Variation in resource utilization in liver transplantation at freestanding children's hospitals.

We sought to examine the relationship between liver transplant-related total cost, patient outcome, and hospital resource utilization at freestanding children's hospitals. Using the PHIS database, a retrospective study of 374 patients that underwent liver transplantation at 15 freestanding children's hospitals from July 2010 to December 2012 was performed. One-year graft failure and patient mortality rates from July 2010 to December 2012 for each center were also obtained from the SRTR. There was a 5.1-fold difference in median cost (median $146 444, range $59 487-302 058, P<.001) between all centers. A 2.4-fold difference existed in median LOS (median 15 days, range 9-22 days, P<.001) across centers. Median postoperative ICU stay varied from 0 to 7 days (median 4 days, P<.001). Overall, 30-day readmission rate was 55% (31.3%-100%, P<.001). One-year graft failure varied from 0% to 19.1%, with an overall rate of 5.5% (P=.279). One-year patient mortality for all centers was 2.3% (range 0%-11.1%, P=.016). Higher total cost did not correlate with lower readmission rates, patient mortality, graft failure, or any other variable. These data suggest that identifying practice patterns at low-cost centers and implementing them at higher-cost centers may decrease the cost of pediatric liver transplantation without compromising outcomes.

YAP Subcellular Localization and Hippo Pathway Transcriptome Analysis in Pediatric Hepatocellular Carcinoma.

Pediatric hepatocellular carcinoma (HCC) is a rare tumor which is associated with an extremely high mortality rate due to lack of effective chemotherapy. Recently, the Hippo pathway and its transcriptional co-activator Yes-associated protein (YAP) have been shown to play a role in hepatocyte proliferation and development of HCC in animal models. Therefore, we sought to examine the activity of YAP and the expression of Hippo pathway components in tumor and non-neoplastic liver tissue from 7 pediatric patients with moderately differentiated HCC. None of the patients had underlying cirrhosis or viral hepatitis, which is commonly seen in adults with HCC. This highlights a major difference in the pathogenesis of HCC between children and adults. We found a statistically significant increase in YAP nuclear localization in 100% of tumors. YAP target gene (CCNE1, CTGF, Cyr61) mRNA expression was also increased in the tumors that had the most significant increase in YAP nuclear localization. Based on Ki67 co-localization studies YAP nuclear localization was not simply a marker of proliferation. Our results demonstrate a clear increase in YAP activity in moderately differentiated pediatric HCC, providing evidence that it may play an important role in tumor survival and propagation.

Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration.

The Hippo signaling pathway has been implicated in mammalian organ size regulation and tumor suppression. Specifically, the Hippo pathway plays a critical role regulating the activity of transcriptional coactivator Yes-associated protein (YAP), which modulates a proliferative transcriptional program. Recent investigations have demonstrated that while this pathway is activated in quiescent livers, its inhibition leads to liver overgrowth and tumorigenesis. However, the role of the Hippo pathway during the natural process of liver regeneration remains unknown. Here we investigated alterations in the Hippo signaling pathway and YAP activation during liver regeneration using a 70% partial hepatectomy (PH) rat model. Our results indicate an increase in YAP activation by 1 day following PH as demonstrated by increased YAP nuclear localization and increased YAP target gene expression. Investigation of the Hippo pathway revealed a decrease in the activation of core kinases Mst1/2 by 1 day as well as Lats1/2 and its adapter protein Mob1 by 3 days following PH. Evaluation of liver-to-body weight ratios indicated that the liver reaches its near normal size by 7 days following PH, which correlated with a return to baseline YAP nuclear levels and target gene expression. Additionally, when liver size was restored, Mst1/2 kinase activation returned to levels observed in quiescent livers indicating reactivation of the Hippo signaling pathway. These findings illustrate the dynamic changes in the Hippo signaling pathway and YAP activation during liver regeneration, which stabilize when the liver-to-body weight ratio reaches homeostatic levels.