Plasma immune signatures can predict rejection-free survival in the first year after pediatric liver transplantation.

BACKGROUND & AIMS: After pediatric liver transplantation (pLT), children undergo life-long immunosuppression since reliable biomarkers for the assessment of rejection probability are scarce. In the multicentre (n=7) prospective clinical cohort "ChilSFree" study, we aimed to characterize longitudinal dynamics of soluble and cellular immune mediators during the first year after pLT and identify early biomarkers associated with outcome. METHODS: Using paired Luminex-based multiplex technique and flow cytometry, we characterized longitudinal dynamics of soluble immune mediators (SIM, n=50) and immune cells in the blood of 244 patients at 8 visits over one year: before, 7/14/21/28 days, 3/6/12 months after pLT. RESULTS: The unsupervised clustering of patients based on SIM profiles revealed 6 unique SIM signatures associated with clinical outcome. From 3 signatures linked to improved outcome, one was associated with one-year-long rejection-free survival and stable graft function and was characterized by low levels of pro-inflammatory (CXCL8/9/10/12, CCL7, SCGF-ß, sICAM-1), high levels of regenerative (SCF, TNF-ß), and pro-apoptotic (TRAIL) SIM (all, p<0.001, fold change >100). Of note, this SIM signature appeared two weeks after pLT and remained stable over the entire year, pointing towards its potential as a novel early biomarker for minimizing or weaning immunosuppression. In the blood of these patients, a higher frequency of CD56bright NK cells (p<0.01), a known hallmark also associated with operationally tolerant pLT patients, was detected. The concordance of the model for prediction of rejection based on identified SIM signatures was 0.715, and 0.795, in combination with living-related transplantation as co-variate, respectively. CONCLUSIONS: SIM blood signatures may enable the non-invasive and early assessment of rejection risks in the first year after pLT, paving the way to improved therapeutic options.

Successful sequential liver and hematopoietic stem cell transplantation in a patient with Fanconi anemia.

BACKGROUND: In Fanconi anemia bone marrow failure is the major cause of morbidity and mortality and hematopoietic stem cell transplantation represents the only curative treatment. Liver disease, in terms of elevated liver function tests, as well as benign and malignant liver tumors, occurs especially in case of androgen treatment. We report a unique case of a child with Fanconi anemia with FANCD2 mutation who developed neonatal cryptogenic liver cirrhosis and bone marrow failure. The child successfully underwent sequential liver transplantation and hematopoietic stem cell transplantation in the first 2 years of life. Nineteen months after hematopoietic stem cell transplantation and 30 months after liver transplantation, the patient is clinically well with normal hematopoietic function and excellent liver function. CONCLUSION: This is the first FA patient who successfully received sequential LT and HSCT highlighting that successful sequential transplantation is feasible in Fanconi anemia patients.

Hepatic hemangioendothelioma of infancy: clinical features of a large cohort of patients and proposed management.

PURPOSE: The management of hepatic hemangioendothelioma (HHE) may be challenging. We aimed to review a large cohort of children who presented to our centers with symptomatic HHE in the last 16 years. METHODS: We collected age at presentation, clinical features, histology, diagnostic process, management and outcome. RESULTS: Twenty seven patients (male/female 5/22), median age 13 days (1-1530) presented with hepatomegaly (24/27), cardiac failure (10/27), cutaneous hemangiomas (8/27), fever and anemia (6/27 each), vomiting (5/27), splenomegaly (4/27). The lesion was focal, multifocal, or diffuse in 9 patients of each group. The management included medical treatment (8/27), embolization (8/27), resection (3/27), observation (6/27), transplantation (2/27). After 16 months' follow-up (30 days-11 years), 23/27 (85%) were alive. Diffuse lesions (4/4), cardiac failure (4/4), type II histology (4/4), age older than 6 months at diagnosis (3/4) predicted mortality (all p < 0.01). Histology showed type 1 lesion in 3/8, type 2 in 3/8, and type 3 in 2/8 with foci of angiosarcoma. CONCLUSION: Most patients with symptomatic HHE can be managed successfully with a combination of medical, radiological and surgical treatments. Patients with diffuse lesions, late presentation, cardiac failure and type II histology have a poor outcome. LEVEL OF EVIDENCE: Diagnostic level IV. Therapeutic level IV.

Incidence, management and outcomes in hepatic artery complications after paediatric liver transplantation: protocol of the retrospective, international, multicentre HEPATIC Registry.

INTRODUCTION: Hepatic artery complications (HACs), such as a thrombosis or stenosis, are serious causes of morbidity and mortality after paediatric liver transplantation (LT). This study will investigate the incidence, current management practices and outcomes in paediatric patients with HAC after LT, including early and late complications. METHODS AND ANALYSIS: The HEPatic Artery stenosis and Thrombosis after liver transplantation In Children (HEPATIC) Registry is an international, retrospective, multicentre, observational study. Any paediatric patient diagnosed with HAC and treated for HAC (at age <18 years) after paediatric LT within a 20-year time period will be included. The primary outcomes are graft and patient survivals. The secondary outcomes are technical success of the intervention, primary and secondary patency after HAC intervention, intraprocedural and postprocedural complications, description of current management practices, and incidence of HAC. ETHICS AND DISSEMINATION: All participating sites will obtain local ethical approval and (waiver of) informed consent following the regulations on the conduct of observational clinical studies. The results will be disseminated through scientific presentations at conferences and through publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: The HEPATIC registry is registered at the ClinicalTrials.gov website; Registry Identifier: NCT05818644.

Prevalence, management and efficacy of treatment in portal vein obstruction after paediatric liver transplantation: protocol of the retrospective international multicentre PORTAL registry.

INTRODUCTION: Portal vein obstruction (PVO) consists of anastomotic stenosis and thrombosis, which occurs due to a progression of the former. The aim of this large-scale international study is to assess the prevalence, current management practices and efficacy of treatment in patients with PVO. METHODS AND ANALYSIS: The Portal vein Obstruction Revascularisation Therapy After Liver transplantation registry will facilitate an international, retrospective, multicentre, observational study, with 25 centres around the world already actively involved. Paediatric patients (aged <18 years) with a diagnosed PVO between 1 January 2001 and 1 January 2021 after liver transplantation will be eligible for inclusion. The primary endpoints are the prevalence of PVO, primary and secondary patency after PVO intervention and current management practices. Secondary endpoints are patient and graft survival, severe complications of PVO and technical success of revascularisation techniques. ETHICS AND DISSEMINATION: Medical Ethics Review Board of the University Medical Center Groningen has approved the study (METc 2021/072). The results of this study will be disseminated via peer-reviewed publications and scientific presentations at national and international conferences. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL9261).

Favorable outcome of primary liver transplantation in children with cirrhosis and hepatocellular carcinoma.

The outcome of HCC after transplantation (OLT) in children is not well known. Unfavorable features based on adult reports may lead to contraindicate OLT even in children. We reviewed a cohort of children with cirrhosis and HCC to evaluate their outcome after primary transplantation. We considered children with cirrhosis and HCC who had a primary OLT. We retrospectively recorded demographic, medical and surgical features, and MC as predictors of outcome. Among 456 children transplanted in the last 15 yr, 10 (2%), median age at diagnosis 1.8 yr (range 0.5-7.2), had HCC in biliary atresia (3), BSEP deficiency (3), tyrosinemia type 1 (2), complications of choledocal cyst and glycogen storage disease type IV (1 each). At HCC discovery, median AFP was 2322 ng/mL (3-35,000), high or rising in 9/10 patients. Six patients were outside the MC. Median time on the waiting list was 38 days (1-152). Two patients died from early complications of OLT. In the other eight patients, there was no tumor recurrence after a median follow-up of four yr. Children with cirrhosis may develop HCC at a very young age. The outcome appears excellent even outside MC. Primary liver transplantation is advisable for children with cirrhosis, HCC, and no extrahepatic disease.

Late graft dysfunction and autoantibodies after liver transplantation in children: preliminary results of an Italian experience.

Late graft dysfunction (GD) associated with the development of autoantibodies is a common event after pediatric liver transplantation (OLTx) and can present in 2 clinicohistological subsets: de novo autoimmune hepatitis (DNAH) and early chronic rejection (ECR). Sixty out of 247 children developed autoantibodies after OLTx. GD was demonstrated in 22 (37%); based on histology, patients were divided in a DNAH and an ECR group. Portal/periportal inflammatory infiltrate with interface/lobular hepatitis was suggestive for DNAH. Pericentral hepatocytes confluent dropout with a variable degree of central vein endothelitis, but not with ductopenia (loss of >50% of interlobular bile ducts), was diagnosed as ECR. Nine patients had DNAH and 13 ECR. Five out of 9 in the DNAH group were on cyclosporin (CsA) and 4/9 were on tacrolimus (Tac). In the ECR group, 11 children were treated with CsA and 2 with Tac. All DNAH patients had normal liver function tests on steroids and azathioprine (AZA). Five patients with ECR recovered by increasing calcineurin inhibitors (CNIs) dosage, but in 8/13, including 7 switched from CsA to Tac, AZA and steroids were added to obtain remission of disease. Two patients developed late chronic rejection. DNAH and ECR associated with autoantibodies are forms of late GD after OLTx. DNAH improves after standard treatment of autoimmune hepatitis. ECR has a good response to increased doses of CNIs, although ductopenic chronic rejection may occur. In conclusion, the early differential diagnosis of these conditions and an appropriate treatment seem to allow good overall results reflected by a graft survival of more than 90%.