• Humans
• Liver Transplantation/adverse effects
• Child
• Immunosuppressive Agents/therapeutic use
• Immunosuppressive Agents/adverse effects
• Immunosuppressive Agents/administration & dosage
• MTOR Inhibitors/therapeutic use
• MTOR Inhibitors/adverse effects
• Graft Rejection/prevention & control
• Calcineurin Inhibitors/therapeutic use
• Calcineurin Inhibitors/adverse effects
• Calcineurin Inhibitors/administration & dosage
• TOR Serine-Threonine Kinases/antagonists & inhibitors

• biliary injury
• immunosuppression
• mammalian target of rapamycin inhibitors

• Humans
• Liver Transplantation
• Graft Rejection/prevention & control
• Male
• Female
• Sirolimus/therapeutic use
• Immunosuppressive Agents/therapeutic use
• Liver Cirrhosis/drug therapy
• Liver Cirrhosis/surgery
• Child
• Child, Preschool
• Infant
• Adolescent
• Retrospective Studies
• Chronic Disease
• Treatment Outcome
• Drug Resistance

• None

• paediatric cancer
• cancer models
• cancer genetics
• cancer therapy
• liver cancer

• Humans
• Animals
• Mice
• Hepatoblastoma/drug therapy
• Hepatoblastoma/genetics
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Doxorubicin/pharmacology
• Doxorubicin/therapeutic use
• Cell Line
• Oncogenes
• Protein-Arginine N-Methyltransferases/genetics
• Repressor Proteins/genetics

• R01 CA229739 NCI NIH HHS
• R01 CA262790 NCI NIH HHS
• U01 CA232488 NCI NIH HHS
• R03 CA212802 NCI NIH HHS
• R01 AI114581 NIAID NIH HHS
• R01 CA266600 NCI NIH HHS
• R01 AI175004 NIAID NIH HHS
• R01 CA247941 NCI NIH HHS
• American Cancer Society (American Cancer Society, Inc.)
• Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
• CIBERehd Proyecto Intramural 2022 and the Scientific Foundation of the Spanish Association Against Cancer (PRYCO223102ARME).

• graft dysfunction
• immunosuppressive therapy
• malignancy
• pediatric liver transplantation
• renal impairment

• AFP
• biliary complication
• hepatoblastoma
• liver malignancy
• long-term outcome
• pediatric liver transplantation
• salvage transplant
• tumor recurrence

Antibody-mediated rejection (AMR) of liver allograft transplantation was considered as anecdotal for many decades. However recently, AMR has gained clinical awareness as a potential cause of chronic liver injury, leading to liver allograft fibrosis and eventual graft failure. (1) Methods: Literature on chronic AMR (cAMR) in pediatric post-liver transplant patients was reviewed for epidemiologic data, physiopathology, diagnosis, and treatment approaches. (2) Results: Accurate incidence of cAMR in pediatric liver transplantation remains unknown. Diagnostic criteria of cAMR were suggested by the Banff Working Group in 2016 and are based on standardized histopathological findings, C4d staining pattern, associated with the presence of donor-specific antibodies (DSA). Physio-pathological mechanisms are not clear for the technically difficult-to-obtain animal models reproducing cAMR. Treatment protocols are not established, being limited to case reports and case series, based on experience in ABO incompatible transplantation and kidney transplantation. Immunosuppression compliance with adequate dose adjustment may prevent cAMR. Conversion of Cyclosporine to Tacrolimus may improve pathological findings if treated in early phase. The association of steroids, Mycophenolate Mofetil (MMF) and mTOR inhibitors have shown some synergistic effects. Second-line treatments such as intravenous immunoglobulin (IVIG) and plasma exchange may decrease antibody titers based on ABO incompatible transplant protocols. The use of anti-CD20 (Rituximab) and proteasome inhibitors (Bortezomib) is controversial due to the lack of qualified studies. Therefore, multicenter randomized trials are needed to establish the best therapeutic strategy. In refractory cases, re-transplantation is the only treatment for allograft failure. (3) Conclusions: This literature review collects recent clinical, histopathological, and therapeutical advances of cAMR in liver allograft transplantation of pediatric patients. There are many physio-pathological aspects of cAMR to be clarified. Further efforts with multicenter prospective protocols to manage patients with cAMR are needed to improve its outcome.

• autoimmune hepatitis
• corticosteroids
• everolimus
• mTOR inhibitors
• pediatric

While liver transplantation was initially considered as a curative treatment modality only for hepatocellular carcinoma, the indication has been increasingly extended to other tumor entities over recent years, most recently to the treatment of non-resectable colorectal liver metastases. Although oncologic outcomes after liver transplantation (LT) are consistently good, organ shortage forces stringent selection of suitable candidates. Dynamic criteria based on tumor biology fulfill the prerequisite of an individual oncological prediction better than traditional morphometric criteria based on tumor burden. The availability of specific (neo-)adjuvant therapies and customized modern immunosuppression may further contribute to favorable post-transplantation outcomes on the one hand and simultaneously open the path to LT as a curative option for advanced stages of tumor patients. Herein, we provide an overview of the oncological LT indications, the selection process, and expected oncological outcome after LT.

• calcineurin inhibitors
• chronic kidney disease
• nephrotoxicity
• pediatric liver transplantation
• renal biomarkers
• renal function estimation

• Acute cellular rejection
• Everolimus
• Immunosuppression
• Rescue therapy
• Sirolimus

• liver transplantation
• mTOR inhibitor
• outcome
• pediatric

• cisplatin
• hepatoblastoma
• immunosuppression
• liver transplantation
• renal insufficiency
• sirolimus
• tacrolimus

• calcineurin inhibitor
• children
• cyclosporine
• everolimus
• liver transplantation
• pediatric
• tacrolimus

• Pediatric immunosuppression
• Pediatric solid-organ transplant

• Calcineurin Inhibitors/administration & dosage
• Drug Therapy, Combination
• Everolimus/adverse effects
• Everolimus/therapeutic use
• Graft Rejection/drug therapy
• Graft Rejection/pathology
• Humans
• Immunosuppressive Agents/adverse effects
• Immunosuppressive Agents/therapeutic use
• Liver Neoplasms/prevention & control
• Liver Transplantation
• Neoplasm Recurrence, Local/prevention & control
• Randomized Controlled Trials as Topic
• Renal Insufficiency, Chronic/physiopathology

During the last 5 decades, liver transplantation has witnessed rapid development in terms of both technical and pharmacologic advances. Since their discovery, calcineurin inhibitors (CNIs) have remained the standard of care for immunosuppression therapy in liver transplantation, improving both patient and graft survival. However, adverse events, particularly posttransplant nephrotoxicity, associated with long-term CNI use have necessitated the development of alternate treatment approaches. These include combination therapy with a CNI and the inosine monophosphate dehydrogenase inhibitor mycophenolic acid and use of mammalian target of rapamycin (mTOR) inhibitors. Everolimus, a 40-O-(2-hydroxyethyl) derivative of mTOR inhibitor sirolimus, has a distinct pharmacokinetic profile. Several studies have assessed the role of everolimus in liver transplant recipients in combination with CNI reduction or as a CNI withdrawal strategy. The efficacy of everolimus-based immunosuppressive therapy has been demonstrated in both de novo and maintenance liver transplant recipients. A pivotal study in 719 de novo liver transplant recipients formed the basis of the recent approval of everolimus in combination with steroids and reduced-dose tacrolimus in liver transplantation. In this study, everolimus introduced at 30 days posttransplantation in combination with reduced-dose tacrolimus (exposure reduced by 39%) showed comparable efficacy (composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, or death) and achieved superior renal function as early as month 1 and maintained it over 2 years versus standard exposure tacrolimus. This review provides an overview of the efficacy and safety of everolimus-based regimens in liver transplantation in the de novo and maintenance settings, as well as in special populations such as patients with hepatocellular carcinoma recurrence, hepatitis C virus-positive patients, and pediatric transplant recipients. We also provide an overview of ongoing studies and discuss potential expansion of the role for everolimus in these settings.

• efficacy
• everolimus
• liver transplantation
• mTOR inhibitors
• safety

• biliary rhabdomyosarcoma
• liver transplantation
• long-term survival
• neoadjuvant chemotherapy

AIM: To assess our experience with the use and management of everolimus-based regimens post-liver transplantation and to redefine the potential role of this drug in current clinical practice.

METHODS: From October 1988 to December 2012, 1023 liver transplantations were performed in 955 patients in our Unit. Seventy-four patients (7.74%) received immunosuppression with everolimus at some time post-transplantation. Demographic characteristics, everolimus indication, time elapsed from transplantation to the introduction of everolimus, doses and levels administered, efficacy, side effects, discontinuation and post-conversion survival were analyzed.

RESULTS: Mean age at the time of conversion to everolimus was 57.7 ± 10 years. Indications for conversion were: refractory rejection 31.1%, extended hepatocellular carcinoma in explanted liver 19%, post-transplant hepatocellular carcinoma recurrence 8.1%, de novo tumour 17.6%, renal insufficiency 8.1%, severe neurotoxicity 10.8%, and others 5.4%. Median time from transplantation to introduction of everolimus was 6 mo (range: 0.10-192). Mean follow-up post-conversion was 22 ± 19 mo (range: 0.50-74). The event for which the drug was indicated was resolved in 60.8% of patients, with the best results in cases of refractory rejection, renal insufficiency and neurotoxicity. Results in patients with cancer were similar to those of a historical cohort treated with other immunosuppressants. The main side effects were dyslipidemia and infections. Post-conversion acute rejection occurred in 14.9% of cases. The drug was discontinued in 28.4% of patients.

CONCLUSION: Everolimus at low doses in combination with tacrolimus is a safe immunosuppressant with multiple early and late indications post-liver transplantation.

• Everolimus
• Liver transplantation
• Indications
• Off-protocol
• Outcome

The evidence base relating to the use of everolimus in heart transplantation has expanded considerably in recent years, providing clinically relevant information regarding its use in clinical practice. Unless there are special considerations to take into account, all de novo heart transplant patients can be regarded as potential candidates for immunosuppression with everolimus and reduced-exposure calcineurin inhibitor therapy. Caution about the use of everolimus immediately after transplantation should be exercised in certain patients with the risk of severe proteinuria, with poor wound healing, or with uncontrolled severe hyperlipidemia. Initiation of everolimus in the early phase aftertransplant is not advisable in patients with severe pretransplant end-organ dysfunction or in patients on a left ventricular assist device beforetransplant who are at high risk of infection or of wound healing complications. The most frequent reason for introducing everolimus in maintenance heart transplant patients is to support minimization or withdrawal of calcineurin inhibitor therapy, for example, due to impaired renal function or malignancy. Due to its potential to inhibit the progression of cardiac allograft vasculopathy and to reduce cytomegalovirus infection, everolimus should be initiated as soon as possible after heart transplantation. Immediate and adequate reduction of CNI exposure is mandatory from the start of everolimus therapy.

• calcineurin inhibitors
• children
• pediatric
• sirolimus
• transplantation

• Adverse events
• Epilepsy
• Everolimus
• SEGA
• Safety
• TSC
• Young children

Kortikosteroide waren die ersten Therapeutika zur Kontrolle von Abstoßungsreaktionen nach Transplantation. Sie sind seit Langem und immer noch wichtiger Bestandteil vieler immunsuppressiver Therapiekonzepte. Kortikosteroide besitzen zahlreiche antiinflammatorische und immunsuppressive Effekte. Sie beeinflussen über die Bindung spezifischer zytoplasmatischer Rezeptoren die Gentranskriptionsrate für zentrale, immunregulatorische Proteine wie Interleukin 1β (IL-1β), IL-6, Tumor-Nekrose-Faktor α (TNF-α) mit resultierender Suppression der Makrophagenfunktion und konsekutiver T-Zell-Aktivierung. Sie inhibieren auch die IL-2-Synthese, hemmen damit die T-Zell-Proliferation und reduzieren die IL- 2-Rezeptorbindungsfähigkeit. Andererseits stimulieren sie die Synthese des inhibierenden Zytokins „transforming growth factor β“ (TGF-β), was in einem „antiinflammatorisch“ geprägten T-Helfer-Zell-2-artigen Zytokinprofil resultiert. Über die Inhibition der Expression von interferonabhängigen Adhäsionsmolekülen (einschließlich MHC-Klasse-II-Moleküle) bewirken Kortikosteroide darüber hinaus die Alteration von Leukozytenverkehr und -transmigration sowie eine Induktion der Lymphozytenapoptose.