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Introduction Obesity is associated with increased morbidity and mortality in children diagnosed with high-risk acute lymphoblastic leukemia (HR-ALL). The mechanism of this adverse influence is thought to be due to adipose tissue and adipokines affecting immune function and/or decreasing chemotherapy efficacy. Adiposity, and not body weight, is therefore the central feature for exploring the influence of obesity on outcome in HR-ALL. To date, multiple international consortia have investigated this association using the surrogate measure of Body Mass Index (BMI). BMI estimates body composition based on height and weight and is therefore not able to distinguish between fat mass, bone density, and lean muscle. While BMI is generally a good indicator of overall adiposity, changes in weight that may occur over the course of therapy reflect not only a change in fat mass, but also changes in other components of body composition. We therefore hypothesized that BMI may not be a sensitive measure for assessing change in adiposity during therapy. Methods Body composition was assessed serially by BMI and the gold-standard Dual-energy X-ray Absorptiometry (DXA) as an ancillary aim in children with newly diagnosed HR-ALL enrolled on a prospective clinical trial investigating bone health. Children were treated as per Children’s Oncology Group HR-ALL regimens (CCG1961, AALL0232, AALL1131). Body composition was compared at three time-points (TP): within 24 hours of diagnosis (TP1), 28 days later (TP2, end of induction), and at the end of delayed intensification (TP3, mean interval of 8.2 months in the cohort). Age and tanner stage at diagnosis, gender, and ethnicity were collected. DXA was used to analyze body composition as defined by total mass of “body minus head” and separated into respective percentages of lean muscle, fat mass, and bone mineral content. BMI was converted to a percentage per Center for Disease Control and Prevention age- and gender- population norms. BMI percentage was compared to body fat percentage (BF%) overall and individually at each TP. Changes in body composition across TPs were evaluated by DXA. IRB approval was obtained and informed consent documented for all subjects. Results Of 51 subjects enrolled in the trial, a sub-cohort of 34 (66.6%) had sufficient DXA data for analysis. Of these, 85% (29/34) had DXA and BMI data at all 3 TPs, while 5/34 were too ill at diagnosis to complete the imaging. There were no significant differences in age, gender, and tanner stage between those included in the DXA sub-cohort and excluded; the cohort with DXA data consisted of a significantly higher prevalence of self-identified Hispanic subjects (31/34, 91% vs 11/17 65%). BF% by DXA was significantly correlated with BMI when observations from all TPs were combined (n=96, Spearman rho 0.6, p=0.002) and at each TP (TP1 rho=0.6, p=0.002; TP2 rho =0.7, p

BACKGROUND: The adverse effects of radiation therapy on endocrine function among pediatric brain tumor patients have been well-documented. Brief (less than 5 months) intensive induction chemotherapy followed by marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and avoidance of CNS irradiation has demonstrated efficacy in the treatment of very young children (less than 6 years of age) with malignant CNS tumors. This study assessed the long-term growth and endocrine effects of young children following chemotherapy-only treatment regimens. METHODS: A retrospective chart review was performed on 99 patients less than 6 years of age with newly-diagnosed malignant brain tumors between May 1991 and October 2010 treated with irradiation-avoiding strategies at CHLA. Thirty patients survived relapse-free post-AuHCR without cranial irradiation for a mean of 8.1 years (range 3.0–22.25 years); one patient expired of a TP53-related adrenocortical carcinoma. The patient cohort consisted of 18 males and 12 females with a mean age at AuHCR of 2.5 years (range: 0.8 to 5.1 years). Tumor pathologies included 20 medulloblastomas, 6 choroid plexus carcinomas, 3 CNS PNET and 1 anaplastic ependymoma. RESULTS: All patients had documented normal age-related free T4, TSH, IGFBP3, prolactin, testosterone and estradiol levels. IGF1 age-related levels were abnormal in one child. FSH and LH levels among females, and cortisol levels, were normal in 93%, 97% and 97%, respectively. Growth charts demonstrated age-associated growth within 2 standard deviations of the mean in 67% patients. Of 10 patients (33%) with short stature, 6 had proportional diminutions in both height and weight. CONCLUSIONS: These findings demonstrate that the use of relatively brief, intensive chemotherapy regimens including marrow-ablative chemotherapy with AuHCR, results in less endocrine and growth abnormalities than treatment schemes utilizing CNS irradiation. However, the documented adverse impact upon physical growth in a proportion of survivors needs to be evaluated further.

Background: The epidemic of childhood obesity poses substantial treatment challenges for the care of children with acute lymphoblastic leukemia (ALL). Obesity at time of diagnosis of ALL is associated with worse survival as well as treatment-related morbidity. Inability to achieve a deep initial remission following Induction as evidenced by persistent MRD in the bone marrow is associated with poor survival and has thus become the predominant modern prognostic indicator. We therefore hypothesized that obesity at time of diagnosis of ALL is associated with MRD positivity at the end-of-Induction disease evaluation. Methods: In a cohort of children 1 - 20 years old treated for B-precursor ALL (BP-ALL) at our institution from 2008 to 2013 on Children's Oncology Group (COG) treatment regimens, we examined MRD at end-of-Induction as determined by multidimensional flow cytometry. A threshold of 0.01% was used to determine MRD positive versus negative as per COG regimens. Overweight and obese categories were defined as 85-95th and ≥95th percentile for body mass index (BMI) according to the CDC population norms. Logistic regression analyses were performed controlling for age, gender, ethnicity/race, presence/absence of Down Syndrome (due to the high prevalence of obesity), National Cancer Institute (NCI) risk category, cytogenetic classification (standard, favorable, unfavorable, unknown), and CNS status at diagnosis. BMI was evaluated as both a continuous variable and also as per normal, overweight, obese categories. Results: We identified 198 patients with BP-ALL and evaluable MRD, 119 with NCI SR-ALL and 79 with NCI HR-ALL. Of these, 55 (27.8%) had positive MRD at end-of-Induction [27 SR-ALL (22.7%), 28 HR-ALL (35.4%). In the obese group, 45.2% (19/42) were MRD+, compared to only 22.8% (29/127) of normal weight and 24.1% (7/29) of overweight patients. After controlling for above covariates, obese patients had a statistically significantly increased risk for MRD positivity at end-of-Induction [Odds Ratio (OR) 2.64, 95 percent Confidence Interval (95%CI) 1.13-6.19, p=0.025]. Similarly, each percentile increase in BMI significantly corresponded to an increased risk for MRD positivity (OR 1.08, 95%CI 1.00-1.17, p=0.046). Conclusion: Obese children at diagnosis of BP-ALL are at significantly increased risk for persistent MRD in the bone marrow at end-of-Induction. With the established strong adverse association of persistent MRD with poorer survival, this implies that obesity adversely influences survival as early as this initial phase of treatment. Our results support the need for further research into mechanisms underlying this phenomenon and potential up-front strategies to improve efficiency of remission induction in this population. Citation Format: Etan Orgel, Jonathan Tucci, Wassem Alhushki, David R. Freyer, Hisham Abdel-Azim, Steven D. Mittelman. Childhood obesity is associated with persistent minimal residual disease (MRD) following induction therapy for pediatric acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2185. doi:10.1158/1538-7445.AM2014-2185

More than 3000 adolescents in the United States die annually from the effects of chronic illness. Providing appropriate end-of-life care for these patients is particularly challenging because of several developmental, ethical, and legal considerations relevant to this age group. Developmental issues relate to the ways in which life-threatening illness alters the normal physical and psychological changes associated with adolescence, including attainment of independence, social skills, peer acceptance, and a healthy self-image. Ethical and legal issues arise from the fact that many terminally ill adolescents

True extrarenal Wilms' tumor is a rare malignant neoplasm most frequently presenting in the retroperitoneal or inguinal regions. We report an unusual subcutaneous lumbosacral (LS) region extrarenal Wilms' tumor without associated teratomatous tumor elements or associated neural tube defect in a 2 1/2-year-old girl. Pathologic review revealed features of true extrarenal Wilms' tumor, and the patient remains in complete remission following surgery and combination chemotherapy. This report illustrates the importance of early surgical intervention and pathologic examination of similar soft tissue masses in children.

10058 Background: Lack of participation in clinical trials has been proposed as a key explanation for the survival deficit of AYAO patients. We compared the proportion of newly diagnosed AYAO patie...

10017 Background: Cisplatin frequently causes irreversible hearing loss in children treated for cancer. STS is a thiol reducing agent shown in preclinical studies to protect hearing but not the tum...

10024 Background: DRZ use as a cardioprotectant in pediatric oncology has been limited by concerns regarding its efficacy and possible induction of second cancers, both of which may compromise over...

Metanephric adenoma is a recently characterized renal tumor that generally occurs in adults and has an excellent prognosis. To date, only one atypical metanephric adenoma has been reported to metastasize. The authors report a case of typical metanephric adenoma that arose in the left kidney of a 7-year-old girl that was associated with metastases to the para-aortic, hilar, and aortic bifurcation lymph nodes. The tumor was 9.5 cm and was composed entirely of epithelial elements arranged in tubules, short papillae, and glomeruloid bodies with scattered psammoma bodies. No atypia and only rare mitotic activity were present. Immunohistochemically, the tumor was negative for epithelial membrane antigen, negative for keratin AE1, and focally positive for both keratin CAM5.2 and cytokeratin 7. Tumor cytogenetics revealed a normal diploid karyotype, and disomy of chromosomes 7 and 17 was confirmed by fluorescence in situ hybridization. The authors conclude that tumors with histologic, immunohistochemical, and genetic features characteristic of typical metanephric adenoma can present with metastatic disease.

Objective. In this successor to a preliminary retrospective study, we sought to confirm the apparent safety and efficacy of intravenous methohexital (MHX) for brief, unconscious sedation of pediatric hematology/oncology outpatients undergoing painful, invasive procedures.Methods. This prospective study was conducted in a children’s hospital-based hematology/oncology clinic. Following published monitoring guidelines for deep pediatric sedation, MHX (1.0 mg/kg) was administered immediately before each procedure, 1% xylocaine was given locally, and additional MHX was titrated to maintain minimal response to pain during the procedure. For each patient, the procedural and physiologic response data reported below were recorded from the onset of sedation through recovery. Behavioral distress responses were measured using a standardized pediatric observational tool (Procedure Behavioral Checklist).Results. Two hundred and thirty-three procedures were carried out in 76 patients ranging .1 to 19.6 years of age. The mean cumulative MHX dose/procedure was 4.6 ± 2.9 mg/kg. The mean lengths of time from initiation of sedation until completion of the invasive procedure, attainment of patient arousability, discontinuation of monitoring, and attainment of patient alertness were 8 ± 5, 19 ± 8, 19 ± 9, and 22 ± 9 minutes, respectively. Relative to presedation values, mean arterial pressure (MAP), heart rate, and respiratory rate showed maximum mean percent changes of −16.6, +17.8, and +13.4, respectively (all clinically insignificant). Complications among procedures were transient and included hiccoughs and myoclonus (each 10%); oropharyngeal secretions (6%); and pain at the injection site, emergence phenomena, and mild stridor (each ≤3%). Of two procedures (.9%) affected by transient upper airway obstruction associated with emesis or secretions, only one briefly needed mask ventilation. No procedures required intubation or early termination. In 49 additional procedures assessed for patient distress, observed pain responses were absent to mild in 45 (92%) and moderate in 4.Conclusion. MHX appropriately administered provides sedation which is effective, safe, well tolerated, and of short duration, making MHX attractive for use in pediatric oncology outpatients and other populations with similar sedation needs. methohexital, pain, procedures, quality of life, sedation.

10020 Background: Anthracyclines are associated with left ventricular (LV) dysfunction in CCS with inevitable progression to congestive heart failure (CHF). Use of ejection fraction (EF) to identify LV dysfunction precludes intervention, because EF decline is a late event in the progression to CHF. Further, better understanding of pathogenesis at the cellular level could facilitate development of targeted interventions. Methods: Study design: Cross-sectional; Biomarkers: Echocardiographic (echo), and blood biomarkers in asymptomatic individuals exposed to anthracyclines ≥300mg/m2 (high-risk [HR]: n=100) compared with: i) CCS exposed to 2 (low-risk [LR]: n=50): and ii) matched healthy controls (Con: n=50). Pathogenesis: Metabolomic analyses (351 plasma metabolites; 64 pathways). Results: Time from dx to study was comparable for HR (12.0y) vs. LR (13.2y, p=0.8). All CCS had EF≥50%. Echo: HR had lower LV chamber thickness-dimension (T-D) ratio (Z-score: -0.62) compared with LR (-0.03) and Con (-0.02; P2, LR: 58 g/cm2, Con: 55 g/cm2, p2 SD ESWS) had reduced plasma carnitine levels (relative ratio [RR]: 0.88, p

Abstract 3574 Intensification of therapy for acute lymphoblastic leukemia (ALL) has improved long-term survival but is associated with considerable treatment-related toxicity (TRT). While obesity has been shown to affect event-free survival (EFS) and overall survival (OS) in ALL, little information exists as to the effect of extremes of weight (underweight or obese) on morbidity due to TRT. To this end, we conducted a secondary analysis of 1,902 children treated on the Children's Oncology Group study CCG-1961 to determine whether weight extremes influence development of TRT and EFS/OS in children with higher risk ALL. CCG-1961 was a randomized study for patients 1–21 years old with National Cancer Institute High-Risk ALL (HR-ALL) that evaluated marrow response at day 7 of Induction and compared regimens of differing intensity and/or duration (for Rapid Early Responders, RER) or anthracycline used in Delayed Intensification (for Slow Early Responders, SER). Weight category was determined using the United States Centers for Disease Control and Prevention Z-scores for body mass index (BMI) by age (age ≥ 2 yrs) and weight by length (age 95th percentile). At diagnosis, 107 patients (5.6%) were underweight and 264 were obese (13.9%). Multivariate linear and logistic regression analyses controlled for age, gender, race/ethnicity, payer type (as a surrogate for socioeconomic status), initial white blood cell count, presence of central nervous system disease, RER/SER status, and phase of treatment independent of regimen. All of the preceding predictors were independently significantly associated with development of grade 3/4 non-hematological toxicity in multivariate analysis (p Our results demonstrate statistically significant increases in toxicity for both extremes of weight. Weight category at start of each phase was predictive of developing grade 3/4 non-hematological toxicity during that phase (p Our data indicate that for children with HR-ALL, extremes of weight are associated with significantly increased risk for TRT that is more infectious/hematopoietic in underweight patients and more hepatic/pancreatic in obese patients. With a median follow-up of 7.1 years, EFS was lower at both weight extremes versus healthy/overweight children, but in this analysis did not reach statistical significance. These findings provide insights into the nutritional status of children and adolescents with ALL that could lead to interventions designed to mitigate the impact of weight extremes upon their tolerance of therapy, quality of life and survival. Disclosures: No relevant conflicts of interest to declare.

Abstract 1510 Historically, AYA patients (>16yrs of age) with HR-ALL have lower event free survival and overall survival compared to younger patients (1–15 yrs of age) with HR-ALL. This inferior outcome is related to both a higher relapse rate and increased toxicity of therapy. Several underlying factors have been identified that may contribute to these differences including leukemia biology, host pharmacodynamics, relative intensity of treatment protocols, adherence to therapy, and supportive care measures, although their relative importance is largely unknown. AALL0232 was a Phase 3 randomized trial for patients 1–30 years old with newly diagnosed B-precursor HR-ALL that utilized a 2 × 2 factorial design with an augmented intensity Berlin- Frankfurt-Münster (BFM) backbone. Patients were randomized to receive dexamethasone versus prednisone during Induction and high dose methotrexate versus escalating Capizzi methotrexate during Interim Maintenance I. The study accrued 3051 eligible, evaluable, non-Down Syndrome patients between January 2004 and January 2011. AYA patients comprised 20% of study enrollments (n=601) with 555 patients in the 16–21 year range and 46 patients in the 22–30 year range. Toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE version 4.0) and all grades 3 and 4 are reported. Bone toxicities including avascular necrosis are not included in this analysis. During Induction, AYA patients when compared to younger patients had lower rates of febrile neutropenia (7.0% versus 13.4%, p Post-induction, AYA patients experienced higher rates of oral mucositis secondary to methotrexate during Interim Maintenance I (18.5% versus 11.3%, p=0.0002), and higher rates of peripheral motor neuropathy during protocol therapy (11.5% versus 7.4%, p=0.0015). Despite lower rates of febrile neutropenia throughout protocol therapy (35.6% versus 48.6%, p In conclusion, AYA patients experienced higher rates of hyperbilirubinemia and hyperglycemia during Induction, oral mucositis during Interim Maintenance I, and peripheral motor neuropathy throughout protocol therapy. Importantly, AYA patients experienced a higher rate of death during remission, predominantly due to infectious etiologies. Further analyses are needed to determine reasons for the increase in treatment related mortality, including, an evaluation of the responsible organisms, identification of periods of increased vulnerability because of concomitant mucositis, neutropenia, and/or delivery of specific chemotherapeutic agents. Disclosures: No relevant conflicts of interest to declare.

9506 Background: In the CCG 2961 trial for newly diagnosed AML, adolescent and young adult patients (aged 16-21 years, AYA) had inferior survival relative to younger patients. To more broadly defin...

e20009 Background: Vitamin D regulates several metabolic and hormonal pathways, which may be important in both the biology of acute lymphoblastic leukemia (ALL) and the pathogenesis of therapy-rela...

9515 Background: Drug dosing is based on a gender-independent estimate of body surface area. In childhood acute lymphoblastic leukemia (ALL), females have a consistently better event-free survival ...

We report on a patient with ocular-ectodermal syndrome who was previously described in 1993 [Am J Med Genet (1993) 45:764-766]. This boy has now developed additional manifestations, including giant cell granulomas and non-ossifying fibromas. This adds to the list of phenotypic manifestations of this condition.

Certain spinal-cord (SC) neoplasms, principally lipomas and dermoid tumors, have been diagnosed in association with characteristic neuroskeletal malformations thought to result from neural-tube defects (NTD). To our knowledge, no such association has been recognized for primary primitive neuroectodermal tumor of the SC (PNET-SC), an SC malignancy which has been reported in only 3 children and 5 adults. We describe here the occurrence and treatment results of PNET-SC in a boy who exhibited several neuroskeletal malformations suggestive of an underlying NTD. By undertaking a comparative analysis of the literature with respect to both the histology and the clinical presentation of this child’s tumor, we document an occurrence of an uncommon malignancy, PNET-SC, and identify PNET-SC as another SC neoplasm which may be associated with NTD.

Mo1, LFA-1, and p150,95 are structurally related glycoproteins of the CD11/CD18 complex that are expressed on the membrane of human leukocytes. In the neutrophil, the surface expression of the CD11/CD18 complex is up-modulated (Mo1 greater than p150,95 much greater than LFA-1) by stimulatory factors that include calcium ionophore A23187, phorbol myristate acetate (PMA), and N-L-formyl-L-leucyl-L-phenylalanine (fMLP). Here, in an immunofluorescence analysis, we have examined CD11/CD18 glycoprotein expression by human monocytes, pulmonary alveolar macrophages (PAM, obtained by bronchoalveolar lavage), and breast milk macrophages (BMM) as compared to neutrophils before and after exposure to A23187 (1 microM), fMLP (0.1 microM), or PMA (0.1 microgram/ml) for 15 min at 37 degrees C. Unstimulated monocytes within unfractionated blood mononuclear cells kept at 4 degrees C (n = 13) expressed all three CD11/CD18 glycoproteins, and exposure to A23187 resulted in significant increases in the surface expression of Mo1 (median of 5.7-fold), LFA-1 (median of 2.1-fold), and p150,95 (median of 7.2-fold). Exposure to fMLP- or PMA-stimulated increases of lesser magnitude. CD11/CD18 expression by PAM (n = 9) was barely detectable and was unaffected by exposure to A23187. In contrast, BMM (n = 11) expressed all three CD11/CD18 glycoproteins (with considerable variability among specimens), but no increase was stimulated by A23187. These results demonstrate that monocytes, like neutrophils, have the capacity to respond to activating factors with an increase in CD11/CD18 glycoprotein expression; macrophage differentiation is accompanied by a loss (PAM) or retention (BMM) of CD11/CD18 expression that is unmodulated in response to activation.

Inasmuch as the recruitment of polymorphonuclear leukocytes (PMNs) to inflammatory foci in vivo involves adhesion-dependent events (e.g., margination, diapedesis, and directed migration), we sought to characterize the relationship between the local accumulation of PMNs in sterile peritonitis and their surface expression of the adhesion-promoting plasma membrane glycoprotein. Mol (CD11b/ CD18). In an immunofluorescence analysis of PMNs isolated from rats injected intraperitoneally with sterile 1% glycogen solution, we detected a significant enhancement of surface Mol expression by exudative peritoneal PMNs. In contrast, no significant rise in Mol expression was noted over time by circulating intravascular PMNs (isolated simultaneously). However, these intravascular PMNs had the capacity to increase their surface Mol density upon exposure to peritoneal fiuid supernatant at 37°C. These results demonstrate that PMNs at sites of inflammation in vivo do up-modulate their surface expression of the adhesion-promoting Mol glycoprotein during their recruitment from the circulating, intravascular leukocyte pool.

CD11/CD18 leukocyte glycoprotein deficiency is a rare, inherited disorder of leukocyte function, manifested by recurrent severe bacterial infections. A deficiency in the expression of a family of leukocyte membrane glycoproteins (the CD11/CD18 glycoproteins) represents the molecular basis for this disease.