despite the incidence of HCC recurrence is highest during the first 5 years post-transplant, one-third of them occur later, indicating the importance of a life-long follow-up of these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lai, Viveiros, Iesari, Vitale, Mennini, Onali, Hoppe-Lotichius, Colasanti, Manzia, Mocchegiani, Spoletini, Agnes, Vivarelli, Tisone, Ettorre, Mittler, Tsochatzis, Rossi, Cillo, Schaefer and Lerut.)

Immunosuppression handling plays a key role in the early and long-term results of transplantation. The development of multiple immunosuppressive drugs led to numerous clincial trials searching to reach the ideal regimen. Due to heterogeneity of the studied patient cohorts and flaws in many, even randomized controlled, study designs, the answer still stands out. Nowadays triple-drug immunosuppression containing a calcineurin inhibitor (preferentially tacrolimus), an antimetabolite (using mycophenolate moffettil or Azathioprine) and short-term steroids with or without induction therapy (using anti-IL2 receptor blocker or anti-lymphocytic serum) is the preferred option in both liver and intestinal transplantation. This chapter aims, based on a critical review of the definitions of rejection, corticoresistant rejection and standard immunosuppression to give some reflections on how to reach an optimal immunosuppressive status and to conduct trials allowing to draw solid conclusions. Endpoints of future trials should not anymore focus on biopsy proven, acute and chronic, rejection but also on graft and patient survival. Correlation between early- and long-term biologic, immunologic and histopathologic findings will be fundamental to reach in much more patients the status of operational tolerance., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: Living-donor liver transplant (LDLT) offers advantages over deceased-donor liver transplant (DDLT) of improved intention-to-treat outcomes and management of the shortage of deceased-donor allografts. However, conflicting data still exist on the outcomes of LDLT in patients with hepatocellular carcinoma (HCC)., Objective: To investigate the potential survival benefit of an LDLT in patients with HCC from the time of waiting list inscription., Design, Setting, and Participants: This multicenter cohort study with an intention-to-treat design analyzed the data of patients aged 18 years or older who had an HCC diagnosis and were on a waiting list for a first transplant. Patients from 12 collaborative centers in Europe, Asia, and the US who were on a transplant waiting list between January 1, 2000, and December 31, 2017, composed the international cohort. The Toronto cohort comprised patients from 1 transplant center in Toronto, Ontario, Canada who were on a waiting list between January 1, 2000, and December 31, 2015. The international cohort centers performed either an LDLT or a DDLT, whereas the Toronto cohort center was selected for its capability to perform both LDLT and DDLT. The benefit of LDLT was tested in the 2 cohorts before and after undergoing an inverse probability of treatment weighting (IPTW) analysis. Data were analyzed from February 1 to May 31, 2020., Main Outcomes and Measures: Intention-to-treat death was defined as a patient death that occurred for any reason and was calculated from the time of waiting list inscription for liver transplant to the last follow-up date (December 31, 2019). Four multivariable Cox proportional hazards regression models for intention-to-treat death were created., Results: A total of 3052 patients were analyzed in the international cohort, of whom 2447 were men (80.2%) and the median (IQR) age at first referral was 58 (53-63) years. The Toronto cohort comprised 906 patients, of whom 743 were men (82.0%) and the median (IQR) age at first referral was 59 (53-63) years. In all the settings, LDLT was an independent protective factor, reducing the risk of overall death by 49% in the pre-IPTW analysis for the international cohort (HR, 0.51; 95% CI, 0.36-0.71; P < .001), 33% in the post-IPTW analysis for the international cohort (HR, 0.67; 95% CI, 0.53-0.85; P = .001), 43% in the pre-IPTW analysis for the Toronto cohort (HR, 0.57; 95% CI, 0.45-0.73; P < .001), and 48% in the post-IPTW analysis for the Toronto cohort (HR, 0.52; 95% CI, 0.42 to 0.65; P < .001). The discriminatory ability of the mathematical models further improved in all of the cases in which LDLT was incorporated., Conclusions and Relevance: This study suggests that having a potential live donor could decrease the intention-to-treat risk of death in patients with HCC who are on a waiting list for a liver transplant. This benefit is associated with the elimination of the dropout risk and has been reported in centers in which both LDLT and DDLT options are equally available.

Competing Interests: The authors declare no funding and conflicts of interest.

Competing Interests: Declaration of Competing Interest Jean Charles Nault received a research grant from Bayer for Inserm UMR1148, Elia Gigante nothing to declare, Quirino Lai nothing to declare, Jan Lerut nothing to declare.

Background: Recent studies indicate that a group of patients with cirrhosis receiving a liver transplantation for hepatocellular cancer (HCC) beyond the Milan Criteria (MC) can achieve a similar outcome compared to patients within these criteria. This study aims to investigate the value of the Asan critera (AC), up-to-7 criteria (UT7), French alpha-foetoprotein (AFP) model and Metroticket 2.0 (MT2.0) model compared to the MC., Methods: 526 patients transplanted for non-metastatic HCC were analyzed. Patient groups within and beyond MC and extended criteria were determined according to radiological assessment and AFP value at listing., Results: Overall survival (OS) and recurrence (RR) rates were similar between patients within MC and all extended criteria. Five-year OS within MC was 71.3% compared to 70.9% for AC, 71.4% for UT7, 69.7% for AFP-model and 71.0% for MT2.0 criteria. Five-year RR within MC was 12.3% compared to 13.5% for AC, 13.0% for UT7, 14.3% for AFP-model and 13.2% for MT2.0 criteria. Patients beyond MC but within the extended criteria had tendency towards higher recurrence., Conclusions: All validated extended criteria (AC, UT7, AFP-model and MT2.0) could be proposed as alternatives to the MC with similar outcome. Prospective data are awaited to assess recurrence beyond MC., Competing Interests: Declaration of competing interest No conflict of interest reported in relation to the presented work., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Extended splanchnic venous thrombosis represents a challenge for the liver transplantation (LT) surgeon. In the absence of large venous tributaries, the cavoportal hemitransposition (CPHTr) and the combined liver-intestinal or multivisceral transplantation are the only technical solutions. Because of the reported high morbidity and mortality rates due to infrequent use and a lack of standardization, the former technique has been almost abandoned by the transplant community. A newly designed technique of CPHTr is presented that is based on the combination of an inferior vena cava (IVC)-sparing hepatectomy and large laterolateral cavocaval and end-to-side cavoportal anastomoses separated only by a double vascular stapler line. This technique allows the splanchnic blood to be completely diverted toward the allograft and to eliminate low-flow IVC areas, which possibly lead to complications. The modified CPHTr technique proposed here offers a valuable alternative to much more complex and invasive intestinal transplantation procedures., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Objective: To characterise gut microbiome in patients with hepatocellular carcinoma (HCC) and evaluate the potential of microbiome as non-invasive biomarkers for HCC., Design: We collected 486 faecal samples from East China, Central China and Northwest China prospectively and finally 419 samples completed Miseq sequencing. We characterised gut microbiome, identified microbial markers and constructed HCC classifier in 75 early HCC, 40 cirrhosis and 75 healthy controls. We validated the results in 56 controls, 30 early HCC and 45 advanced HCC. We further verified diagnosis potential in 18 HCC from Xinjiang and 80 HCC from Zhengzhou., Results: Faecal microbial diversity was increased from cirrhosis to early HCC with cirrhosis. Phylum Actinobacteria was increased in early HCC versus cirrhosis. Correspondingly, 13 genera including Gemmiger and Parabacteroides were enriched in early HCC versus cirrhosis. Butyrate-producing genera were decreased, while genera producing-lipopolysaccharide were increased in early HCC versus controls. The optimal 30 microbial markers were identified through a fivefold cross-validation on a random forest model and achieved an area under the curve of 80.64% between 75 early HCC and 105 non-HCC samples. Notably, gut microbial markers validated strong diagnosis potential for early HCC and even advanced HCC. Importantly, microbial markers successfully achieved a cross-region validation of HCC from Northwest China and Central China., Conclusions: This study is the first to characterise gut microbiome in patients with HCC and to report the successful diagnosis model establishment and cross-region validation of microbial markers for HCC. Gut microbiota-targeted biomarkers represent potential non-invasive tools for early diagnosis of HCC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular tumor which has an intermediate aggressive behavior. Although the value of liver transplantation (LT) is well established, its place in the management of HEHE is still unclear. The aim of this study is to confirm, based on a very large patient cohort, the value of LT in the management of HEHE and to identify risk factors for post-LT recurrence., Methods: The outcome of 149 transplant recipients with HEHE recorded in the European Liver Transplant Registry during the period November 1984 to May 2014 was analyzed. Median post-LT follow-up was 7.6 years (interquartile range, 2.8-14.4)., Results: Cox regression analysis showed that macrovascular invasion (hazard ratio [HR], 4.8; P < 0.001), pre-LT waiting time of 120 days or less (HR, 2.6; P = 0.01) and hilar lymph node invasion (HR = 2.2; P = 0.03), but not pre-LT extrahepatic disease, were significant risk factors for recurrence. These findings, which were also confirmed in a propensity score analysis, allowed the development of a HEHE-LT score enabling stratification of patients in relation to their risk of tumor recurrence. Patients with a score of 2 or less had a much better 5-year disease-free survival compared to those having a score of 6 or higher (93.9% vs 38.5%; P < 0.001)., Conclusions: The analysis of this (largest in the world) HEHE adult liver recipient cohort clearly confirms the value of LT in the treatment of this rare disorder and also permits identification of patients at risk of posttransplant recurrence. Posttransplant follow-up should take the HEHE-LT score into account. Extrahepatic disease localization is reconfirmed not to be a contraindication for LT.

Donation after circulatory death (DCD) liver transplantation (LT) may imply a risk for decreased graft survival, caused by posttransplantation complications such as primary nonfunction or ischemic-type biliary lesions. However, similar survival rates for DCD and donation after brain death (DBD) LT have been reported. The objective of this study is to determine the longterm outcome of DCD LT in the Eurotransplant region corrected for the Eurotransplant donor risk index (ET-DRI). Transplants performed in Belgium and the Netherlands (January 1, 2003 to December 31, 2007) in adult recipients were included. Graft failure was defined as either the date of recipient death or retransplantation whichever occurred first (death-uncensored graft survival). Mean follow-up was 7.2 years. In total, 126 DCD and 1264 DBD LTs were performed. Kaplan-Meier survival analyses showed different graft survival for DBD and DCD at 1 year (77.7% versus 74.8%, respectively; P = 0.71), 5 years (65.6% versus 54.4%, respectively; P = 0.02), and 10 years (47.3% versus 44.2%, respectively; P = 0.55; log-rank P = 0.038). Although there was an overall significant difference, the survival curves almost reach each other after 10 years, which is most likely caused by other risk factors being less in DCD livers. Patient survival was not significantly different (P = 0.59). Multivariate Cox regression analysis showed a hazard ratio of 1.7 (P < 0.001) for DCD (corrected for ET-DRI and recipient factors). First warm ischemia time (WIT), which is the time from the end of circulation until aortic cold perfusion, over 25 minutes was associated with a lower graft survival in univariate analysis of all DCD transplants (P = 0.002). In conclusion, DCD LT has an increased risk for diminished graft survival compared to DBD. There was no significant difference in patient survival. DCD allografts with a first WIT > 25 minutes have an increased risk for a decrease in graft survival. Liver Transplantation 22 1107-1114 2016 AASLD., (© 2016 American Association for the Study of Liver Diseases.)

Intestinal transplantation (ITx) has evolved from an experimental procedure toward a clinical reality but remains a challenging procedure. The aim of this survey was to analyze the multicenter Belgian ITx experience. From 1999 to 2014, 24 ITx in 23 patients were performed in Belgium, divided over five centers. Median recipient age was 38 years (8 months-57 years); male/female ratio was 13/10; six were children; and 17 adults. Intestinal failure was related to intestinal ischemia (n = 5), volvulus (n = 5), splanchnic thrombosis (n = 4), Crohn (n = 2), pseudo-obstruction (n = 2), microvillus inclusion (n = 2), Churg-Strauss (n = 1), necrotizing enterocolitis (n = 1), intestinal atresia (n = 1), and chronic rejection (n = 1). Graft type was isolated ITx (n = 9), combined liver-ITx (n = 11) and multivisceralTx (n = 4). One was a living donor-related transplantation and five patients received simultaneously a kidney graft. Early acute rejection occurred in 8; late acute rejection in 4; and chronic rejection in 2. Two patients developed a post-transplant lymphoproliferative disease. Nine patients have died. Among 14 survivors at last follow-up, 11 have been transplanted for more than 1 year. None of the latter has developed renal failure, and all were nutritionally independent with a Karnofsky score > 90%. One-/five-year patient and graft survivals were 71.1%, 62.8%, 58.7% and 53.1%, respectively. Based on this experience, ITx has come of age in Belgium as a lifesaving and potentially quality of life restoring therapy., (© 2015 Steunstichting ESOT.)

Although xenografts have always held immeasurable potential as an inexhaustible source of donor organs, immunological barriers and physiological incompatibility have proved to be formidable obstacles to clinical utility. An exciting, new regenerative medicine-based approach termed "semi-xenotransplantation" (SX) seeks to overcome these obstacles by combining the availability and reproducibility of animal organs with the biocompatibility and functionality of human allografts. Compared to conventional xenotransplantation wherein the whole organ is animal-derived, SX grafts are cleansed of their antigenic cellular compartment to produce whole-organ extracellular matrix scaffolds that retain their innate structure and vascular channels. These scaffolds are then repopulated with recipient or donor human stem cells to generate biocompatible semi-xenografts with the structure and function of native human organs. While numerous hurdles must be still overcome in order for SX to become a viable treatment option for end-stage organ failure, the immense potential of SX for meeting the urgent needs for a new source of organs and immunosuppression-free transplantation justifies the interest that the transplant community is committing to the field., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To investigate the safety of minimal immunosuppression (IS) in liver transplantation (LT)., Background: The lack of long-term follow-up studies, including pathologic data, has led to a protean handling of IS in LT., Methods: Between February 2000 and September 2004, 156 adults were enrolled in a prospective, randomized, double-blind, placebo-controlled minimization trial comparing tacrolimus placebo (TAC-PLAC) and TAC short-term steroid (TAC-STER) IS. All patients had a minimum clinical, biochemical, and histological follow-up of 5 years., Results: Five-year actual patient and graft survival rates in TAC-PLAC and TAC-STER groups were 78.1% and 82.1% (P=0.89) and 74.2% and 76.9% (P=0.90), respectively. Five-year biopsies were available in 112 (89.6%) of 125 survivors. Twelve patients refused a biopsy because of their excellent evolution; tissue material was insufficient in 1 patient; 11 had normal liver tests; and 2 patients had developed alcoholic and secondary biliary cirrhosis. Histology was normal in 44 (39.3%) patients; 35 (31.3%) had disease recurrence. The remaining biopsies showed nonspecific chronic hepatitis (14.3%), mild inflammatory infiltrates (10.7%), and steatosis (3.5%). All findings were equally distributed between both groups. In each group, 3 patients (4.8%) presented with acute cellular rejection after the first year and only 1 (0.9%) TAC-PLAC patient developed chronic rejection after IS withdrawal because of pneumonitis. Arterial hypertension, diabetes mellitus, renal insufficiency, hypercholesterolemia, gout, and obesity were equally low in both groups., Conclusions: Excellent long-term results can be obtained under minimal IS and absence of steroids. TAC-based monotherapy is feasible in most adult liver recipients until 5 years of follow-up.

Purpose of Review: Liver transplantation is a validated treatment of primary hepatobiliary tumours. Over the last decade, a renewed interest for liver transplantation as a curative treatment of colorectal liver metastasis (CR-LM) and neuro-endocrine metastasis (NET-LM) has developed., Recent Findings: The ELTR and UNOS analyses showed that liver transplantation may offer excellent disease-free survival (ranging from 30 to 77%) in case of NET-LM, on the condition that stringent selection criteria are implemented. The interest for liver transplantation in the treatment of CR-LM has been fostered by the Norwegian SECA study. Five-year A 5-year survival rate of 60% could be reached. Despite the high recurrence rate (90%), one-third of patients were disease free following pulmonary surgery for metastases., Summary: Liver transplantation will take a more prominent place in the therapeutic algorithm of CR-LM and NET-LM. Larger experiences are necessary to improve knowledge about tumour biology and to refine selection criteria. A multimodal approach adding neo and adjuvant medical treatment to the transplant procedure will be key to bring this oncologic transplant project into the clinical arena. The preserved liver function in these patients will allow a more deliberate access to split liver and living donation for these indications.

Purpose of Review: The Milan criteria are still considered to be the best ones to select patients with hepatocellular cancer (HCC) for liver transplantation. Although the Milan criteria allowed lowering the incidence of tumor recurrence to a remarkable 10%, there is growing evidence that high numbers of patients were unrightfully excluded from a curative liver transplantation when exceeding these criteria. New strategies have been advocated during recent years with the intent not only to enlarge the number of potential transplant candidates, but also to select recipients with the lowest biological risk of recurrence., Recent Findings: Different 'biological' and 'dynamic' parameters have been proposed both in western and eastern scenarios, such as α-fetoprotein dynamics, radiological response to locoregional treatments and several inflammatory markers, the neutrophil-to-lymphocyte ratio being the most promising one., Summary: The paradigm that HCC patients should be selected according to morphological aspects (tumor numbers and diameters) only, based on the almost 20-year old success story of the Milan criteria, should be modified by combining these parameters with newer biological tumor markers in order to further refine the selection for liver transplantation. Such therapeutic algorithm will allow to further improve selection for and thus outcome after liver transplantation for HCC patients.

This review illustrates promising regenerative medicine technologies that are being developed for the treatment of gastrointestinal diseases. The main strategies under validation to bioengineer or regenerate liver, pancreas, or parts of the digestive tract are twofold: engineering of progenitor cells and seeding of cells on supporting scaffold material. In the first case, stem cells are initially expanded under standard tissue culture conditions. Thereafter, these cells may either be delivered directly to the tissue or organ of interest, or they may be loaded onto a synthetic or natural three-dimensional scaffold that is capable of enhancing cell viability and function. The new construct harbouring the cells usually undergoes a maturation phase within a bioreactor. Within the bioreactor, cells are conditioned to adopt a phenotype similar to that displayed in the native organ. The specific nature of the scaffold within the bioreactor is critical for the development of this high-function phenotype. Efforts to bioengineer or regenerate gastrointestinal tract, liver and pancreas have yielded promising results and have demonstrated the immense potential of regenerative medicine. However, a myriad of technical hurdles must be overcome before transplantable, engineered organs become a reality.

Based on analysis of the literature and of the audited ELITA (European Liver Intestinal Transplant Association)-ELTR (European Liver Transplant Registry) data, the place of liver transplantation (LT) in the treatment of vascular tumours is discussed. Hepatic epithelioid haemangioendothelioma has currently become a good indication for LT with 5- and 10-year post-LT patient survival rates of 83% and 74% respectively and 5- and 10-year recurrence-free survival rates of 82% and 64% respectively. In contrast, the results of LT for haemangiosarcoma (HAS) are disastrous with an universal tumour recurrence within 6 months and no single patient survival after 2 years. Therefore, HAS remains an absolute contraindication to LT. The value of LT in the treatment of infantile haemangioendothelioma is more difficult to evaluate because of the very reduced number of reported cases and because of the often difficult differential diagnosis with angiosarcoma. LT should be reserved to those children not responding to medical treatment on the condition that sarcomatous modifications are excluded by expert pathologists to avoid a futile transplant procedure.

Background: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC., Methods/design: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating., Discussion: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC., Trial Register: Trial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36).

Background: Hepatic epitheloid hemangioendothelioma (HEHE) is a rare low-grade vascular tumor. Its treatment algorithm is still unclear mainly due to a lack of larger clinical experiences with detailed long-term follow-up., Material and Methods: Fifty-nine patients, reported to the European Liver Transplant Registry, were analyzed to define the role of liver transplantation (LT) in the treatment of this disease. Eleven (19%) patients were asymptomatic. Eighteen (30.5%) patients had pre-LT surgical [hepatic (7 patients) and extrahepatic (3 patients)] and/or systemic or locoregional (10 patients) medical therapy. Ten (16.9%) patients had extrahepatic disease localization before or at the time of LT. Follow-up was complete for all patients with a median of 92.5 (range, 7-369) from moment of diagnosis and a median of 78.5 (range, 1-245) from the moment of LT., Results: HEHE was bilobar in 96% of patients; 86% of patients had more than 15 nodules in the liver specimen. Early (<3 months) and late (>3 months) post-LT mortality was 1.7% (1 patient) and 22% (14 patients). Fourteen (23.7%) patients developed disease recurrence after a median time of 49 months (range, 6-98). Nine (15.3%) patients died of recurrent disease and 5 are surviving with recurrent disease. One-, 5-, and 10- year patient survival rates from moment of transplantation for the whole series are 93%, 83%, 72%. Pre-LT tumor treatment (n = 18) (89%, 89%, and 68% 1-, 5-, and 10-year survival rates from moment of LT vs. 95%, 80%, and 73% in case of absence of pre-LT treatment), lymph node (LN) invasion (n = 18) (96%, 81%, and 71% 1-, 5-, and 10-year survival rates vs. 83%, 78%, and 67% in node negative patients) and extrahepatic disease localization (n = 10) (90%, 80%, and 80% 1-, 5-, and 10-year survival rates vs. 94%, 83%, and 70% in case of absence of extrahepatic disease) did not significantly influence patient survival whereas microvascular (n = 24) (96%, 75%, 52% 1-, 5-, and 10-year survival vs. 96%, 92%, 85% in case of absence of microvascular invasion) and combined micro- and macrovascular invasion (n = 28) (90%, 72%, and 54% 1-,5-, and 10-year survival vs. 96%, 92%, and 85% in case of absence of vascular invasion, P = 0.03) did. Disease-free survival rates at 1, 5, and 10 years post-LT are 90%, 82%, and 64%. Disease-free survival is not significantly influenced by pre-LT treatment, LN status, extrahepatic disease localization, and vascular invasion., Conclusions: The results of the largest reported transplant series in the treatment of HEHE are excellent. Preexisting extrahepatic disease localization as well as LN involvement are not contraindications to LT. Microvascular or combined macro-microvascular invasion significantly influence survival after LT. LT therefore should be offered as a valid therapy earlier in the disease course of these, frequently young, patients. Recurrent (allograft) disease should be treated aggressively as good long-term survivals can be obtained. Long-term prospective follow-up multicenter studies as well as the evaluation of antiangiogenic drugs are necessary to further optimize the treatment of this rare vascular hepatic disorder.

Hepatic epithelioid haemangioendotheliomas (HEHEs) are rare, low-grade vascular tumours. Five adults with HEHEs and one adult with a vascular tumour showing combined features of haemangioma and haemangioendothelioma underwent liver transplantation. Two HEHE patients had extrahepatic metastases at the time of transplantation. Median survival time following diagnosis was 10.7 years (range 40 months to 195 months). One patient needed resection of a HEHE in the breast 13 years post-transplantation. All six patients are surviving free from disease 22 to 166 months after transplantation (median 77 months). One HEHE-patient who had been treated for 8 years for vertebral and cerebral localisations is free of disease without immunosuppression 56 months after transplantation. We can conclude that liver transplantation is a valuable treatment for hepatic haemangioendothelioma, even in cases of extrahepatic localisation of the disease.

Eurotransplant introduced a new allocation policy in January 2003 to increase the number of liver transplants by offering centers an incentive to split deceased donor livers for 2 recipients. Centers were granted the option of choosing a suitable recipient for the second portion of the split liver from their own waiting list and, to increase the awareness for liver splitting, centers were asked by the Eurotransplant duty officer whether they would consider splitting whenever a liver that met the 50/50 rule (donor age <50 and weight >50 kg) was available. During the first year after implementing this policy, split-liver transplants increased by 67% and again by 10% during the second year (a total of 288 transplants in the 2-year period). The number of pediatric recipients of a split liver increased from 44 in 2002 to 76 in 2004 and the pediatric waiting list decreased by 36% (73 to 47) one year after implementation of the new policy. More than 95% of the 288 split liver transplants involved one adult and one pediatric recipient. Nearly three-quarters of the split liver transplants were performed at 3 centers with both a pediatric and adult waiting list and with surgeons experienced in the procedure. We conclude that Eurotransplant's liver allocation policy has increased the number of liver transplants, particularly among children, by rewarding centers that split livers for transplantation to 2 recipients without prolonging cold ischemia time. The number of centers that could benefit from this policy will increase as more surgeons are trained in the splitting procedure.

We report on two cases of type I glycogen storage disease (GSD) complicated by malignant tumors. A 23-year-old man had GSD Ia with adenomatosis. He underwent transplantation for rapidly growing and radiologically changing adenomata. At histological examination, one adenoma had become a hepatocellular carcinoma. A 22-year-old, HBV-infected woman had GSD type Ib with adenomatosis. At follow-up, several tumors showed changing morphological characteristics. Pre-transplant laparotomy confirmed the presence of a metastatic cholangiocarcinoma. Liver transplantation should be considered in GSD type I patients with adenomatosis, especially when tumor characteristics change. Regular detailed Doppler ultrasound and magnetic nuclear resonance screening during childhood and adolescence are, therefore, mandatory in order for the timing of transplantation to be optimized.

The excellent results obtained today in solid-organ transplantation allow the envisaging of an improvement in long-term quality of life with a functioning graft. One way for this to be achieved is by the reduction, or even better, the avoidance, of steroid-based immunosuppression. Avoidance of steroids is indeed known to enhance the physical and psychological well being of the allograft recipient. This paper reviews the current status of steroid-free immunosuppression in renal, pancreatic, hepatic, intestinal, and cardiac transplantation.

New immunosuppressants are said to be superior to cyclosporine due to their higher incidence of steroid sparing and to the reduced incidence of side-effects. From May 1992 to February 1995, 79 adults underwent primary liver transplantation using cyclosporine A (Sandimmun)-based triple drug immunosuppression. Nine patients who died early after liver transplantation due to reasons unrelated to immunological problems were excluded from this analysis. The long-term outcome of the remaining 70 patients was prospectively studied in relation to steroid and azathioprine withdrawal. They were re-evaluated 6-monthly in relation to liver and kidney function; cholesterolemia, infection, de novo diabetes mellitus and arterial hypertension, malignancy, ophthalmological and osteomuscular diseases. In case of rejection occurring during or after steroid tapering, patients were switched, by protocol, to tacrolimus therapy. Median follow-up was 81 months (range 60-96). Forty-four patients (62.8 %) were biopsied 5 years after transplant; 20 patients (28.6 %) were biopsied at a median follow-up of 32 months (range 7.8-47). Six patients (8.6 %) who refused biopsies more than 1 year after liver transplantation had normal liver values throughout the whole follow-up period. Five-year actual patient and graft survivals were 75 % and 65.8 %, respectively, for the whole group (n = 79) and 85.7 % and 74.3 % for the studied group (n = 70). Steroids could be withdrawn in all but two patients (97.1 %) at a median time of 7 months (range 3-42). Steroids were restarted in six patients (8.6 %) for extrahepatic reasons. Freedom from steroids was thus observed in 62 patients (88.6 %). Seven patients (10 %) had rejection after steroid tapering; six were switched to tacrolimus. Two patients (2.9 %) needed retransplantation because of acute and chronic rejection whilst still being on full immunosuppression. In total, three patients (4.3 %) had histological signs of chronic rejection during follow-up. At 5 years post-transplant, 66.6 % and 13.3 % of the 60 patients at risk were on cyclosporine and tacrolimus monotherapy, respectively; 93.3 % were steroid-free. Mean creatinine and cholesterol levels were 1.56 +/- 1.3 mg/dl and 193.5 +/- 56.6 mg/dl; incidences of de novo arterial hypertension, insulin dependent diabetes mellitus were 26.6 % and 13.3 %. Two patients (2.8 %) developed post-transplant lymphoproliferative disease, two (2.8 %) had skin cancer. Cyclosporine-based immunosuppression allows safe steroid withdrawal in most patients and cyclosporine monotherapy can be achieved in two-thirds without compromising graft and patient survival. Results of new immunosuppressive strategies should be approached with caution, especially when considering steroid sparing and the incidence of side-effects.

The number of adult patients on the liver transplantation waiting lists is growing steadily. Adult living related liver transplantation (LRLT) represents the ultimate means to expand the donor pool. The success of this model of "small for size" grafting relies on strict donor and recipient selection. The choice of the graft (2 left and 4 right hepatectomies) was made on the minimal ratio between estimated graft and recipient body weights (0.8-1%), necessary to meet the recipient's metabolic demands. Our experience with six adults is reported. Donor morbidity was minimal (one wound infection); there was no mortality. Four (66%) recipients are doing well, two died of infectious complications. All recipients had a complicated post-transplant course. Due to its complexity, both in donor and recipient, LRLT should only be developed very carefully in experienced liver transplant centers.

Background: Transjugular intrahepatic portosystemic shunting (TIPS) has become an effective treatment for the complications of portal hypertension. We assessed the feasibility and outcome of TIPS in liver transplant recipients., Methods: During the period from December 1992 to January 1998, eight adults presenting recurrent hepatitis C virus (five patients) and hepatitis B virus (one patient) infection, veno-occlusive disease (one patient), and secondary biliary cirrhosis (one patient) had TIPS because of refractory ascites (five patients), bleeding esophageal varices (one patient), refractory hepatic hydrothorax (one patient), retransplantation (two patients), and redo-biliary surgery (one patient)., Results: In two patients, the procedure was difficult due to cavo-caval implantation. Ascites, hydrothorax, and variceal bleeding were controlled in all patients. Moderate to severe encephalopathy developed in four patients; two patients had worsening of their existing encephalopathy. Three of five patients treated with cyclosporine needed a drastic dose reduction due to the development of severe side effects. No long-term survivor developed shunt stenosis or occlusion. Two patients did moderately well at 6 and 14 months, respectively; the former died due to chronic rejection while waiting for a retransplantation. Three did well at 14, 36, and 28 months, respectively; the latter patient died of liver failure 32 months after TIPS. One jaundiced patient died after 1.5 months due to necrotic pancreatitis. Two patients died after 4 and 8.5 months, respectively, due to liver failure; the latter was doing well until 7 months after TIPS., Conclusions: TIPS is feasible in transplant recipients in cases of decompensated allograft cirrhosis, of allograft veno-occlusive disease or when retransplantation or redo-biliary surgery are scheduled in the presence of portal hypertension. At transplantation, the surgeon should keep in mind the eventuality of a later TIPS procedure. Close immunosuppression monitoring is warranted because modified metabolization of cyclosporine (and probably tacrolimus) may cause serious side effects.

Background/aims: The place of liver transplantation in hepatitis B viral (HBV)-related diseases remains controversial because of the high rate of reinfection. The aim of this study was to define the determinants of long-term prognosis after transplantation., Methods: Fifty-eight patients were transplanted during the period February 1984-September 1996. Six patients died during the early (< 3 months) posttransplant period from causes unrelated to HBV infection. All 52 long-term (> 3 months) survivors were evaluated in relation to the mode of presentation, viral replication at time of transplantation, absence of hepatocellular cancer at time of transplantation and use of adequate immunoprophylaxis (IP). Adequate immunoprophylaxis, defined as maintenance of anti-HBs levels over 100 mUI/ml, was introduced in December 1989. Intention-to-treat IP analysis compared patients transplanted before and after this date. The median follow-up was 74 months (range 4 to 131). Forty-seven patients (90%) had a minimal follow-up of 3 years., Results: Five-year actuarial survival rates of 58 patients and of 52 long-term survivors were 72 +/- 6% and 80 +/- 6%, respectively. Univariate analysis showed that delta co-infection (n = 25) significantly improved survival (p < 0.001) [96 +/- 4% vs 63 +/- 10% in HBV patients (n = 27) at 5 years] as did absence of hepatocellular cancer (n = 36) (p = 0.020) [89 +/- 5% vs 61 +/- 12% in 16 non-cancer patients]. IP, however, significantly influenced 5-year survival in the HBV-patient group (n = 17) (p = 0.001) [85 +/- 10% vs 30 +/- 14% in 10 patients without IP). Multivariate analysis selected delta co-infection (p = 0.002) and IP (p = 0.01) as the significant determinants of prognosis independently influencing survival. Uni- and multivariate analyses showed that survival without reinfection was significantly influenced by IP (p = 0.002) [73 +/- 8% (n = 31) versus 33 +/- 12% in 15 non-treated patients)., Conclusions: Delta virus co-infection and immunoprophylaxis are the most important prognostic factors after transplantation for postnecrotic HBsAg-positive cirrhosis. Transplantation can be proposed as a therapeutic tool only if life-long adequate adjuvant therapy can be achieved. Under this condition good results can even be obtained if there is viral replication at the time of transplantation.

Orthotopic liver transplantation can be performed successfully in thalassemia. In this article, we describe a case of liver transplantation in a patient with sickle cell/beta-thalassemia complicated by liver sickling. Intrahepatic sickling must be considered in case of allograft dysfunction. This condition can easily be diagnosed by biochemical investigation and liver ultrasonography.