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The application of nontargeted metabolomic profiling has recently become a powerful noninvasive tool to discover new clinical biomarkers. This study aimed to identify metabolic pathways that could be exploited for prognostic and therapeutic purposes in hepatorenal dysfunction in cirrhosis. One hundred three subjects with cirrhosis had glomerular filtration rate (GFR) measured using iothalamate plasma clearance, and were followed until death, transplantation, or the last encounter. Concomitantly, plasma metabolomic profiling was performed using ultrahigh performance liquid chromatography-tandem mass spectrometry to identify preliminary metabolomic biomarker candidates. Among the 1028 metabolites identified, 34 were significantly increased in subjects with high liver and kidney disease severity compared with those with low liver and kidney disease severity. The highest average fold-change (2.39) was for 4-acetamidobutanoate. Metabolite-based enriched pathways were significantly associated with the identified metabolomic signature (P values ranged from 2.07E-06 to 0.02919). Ascorbate and aldarate metabolism, methylation, and glucuronidation were among the most significant protein-based enriched pathways associated with this metabolomic signature (P values ranged from 1.09E-18 to 7.61E-05). Erythronate had the highest association with measured GFR (R-square = 0.571, P <0.0001). Erythronate (R = 0.594, P <0.0001) and N6-carbamoylthreonyladenosine (R = 0.591, P <0.0001) showed stronger associations with measured GFR compared with creatinine (R = 0.588, P <0.0001) even after controlling for age, gender, and race. The 5 most significant metabolites that predicted mortality independent of kidney disease and demographics were S-adenosylhomocysteine (P = 0.0003), glucuronate (P = 0.0006), trans-aconitate (P = 0.0018), 3-ureidopropionate (P = 0.0021), and 3-(4-hydroxyphenyl)lactate (P = 0.0047). A unique metabolomic signature associated with hepatorenal dysfunction in cirrhosis was identified for further investigations that provide potentially important mechanistic insights into cirrhosis-altered metabolism., (Published by Elsevier Inc.)

Background: Vascular anomalies currently are classified according to their clinical and histological characteristics. Recent advances in molecular genetics have enabled the identification of somatic mutations in most types of vascular anomalies. The purpose of this study was to collate information regarding the genetic basis of vascular anomalies., Methods: The PubMed literature was reviewed for all citations that identified a mutation in a vascular anomaly between 1994 and 2017. Search terms included "vascular anomaly," "mutation," "gene," "hemangioma," "pyogenic granuloma," "kaposiform hemangioendothelioma," "capillary malformation," "venous malformation," lymphatic malformation," "arteriovenous malformation," and "syndrome." Articles that identified both germline and somatic mutations in vascular anomalies were analyzed. Mutations were categorized by type (germline or somatic), gene, signaling pathway, and cell(s) enriched for the mutation., Results: The majority of vascular anomalies had associated mutations that commonly affected tyrosine kinase receptor signaling through the RAS or PIK3CA pathways. Mutations in PIK3CA and G-protein-coupled receptors were most frequently identified. Specific types of vascular anomalies usually were associated with a single gene. However, mutations in the same gene occasionally were found in different vascular lesions, and some anomalies had a mutation in more than one gene. Mutations were most commonly enriched in endothelial cells., Conclusions: Identification of somatic mutations in vascular anomalies is changing the paradigm by which lesions are diagnosed and understood. Mutations and their pathways are providing potential targets for the development of novel pharmacotherapy. In the future, vascular anomalies will be managed based on clinical characteristics and molecular pathophysiology.

Introduction: The life cycle of infantile hemangioma (IH) and secretion of follicle-stimulating hormone (FSH) are identical. We previously have shown that IH contains the FSH receptor (FSHR). The purpose of this study was to identify which cell type(s) in IH expresses FSHR., Methods: Human proliferating IH tissues obtained during a clinically indicated surgical procedure were used. Paraffin sections and isolated cell populations (endothelial, pericyte, stem cell) were subjected to immunofluorescence for FSHR. Tissues were costained with DAPI, anti-α smooth muscle actin, or biotinylated Ulex Europaeus Agglutinin I to identify nuclei, pericytes, and endothelial cells, respectively. Whole tissue and purified single cell populations underwent polymerase chain reaction (PCR) for FSHR. Positive control specimens (ovary, sertoli cells) and negative control tissues (skin/subcutis, hepatic cells) were included., Results: Immunofluorescence of 9 IHs demonstrated that FSHR was enriched in pericytes compared with endothelial cells. Follicle-stimulating hormone receptor was expressed in 6 of 6 whole tissue IHs along with the positive control via PCR. Follicle-stimulating hormone receptor was not present in the negative control samples. Four of 5 sets of pericytes expressed FSHR by PCR. Neither IH endothelial cells, IH stem cells, nor negative control cells exhibited FSHR by PCR., Conclusions: Because the secretion of FSH correlates with the growth pattern of IH, FSH might be involved in the disease process. Follicle-stimulating hormone receptor is enriched in the pericytes of IH, suggesting that this cell type may be involved in the pathogenesis of the tumor.

Background: Lower serum Cr levels in women as compared to men result in underestimation of renal dysfunction and lower model for end-stage liver disease-sodium scores leading to reduced access to liver transplantation in women compared to men with comparable hepatic dysfunction., Aim: The aim of this study was to determine the gender differences in serum Cr, cystatin C, and other endogenous glomerular filtration rate (GFR) biomarkers, measured and estimated GFR, Cr clearance, and Cr production rates., Methods: We measured GFR by iothalamate plasma clearance in 103 patients with cirrhosis and assessed gender differences in GFR, Cr clearance and production rate, serum Cr, cystatin C and other endogenous GFR biomarkers including beta-trace protein, beta-2 microglobulin, and dimethylarginines., Results: Comparison of men and women showed significantly lower values for mean serum Cr (0.97 vs. 0.82 mg/dl, P = 0.023), and Cr production rate (13.37 vs. 11.02 mg/kg/day, P = 0.022). In contrast to the serum Cr and Cr production rate, men and women exhibited no significant differences in the means of serum cystatin C and other GFR biomarkers, measured GFR, GFR estimated using Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearances. After controlling for age, race, weight, height, and GFR, female gender remained associated with lower serum Cr levels (P = 0.003). Serum cystatin C levels were not associated with gender, age, race, weight, height, C-reactive protein, and history of hypothyroidism., Conclusions: Our results suggest that cystatin C and endogenous GFR biomarkers other than Cr, measured GFR, GFR estimated by Cr-cystatin C GFR equation for cirrhosis, measured and estimated Cr clearance minimized between-gender biases in accounting for renal function in patients with cirrhosis. Therefore, serum cystatin C should be measured as a complementary test to serum Cr when renal function is assessed in patients with cirrhosis, particularly in women and those with sarcopenia.

Stress-induced heart failure, also known as Broken Heart Syndrome or Takotsubo Syndrome, is a phenomenon characterized as rare but well described in the literature, with increasing incidence. While more commonly associated with postmenopausal women with psychiatric disorders, this entity is found in the postoperative patient. The nonischemic cardiogenic shock manifests as biventricular failure with significant decreases in ejection fraction and cardiac function. In a review of over 3000 kidney and liver transplantations over the course of 17 years within two transplant centers, we describe a series of 7 patients with Takotsubo Syndrome after solid organ transplantation. Furthermore, we describe a novel approach of successfully treating the transient, though potentially fatal, cardiogenic shock with a percutaneous ventricular assistance device in two liver transplant patients, while treating one kidney transplant patient medically and the remaining four liver transplant patients with an intra-aortic balloon pump. We describe our experience with Takotsubo's Syndrome and compare the three modalities of treatment and cardiac augmentation. Our series is novel in introducing the percutaneous ventricular assist device as a more minimally invasive intervention in treating nonischemic heart failure in the solid organ transplant patient, while serving as a comprehensive overview of treatment modalities for stress-induced heart failure.

Vascular tumors are benign neoplasms, which result from proliferating endothelial cells. These lesions present during infancy or childhood, may affect any location, and exhibit postnatal growth. Local complications include bleeding, tissue destruction, and pain whereas systemic sequelae include thrombocytopenia, congestive heart failure, and death. Vascular tumors should be differentiated from vascular malformations, which present at birth, have a quiescent endothelium, and grow in proportion to the child. Together, vascular tumors and malformations comprise the field of vascular anomalies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Lymphedema often is confused with other causes of extremity edema and enlargement. Understanding the risk factors and physical examination signs of lymphedema can enable the health care practitioner to accurately diagnose patients ∼90% of the time. Confirmatory diagnosis of the disease is made using lymphoscintigraphy. It is important to correctly diagnose patients with lymphedema so that they can be managed appropriately.

Organ-on-chip platforms aim to improve preclinical models for organ-level responses to novel drug compounds. Heart-on-a-chip assays in particular require tissue engineering techniques that rely on labor-intensive photolithographic fabrication or resolution-limited 3D printing of micropatterned substrates, which limits turnover and flexibility of prototyping. We present a rapid and automated method for large scale on-demand micropatterning of gelatin hydrogels for organ-on-chip applications using a novel biocompatible laser-etching approach. Fast and automated micropatterning is achieved via photosensitization of gelatin using riboflavin-5'phosphate followed by UV laser-mediated photoablation of the gel surface in user-defined patterns only limited by the resolution of the 15 μm wide laser focal point. Using this photopatterning approach, we generated microscale surface groove and pillar structures with feature dimensions on the order of 10-30 μm. The standard deviation of feature height was 0.3 μm, demonstrating robustness and reproducibility. Importantly, the UV-patterning process is non-destructive and does not alter gelatin micromechanical properties. Furthermore, as a quality control step, UV-patterned heart chip substrates were seeded with rat or human cardiac myocytes, and we verified that the resulting cardiac tissues achieved structural organization, contractile function, and long-term viability comparable to manually patterned gelatin substrates. Start-to-finish, UV-patterning shortened the time required to design and manufacture micropatterned gelatin substrates for heart-on-chip applications by up to 60% compared to traditional lithography-based approaches, providing an important technological advance enroute to automated and continuous manufacturing of organ-on-chips.

Kaposiform hemangioendotheliomas are pediatric vascular tumors that do not metastasize. We present a patient with a thigh kaposiform hemangioendothelioma successfully treated using a systemic corticosteroid during infancy who was diagnosed with lymphedema in the extremity 9 years later. The observation that extremity kaposiform hemangioendothelioma could possibly be associated with lymphedema has implications for the care of patients with kaposiform hemangioendothelioma., (© 2017 Wiley Periodicals, Inc.)

An index to predict hospital length of stay after liver transplantation could address unmet clinical needs. Length of stay is an important surrogate for hospital costs and efforts to limit stays can preserve our healthcare resources. Here, we devised a scoring system that predicts hospital length of stay following liver transplantation. We used univariate and multivariate analyses on 73 635 adult liver transplant recipient data and identified independent recipient and donor risk factors for prolonged hospital stay (>30 days). Multiple imputation was used to account for missing variables. We identified 22 factors as significant predictors of prolonged hospital stay, including the most significant risk factors: intensive care unit (ICU) admission (OR 1.75, CI 1.58-1.95) and previous transplant (OR 1.60, CI 1.47-1.75). The length of stay (LOS) index assigns weighted risk points to each significant factor in a scoring system to predict prolonged hospital stay after liver transplantation with a c-statistic of 0.75. The LOS index demonstrated good discrimination across the entire population, dividing the cohort into tertiles, which had odds ratios of 2.25 (CI 2.06-2.46) and 7.90 (7.29-8.56) for prolonged hospital stay (>30 days). The LOS index utilizes 22 significant donor and recipient factors to accurately predict hospital length of stay following liver transplantation. The index further demonstrates the basis for a clear clinical recommendation to mitigate risk of long hospitalization by minimizing cold ischemia time., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Oral propranolol has become first-line intervention for problematic infantile hemangioma (IH) that is not amenable to topical or intralesional therapies. Consensus data supporting its efficacy for other vascular anomalies does not exist. The purpose of this study was to determine the frequency and causes of propranolol use for vascular lesions other than IH., Methods: Referrals to our Vascular Anomalies Center between 2008 and 2017 were reviewed for patients treated with propranolol at an outside institution. Patient history, photographs, imaging studies, and/or histopathology were evaluated by an interdisciplinary team to diagnose the vascular anomaly. Our center's diagnosis was compared to the referral diagnosis to categorize patients into 3 groups: Group 1 (patients were appropriately labeled with an IH); Group 2 (individuals were erroneously diagnosed with IH); and Group 3 (subjects were diagnosed with a vascular anomaly other than IH)., Results: Two hundred thirty-six patients met inclusion criteria. Group 1 (39%; n = 91) had an IH and were treated appropriately. Group 2 (20%; n = 49) was misdiagnosed with IH and incorrectly received propranolol. Group 3 (41%; n = 96) was given propranolol to treat another vascular anomaly. Propranolol did not have efficacy for vascular anomalies other than IH., Conclusions: Propranolol commonly is used to treat lesions other than IH; misdiagnosis of a lesion as IH is a common cause. Propranolol should be used with caution to treat other types of vascular anomalies because patients are subjected to the risks of the drug without data supporting its efficacy.

Background & Aims: Environmental factors have been identified that affect risk of hepatocellular carcinoma (HCC), but little is known about the effects of sex hormones on liver cancer development or outcome. The authors investigated whether menopause hormone therapy (MHT) affects risk, age at onset, or outcome of HCC., Methods: We performed a case-control study of 234 female patients treated for HCC at a tertiary medical center and with 282 healthy women (controls) from January 1, 2004 through May 31, 2015. We collected detailed information on environmental exposures, ages of menarche and menopause, hysterectomies, and uses of birth control and MHT. We performed multivariable logistic and Cox regression analyses to determine the independent effects of factors associated with women on risk and clinical outcome in HCC. The primary outcomes were effect of MHT on HCC risk, the relationship between MHT with hepatitis virus infection on HCC development, and effect of MHT on age at HCC onset or survival after diagnosis of HCC., Results: The estimated adjusted odds ratio (AOR) for HCC in women who ever used estrogen was 0.53 (95% confidence interval [CI], 0.32-0.88). This association was supported by the older age of HCC onset among estrogen users (mean, 64.5 ± 0.9 years) vs nonusers (mean 59.2 ± 1.1 years; P = .001) and the reduced risk of HCC among long-term users (more than 5 years) (AOR, 0.36; 95% CI, 0.20-0.63). Users of estrogen also had a reduced risk for hepatitis-associated HCC: AOR for users, 4.37 (95% CI, 1.67-11.44) vs AOR for nonusers, 17.60 (95% CI, 3.88-79.83). Estrogen use reduced risk of death from HCC (hazard ratio, 0.55; 95% CI, 0.40-0.77; P = .01). Median overall survival times were 33.5 months for estrogen users (95% CI, 25.7-41.3 months) and 24.1 months for nonusers (95% CI, 19.02-29.30 months; P = .008)., Conclusion: In a case-control study of women with HCC vs female control subjects at a single center, we associated use of estrogen MHT with reduced risk of HCC and increased overall survival times of patients with HCC. Further studies are needed to determine the benefits of estrogen therapy for women and patients with HCC, and effects of tumor expression of estrogen receptor., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Drowning, a common cause of death in the pediatric population, is a potentially large donor pool for OLT. Anecdotally, transplant centers have deemed these organs high risk over concerns for infection and graft dysfunction. We theorized drowned donor liver allografts do not portend worse outcomes and therefore should not be excluded from the donation pool. We reviewed our single-center experience of pediatric OLTs between 1988 and 2015 and identified 33 drowned donor recipients. These OLTs were matched 1:2 to head trauma donor OLTs from our center. A chart review assessed postoperative peak AST and ALT, incidence of HAT, graft and recipient survival. Recipient survival at one year between patients with drowned donor vs head trauma donor allografts was not statistically significant (94% vs 97%, P=.63). HAT incidence was 6.1% in the drowned donor group vs 7.6% in the control group (P=.78). Mean postoperative peak AST and ALT was 683 U/L and 450 U/L for drowned donors vs 1119 U/L and 828 U/L in the matched cohort. These results suggest drowned donor liver allografts do not portend worse outcomes in comparison with those procured from head trauma donors., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Capillary malformation is a cutaneous vascular anomaly that is present at birth, darkens over time, and can cause overgrowth of tissues beneath the stain. The lesion is caused by a somatic activating mutation in GNAQ. In a previous study, we were unable to identify a GNAQ mutation in patients with a capillary malformation involving an overgrown lower extremity. We hypothesized that mutations in GNA11 or GNA14, genes closely related to GNAQ, also may cause capillary malformations., Methods: Human capillary malformation tissue obtained from 8 patients that had tested negative for GNAQ mutations were studied. Lesions involved an extremity (n = 7) or trunk (n = 1). Droplet digital PCR (ddPCR) was used to detect GNA11 or GNA14 mutant cells (p.Arg183) in the specimens. Single molecule molecular inversion probe sequencing (smMIP-seq) was performed to search for other mutations in GNA11. Mutations were validated by subcloning and sequencing amplimers., Results: We found a somatic GNA11 missense mutation (c.547C > T; p.Arg183Cys) in 3 patients with a diffuse capillary malformation of an extremity. Mutant allelic frequencies ranged from 0.3 to 5.0%. GNA11 or GNA14 mutations were not found in 5 affected tissues or in unaffected tissues (white blood cell DNA)., Conculsions: GNA11 mutations are associated with extremity capillary malformations causing overgrowth. Pharmacotherapy that affects GNA11 signaling may prevent the progression of capillary malformations.

Tissue engineered scaffolds have emerged as a promising solution for heart valve replacement because of their potential for regeneration. However, traditional heart valve tissue engineering has relied on resource-intensive, cell-based manufacturing, which increases cost and hinders clinical translation. To overcome these limitations, in situ tissue engineering approaches aim to develop scaffold materials and manufacturing processes that elicit endogenous tissue remodeling and repair. Yet despite recent advances in synthetic materials manufacturing, there remains a lack of cell-free, automated approaches for rapidly producing biomimetic heart valve scaffolds. Here, we designed a jet spinning process for the rapid and automated fabrication of fibrous heart valve scaffolds. The composition, multiscale architecture, and mechanical properties of the scaffolds were tailored to mimic that of the native leaflet fibrosa and assembled into three dimensional, semilunar valve structures. We demonstrated controlled modulation of these scaffold parameters and show initial biocompatibility and functionality in vitro. Valves were minimally-invasively deployed via transapical access to the pulmonary valve position in an ovine model and shown to be functional for 15 h., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Low case volume has been associated with poor outcomes in a wide spectrum of procedures. Our objective was to study the association of low case volume and worse outcomes in pediatric heart transplant centers, taking the novel approach of including waitlist outcomes in the analysis. We studied a cohort of 6482 candidates listed in the Organ Procurement and Transplantation Network for pediatric heart transplantation between 2002 and 2014; 4665 (72%) of the candidates underwent transplantation. Candidates were divided into groups according to the average annual transplantation volume of the listing center during the study period: more than 10, six to 10, three to five, or fewer than three transplantations. We used multivariate Cox regression analysis to identify independent risk factors for waitlist and posttransplantation mortality. Of the 6482 candidates, 24% were listed in low-volume centers (fewer than three annual transplantations). Of these listed candidates in low-volume centers, only 36% received a transplant versus 89% in high-volume centers (more than 10 annual transplantations) (p < 0.001). Listing at a low-volume center was the most significant risk factor for waitlist death (hazard ratio [HR] 4.5, 95% confidence interval [CI] 3.5-5.7 in multivariate Cox regression and HR 5.6, CI 4.4-7.3 in multivariate competing risk regression) and was significant for posttransplantation death (HR 1.27, 95% CI 1.0-1.6 in multivariate Cox regression). During the study period, one-fourth of pediatric transplant candidates were listed in low-volume transplant centers. These children had a limited transplantation rate and a much greater risk of dying while on the waitlist., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Introduction: The data regarding vascular invasion as a prognostic factor in hepatoblastoma (HB) are conflicted. The purpose of this study is to examine the relationship between vascular invasion and outcomes., Methods: This is a retrospective review of patients <18 years old who underwent resection for hepatoblastoma from 1998 to 2015. Pathology reports were used to identify patients who had pathologic vascular invasion (VI), and those who did not (NVI)., Results: Sixty-six children were identified with a median age at diagnosis of 21months (interquartile range: 10-33months). Pathologic vascular invasion was present in 42/66 (64%) patients. A significant difference (P=0.02) in 3-year overall survival (3YOS) was detected between NVI (95%) and VI (61%). Recurrent disease was present in 8/66 (12%) patients. A marginally significant difference (P=0.08) was found in 3-year recurrence free survival (3YRFS) between NVI (94%) and the VI (76%) groups. Patients with NVI had no metastatic disease, had a lower recurrence rate, universally responded to neoadjuvant chemotherapy, and were less likely to have small cell undifferentiated histology. Twenty-one children underwent orthotopic liver transplant (OLT), with no difference in 3YROS or 3YRFS., Conclusion: Pathologic vascular invasion is associated with significantly worse 3YOS in HB, and lack of vascular invasion was associated with more favorable disease characteristics. The presence of pathologic vascular invasion did not confer a worse outcome in patients treated with liver transplantation in this cohort of patients., Type of Study: Retrospective review., Level of Evidence: Level III., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Arteriovenous malformation (AVM) is a fast-flow, congenital vascular anomaly that may arise anywhere in the body. AVMs typically progress, causing destruction of surrounding tissue and, sometimes, cardiac overload. AVMs are difficult to control; they often re-expand after embolization or resection, and pharmacologic therapy is unavailable. We studied extracranial AVMs in order to identify their biological basis. We performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) on AVM tissue from affected individuals. Endothelial cells were separated from non-endothelial cells by immune-affinity purification. We used droplet digital PCR (ddPCR) to confirm mutations found by WES and WGS, to determine whether mutant alleles were enriched in endothelial or non-endothelial cells, and to screen additional AVM specimens. In seven of ten specimens, WES and WGS detected and ddPCR confirmed somatic mutations in mitogen activated protein kinase kinase 1 (MAP2K1), the gene that encodes MAP-extracellular signal-regulated kinase 1 (MEK1). Mutant alleles were enriched in endothelial cells and were not present in blood or saliva. 9 of 15 additional AVM specimens contained mutant MAP2K1 alleles. Mutations were missense or small in-frame deletions that affect amino acid residues within or adjacent to the protein's negative regulatory domain. Several of these mutations have been found in cancers and shown to increase MEK1 activity. In summary, somatic mutations in MAP2K1 are a common cause of extracranial AVM. The likely mechanism is endothelial cell dysfunction due to increased MEK1 activity. MEK1 inhibitors, which are approved to treat several forms of cancer, are potential therapeutic agents for individuals with extracranial AVM., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Introduction: Choledochal cysts are rare congenital dilations of the biliary tree that can present with non-specific symptoms such as abdominal pain, jaundice, cholelithiasis and pancreatitis. Although most commonly identified in children, they can be found in the adult population. However, because of the non-specific symptoms, this diagnosis may be difficult to make in the adult. A physician therefore must keep this diagnosis within their differential, as it may arise in an unexpected patient population who may present with a convoluted work up., Case Presentation: In this report, we present the case of a 50-year-old African American woman with recurrent cholelithiasis, cholangitis and eventually obstructive jaundice despite undergoing a laparoscopic cholecystectomy six years prior. Her only work up at that point was a right upper quadrant ultrasound revealing gallbladder sludge, which led to her cholecystectomy. It was the persistence of her symptoms-abdominal pain, cholangitis and obstructive jaundice-previously attributed to chronic cholecystitis and choledocholithiasis that warranted further work up. After multiple physician visits, she was referred to our academic center after an ERCP was performed and she was found to have a dilation of her common bile duct consistent with a choledochal cyst. Furthermore, the ERCP identified multiple bile duct stones within the cyst. This was not identified on her original ultrasound or prior ERCPs. The patient underwent a complete cyst excision with Roux-en-Y hepaticojejunostomy and did well post-operatively., Discussion: This report illustrates how choledochal cysts can be an elusive diagnosis, but may present with repeated infections, recurrent biliary stones, and biliary obstruction despite a cholecystectomy. Had she an MRCP prior to her cholecystectomy, she would likely have avoided multiple surgeries, and years of persistent symptoms. Choledochal cysts are associated with an increased risk of biliary malignancy and therefore cyst excision is the standard of care., Conclusion: Although rare, physicians need to keep this diagnosis in mind, and be aware of the clinical and imaging findings consistent with a choledochal cyst in order to facilitate appropriate work up, referral and treatment., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Young children < 2 years of age with chronic end-stage liver disease (YC2) are a uniquely vulnerable group listed for liver transplantation, characterized by a predominance of biliary atresia (BA). To investigate wait-list mortality, associated risk factors, and outcomes of YC2, we evaluated United Network for Organ Sharing registry data from April 2003 to March 2013 for YC2 listed for deceased donor transplant (BA = 994; other chronic liver disease [CLD] = 221). Overall, wait-list mortality among YC2 was 12.4% and posttransplant mortality was 8%, accounting for an overall postlisting mortality of 19.6%. YC2 demonstrated 12.2%, 18.7%, and 20.6% wait-list mortality by 90, 180, and 270 days, respectively. YC2 with CLD demonstrated significantly higher wait-list mortality compared with BA among YC2 (23.9% versus 9.8%; P < 0.05). Multivariate analyses revealed that listing Pediatric End-Stage Liver Disease [PELD] > 21 (hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.6-6.5), lack of exception (HR, 5.8; 95% CI, 2.8-11.8), listing height < 60.6 cm (HR, 2.1; 95% CI, 1.4-3.1), listing weight  > 10 kg (HR, 3.8; 95% CI, 1.5-9.2), and initial creatinine > 0.5 (HR, 6.8; 95% CI, 3.4-13.5) were independent risk factors for YC2 wait-list mortality (P < 0.005 for all). Adjusting for all variables, the risk of death among CLD patients was 2 (95% CI, 1.3-3.1) times greater than patients with BA + surgery (presumed Kasai). Furthermore, the risk of death in BA without surgery was 1.9 (95% CI, 1‐3.4) times greater than BA with presumed Kasai. Our data highlight unacceptably high wait-list and early post-liver transplant mortality in YC2 not predicted by PELD and suggest key risk factors deserving of further study in this age group. Liver Transplantation 22 1584-1592 2016 AASLD., Competing Interests: The authors report no relevant conflicts of interest or financial affiliations., (© 2016 by the American Association for the Study of Liver Diseases.)

Background: Careful management of induction and maintenance of immunosuppression is paramount to prevent acute rejection in liver transplantation. A methodical analysis of risk factors for acute cellular rejection may provide a more comprehensive method to profile the immunologic risk of candidates., Methods: Using registry data from the Organ Procurement and Transplantation Network (OPTN), we identified 42,508 adult recipients who underwent orthotopic liver transplant (OLT) between 2002 and 2013. We excluded recipients with a blank entry for treated rejection. We analyzed this all inclusive cohort in addition to a subset of 27,493 patients with just tacrolimus immunosuppression. Multivariate logistic regression was used on both cohorts and identified independent risk factors for treated acute rejection at one year., Results: Recipient age (reference group was 40 to 60years) was a dominant risk factor for rejection in both cohorts and had a dose response relationship. The strongest risk factors in the inclusive cohort were: age 18-25 (OR 2.20), age 26-29 (OR 2.03), and primary biliary cholangitis (OR 1.55). The most protective factors were age 70 and older (OR 0.68), and age 65-69 (OR 0.70). The rates of rejection had a similar pattern., Conclusions: Although prior studies have suggested age as a risk factor for rejection in liver transplantation, this is the first study of national-level data to demonstrate a robust dose dependent relationship between age and risk for rejection at one year. Clinicians should place significant weight on recipient age when they assess their recipients for the immunologic risk of rejection., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Pharmaceutical screening based on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and multi electrode arrays (MEAs) have been proposed as a complementary method for electrophysiological safety and efficacy assessment in drug discovery and development. Contrary to animal models, these cells offer a human genetic background but, at present, fail to recapitulate the mechanical and structural properties of the native human myocardium. Here, we report that topographical cues on soft micromolded gelatin can coax hiPSC-CMs to form laminar cardiac tissues that resemble the native architecture of the heart. Importantly, using this method we were able to record tissue-level electrophysiological responses with a commercially available MEA setup. To validate this platform, we recorded cardiac field potentials at baseline and after pharmacological interventions with a β-adrenergic agonist (isoproterenol). Further, we tested the ability of our system to predict the response of laminar human cardiac tissues to a cardiotoxic pro-drug (terfenadine) and its non-cardiotoxic metabolite (fexofenadine). Finally, we integrated our platform with microfluidic components to build a heart-on-a-chip system that can be fluidically linked with other organs-on-chips in the future.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive pediatric malignancy. The purpose of this study was to review the clinical, radiologic, and pathologic features and outcome of children with UESL at our institution, in the United Network of Organ Sharing database and to review the existing literature to define the state of the art for children with UESL. Six children were diagnosed with UESL at the Texas Children's Cancer Center between 1993 and 2014, 12 children underwent liver transplantation registered in the United Network of Organ Sharing database, and 198 children with UESL were described in 23 case series during 1978 to 2014. Patients were treated with multimodal treatment approaches including primary surgical resection, neoadjuvant and/or adjuvant chemotherapy, and liver transplantation resulting in overall survival reported between 20% and 100% with significant improvement over the recent years. We show that complete tumor removal remains the key element of treatment and our single-institutional experience and data in the published literature suggest that combination chemotherapy with ifosfamide and doxorubicin to facilitate complete surgical resection is an effective approach to cure children with UESL.

Background: The initial experience with ABO incompatible (ABOi) orthotopic liver transplantations (OLTs) was dismal. In the current study, we investigated whether ABOi pediatric OLTs could achieve acceptable patient outcomes. The option for ABOi transplantation is vital because critically ill children have limited access to donor liver allografts., Study Design: Kaplan-Meier and multivariate Cox analysis was performed on data collected from 13,179 pediatric OLT recipients in the United Network for Organ Sharing database, including 540 ABOi recipients. We also analyzed 18 pediatric recipients of ABOi OLTs at Texas Children's Hospital. Recipients were divided into 2 groups: transplanted between 1987 to 2002 (remote era) and 2002 to 2013 (modern era)., Results: Analysis revealed 4 main points. First, there was a significant (p < 0.01) improvement in ABOi OLT survival in the modern era. Second, threshold analysis revealed superior outcomes (p < 0.01) for OLT recipients younger than 2 years of age. Third, survival outcomes for ABOi and ABO-identical OLTs were the same for recipients younger than 2 years: ABOi was 91.8% (1 year) and 88.4% (5 year), and ABO identical was 91.5% (1 year) and 86.7% (5 year) (p = 0.94). Lastly, we found identical OLT results when analyzing our own institutional experience. To date, there has been a 92.9% survival rate in the modern era compared with 75% in the remote era. All recipients younger than 2 years (n = 9) are still alive, compared with 78% of those older than 2 years., Conclusions: This analysis revealed a significant improvement in the survival of ABOi liver transplant recipients in the modern era. Importantly, ABOi liver transplantation can be performed in recipients younger than 2 years of age with equivalent outcomes compared with ABO-identical recipients., (Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Unlabelled: P2 purinergic receptors are overexpressed in certain cancer tissues, but the pathophysiologic relevance of purinergic signaling in hepatocellular carcinoma (HCC) remains unknown. To examine the role of P2 purinergic signaling in the pathogenesis of HCC and characterize extracellular nucleotide effects on HCC cell proliferation, two independent HCC patient cohorts were analyzed for P2 purinergic receptor expression, and nucleotide treated HCC cell lines were evaluated for effects on proliferation and cell cycle progression. Our studies suggest that multiple P2 purinergic receptor isoforms are overexpressed in liver tumors, as compared to uninvolved liver, and dysregulation of P2 purinergic receptor expression is apparent in HCC cell lines, as compared to human primary hepatocytes. High P2X3 purinergic receptor expression is associated with poor recurrence-free survival (RFS), while high P2Y13 expression is associated with improved RFS. Extracellular nucleotide treatment alone is sufficient to induce cell cycle progression, via activation of JNK signaling, and extracellular ATP-mediated activation of P2X3 receptors promotes proliferation in HCC cells., Conclusion: Our analysis of HCC patient livers and HCC cells in vitro identifies a novel role for dysregulation of P2 purinergic signaling in the induction of hyper-proliferative HCC phenotype and identifies P2X3 purinergic receptors as potential new targets for therapy.

Mechanical stresses on the myocyte nucleus have been associated with several diseases and potentially transduce mechanical stimuli into cellular responses. Although a number of physical links between the nuclear envelope and cytoplasmic filaments have been identified, previous studies have focused on the mechanical properties of individual components of the nucleus, such as the nuclear envelope and lamin network. The mechanical interaction between the cytoskeleton and chromatin on nuclear deformability remains elusive. Here, we investigated how cytoskeletal and chromatin structures influence nuclear mechanics in cardiac myocytes. Rapid decondensation of chromatin and rupture of the nuclear membrane caused a sudden expansion of DNA, a consequence of prestress exerted on the nucleus. To characterize the prestress exerted on the nucleus, we measured the shape and the stiffness of isolated nuclei and nuclei in living myocytes during disruption of cytoskeletal, myofibrillar, and chromatin structure. We found that the nucleus in myocytes is subject to both tensional and compressional prestress and its deformability is determined by a balance of those opposing forces. By developing a computational model of the prestressed nucleus, we showed that cytoskeletal and chromatin prestresses create vulnerability in the nuclear envelope. Our studies suggest the cytoskeletal-nuclear-chromatin interconnectivity may play an important role in mechanics of myocyte contraction and in the development of laminopathies by lamin mutations., (© 2015 by the Society for Experimental Biology and Medicine.)

Background: Primary hepatic neoplasms in children are rare tumors. All malignant and medically refractive benign primary pediatric liver tumors ultimately require surgical resection for cure. Accurate preoperative imaging including multidetector helical computerized tomography or magnetic resonance imaging (MRI) is necessary to determine resectability. In the literature intraoperative ultrasound (IOUS) has proven to be a vital adjunct to liver surgery in adults, but this is not well established in children., Materials and Methods: Between April 2003 and November 2014, children (<18-y-old) with a primary liver neoplasm, preoperatively evaluated with multidetector helical computerized tomography or MRI, who had IOUS used at the time of surgery were retrospectively reviewed., Results: Preoperative evaluation with high-resolution MRI and IOUS were discordant in 4 of 19 patients (21%). In one case, right hepatic vein involvement was not accurately assessed with MRI. Two cases showed tumor involvement in segment IV by MRI; however, IOUS revealed no medial segment involvement. The final patient had a large (>5 cm), solitary hepatic adenoma on MRI, but IOUS in this case revealed diffuse adenomatosis. The operative management was altered in three of these cases., Conclusions: Although MRI can provide a detailed view of the hepatic anatomy and is an invaluable tool for preoperative planning for the pediatric patient with a primary liver neoplasm, IOUS may provide further and more up to date delineation of tumor extent and should be considered a crucial element in operative planning for hepatectomy in children., (Copyright © 2015 Elsevier Inc. All rights reserved.)

MCPH1, also known as BRIT1, has recently been identified as a novel key regulatory gene of the DNA damage response pathway. MCPH1 is located on human chromosome 8p23.1, where human cancers frequently show loss of heterozygosity. As such, MCPH1 is aberrantly expressed in many malignancies, including breast and ovarian cancers, and the function of MCPH1 has been implicated in tumor suppression. However, it remains poorly understood whether MCPH1 deficiency leads to tumorigenesis. Here we generated and studied both Mcph1(-/-) and Mcph1(-/-)p53(-/-) mice; we showed that Mcph1(-/-) mice developed tumors with long latency, and that primary lymphoma developed significantly earlier in Mcph1(-/-)p53(-/-) mice than in Mcph11(+/+)p53(-/-) and Mcph1(+/-)p53(-/-) mice. The Mcph1(-/-)p53(-/-) lymphomas and derived murine embryonic fibroblasts (MEFs) were both more sensitive to irradiation. Mcph1 deficiency resulted in remarkably increased chromosome and chromatid breaks in Mcph1(-/-)p53(-/-) lymphomas and MEFs, as determined by metaphase spread assay and spectral karyotyping analysis. In addition, Mcph1 deficiency significantly enhanced aneuploidy as well as abnormal centrosome multiplication in Mcph1(-/-)p53(-/-) cells. Meanwhile, Mcph1 deficiency impaired double strand break (DSB) repair in Mcph1(-/-)p53(-/-) MEFs as demonstrated by neutral Comet assay. Compared with Mcph1(+/+)p53(-/-) MEFs, homologous recombination and non-homologous end-joining activities were significantly decreased in Mcph1(-/-)p53(-/-) MEFs. Notably, reconstituted MCPH1 rescued the defects of DSB repair and alleviated chromosomal aberrations in Mcph1(-/-)p53(-/-) MEFs. Taken together, our data demonstrate MCPH1 deficiency promotes genomic instability and increases cancer susceptibility. Our study using knockout mouse models provides convincing genetic evidence that MCPH1 is a bona fide tumor suppressor gene. Its deficiency leading to defective DNA repair in tumors can be used to develop novel targeted cancer therapies in the future.

A prognostic index to predict survival after liver transplantation could address several clinical needs. Here, we devised a scoring system that predicts recipient survival after pediatric liver transplantation. We used univariate and multivariate analysis on 4565 pediatric liver transplant recipients data and identified independent recipient and donor risk factors for posttransplant mortality at 3 months. Multiple imputation was used to account for missing variables. We identified five factors as significant predictors of recipient mortality after pediatric liver transplantation: two previous transplants (OR 5.88, CI 2.88-12.01), one previous transplant (OR 2.54, CI 1.75-3.68), life support (OR 3.68, CI 2.39-5.67), renal insufficiency (OR 2.66, CI 1.84-3.84), recipient weight under 6 kilograms (OR 1.67, CI 1.12-2.36) and cadaveric technical variant allograft (OR 1.38, CI 1.03-1.83). The Survival Outcomes Following Pediatric Liver Transplant score assigns weighted risk points to each of these factors in a scoring system to predict 3-month recipient survival after liver transplantation with a C-statistic of 0.74. Although quite accurate when compared with other posttransplant survival models, we would not advocate individual clinical application of the index., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Low case volume has been associated with poorer surgical outcomes in a multitude of surgical procedures. We studied the association among low case volume, outcomes, and the likelihood of pediatric liver transplantation., Methods: We studied a cohort of 6628 candidates listed in the Organ Procurement and Transplantation Network for primary pediatric liver transplantation between 2002 and 2012; 4532 of the candidates went on to transplantation. Candidates were divided into groups according to the average volume of yearly transplants performed in the listing center over 10 years: >15, 10 to 15, 5 to 9, and <5. We used univariate and multivariate Cox regression analyses with bootstrapping on transplant recipient data and identified independent recipient and donor risk factors for wait-list and posttransplant mortality., Results: 38.5% of the candidates were listed in low-volume centers, those in which <5 transplants were performed annually. These candidates had severely reduced likelihood of transplantation with only 41% receiving a transplant. For the remaining candidates, listed at higher volume centers, the transplant rate was 85% (P < .001). Being listed at a low-volume center was a significant risk factor in multivariate Cox regression analysis for both wait-list mortality (hazard ratio, 3.27; confidence interval, 2.53-4.23) and posttransplant mortality (hazard ratio, 2.21; confidence interval, 1.43-3.40)., Conclusions: 38.5% of pediatric transplant candidates are listed in low-volume transplant centers and have lower likelihood of transplantation and poorer outcomes. If further studies substantiated these findings, we would advocate consolidating pediatric liver transplantation in higher volume centers., (Copyright © 2015 by the American Academy of Pediatrics.)

Diseases of lipid metabolism are a major cause of human morbidity, but no animal model entirely recapitulates human lipoprotein metabolism. Here we develop a xenograft mouse model using hepatocytes from a patient with familial hypercholesterolaemia caused by loss-of-function mutations in the low-density lipoprotein receptor (LDLR). Like familial hypercholesterolaemia patients, our familial hypercholesterolaemia liver chimeric mice develop hypercholesterolaemia and a 'humanized' serum profile, including expression of the emerging drug targets cholesteryl ester transfer protein and apolipoprotein (a), for which no genes exist in mice. We go on to replace the missing LDLR in familial hypercholesterolaemia liver chimeric mice using an adeno-associated virus 9-based gene therapy and restore normal lipoprotein profiles after administration of a single dose. Our study marks the first time a human metabolic disease is induced in an experimental animal model by human hepatocyte transplantation and treated by gene therapy. Such xenograft platforms offer the ability to validate human experimental therapies and may foster their rapid translation into the clinic.

Background: Focal nodular hyperplasia (FNH) is uncommonly diagnosed in pediatric patients and may be difficult to distinguish from a malignancy. We present a review of all children with a tissue diagnosis of FNH at our institution, describe the diagnostic modalities, and provide recommendations for diagnosis and follow-up based on our experience and review of the literature., Methods: A retrospective review of children <18years of age diagnosed with FNH at a single institution was performed from 2000 to 2013., Results: Twelve patients were identified with a tissue diagnosis of FNH. Two patients required surgical resection of their lesion owing to concern for malignancy. Ten patients were managed expectantly with imaging surveillance after biopsy confirmed a diagnosis of FNH. All patients who underwent MRI had very typical findings including hypointensity on T1 weighted sequences, hyperintensity on T2, and homogenous uptake of contrast on the arterial phase. On follow-up all patients had either a stable lesion or reduction in size., Conclusions: Focal nodular hyperplasia presents typically in children with liver disease, have undergone chemotherapy, and adolescent females. Young children, particularly <5years of age, without underlying liver disease or history of chemotherapy can pose a diagnostic dilemma. In this unique subgroup of children with FNH, MRI and/or needle biopsy should be adequate diagnostic modalities for these lesions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Hepatoblastoma (HB) is the most common primary liver tumor in children and accounts for two-thirds of all malignant liver neoplasms in the pediatric population. For patients with advanced HB (unresectable or unresponsive to chemotherapy), combined treatment with chemotherapy and liver transplantation is an excellent option. The etiology of HB is mostly obscure because of its extreme rarity although some inherited syndromes and very low birth weight have been associated with it. The prognosis for children with HB has significantly improved in the past three decades thanks to advancements in chemotherapy, surgical resection and postoperative care. In 2002 a surgical staging system called pretreatment extent of disease (PRETEXT) was designed to allow a universal, multidisciplinary approach to patients with HB. Between one-third to two-thirds of patients initially present with unresectable tumors or distant metastases, but up to 85% of these tumors become operable after neoadjuvant chemotherapy. Patients with PRETEXT categories 1, 2, and some 3 are referred for neoadjuvant chemotherapy followed by surgical resection with the goal of complete tumor removal. Classic treatments regimens include a combination of cisplatin, fluorouracil, and vincristine or cisplatin and doxorubicin. Liver transplantation is the only treatment option for unresectable HB. In 2010 the pediatric end-stage liver disease, a pediatric-specific scoring system that determines a patient's ranking on the liver transplant list, began to award additional "exception" points for patients with HB. We analyzed the Standard Transplant Analysis and Research dataset to assess the impact of changes in exception point criteria for HB on outcomes after liver transplantation at Texas Children's Hospital in Houston, Texas. We found that patients who were listed for transplantation with current HB exception criteria experienced a shorter waitlist time but survival was similar between the two eras.

Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.

The bulk production of polymeric nanofibers is important for fabricating high-performance, nanoscale materials. Rotary jet spinning (RJS) enables the mass production of nanostructured fibers by centrifugal forces but may result in inconsistent surface morphologies. Because nanofiber performance is dependent upon its surface features, we asked which parameters must be optimized during production to control fiber morphology. We developed and tested a mathematical model that describes how the competition between fluid instability and solvent removal in RJS regulates the degree of beading in fibers. Our data suggest that solvent evaporation during the spinning process causes an increase in jet viscosity and that these changes inhibit both bead formation and jet thinning. The RJS was used to vary experimental parameters, showing that fiber beading can be reduced by increasing solvent volatility, solution viscosity, and spinning velocity. Collectively, our results demonstrate that nanofiber morphology and diameter can be precisely controlled during RJS manufacturing.

Purpose of Review: Orthotopic liver transplantation in the pediatric population is a technically challenging undertaking, requiring highly specialized surgical techniques unique to this group. This review describes the most current method of transplantation for these patients., Recent Findings: Pediatric liver transplantation employs multiple modifications of standard transplant technique, including alternative methods of vascular and biliary anastomoses as well as technical variant grafts. We herein describe how these methods are employed in procurement, back-table preparation, hepatectomy, and allograft implantation., Summary: This review provides concise direction of surgical technique for pediatric liver transplant recipients.

Biliary atresia (BA), a chronic progressive cholestatic disease of infants, is the leading cause for liver transplant in children, especially in patients under two years of age. BA can be successfully treated with the Kasai portoenterostomy; however most patients still require a liver transplant, with up to one half of BA children needing a transplant by age two. In the current pediatric end-stage liver disease system, children with BA face the risk of not receiving a liver in a safe and timely manner. In this review, we discuss a number of possible solutions to help these children. We focus on two general approaches: (1) preventing/delaying need for transplantation, by optimizing the success of the Kasai operation; and (2) expediting transplantation when needed, by performing techniques other than the standard deceased-donor, whole, ABO-matched organ transplant.

The number of children affected by the hepatitis C virus (HCV) in the United States is estimated to be between 23000 to 46000. The projected medical cost for children with HCV in the United States is $199-366 million over the next decade. The implementation of routine screening of blood supply has virtually eliminated transmission via transfusion and vertical transmission is now the most common mode of infection in children. Infections acquired during infancy are more likely to spontaneously resolve and fibrosis of the liver tends to increase with age suggesting slow progressive histologic injury. Anti-viral treatment may be warranted in children with persistently elevated liver enzymes or with significant fibrosis on liver biopsy. Current standard of care includes weekly pegylated interferon and ribavirin twice daily. Predictors of high sustained viral response include genotype 2 and 3 and low viral load in children with genotype 1 (< 600000 IU/mL). Phase 1 and 2 trials with triple therapy (interferon, ribavirin, and a protease inhibitor) are ongoing. Triple therapy is associated with a significantly higher rate of sustained virologic response (> 90%). Only 34 pediatric patients were transplanted with hepatitis C between January 2008 and April 2013. The majority of pediatric patients were born prior to universal screening of blood products and, as of June 2013, there are only two pediatric patients awaiting liver transplantation for end-stage liver disease secondary to hepatitis C. Pediatric survival rates post-transplant are excellent but graft survivals are noticeably reduced compared to adults (73.73% for pediatric patients at one year compared to 87.69% in adult patients). New safe and effective antiviral therapies for recurrent HCV should help increase graft survival.