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Regulation of the MYC oncogene remains unclear. Using 10058-F4, a compound that inhibits MYC-MAX transcription factor, MYC protein and gene expression were down-regulated in Namalwa cells, a Burkitt lymphoma. Compound 10058-F4 decreased MYC mRNA (45%), MYC protein (50%), and cell growth (32%). MYC-MAX transcription factor was disrupted 24 h after treatment, resulting in transcriptional inhibition of target genes. Because microRNAs (miRNA) disrupt mRNA translation, let-7a, let-7b, and mir-98 were selected using bioinformatics for targeting MYC. Inhibition of MYC-MAX transcription factor with 10058-F4 increased levels of members of the let-7 family. In inhibited cells at 24 h, let-7a, let-7b, and mir-98 were induced 4.9-, 1.3-, and 2.4-fold, respectively, whereas mir-17-5p decreased 0.23-fold. These results were duplicated using microRNA multianalyte suspension array technology. Regulation of MYC mRNA by let-7a was confirmed by transfections with pre-let-7a. Overexpression of let-7a (190%) decreased Myc mRNA (70%) and protein (75%). Down-regulation of Myc protein and mRNA using siRNA MYC also elevated let-7a miRNA and decreased Myc gene expression. Inverse coordinate regulation of let-7a and mir-17-5p versus Myc mRNA by 10058-F4, pre-let-7a, or siRNA MYC suggested that both miRNAs are Myc-regulated. This supports previous results in lung and colon cancer where decreased levels of the let-7 family resulted in increased tumorigenicity. Here, pre-let-7a transfections led to downregulation of expression of MYC and its target genes and antiproliferation in lymphoma cells. These findings with let-7a add to the complexity of MYC regulation and suggest that dysregulation of these miRNAs participates in the genesis and maintenance of the lymphoma phenotype in Burkitt lymphoma cells and other MYC-dysregulated cancers. [Cancer Res 2007;67(20):9762-70]

This multicenter study compared health-related quality of life (HRQOL) and family function of pediatric liver transplant recipients to those of healthy children to determine if this population differed from a healthy population and to distinguish which pretransplant and posttransplant factors impact HRQOL and family function. HRQOL data from 102 patients achieving 2-year survival were collected with the Infant Toddler Quality of Life Instrument or the Child Health Questionnaire Parent Form 50 parent surveys. Family functioning was assessed with the Family Assessment Device (FAD) completed by each participant's family members. Demographic and clinical information were retrieved from the Studies of Pediatric Liver Transplant database. Recipients 5 years of age and older scored lower than a normative sample in physical health (P Ͻ 0.001), general health (P Ͻ 0.001), parental emotional impact (P Ͻ 0.001), and disruption of family activities (P Ͻ 0.001). Younger children, 2 to 5 years of age, scored lower than controls in global health (P ϭ 0.004) and general health perceptions (P Ͻ 0.001) but did not differ in subscales measuring physical and psychosocial outcomes. Univariate analysis among the subscales identified demographic but not clinical variables as significant predictors of HRQOL. Mean scores of FAD scales were below published thresholds indicating healthy family functioning. As reported in previous studies, parents of older recipients reported higher levels of stress, although their level of family function appears normal. Significant associations were also observed between FAD scores and demographic variables, suggesting that further investigation of the impact of race, parental marital status, and socio-economic status on the patient rehabilitation process is needed. Liver Transpl 14: 460-468, 2008. © 2008 AASLD. Received May 9, 2007 accepted August 17, 2007. See Editorial on Page 415Children account for 12%-15% of all liver transplants performed each year in the United States. Liver transplantation is an expensive, complex intervention for children with life-threatening liver disease. With improved immunosuppressive regimens and operative techniques, 10-year patient survival rates currently approach 80%.1 Yet, patient and graft survival are not the only outcomes of interest in this population. The expectation is that these survivors will lead healthy lives, performing everyday activities, free from the burden of chronic illness. Analysis of health-related quality of life (HRQOL) in these patients is an initial step in determining if these expectations are being fulfilled. HRQOL refers to those aspects of quality of life that are directly related to health and are potentially affected by the health-care system. The 5 aspects of health that comprise HRQOL include physical health, mental

Post transplant lymphoproliferative disorder (PTLD) causes significant morbidity and mortality in pediatric recipients of liver transplantation (LT). Objective Describe the incidence of PTLD and symptomatic Epstein Barr virus disease (SEBV) in a large multicenter cohort of children who have undergone LT focused on the risk factors and changes in incidence over time. Methods Prospective determination of SEBV and PTLD in 2283 subjects who had undergone a first LT with at least 1 year of follow up in the Studies of Pediatric Liver Transplantation database. SEBV was defined by specific criteria and PTLD required tissue confirmation. Incidences of SEBV and PTLD were determined by Kaplan Meier. Univariate and multivariate modeling of risk factors were performed using standard methods. Results SEBV occurred in 199, of whom 174 (87.4%) were EBV negative at LT. 75 patients developed PTLD of whom 64 (85.3%) were EBV negative at LT. Of 2048 patients with at least 2 years of follow-up, 8.3% developed SEBV and 2.8% PTLD by the second year post-LT. There was a lower incidence of SEBV (11.3% vs 5.9, p<0.0001) and PTLD (4.2 vs. 1.7, p=0.0011) in 2002-07 compared to 1995-2001. Tacrolimus and cyclosporine trough blood levels in the first year post transplant were significantly lower and fewer children were receiving steroids in 02-07. Era of LT, EBV negative recipient status, younger age, biliary atresia and frequent rejection episodes were associated with an increased risk for SEBV and PTLD in univariate analysis. Age, biliary atresia and EBV recipient status were correlated. In multivariate analysis era of LT, EBV recipient status and frequent rejection episodes was associated with SEBV and PTLD. Conclusions The incidence of SEBV and PTLD is decreasing in pediatric LT recipients coincident with a reduction in immunosuppression. Younger recipients and those with multiple rejections remain at higher risk for SEBV and PTLD.

Objective-To determine whether endothelial cell loss 5 years after successful corneal transplantation is related to the age of the donor. Design-Multicenter, prospective, double-masked clinical trial.Participants-Three hundred forty-seven subjects participating in the Cornea Donor Study who had not experienced graft failure 5 years after corneal transplantation for a moderate-risk condition (principally Fuchs' dystrophy or pseudophakic corneal edema).Testing-Specular microscopic images of donor corneas obtained before surgery and postoperatively at 6 months, 12 months, and then annually through 5 years were submitted to a central reading center to measure endothelial cell density (ECD). Main Outcome Measure-Endothelial cell density at 5 years.Results-At 5 years, there was a substantial decrease in ECD from baseline for all donor ages. Subjects who received a cornea from a donor 12 to 65 years old experienced a median cell loss of 69% in the study eye, resulting in a 5-year median ECD of 824 cells/mm 2 (interquartile range, 613-1342), whereas subjects who received a cornea from a donor 66 to 75 years old experienced a cell loss of 75%, resulting in a median 5-year ECD of 654 cells/mm 2 (interquartile range, 538-986) (P [adjusted for baseline ECD] = 0.04). Statistically, there was a weak negative association between ECD and donor age analyzed as a continuous variable (r [adjusted for baseline ECD] = −0.19; 95% confidence interval, −0.29 to −0.08).Conclusions-Endothelial cell loss is substantial in the 5 years after corneal transplantation. There is a slight association between cell loss and donor age. This finding emphasizes the importance of longer-term follow-up of this cohort to determine if this relationship affects graft survival.Corneal clarity after penetrating keratoplasty can be affected by endothelial cell loss over time. The exact cause of postoperative cell loss is unknown but may be a result of donor or preservation factors, surgical stress, cellular interactions between the donor and recipient, immune reaction, normal or accelerated cellular aging, or glaucoma. The Eye Bank Association of America requires endothelial cell density (ECD) determination via specular microscopy as a standard corneal tissue evaluation method but does not require a minimum cell density for transplant suitability. 1 Clinicians typically prefer donor corneas with a high pre-operative ECD in order to offset posttransplant cell loss under the belief that this will improve the probability of graft survival. Past studies evaluating endothelial cell loss after corneal transplantation have produced conflicting results with regard to the effect of donor age. Some studies suggest that there is no difference in endothelial cell loss comparing older and younger donor tissue, 2-5 whereas other studies suggest that there is a relationship between endothelial cell loss and donor age. 6 -8The Cornea Donor Study (CDS) has evaluated the effect of donor age on 5-year graft survival in eyes undergoing cornea transplantation for a corne...

Data sharingThe Children's Oncology Group Data Sharing policy describes the release and use of Children's Oncology Group individual subject data for use in research projects in accordance with National Clinical Trials Network (NCTN) Program and NCI Community Oncology Research Program (NCORP) guidelines. Only data expressly released from the oversight of the relevant Children's Oncology Group Data and Safety Monitoring Committee are available to be shared. Data sharing will ordinarily be considered only after the primary study manuscript is accepted for publication. For phase 3 studies, individual-level de-identified datasets that would be sufficient to reproduce results provided in a publication containing the primary study analysis can be requested from the NCTN/ NCORP data archive. Data are available to researchers who wish to analyse the data in secondary studies to enhance the public health benefit of the original work and agree to the terms and conditions of use. For non-phase 3 studies, data are available following the primary publication. An individual-level de-identified dataset containing the variables analysed in the primary results paper can be expected to be available upon request. Requests for access to Children's Oncology Group protocol research data should be sent to:

PURPOSE The identification of new therapies for high-risk (HR) hepatoblastoma (HB) is challenging. Children’s Oncology Group Study AHEP0731 included a HR stratum to explore the efficacy of novel agents. We report the response rate to vincristine/irinotecan and the outcome of high-risk HB patients. PATIENTS AND METHODS Patients with newly diagnosed metastatic HB or those with a serum alpha-fetoprotein (AFP) < 100 ng/ml were eligible. Patients received 2 cycles of vincristine (V) 1.5 mg/m2/day intravenously, on days 1 and 8 and irinotecan (I) 50 mg/m2/day, intravenously, on days 1-5. Patients were defined as responders if they had either a 30% decrease in tumor burden according to RECIST criteria or a 90% (> 1 log10) decline in the AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of cisplatin/doxorubicin/5-fluorouracil/vincristine (C5VD). Non-responders were to receive 6 cycles of C5VD alone. RESULTS Thirty-two patients (median age at diagnosis, 26 months, range: 11-159) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP = 6, RECIST only = 3, AFP only = 5). The median AFP decline following 2 cycles of VI for the entire group was 345,565 ng/ml (85%) of the initial AFP. Three-year event-free and overall survival was 49% (95% confidence interval-CI: 30-65%) and 62% (CI: 42-77%) respectively. CONCLUSION The combination of vincristine and irinotecan has substantial activity against HR hepatoblastoma. The ultimate impact of this regimen in improving outcomes of children with HR hepatoblastoma remains to be determined.

Technical variant techniques expand the pediatric donor pool and reduce time from listing to transplant, but they are associated with increased morbidity and mortality.