Acute Liver Failure in Children.

Pediatric acute liver failure is a rare diagnosis which can result in death or multiorgan system failure with a potential need for liver transplantation. The causative factors are many, but etiology, definitive pathophysiology, and directed therapies are still under investigation contributing to the difficulty in planning and providing both medical and nursing care. Clinical practice guidelines for acute liver failure are available for adult patients and through a national published position paper for pediatrics, but quality evidence is limited, especially with regard to testing and treatment recommendations, providing challenges in pediatric critical care decision making.

Prostate cancer-derived holoclones: a novel and effective model for evaluating cancer stemness.

Prostate cancer accounts for approximately 13.5% of all newly diagnosed male cancer cases. Significant clinical burdens remain in terms of ineffective prognostication, with overtreatment of insignificant disease. Additionally, the pathobiology underlying disease heterogeneity remains poorly understood. As the role of cancer stem cells in the perpetuation of aggressive carcinoma is being substantiated by experimental evidence, it is crucially important to understand the molecular mechanisms, which regulate key features of cancer stem cells. We investigated two methods for in vitro cultivation of putative prostate cancer stem cells based on 'high-salt agar' and 'monoclonal cultivation'. Data demonstrated 'monoclonal cultivation' as the superior method. We demonstrated that 'holoclones' expressed canonical stem markers, retained the exclusive ability to generate poorly differentiated tumours in NOD/SCID mice and possessed a unique mRNA-miRNA gene signature. miRNA:Target interactions analysis visualised potentially critical regulatory networks, which are dysregulated in prostate cancer holoclones. The characterisation of this tumorigenic population lays the groundwork for this model to be used in the identification of proteomic or small non-coding RNA therapeutic targets for the eradication of this critical cellular population. This is significant, as it provides a potential route to limit development of aggressive disease and thus improve survival rates.

Integrating biomarkers across omic platforms: an approach to improve stratification of patients with indolent and aggressive prostate cancer.

Classifying indolent prostate cancer represents a significant clinical challenge. We investigated whether integrating data from different omic platforms could identify a biomarker panel with improved performance compared to individual platforms alone. DNA methylation, transcripts, protein and glycosylation biomarkers were assessed in a single cohort of patients treated by radical prostatectomy. Novel multiblock statistical data integration approaches were used to deal with missing data and modelled via stepwise multinomial logistic regression, or LASSO. After applying leave-one-out cross-validation to each model, the probabilistic predictions of disease type for each individual panel were aggregated to improve prediction accuracy using all available information for a given patient. Through assessment of three performance parameters of area under the curve (AUC) values, calibration and decision curve analysis, the study identified an integrated biomarker panel which predicts disease type with a high level of accuracy, with Multi AUC value of 0.91 (0.89, 0.94) and Ordinal C-Index (ORC) value of 0.94 (0.91, 0.96), which was significantly improved compared to the values for the clinical panel alone of 0.67 (0.62, 0.72) Multi AUC and 0.72 (0.67, 0.78) ORC. Biomarker integration across different omic platforms significantly improves prediction accuracy. We provide a novel multiplatform approach for the analysis, determination and performance assessment of novel panels which can be applied to other diseases. With further refinement and validation, this panel could form a tool to help inform appropriate treatment strategies impacting on patient outcome in early stage prostate cancer.

One Health Economics to confront disease threats.

Global economic impacts of epidemics suggest high return on investment in prevention and One Health capacity. However, such investments remain limited, contributing to persistent endemic diseases and vulnerability to emerging ones. An interdisciplinary workshop explored methods for country-level analysis of added value of One Health approaches to disease control. Key recommendations include: 1. systems thinking to identify risks and mitigation options for decision-making under uncertainty; 2. multisectoral economic impact assessment to identify wider relevance and possible resource-sharing, and 3. consistent integration of environmental considerations. Economic analysis offers a congruent measure of value complementing diverse impact metrics among sectors and contexts.

Selection of live-related liver transplantation candidates.

PURPOSE: Living donor liver transplantation (LR) is an important alternative for children. We compared our outcomes of LR and cadaveric (CAD) graft recipients, with attention to the pediatric end-stage liver disease (PELD) score and perioperative morbidity and mortality to identify appropriate candidates for LR. METHODS: Our transplant database and electronic medical records were searched for demographics and outcome measures. RESULTS: From 2000 to 2008, 81 children underwent liver transplantation from 37 LR and 44 CAD donors. There were no significant differences in graft or overall survival at 3 months or 1 year. The LR group was significantly younger (4.46 +/- 5.2 years vs 7.41 +/- 6.6 years; P = .03) and had a significantly lower PELD score (12.7 +/- 13 vs 22 +/- 12; P = .001) at the time of transplantation. Ten patients were transplanted for unresectable tumor in the LR group vs 4 CAD (P = .03). Significantly fewer LR recipients required return to the operating room in the first 30 days posttransplant (13.9% vs 34.1%; P = .03). The LR recipients had a higher rate of biliary stricture requiring reoperation (22.2% vs 2.3%; P = .005). CONCLUSIONS: The LR liver transplantation is highly selected for patients with a parent donor who will need transplant but do not yet have a high PELD score. A lower PELD score at operation may have contributed to the lower incidence of postoperative complications requiring reoperation.

Failure of immunosuppressive drug levels to predict T-cell reactivity in pediatric transplant patients.

PURPOSE: In children, therapeutic management of immunosuppression relies on allograft function, drug levels, and clinical insight. Using a Food and Drug Administration-approved test for T-cell response, T-cell activation in vitro can be measured to monitor the immune response. METHODS: In a retrospective study, 92 posttransplant children who received either a liver and/or kidney transplant and were followed by routine screening had their T-cell response tested by the Cylex ImmuKnow assay (Columbia, MD). After phytohemagglutinin-L stimulation of T-cells, adenosine triphosphate (ATP) concentrations were measured. In this assay, light emission at lambda = 562 nm is proportional to the ATP concentration (ng/mL). Immunosuppressive drug trough levels were also measured. Quantitative real-time polymerase chain reaction Epstein-Barr virus (EBV) viral titers were determined for 2 patients. RESULTS: Separating the results into younger than 12 years and 12-year or older populations, we found that for the younger than 12 years, 28% of patients were in the low immune function category, 47% in the moderate, and 25% in the high category. For the 12 years or older, 25% of patients were in the low immune function category, 47% in the moderate, and 28% in the high category. The immune function distribution was not different (P = not significant) between the younger than 12 years and 12-year or older groups. Tacrolimus trough levels were 6.3 +/- 2.4 ng/mL for younger than 12 years and 5.6 +/- 3.3 ng/mL for 12 years or older (P = not significant), and rapamycin was similar, but both showed no correlation to immune function. We observed increased ATP values with decreased EBV viral loads. CONCLUSIONS: These results suggest that tacrolimus and/or rapamycin levels do not adequately determine the biologic effect of immunosuppression. We expect that future T-cell activation monitoring will allow us to diminish rejection and infection events posttransplantation and lead to a healthier pediatric transplant population.

Arterial-venous fistulas following pediatric liver transplant case studies.

AV fistula is a rare but serious complication following pediatric liver transplant and may lead to graft loss. Our aim was to describe two pediatric centers' experience with the diagnosis, treatment and outcomes of children who presented with AV fistulas post-liver transplantation We report five cases of late arterio-portal fistula following liver transplantation. Four children were successfully treated with coil embolization. All of the children in this series had liver biopsies within 2-6 months of their AV fistula diagnosis. All biopsies were performed using a Bard Monopty 18 gauge needle with no ultrasound guidance and only one pass per biopsy. Two children also had PTC 4-8 months prior to their diagnosis of AV fistula. Three of the five children in this series had GI bleeds requiring banding or sclerotherapy. The other two had varices found on CT scan. All five cases in this series had ascites on their initial presentation. Four out of the five children had a history of non-compliance and the other child had a history of malabsorption and chronic diarrhea.

Successful liver transplant for unresectable hepatoblastoma.

BACKGROUND: Treatment of children with stage III and IV hepatoblastoma has shown little improvement with 5-year survival rates of 64% and 25%, respectively (J Clin Oncol 2000;18:2665-75). A timely and organized treatment program including preoperative chemotherapy combined with living donor liver transplantation and postoperative chemotherapy has been used seeking improved long-term survival in stage III and IV cases. METHODS: A retrospective review of 8 patients with stage III and IV hepatoblastoma unresectable by conventional resection were treated with complete hepatectomy and transplantation. Approval was obtained from our institutional review board. RESULTS: Since August of 2001, we have treated 6 patients with stage III hepatoblastoma and 2 patients with initial stage IV hepatoblastoma. These patients (age, 23 months-9 years) had all received extensive chemotherapy or prior resections. After chemotherapy, none had gross tumor documented outside of the liver at time of transplantation. All underwent hepatectomy including vena cava resection, in selected cases, with living donor orthotopic liver transplantation. All patients had at least 2 cycles of postoperative chemotherapy. Of 8 patients, 6 are alive and well with normalized alpha-fetoprotein levels. There were 2 late deaths from recurrent disease. Length of follow-up ranged from 7 to 53 months. CONCLUSION: Complete hepatectomy with living donor liver transplantation provides optimal surgical treatment in unresectable stage III and initial stage IV disease confined to the liver at resection. This series indicates that children tolerate complete hepatectomy, transplantation, and postoperative chemotherapy well. Referral to a transplant center during the first 3 cycles of chemotherapy appears to offers the best opportunity for long-term survival.

Non-compliance in children post-liver transplant. Who are the culprits?

Although non-compliance in pediatric liver transplants is known to be a major cause of late graft loss and patient mortality, follow-up seems inconsistent. As liver transplant becomes a luxury because of the shortage of organs, the need to maximize graft and patient survival by intense monitoring becomes a necessity. When evaluating children with elevated liver enzymes post-transplant, early or late non-compliance should always be suspected. The risk of non-compliance in children with chronic illness varies from 10 to 89%. In a study by Sudan et al. non-compliance was one of the leading causes of late mortality in children age 10-17 yr. Although it is well documented that teenagers have a high rate of non-compliance, the rate in the younger children has not been documented. In our series, we found that parental non-compliance comprises the majority of our problems with liver dysfunction, hospitalization, and graft loss. The purpose of this study was to evaluate the incidence of non-compliance in children post-liver transplant. A retrospective chart review of patient records from admissions and outpatient records was performed for documentation of elevated enzymes and low immunosuppressive levels. From July 1987 to December 2002, our program performed 266 liver transplants in 234 children, with 1-yr graft survival of 84% and 1-yr patient survival of 90%. Our overall patient survival was 85% with 77% graft survival. There were 40 children with documented non-compliance with mild to severe liver dysfunction in this study. Twenty-eight of these children were younger than 10 yr [28 of 40 (46%) <5 yr], and 12 (30%) were older than 10 yr at the time of rejection. In 10 of 40 children, there was one documented incident of non-compliance, while 26 of 40 had two to four incidents, and four had five or more documented events. Our children (50%) came from two-parent households. The remaining 50% were from single households. In 27 of 40 (68%) children, rejection was confirmed by liver biopsy. In children on cyclosporine (Neoral; Novartis, East Hanover, NJ, USA) with a known history of non-compliance and low immunosuppressive levels, C2 monitoring was performed to verify absorption. Admission for drug monitoring and verification of non-compliance was accomplished in 32 of 40 (80%). Four of the 40 children (10%) were retransplanted, and one child had died. In conclusion, non-adherence to medications remains a major source of graft loss and morbidity post-transplant. We found that non-compliance crosses all socio-economic and cultural groups and that flexibility of clinic hours, shortened time between visits, and decreased numbers and times of medication will increase adherence.

Improvement in renal function and rejection control in pediatric liver transplant recipients with the introduction of sirolimus.

Calcineurin inhibitors have dramatically improved the outcomes of pediatric liver transplantation. However, calcineurin inhibitor use is associated with a 50% reduction in glomerular filtration rate in the first year post-transplant. Nephrotoxicity can be difficult to manage, especially in the pediatric population. We hypothesized that the addition of an mTOR inhibitor with decreased calcineurin inhibitor levels might improve or prevent renal insufficiency and improve control of rejection. A retrospective chart review was performed on the patients treated with sirolimus who had undergone an orthotopic liver transplant between January 2000 and February 2003. Thirty-eight patients were identified. Mean age was 8.6 yr. Fourteen patients were male and 24 were female. Mean weight was 30.3 kg. The most common indications for starting sirolimus were rejection (42%) and renal impairment (29%). Seventy-three percent of patients begun on sirolimus remain on the medication. Those with renal impairment (11 patients) showed improvement in their creatinine levels from a mean baseline of 1.3 to 0.8 mg/dL. Their calculated creatinine clearance (Schwartz formula) improved from 63.7 to 84.8 mL/min (p = 0.03). Patients started on sirolimus for rejection showed significant improvement in hepatocellular enzymes despite a reduction in the tacrolimus level from 12.2 to 7.5 ng/mL. The mean alanine aminotransferase level improved from 221 to 100 units/L (p = 0.02), and the mean aspartate aminotransferase improved from 121 to 99 units/L (p = 0.59). Addition of sirolimus to a tacrolimus-based regimen with lower target tacrolimus levels improved liver function in patients with rejection. Addition of sirolimus significantly improved renal function as shown by creatinine level and calculated creatinine clearance in those children with renal impairment. The effect of combined immunosuppressant treatment with tacrolimus and sirolimus on long-term renal function needs to be evaluated.

Domino as a bridge to definitive liver transplantation in a neonate.

An interim liver transplant was used to extend survival in a neonate. This was accomplished by the initial transplant of a left-lateral segment of a metabolically abnormal liver obtained from a 7-yr-old patient with primary oxalosis. This bridging strategy was required because our neonatal patient was dying of fulminant hepatic failure caused by hepatic vein thrombosis and a small liver or liver segment could not be found. Although problems with hyperoxaluria were encountered in the neonate post-transplant, the interim liver transplant enabled the baby to survive and grow until the age of 4 months. At that time, a definitive transplant was performed using the left-lateral segment of his mother's liver. This case represents the first reported use of a pediatric domino transplant where a metabolically abnormal liver was used to allow sufficient growth to permit a definitive liver transplantation.