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1.  High Rates of Recurrent Biliary Tract Obstruction in Children with Sickle Cell Disease 
Pediatric blood & cancer  2012;60(4):650-652.
BACKGROUND
Individuals with sickle cell disease (SCD) have an increased risk of cholelithiasis from bilirubin stones. Symptomatic biliary tract disease (BTD) includes acute and chronic cholecystitis, obstruction of the common bile duct (CBD), cholangitis, and gallstone pancreatitis. Cholecystectomy is the main treatment strategy for symptomatic patients; however, the prevalence of recurrent BTD following cholecystectomy has not been systematically evaluated. We conducted a retrospective cohort study to describe the recurrence of BTD after cholecystectomy and characterize risk factors for recurrent disease.
PROCEDURE
We identified patients <22 years of age who presented to the Johns Hopkins Children Center with symptomatic BTD from July 1993 to June 2008.
RESULTS
We identified 56 patients with a total of 76 episodes of symptomatic BTD (median age at first event 15.9, range 4.6 to 21.5 years). Eleven of the 56 patients (19.6%) had at least one episode of recurrent symptomatic BTD (median follow-up of 5.3 years). Baseline characteristics were similar between the patients with a single episode of BTD and those with recurrent BTD.
CONCLUSIONS
These results demonstrate that recurrent BTD is a frequent complication of SCD (20% by age 4 years) and often presents as CBD obstruction by stone, despite cholecystectomy. In our cohort, recurrence was not associated with age at first episode, baseline total bilirubin, gender, or genotype of SCD.
doi:10.1002/pbc.24413
PMCID: PMC3977003  PMID: 23255346
sickle cell disease; cholecystitis; cholangitis
2.  Clinical features and outcomes in patients with secondary Ewing sarcoma 
Pediatric blood & cancer  2012;60(4):611-615.
Background
Ewing sarcoma (EWS) is rarely diagnosed as a second malignancy. We sought to describe a cohort of patients with secondary EWS and investigate if patient characteristics and survival differ between patients with secondary and primary EWS.
Procedure
Patients with EWS or peripheral primitive neuroectodermal tumor (PNET) reported to the SEER database from 1973 to 2008 were evaluated based on primary or secondary tumor sequence. Overall survival was estimated by Kaplan-Meier methods and evaluated using the log-rank test. Competing risk analysis was used to describe risk of death due to malignancy rather than other causes.
Results
58 cases of secondary EWS were reported, accounting for 2.1% of all EWS cases. The median latency from primary malignancy to secondary EWS was 64 months (range 1–282 months). 12.1% of patients with secondary EWS received radiation to the site of secondary tumor during therapy for their primary malignancy. Patients with secondary EWS were more likely to have axial tumors (77.4% vs. 62.5%; p = 0.03) and smaller tumors (75.0% vs. 48.2% < 8 cm; p = 0.001). Five-year overall survival from diagnosis was inferior for patients with secondary compared to primary EWS (34.3% vs. 52.2%; p = 0.002). However, patients with secondary tumors were less likely than those with primary EWS to die from their malignancy (hazard ratio 0.44; 95% CI 0.23–0.85).
Conclusions
Secondary EWS accounts for a minority of cases of EWS. Tumor size and site and patient survival differ among patients with primary and secondary EWS.
doi:10.1002/pbc.24251
PMCID: PMC3488141  PMID: 22847990
3.  Late Effects of Total Body Irradiation and Hematopoietic Stem Cell Transplant in Children Under Three Years of Age 
Pediatric blood & cancer  2012;60(4):700-704.
Background
Total body irradiation (TBI) is an important component of hematopoietic stem cell transplant (SCT) for pediatric malignancies. With increasing survival rates, late effects of SCT become more important. Younger children may be at particular risk of late effects of radiation and SCT.
Methods
We retrospectively reviewed outcomes of children less than three years of age who received TBI as part of their preparative regimen for SCT at Children’s Hospital Colorado. Clinical information including the date of last follow up, most recent lab values, and physiologic tests were extracted from the medical record.
Results
Of 81 patients who underwent SCT, 19 received TBI and of those, 15 were long-term survivors available for review. Late effects occurring in greater than 50% of the children included abnormalities involving endocrine, metabolic, renal, cataracts and neurocognitive systems. Other organs involved less commonly included liver, skeletal, and cardiac abnormalities. Solid tumors were a rare finding with only 1 patient developing a benign osteochondroma and no identified secondary malignancies.
Conclusions
TBI has been shown to be an important part of the preparative regimen for patients undergoing SCT. Our results, similar to other studies, suggest TBI in patients less than three years of age will likely result in multi-organ dysfunction including endocrine, metabolic, renal, eye, and neurocognitive abnormalities. A longitudinal study with standardized testing of these systems would further clarify the late effects concerns in this patient population.
doi:10.1002/pbc.24252
PMCID: PMC3488362  PMID: 22848000
BMT; Late effects of cancer treatment; Radiation therapy; ALL; Total body irradiation
4.  Initial Testing of the MDM2 Inhibitor RG7112 by the Pediatric Preclinical Testing Program 
Pediatric blood & cancer  2012;60(4):633-641.
Background
RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies.
Procedures
RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hour exposure (1 nM to 10 µM). It was tested against the PPTP in vivo panel focusing on p53 wild-type (WT) xenografts at a dose of 100 mg/kg daily for 14 days followed by 4 weeks of observation. Response outcomes were related to MDM2 and p53 expression datasets (http://pptp.nchresearch.org/data.html).
Results
RG7112 demonstrated cytotoxic activity with a lower median IC50 for p53 WT versus p53 mutant cell lines (approximately 0.4 µM versus > 10 µM, respectively). RG7112 induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C > 2) in 10 of 26 (38%) solid tumor xenografts. Objective responses included medulloblastoma, alveolar rhabdomyosarcoma, Wilms, rhabdoid and Ewing sarcoma xenografts. For the ALL panel, there was 1 partial response, 5 complete responses and 1 maintained complete response. The ALL xenografts expressed the highest levels of p53 among the PPTP panels.
Conclusions
RG7112 induced tumor regressions in solid tumors from different histotype panels, and exhibited consistent high-level activity against ALL xenografts. This high level of activity supports prioritization of RG7112 for further evaluation.
doi:10.1002/pbc.24235
PMCID: PMC3495996  PMID: 22753001
Preclinical Testing; Developmental Therapeutics; RG7112
5.  An fMRI Investigation of Working Memory and its Relationship with Cardiorespiratory Fitness in Pediatric Posterior Fossa Tumor Survivors who received Cranial Radiation Therapy 
Pediatric blood & cancer  2012;60(4):669-675.
Background
The present study investigated the relationship between cardiorespiratory fitness and executive functioning in pediatric brain tumor survivors who received cranial radiation. This population is known to show executive dysfunction and lower rates of aerobic exercise compared to peers.
Procedure
Nine adolescent survivors of pediatric posterior fossa tumor completed an n-back working memory task during a functional MRI scan, as well as cardiorespiratory fitness testing on a cycle ergometer.
Results
Neuroimaging findings indicated typical activation patterns associated with working memory, mainly in the frontal-parietal network. Higher cardiorespiratory fitness was related to better performance on a behavioral measure of working memory and more efficient neural functioning.
Conclusions
This study provides preliminary evidence that cardiorespiratory fitness may be related to executive functioning, particularly working memory, in pediatric brain tumor survivors. Descriptions of the brain regions recruited for working memory by pediatric brain tumor survivors may be used to inform future interventions or indicators of treatment efficacy.
doi:10.1002/pbc.24331
PMCID: PMC3541446  PMID: 23042746
Brain Neoplasms; Neuropsychology; Executive Function; Physical Fitness; Magnetic Resonance Imaging
6.  Glutathione S-Transferase P1 Single Nucleotide Polymorphism Predicts Permanent Ototoxicity in Children with Medulloblastoma 
Pediatric blood & cancer  2012;60(4):593-598.
Background
Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy and clearing reactive oxygen species formed by radiation. We explored the relationship between the host GSTP1 105 A>G polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1 105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events.
Procedure
The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children’s Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and logistic regression for toxicity comparisons.
Results
Patients with a GSTP1 105 AG/GG genotype (vs. AA) or who had received high dose craniospinal radiation (≥ 34 Gy vs. <26 Gy) had a greater risk of requiring hearing aids than their counterparts (OR 4.0, 95%CI 1.2-13.6, and OR 3.1, 95%CI 1.1-8.8, respectively, n=69). Additionally, there was a statistically significant interaction between these variables. Compared with the lowest risk group (GSTP1 105 AA-low dose radiation), patients with a GSTP1 105 AG/GG genotype who received high dose radiation were 8.4 times more likely to require hearing aids (95%CI 1.4-49.9, p-trend=0.005, n=69). When adjusted for age, cumulative cisplatin dose, and amifostine use, the association remained.
Conclusions
The GSTP1 105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. Patients with this allele should be considered for clinical trials employing radiation dose modifications and cytoprotectant strategies.
doi:10.1002/pbc.24366
PMCID: PMC3549321  PMID: 23065688
Glutathione S-Transferase; Polymorphism; Radiation; Ototoxicity; Medulloblastoma
7.  Glucocorticoids and insulin resistance in children with acute lymphoblastic leukemia 
Pediatric blood & cancer  2012;60(4):621-626.
Background
Children treated for acute lymphoblastic leukemia (ALL) are more likely to become overweight. Prolonged exposure to high-dose glucocorticoids may cause insulin resistance and facilitate development of this phenotype.
Procedure
Body mass indices (BMI) and insulin resistance (HOMA-IR) were prospectively measured among on- (n=31) and off-therapy participants (n=29). On-therapy participants were assessed prior to and while on glucocorticoids (5 days of prednisone 40 mg/m2 or dexamethasone 6 mg/m2) given as part of routine maintenance chemotherapy, with a subset (n=10) receiving an intravenous glucose tolerance test (IVGTT) while on glucocorticoids.
Results
Baseline HOMA-IR values among on- and off-therapy participants were similar, but among on-therapy participants, HOMA-IR increased significantly with glucocorticoid exposure (median 3.39 vs. 1.26; p<0.01) with 45.2% of participants having values >4.39 (upper 2.5th percentile among normal weight adolescents). Although baseline HOMA-IR was significantly correlated with current BMI (r=0.48, p<0.01), change in HOMA-IR following steroid exposure was not correlated with any demographic or treatment characteristic including current BMI. Among those with IVGTT data, HOMA estimates in general correlated with values derived from a minimal model analysis (r~0.7).
Conclusions
High-dose glucocorticoids given as part of routine chemotherapy were associated with a significantly increased insulin resistant state. Given the amount and duration of glucocorticoids children with ALL experience, these physiologic changes could be an important contributor to the development of therapy-related obesity.
doi:10.1002/pbc.24364
PMCID: PMC3568436  PMID: 23042765
acute lymphoblastic leukemia; glucocorticoid; insulin resistance; obesity; survivor
8.  A Phase 1 Pharmacokinetic Optimal Dosing Study of Intraventricular Topotecan for Children with Neoplastic Meningitis: A Pediatric Brain Tumor Consortium Study 
Pediatric blood & cancer  2012;60(4):627-632.
Purpose
We performed a phase 1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), administered daily × 5, to determine whether the maximum tolerated dose of IT topotecan was also the pharmacokinetic optimal dose.
Patients and Methods
Patients received topotecan administered through an intraventricular access device (0.1 or 0.2 mg/dose), daily × 5 every other week × 2 (Induction); every 3 weeks × 2 (Consolidation); then every 4 weeks for up to 11 courses (Maintenance). Ventricular CSF pharmacokinetic studies were performed on day 1, week 1 of induction, and in a subset of patients after a single intralumbar topotecan dose on day 1, week 3.
Results
Nineteen patients were enrolled. All were evaluable for toxicity and 18 were assessable for pharmacokinetics. Arachnoiditis requiring corticosteroid therapy occurred in 1/3 patients at the 0.1 mg dose level and 2 of the initial 3 patients enrolled at the 0.2 mg dose level. All subsequent patients were therefore treated with concomitant dexamethasone. Pharmacokinetic evaluation after accrual of the first 7 patients revealed that a topotecan lactone concentration > 1 ng/ml for 8 hours was attained in all patients and thus further dose escalation was not pursued. Results of simulation studies showed that at the dose levels evaluated, >99.9% of patients are expected to achieve CSF topotecan lactone concentrations > 1 ng/mL for at least 8 h.
Conclusion
Intraventricular topotecan, 0.2 mg, administered daily for 5 days with concomitant dexamethasone is well tolerated and was defined to be the pharmacokinetic optimal dose in this trial.
doi:10.1002/pbc.24309
PMCID: PMC3573253  PMID: 23002039
topotecan; intraventricular; neoplastic meningitis; leptomeningeal; pharmacokinetic
9.  Parental and Other Factors Associated with Hydroxyurea Use for Pediatric Sickle Cell Disease 
Pediatric blood & cancer  2012;60(4):653-658.
Background
Hydroxyurea (HU) is highly effective treatment for Sickle Cell Disease (SCD). While pediatric use of HU is accepted clinical practice, barriers to use may impede its potential benefit.
Procedure
A survey of parents of children ages 5–17 years with SCD was performed across five institutions to assess factors associated with HU use.
Results
Of the 173 parent responses, 65 (38%) had children currently taking HU. Among parents of children not taking HU, the most commonly cited reasons were that their hematology provider had not offered it, their child was not sufficiently symptomatic and concerns about potential side effects. Even parents of HU users reported widespread concern about effectiveness, long-term safety and off-label use. In bivariate analyses, children’s ages, parental demographics such as education level, or travel time to their hematology provider were not correlated with HU use. Bivariate analysis and multivariate logistic regression revealed three significant factors associated with current HU use: better parental knowledge about its major therapeutic effects (p<0.001), sickle genotype (p=0.005) and institution of clinical care (p=0.04).
Conclusions
Pervasive concerns about HU safety exist, even among parents of current users. Varying knowledge among parents appears to be independent of their demographics, and is associated with HU use. Inter-institutional variability in parental knowledge and drug uptake highlights potentially potent site-specific influences on likelihood of HU use. Overall, these survey data underscore the need for strategies to bolster parental understanding about benefits of HU and address concerns about its safety.
doi:10.1002/pbc.24381
PMCID: PMC3625668  PMID: 23129068
Hydroxyurea; sickle cell disease; knowledge; and barriers; outcomes research
10.  Early Hematopoietic Stem Cell Transplant is Associated with Favorable Outcomes in Children with MDS 
Pediatric blood & cancer  2012;60(4):705-710.
Background
Although hematopoietic stem cell transplantation (HSCT) is the treatment of choice for childhood myelodysplastic syndrome (MDS), there is no consensus regarding patient or disease characteristics that predict outcomes.
Procedure
We reviewed 37 consecutive pediatric MDS patients who received myeloablative HSCT between 1990 and 2010 at a single center.
Results
Twenty had primary MDS and 17 had secondary MDS. Diagnostic cytogenetics included monosomy 7 (n=21), trisomy 8 (n=7) or normal/other (n=8). According to the modified WHO MDS classification, thirty had refractory cytopenia and 7 had refractory anemia with excess blasts. IPSS scores were: low risk (n=1), intermediate-1 (n=15), and intermediate-2 (n=21). OS and DFS at 10-years in the entire cohort was 53% and 45%. Relapse at 10-years was 26% and 1-year TRM was 25%. In multivariate analysis, factors associated with improved 3-year DFS were not receiving pre-HSCT chemotherapy (RR=0.30, 95% CI 0.10–0.88; p=0.03) and a shorter interval (<140 days) from time of diagnosis to transplant (RR=0.27, 95% CI 0.09–0.80; p=0.02). 3-year DFS in patients who did not receive pre-HSCT chemotherapy and those who had a shorter interval to transplant (n=16) was 80%.
Conclusion
These results suggest that children with MDS should be referred for allogeneic HSCT soon after diagnosis and that pre-HSCT chemotherapy does not appear to improve outcomes.
doi:10.1002/pbc.24390
PMCID: PMC3668778  PMID: 23152304
11.  A Worldwide Collaboration To Harmonize Guidelines For The Long-Term Follow-Up Of Childhood And Young Adult Cancer Survivors: A Report From The International Late Effects Of Childhood Cancer Guideline Harmonization Group 
Pediatric blood & cancer  2012;60(4):10.1002/pbc.24445.
Childhood and young adult cancer survivors should receive optimum care to reduce the consequences of late effects and improve quality of life. We can facilitate achieving this goal by international collaboration in guideline development. In 2010 the International Late Effects of Childhood Cancer Guideline Harmonization Group was initiated. The aim of the harmonization endeavor is to establish a common vision and integrated strategy for the surveillance of late effects in childhood and young adult cancer survivors. With the implementation of our evidence-based methods we provide a framework for the harmonization of guidelines for the long-term follow-up of childhood and young adult cancer survivors.
doi:10.1002/pbc.24445
PMCID: PMC3819170  PMID: 23281199
Guidelines; Late effects; Childhood and young adult cancer survivors; Collaboration
12.  Expression of c-FLIP in pulmonary metastases in osteosarcoma patients and human xenografts 
Pediatric blood & cancer  2012;60(4):10.1002/pbc.24412.
Objective(s)
We have previously shown that Fas expression inversely correlates with the metastatic potential of osteosarcoma (OS) to the lung. FasL is constitutively expressed in the lung microenvironment and eliminates Fas+ osteosarcoma cells leaving Fas− cells to form metastases. Absence of FasL in the lung epithelium or blocking the Fas-signaling pathway interfered with this clearance mechanism allowing Fas+ cells to remain and form lung metastases. We also demonstrated that while the majority of patient OS lung metastases were Fas−, 10-20% of the lesions contain Fas+ cells, suggesting that these cells were not sensitive to FasL-induced apoptosis. The expression of c-FLIP, an inhibitor of the Fas pathway, has been associated with tumor development, progression, and resistance to chemotherapy. We therefore evaluated the expression of c-FLIP in OS patient tumor specimens and human xenograft lung metastases.
Methods
Osteosarcoma patient tissues, which included both primary and metastatic lesions, were evaluated for the expression of c-FLIP. In addition, tumors from human osteosarcoma xenografts were examined for c-FLIP expression.
Results
c-FLIP expression was significantly higher in the lung metastases than in the primary tumors.
Conclusion(s)
c-FLIP may play an important role in the metastatic potential of osteosarcoma to the lung. Inhibition of c-FLIP may be a future therapeutic target.
doi:10.1002/pbc.24412
PMCID: PMC3883385  PMID: 23255321
Osteosarcoma; pulmonary metastasis; c-FLIP; Fas/FasL pathway
13.  Dexrazoxane Use in Pediatric Patients with Acute Lymphoblastic or Myeloid Leukemia From 1999 and 2009: Analysis of a National Cohort of Patients in the Pediatric Health Information Systems Database 
Pediatric blood & cancer  2012;60(4):616-620.
Background
Acute lymphoblastic (ALL) and myeloid leukemia (AML) account for approximately 26% of pediatric cancers. Anthracyclines are widely used to treat these leukemias, but dosing is limited by cardiotoxicity. Data support the efficacy of dexrazoxane as a cardioprotectant in children; however, dexrazoxane use in children is not universally accepted due to concerns about toxicity, impact on the antitumor effect of anthracyclines, and risk of secondary malignant neoplasms (SMN).
Procedure
We conducted a retrospective cohort study to describe patterns of dexrazoxane use in pediatric patients with ALL or AML using the Pediatric Health Information Systems (PHIS) database. Patients identified as having de novo ALL and AML at these PHIS hospitals were included.
Results
Of 8733 patients with ALL and 2556 with AML, 207 (2.4%) and 52 (2.0%) received dexrazoxane, respectively. Dexrazoxane use was greater in older children with ALL and AML and in black patients and males with ALL. Dexrazoxane use varied across time and by region in ALL, but not in AML. Prescribing practices differed across institutions and most patients received the first dose early or late after the start of leukemia treatment.
Conclusions
Dexrazoxane administration is limited in patients with ALL and AML and prescribing practices vary across the country. Further work is necessary to understand how dexrazoxane is used in patients at highest risk of developing cardiotoxicity and to define its true effect on the development of SMNs.
doi:10.1002/pbc.24270
PMCID: PMC3918414  PMID: 22948886
acute lymphoblastic leukemia; acute myelogenous leukemia; cardiotoxicity; dexrazoxane; pharmacoepidemiology
14.  Sustained Remission of Severe Multicentric Castleman Disease Following Multiagent Chemotherapy and Tocilizumab Maintenance 
Pediatric blood & cancer  2013;61(4):737-739.
Castleman disease is a rare lymphoproliferative disorder, which presents in a unicentric or multicentric fashion. Multicentric Castleman disease (MCD) is associated with significant systemic symptoms, in part related to the underlying role of interleukin-6 in disease pathogenesis. Treatment for MCD has not been well established and prognosis has historically been poor. We present a case of severe MCD in a pediatric patient who has shown sustained remission following multi-agent chemotherapy and targeted maintenance therapy with the interleukin-6 receptor inhibitor, tocilizumab. This represents the first case report of sustained remission of MCD in a pediatric patient following discontinuation of tocilizumab therapy.
doi:10.1002/pbc.24761
PMCID: PMC3946294  PMID: 24019247
Multicentric Castleman disease; tocilizumab; anakinra; CHOP
15.  Pediatric Oncology Providers Perceptions of Barriers and Facilitators to Early Integration of Pediatric Palliative Care 
Pediatric blood & cancer  2013;60(11):1875-1881.
Background
Pediatric patients experience significant symptoms during cancer treatment. Symptom management is frequently inadequate. We studied perceptions of pediatric oncology care providers regarding early integration of palliative care (PC) for pediatric patients to identify barriers and facilitators that might assist in understanding how care could be improved.
Procedures
Pediatric oncology providers were recruited to participate in four focus groups. A proposal for early integration of a pediatric palliative care team (PPCT) was presented and followed by a facilitated discussion. Data were analytically categorized into themes by three independent coders using constant comparative analysis and crystallization techniques. A consensus approach was used to indentify final themes.
Results
Barriers to the proposed care model of early integration of a PPCT included provider role, conflicting philosophy, patient readiness and emotional influence and were more prevalent in the physician participants compared to nurse practitioner, nursing, and social work participants. Facilitators included patient eligibility, improved patient care, education, and evidence-based medicine. Though all participants were invested in providing optimal patient care, physician participants believed the current standard of care model is meeting the needs of patients and family, while the nurse practitioner, nursing, and social work participants working on the same healthcare team believed the proposed care model would improve the overall care of children diagnosed with cancer.
Conclusions
Differing perceptions among healthcare providers regarding the care of children with cancer suggest that team functioning could be improved. Avenues for pilot testing early integration of PC could provide useful information for a next study.
doi:10.1002/pbc.24673
PMCID: PMC3966071  PMID: 23840035
Palliative care; Pediatric; Oncology; Perceptions; Barriers
16.  Aberrant Activation, Nuclear Localization, and Phosphorylation of Yes-Associated Protein-1 in the Embryonic Kidney and Wilms Tumor 
Pediatric blood & cancer  2013;61(2):198-205.
Background
The Yes-associated-protein-1 (YAP1) is a novel, direct regulator of stem cell genes both in development and cancer. FAT4 is an upstream regulator that induces YAP1 cytosolic sequestering by phosphorylation (p-Ser 127) and therefore inhibits YAP1-dependent cellular proliferation. We hypothesized that loss of FAT4 signaling would result in expansion of the nephron progenitor population in kidney development and that YAP1 subcellular localization would be dysregulated in Wilms tumor (WT), an embryonal malignancy that retains gene expression profiles and histologic features reminiscent of the embryonic kidney.
Methods
Fetal kidneys from Fat4−/− mice were harvested at e18.5 and markers of nephron progenitors were investigated using immunohistochemical analysis. To examine YAP1 subcellular localization in WT, a primary WT cell line (VUWT30) was analyzed by immunofluorescence. Forty WT specimens evenly distributed between favorable and unfavorable histology (n = 20 each), and treatment failure or success (n = 20 each) was analyzed for total and phosphorylated YAP1 using immunohistochemistry and Western blot.
Results
Fat4−/− mouse fetal kidneys exhibit nuclear YAP1 with increased proliferation and expansion of nephron progenitor cells. In contrast to kidney development, subcellular localization of YAP1 is dysregulated in WT, with a preponderance of nuclear p-YAP1. By Western blot, median p-YAP1 quantity was 5.2-fold greater in unfavorable histology WT (P = 0.05).
Conclusions
Fetal kidneys in Fat4−/− mice exhibit a phenotype reminiscent of nephrogenic rests, a WT precursor lesion. In WT, YAP1 subcellular localization is dysregulated and p-YAP1 accumulation is a novel biomarker of unfavorable histology.
doi:10.1002/pbc.24788
PMCID: PMC3955491  PMID: 24115727
anaplasia; biomarker; nephrogenic rests; Wilms tumor; YAP1
17.  Assembly of a Cohort of Children Treated for Acute Myeloid Leukemia at Free-Standing Children’s Hospitals in the United States Using an Administrative Database 
Pediatric blood & cancer  2012;60(3):508-511.
Pediatric Health Information System data were used to establish a multi-center cohort of 1,686 children treated for newly diagnosed acute myeloid leukemia (AML). The cohort assembly process, which included myeloid leukemia ICD-9 discharge diagnosis codes and manual review of induction chemotherapy, was validated by chart review at a single institution. The use of ICD-9 codes alone resulted in a poor positive predictive value (PPV; 31%). Inclusion of the results from the chemotherapy review improved the PPV to 100% without compromising sensitivity (95.7%). This cohort provides a reliable source for future comparative effectiveness and clinical epidemiology studies in pediatric AML.
doi:10.1002/pbc.24402
PMCID: PMC3684426  PMID: 23192853
cohort validation; health administrative data; pediatric acute myeloid leukemia
18.  Peripheral Neuroblastic Tumors with Genotype-Phenotype Discordance: A Report from the Children’s Oncology Groupand the International Neuroblastoma Pathology Committee 
Pediatric blood & cancer  2012;60(3):363-370.
Background
Of 4,706 peripheral neuroblastic tumors (pNTs) registered on the Children’s Cancer Group and Children’s Oncology Group Neuroblastoma Study between 1989 and 2010, 51 cases (1.1%) had genotype-phenotype discordance characterized by MYCN amplification (indicating poor prognosis) and Favorable Histology (indicating better prognosis).
Procedure
To distinguish prognostic subgroups in the genotype-phenotype discordant pNTs, two subgroups, “conventional” and “bull’s eye”, were identified based on the nuclear morphology. The “conventional” tumors (35 cases) included: Neuroblastoma, Poorly differentiated subtype (NB-PD, 26 cases) with “salt-and-pepper” nuclei; Neuroblastoma, Differentiating subtype (4 cases); Ganglioneuroblastoma, Intermixed (3 cases); and Ganglioneuroma, Maturing subtype (2 cases). The “bull’s eye” tumors included NB-PD with prominent nucleoli (16 cases). Clinicopathologic characteristics of these two subgroups were analyzed. N-myc protein expression was tested immunohistochemically on available tumors.
Results
No significant difference was found between these two subgroups in the distribution of prognostic factors such as age at diagnosis, clinical stage, histopathology category/subtype, mitosis-karyorrhexis index, ploidy, 1p LOH, and unbalanced 11qLOH. However, prognosis of the patients with “conventional” tumors (5-year EFS 85.7±12.2%; OS 89.3±10.3%) was significantly better than those with “bull’s eye” tumors (EFS 31.3±13.0%; OS 42.9±16.2%) (P=0.0010 and 0.0008, respectively). Immunohistochemically all (11/11) tested “conventional” tumors were negative, and 10/11 tested “bull’s eye” tumors were positive for N-myc protein expression.
Conclusions
Based on the presence or absence of prominent nucleoli (the putative site of RNA synthesis/accumulation leading to N-myc protein expression), two prognostic subgroups, “conventional” with a better prognosis and “bull’s eye” with a poor prognosis, were distinguished among the genotype-phenotype discordant pNTs.
doi:10.1002/pbc.24238
PMCID: PMC3397468  PMID: 22744966
neuroblastoma; International Neuroblastoma Pathology Classification; MYCN; genotype-phenotype correlation; prognosis; immunohistochemistry
19.  Psychoactive Medication Use and Neurocognitive Function in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2012;60(3):486-493.
Background
Adult survivors of childhood cancer are at risk for long-term morbidities, which may be managed pharmacologically. Psychoactive medication treatment has been associated with adverse effects on specific neurocognitive processes in non-cancer populations, yet these associations have not been examined in adult survivors of childhood cancer.
Procedure
Outcomes were evaluated in 7,080 adult survivors from the Childhood Cancer Survivor Study using a validated self-report Neurocognitive Questionnaire. Multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for neurocognitive impairment using demographic and treatment factors and survivors’ report of prescription medication use.
Results
Controlling for cranial radiation, pain, psychological distress, and stroke/seizure, use of antidepressant medications was associated with impaired task efficiency (OR=1.80, 95% CI=1.47–2.21), organization (OR=1.83, 95% CI=1.48–2.25), memory (OR=1.53, 95% CI=1.27–1.84) and emotional regulation (OR=2.06, 95% CI=1.70–2.51). Neuroleptics and stimulants were associated with impaired task efficiency (OR=2.46, 95% CI=1.29–4.69; OR=2.82, 95% CI=1.61–4.93, respectively) and memory (OR=2.08, 95% CI=1.13–3.82; OR=2.69, 95% CI=1.59–4.54, respectively). Anticonvulsants were associated with impaired task efficiency, memory and emotional regulation, although survivors who use these medications may be at risk for neurocognitive impairment on the basis of seizure disorder and/or underlying tumor location (CNS).
Conclusions
These findings suggest that specific psychoactive medications and/or mental health conditions may be associated with neurocognitive function in adult survivors of childhood cancer. The extent to which these associations are causal or indicative of underlying neurological impairment for which the medications are prescribed remains to be ascertained.
doi:10.1002/pbc.24255
PMCID: PMC3494805  PMID: 22848025
psychoactive medication; neurocognition; survivorship
20.  A Phase I Trial of Vorinostat and Bortezomib in Children with Refractory or Recurrent Solid Tumors: A Children’s Oncology Group Phase I Consortium Study (ADVL0916) 
Pediatric blood & cancer  2012;60(3):390-395.
Background
A pediatric phase I trial was performed to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors.
Procedure
Oral vorinostat was administered on days 1–5 and 8–12 of a 21 day cycle (starting dose 180 mg/m2/day with dose escalations to 230 and 300 mg/m2/day). Bortezomib (1.3 mg/m2 i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlative biology studies were performed during cycle 1.
Results
Twenty-three eligible patients [17 male, median age 12 years (range, 1–20)] were enrolled of whom 17 were fully evaluable for toxicity. Cycle 1 DLTs that occurred in 2/6 patients at dose level 3 (vorinostat 300 mg/m2/day) were grade 2 sensory neuropathy that progressed to grade 4 (n=1) and grade 3 nausea and anorexia (n=1). No objective responses were observed. There was wide interpatient variability in vorinostat PK parameters. Bortezomib disposition was best described by a three-compartment model that demonstrated rapid distribution followed by prolonged elimination. We did not observe a decrease in NF-κB activity or Grp78 induction after bortezomib treatment in PBMCs from solid tumor patients.
Conclusion
The recommended phase 2 dose and schedule is vorinostat (230 mg/m2/day PO on days 1–5 and 8–12) in combination with bortezomib (1.3 mg/m2/day i.v. on days 1,4, 8, and 11 of a 21 day cycle) in children with recurrent or refractory solid tumors.
doi:10.1002/pbc.24271
PMCID: PMC3511610  PMID: 22887890
vorinostat; bortezomib; phase I trial; pediatric cancer; solid tumors; Children’s Oncology Group
21.  Blunted Response to a Growth Hormone Stimulation Test is Associated with Unfavorable Cardiovascular Risk Factor Profile in Childhood Cancer Survivors 
Pediatric blood & cancer  2012;60(3):467-473.
Background
Childhood cancer survivors (CCS) are at risk for growth hormone (GH) deficiency. CCS are also at increased risk for early mortality from cardiovascular (CV) disease, but the association between GH levels and CV risk remains poorly understood. The goal of this study was to examine the cross-sectional association between stimulated GH levels and CV risk factors in CCS younger than 18 years.
Procedure
276 CCS (147 males, 14.4±2.6 years) ≥5 years after cancer diagnosis, and 208 sibling controls (112 males, 13.6±2.4 years) participated in this cross-sectional study, which included anthropometry, body composition, and metabolic studies. Blunted response (BR) was defined as peak GH level <7 μg/L after clonidine and arginine. Insulin sensitivity (Mlbm) was measured by euglycemic hyperinsulinemic clamp. Statistical analyses used linear and logistic regression accounting for sibling clustering, adjusted for age, sex, Tanner stage, and adiposity.
Results
34 (12%) CCS showed BR to GH stimulation. BR CCS were shorter and had a lower IGF-1 than controls; only 6 of 34 received cranial radiation therapy. CCS with normal stimulated GH response were similar to controls for CV risk factors. Conversely, BR CCS had greater adiposity, higher lipids, and lower Mlbm than controls. Differences in lipids and Mlbm between BR CCS and controls remained significant after adjustment for BMI or visceral fat.
Conclusions
Blunted response to GH stimulation is prevalent in CCS youth and is associated with an unfavorable CV risk factor profile. Further studies are needed to establish the mechanisms of these associations.
doi:10.1002/pbc.24308
PMCID: PMC3529966  PMID: 23002034
cardiovascular risk; growth hormone deficiency; cancer survivors; chemotherapy; insulin resistance; children
22.  Melanoma as a Subsequent Neoplasm in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2012;60(3):461-466.
Background
Childhood cancer survivors have a six fold increased risk of developing subsequent neoplasms when compared to the general population. We sought to describe the occurrence of melanoma as a subsequent neoplasm among adult survivors of childhood cancer.
Patients and Methods
Among 14,358 5-year survivors of childhood cancer diagnosed between 1970–86, we calculated the cumulative incidence, standardized incidence ratio (SIR), and absolute excess risk (AER) of subsequent melanoma. Potential risk factors were assessed using a cause-specific hazards model.
Results
57 melanomas (46 invasive, 2 ocular and 9 in situ) occurred in 51 survivors. The median time to the development of melanoma was 21.0 years (range 5.6–35.4 years) and the median age at melanoma was 32.3 years (range 10.9 – 49.0 years). Initial cancer diagnoses included soft tissue and bone sarcoma (n=15), leukemia (13), lymphoma (14), central nervous system malignancy (5), Wilms’ tumor (3), and neuroblastoma (1). The cumulative incidence of first subsequent melanoma at 35 years from initial cancer diagnosis was 0.55% (95% CI 0.37–0.73). The SIR of subsequent invasive malignant melanoma of the skin was 2.42 (95% CI 1.77 – 3.23), and the AER was 0.10 (95% CI 0.05 – 0.15) per 1,000 person years. No statistically significant associations were found between melanoma risk and family history of cancer, demographic, or treatment-related factors.
Conclusion
Survivors of childhood cancer have an approximate 2.5-fold increased risk of melanoma. Early screening and prevention strategies are warranted.
doi:10.1002/pbc.24266
PMCID: PMC3538914  PMID: 22887858
23.  Oxidative Stress and Executive Function in Children Receiving Chemotherapy for Acute Lymphoblastic Leukemia 
Pediatric blood & cancer  2009;53(4):551-556.
Background
Neurocognitive sequelae following treatment for pediatric acute lymphoblastic leukemia (ALL) has been reported in a significant proportion of survivors, including those treated only with chemotherapy. Early identification of children “at risk” for neurocognitive problems is not yet reliable. Biomarkers of oxidative stress (e.g., oxidated phosphatidylcholine) in cerebral spinal fluid (CSF) have been correlated with intensity of methotrexate (MTX) treatment, suggesting an association with acute central nervous system toxicity.
Procedure
This study examined the association between oxidized CSF phospholipids and executive functions throughout chemotherapy. Measures of oxidative stress and executive functions were examined in 88 children newly diagnosed with ALL. The children were followed over three years with neurocognitive testing and parent ratings of executive functions.
Results
Results demonstrated an association between increased oxidative stress following induction and consolidation and decreased executive function two years later. Younger age at diagnosis was associated with both an increase in oxidative stress and in executive dysfunction; younger age was associated with poorer ability to organize materials in one's environment (r(48) = 0.28, p < 0.05) and with greater oxidated phosphatidylcholine in CSF at the end of chemotherapy ( r(48) = −0.27, p < 0.05). As such, younger age appears to be the most prominent moderator of neurocognitive decline.
Conclusions
These results link functional changes to CSF biomarkers and underscore the importance of monitoring cognitive development in young children treated for ALL. Children with less advanced central nervous system development may be particularly vulnerable to the effects of chemotherapy.
doi:10.1002/pbc.22128
PMCID: PMC3928629  PMID: 19499584
oxidative stress; neurocognitive; leukemia
24.  Induction Mortality, ATRA Administration, and Resource Utilization in a Nationally Representative Cohort of Children With Acute Promyelocytic Leukemia in the United States From 1999 to 2009 
Pediatric blood & cancer  2013;61(1):68-73.
Background
Limited data exist on induction mortality of pediatric patients with acute promyelocytic leukemia in the United States, usage of all-trans retinoic acid (ATRA) during acute promyelocytic leukemia induction, and the resources needed to deliver induction therapy.
Procedure
Using the Pediatric Health Information System database we established a retrospective cohort of patients treated for newly diagnosed acute promyelocytic leukemia with ATRA between January 1999 and September 2009 in 32 of 43 PHIS contributing free-standing pediatric hospitals in the United States. Standard statistical methods were used to determine inhospital induction mortality, ATRA administration, and resource utilization during a 60-day observation period.
Results
A total of 163 children were identified who met eligibility criteria for cohort inclusion; 52% were female and 76% were white with an average age of 12.7 years. A total of 12 patients (7.4%) died, with 7 (58.3%) dying within the first 7 days of first admission. The mean time to first ATRA exposure increased with decreasing age (P=0.0016). Resource utilization for management of retinoic acid syndrome was higher than anticipated based on prior studies and differed significantly from patients with non-M3 acute myeloid leukemia.
Conclusions
The induction mortality for pediatric acute promyelocytic leukemia remains substantial with wide variation in ATRA administration and high rates of resource utilization.
doi:10.1002/pbc.24585
PMCID: PMC3927454  PMID: 23868668
APL; ATRA; induction mortality; resource utilization; retinoic acid syndrome
25.  Identification of TP53 as an Acute Lymphocytic Leukemia Susceptibility Gene Through Exome Sequencing 
Pediatric blood & cancer  2012;60(6):E1-E3.
Although acute lymphocytic leukemia (ALL) is the most common childhood cancer, genetic predisposition to ALL remains poorly understood. Whole-exome sequencing was performed in an extended kindred in which five individuals had been diagnosed with leukemia. Analysis revealed a nonsense variant of TP53 which has been previously reported in families with sarcomas and other typical Li Fraumeni syndrome-associated cancers but never in a familial leukemia kindred. This unexpected finding enabled identification of an appropriate sibling bone marrow donor and illustrates that exome sequencing will reveal atypical clinical presentations of even well-studied genes.
doi:10.1002/pbc.24417
PMCID: PMC3926299  PMID: 23255406
exome sequencing; acute lymphocytic leukemia; genetic predisposition to disease; genetic testing

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