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Item Benign Hepatic Nodules Mimicking Hepatocellular Carcinoma in the Setting of Fontan-associated Liver Disease: A Case Report(JAYPEE, 2020-06-01) Çolaklar, Anıl; Lehnert, Stephen J; Tirkes, Temel; Radiology and Imaging Sciences, School of MedicineFontan procedure, in which systemic circulation is redirected into pulmonary circulation by a baffle, is a palliative surgical strategy for patients born with single ventricle congenital heart disease. Hemodynamic changes secondary to Fontan procedure, also termed as Fontan physiology, result in end-organ damage, especially of the liver. Fontan-associated liver disease (FALD) represents a spectrum of pathologies ranging from mild liver fibrosis to advanced liver cirrhosis and hepatocellular carcinoma (HCC). Hepatic nodules, some of which have been documented as HCC in several case series and reports, are a recognized complicated feature of FALD. Herein, we report a case with benign hepatic nodules mimicking HCC by imaging characteristics, emphasizing the fact that arterially enhancing lesions with delayed washout appearance may reflect benign regenerative or focal nodular hyperplasia-like nodules in patients with Fontan physiology.Item Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation(Elsevier, 2017-06) Goldberg, David J.; Zak, Victor; Goldstein, Bryan H.; Chen, Shan; Hamstra, Michelle S.; Radojewski, Elizabeth A.; Maunsell, Eileen; Mital, Seema; Menon, Shaji C.; Schumacher, Kurt R.; Payne, R. Mark; Stylianou, Mario; Kaltman, Jonathan R.; deVries, Tina M.; Yeager, James L.; Paridon, Stephen M.; Pediatric Heart Network Investigators; Pediatrics, School of MedicineBACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. CONCLUSIONS: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial.Item Results of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial(American Heart Association, 2020-02-25) Goldberg, David J.; Zak, Victor; Goldstein, Bryan H.; Schumacher, Kurt R.; Rhodes, Jonathan; Penny, Daniel J.; Petit, Christopher J.; Ginde, Salil; Menon, Shaji C.; Kim, Seong-Ho; Kim, Gi Beom; Nowlen, Todd T.; DiMaria, Michael V.; Frischhertz, Benjamin P.; Wagner, Jonathan B.; McHugh, Kimberly E.; McCrindle, Brian W.; Shillingford, Amanda J.; Sabati, Arash A.; Yetman, Anji T.; John, Anitha S.; Richmond, Marc E.; Files, Matthew D.; Payne, R. Mark; Mackie, Andrew S.; Davis, Christopher K.; Shahanavaz, Shabana; Hill, Kevin D.; Garg, Ruchira; Jacobs, Jeffrey P.; Hamstra, Michelle S.; Woyciechowski, Stacy; Rathge, Kathleen A.; McBride, Michael G.; Frommelt, Peter C.; Russell, Mark W.; Urbina, Elaine M.; Yeager, James L.; Pemberton, Victoria L.; Stylianou, Mario P.; Pearson, Gail D.; Paridon, Stephen M.; Pediatrics, School of MedicineBackground: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold.