Impact of psychosocial factors on medication level variability index and outcomes in pediatric liver transplant recipients.

BACKGROUND: Caregivers play an important role in maintaining a functioning graft after pediatric liver transplantation. Therefore, the psychosocial factors of both patients and caregivers can have a critical impact on transplant outcomes. Appropriate assessment and recognition of these factors pre-transplantation may allow transplant teams to better define the needs of pediatric organ recipients and develop specific countermeasures, which may then contribute toward improving transplant outcomes. METHODS: We studied 136 pediatric LT recipients followed at Texas Children's Hospital. Licensed social workers conducted comprehensive pre-transplant assessments on each patient, consisting of 22 psychosocial variables that were thought to impact adherence, which were reviewed during our study period. Non-adherence was determined using the MLVI for up to 4 years after transplantation. Biopsy-confirmed rejection episodes were assessed in the first 3 years after liver transplantation. RESULTS: Factors significantly associated with non-adherence (defined as MLVI >2) included parental age and parental education level at assessment, type of insurance, and household income. The number of ACR episodes trended higher in patients with non-adherence, and these patients had a higher number of moderate to severe rejection episodes but this trend was not statistically significant. CONCLUSIONS: Psychosocial characteristics such as parental age, education level, insurance, and household income may contribute significantly to suboptimal adherence to medications after transplantation. Identification of these psychosocial factors and early intervention is essential to the success and equitable care of our pediatric LT recipients.

The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children.

BACKGROUND AND AIMS: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC. APPROACH AND RESULTS: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well. CONCLUSIONS: The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.

Gamma Glutamyltransferase Reduction Is Associated With Favorable Outcomes in Pediatric Primary Sclerosing Cholangitis.

Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long-term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event-free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver-related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, P= not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, P= 0.002), but 5-year event-free survival was similar (74% versus 77%, P= NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5-year event-free survival was better (91% versus 67%, P< 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5-year event-free survival 88% versus 61%, P= 0.005). Conclusion:A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5-year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.

The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration.

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long-term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long-term outcome. We identified 781 patients, median age 12 years, with 4,277 person-years of follow-up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event-free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC-inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5-0.9, and 0.7, 95% confidence interval 0.5-0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long-term outcome. CONCLUSION: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC-inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518-527).

Unique Inflammatory Bowel Disease Phenotype of Pediatric Primary Sclerosing Cholangitis: A Single-Center Study.

OBJECTIVES: In adults, primary sclerosing cholangitis (PSC), a cholestatic liver disease characterized by inflammation/fibrosis of intra/extrahepatic bile ducts, associates with a milder form of inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). The pediatric PSC-IBD phenotype is less well characterized. METHODS: We performed a retrospective, single-center study examining patients with PSC-IBD at Texas Children's Hospital between 2000 and 2015. IBD-phenotype (Modified Montreal Classification), medications, laboratory values, endoscopic records, and IBD-based hospital admissions were collected. PSC-UC phenotype was compared to UC, non-PSC patients (n = 95) from Texas Children's Hospital. Elevated gamma-glutamyl transpeptidase levels were compared to calprotectin levels and IBD-flare activity, that is, gastrointestinal symptoms resulting in office/emergency department visits or hospital admission. RESULTS: Of 39 patients with PSC-IBD, 34 (87.2%) had UC (PSC-UC) and 5 (12.8%) had Crohn disease. Pancolitis was more common in PSC-UC than UC, non-PSC (96.3%, 64%, P = 0.0009). Patients with PSC-UC required less treatment with steroids (76.5%, 91.6%, P = 0.0326) or infliximab (8.8%, 37.9%, P = 0.0011), and fewer had at least 1 IBD-related hospital admission (32.4%, 63.2%, P = 0.0025) than UC, non-PSC. Progression to colectomy was significantly less (5.8%, 24.2%, P = 0.0223) in PSC-UC. Median diagnosis-to-colectomy time tended to be longer in PSC-UC (6.37, 2.5 years, P = 0.0792). In 2 smaller subsets, gamma-glutamyl transpeptidase did not correlate with calprotectin in PSC-UC (n = 11, P = 0.7922) and less strongly associated with IBD-flares in PSC-UC than UC, non-PSC (n = 33, n = 67; 15.2%, 41.8%, P = 0.0120). CONCLUSIONS: Pediatric PSC appears to associate with milder pancolitic-UC. PSC and IBD activity do not appear to correlate. Our findings may provide useful information toward etiology and management of pediatric PSC-IBD.

Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer.

BACKGROUND & AIMS: Pediatric liver cancer is a rare but serious disease whose incidence is rising, and for which the therapeutic options are limited. Development of more targeted, less toxic therapies is hindered by the lack of an experimental animal model that captures the heterogeneity and metastatic capability of these tumors. METHODS: Here we established an orthotopic engraftment technique to model a series of patient-derived tumor xenograft (PDTX) from pediatric liver cancers of all major histologic subtypes: hepatoblastoma, hepatocellular cancer and hepatocellular malignant neoplasm. We utilized standard (immuno) staining methods for histological characterization, RNA sequencing for gene expression profiling and genome sequencing for identification of druggable targets. We also adapted stem cell culturing techniques to derive two new pediatric cancer cell lines from the xenografted mice. RESULTS: The patient-derived tumor xenografts recapitulated the histologic, genetic, and biological characteristics-including the metastatic behavior-of the corresponding primary tumors. Furthermore, the gene expression profiles of the two new liver cancer cell lines closely resemble those of the primary tumors. Targeted therapy of PDTX from an aggressive hepatocellular malignant neoplasm with the MEK1 inhibitor trametinib and pan-class I PI3 kinase inhibitor NVP-BKM120 resulted in significant growth inhibition, thus confirming this PDTX model as a valuable tool to study tumor biology and patient-specific therapeutic responses. CONCLUSIONS: The novel metastatic xenograft model and the isogenic xenograft-derived cell lines described in this study provide reliable tools for developing mutation- and patient-specific therapies for pediatric liver cancer. LAY SUMMARY: Pediatric liver cancer is a rare but serious disease and no experimental animal model currently captures the complexity and metastatic capability of these tumors. We have established a novel animal model using human tumor tissue that recapitulates the genetic and biological characteristics of this cancer. We demonstrate that our patient-derived animal model, as well as two new cell lines, are useful tools for experimental therapies.