There is warranted interest in assessing the association between residential radon exposure and the risk of childhood cancer. We sought to evaluate the association between residential radon exposure and the incidence of childhood lymphoma in Texas. The Texas Cancer Registry (n = 2147) provided case information for the period 1995–2011. Denominator data were obtained from the United States Census. Regional arithmetic mean radon concentrations were obtained from the Texas Indoor Radon Survey and linked to residence at diagnosis. Exposure was assessed categorically: ≤25th percentile (reference), >25th to ≤50th percentile, >50th to ≤75th percentile, and >75th percentile. Negative binomial regression generated adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI). We evaluated lymphoma overall and by subtype: Hodgkin (HL; n = 1248), Non-Hodgkin excluding Burkitt (non-BL NHL; n = 658), Burkitt (BL; n = 241), and Diffuse Large B-cell (DLBCL; n = 315). There was no evidence that residential radon exposure was positively associated with lymphoma overall, HL, or BL. Areas with radon concentrations >75th percentile had a marginal increase in DLBCL incidence (aIRR = 1.73, 95% CI: 1.03–2.91). In one of the largest studies of residential radon exposure and the incidence of childhood lymphoma, we found little evidence to suggest a positive or negative association; an observation consistent with previous studies.

Aim Medulloblastoma is the most frequent malignant pediatric brain tumor. While survival rates have improved due to multimodal treatment including cisplatin-based chemotherapy, there are few prognostic factors for adverse treatment outcomes. Notably, genes involved in the nucleotide excision repair pathway, including ERCC2, have been implicated in cisplatin sensitivity in other cancers. Therefore, this study evaluated the role of ERCC2 DNA methylation profiles on pediatric medulloblastoma survival. Methods The study population included 71 medulloblastoma patients (age <18 years at diagnosis) and recruited from Texas Children’s Cancer Center between 2004 and 2009. DNA methylation profiles were generated from peripheral blood samples using the Illumina Infinium Human Methylation 450 Beadchip. Sixteen ERCC2-associated CpG sites were evaluated in this analysis. Multivariable regression models were used to determine the adjusted association between DNA methylation and survival. Cox regression and Kaplan-Meier curves were used to compare 5-year overall survival between hyper- and hypo-methylation at each CpG site. Results In total, 12.7% (n=9) of the patient population died within five years of diagnosis. In our population, methylation of the cg02257300 probe (Hazard Ratio = 9.33; 95% Confidence Interval: 1.17–74.64) was associated with death (log-rank p=0.01). This association remained suggestive after correcting for multiple comparisons (FDR p<0.2). No other ERCC2-associated CpG site was associated with survival in this population of pediatric medulloblastoma patients. Conclusion These findings provide the first evidence that DNA methylation within the promoter region of the ERCC2 gene may be associated with survival in pediatric medulloblastoma. If confirmed in future studies, this information may lead to improved risk stratification or promote the development of novel, targeted therapeutics.

Objectives: To establish the incidence, risk factors and correlation with survival of thrombocytopenia and thrombocytosis (T/T) among children with HIV infection (CWH).Design: A retrospective nested case control study of patients 0-18 years in five Baylor International Pediatric AIDS Initiative (BIPAI) centers in sub-Sahara Africa, 2004Africa, -2014 Methods: Clinical and laboratory variables including complete blood counts (CBC) were extracted from the BIPAI electronic medical record system. Incident cases of T/T were identified and frequency-matched on follow-up time with controls with normal platelets. We calculated the prevalence and incidence density of T/T and used conditional logistic regression to evaluate their association with selected clinical variables. We constructed Kaplan-Meier curves and a Cox proportional hazards model to evaluate the impact of T/T on survival.Results: Two thousand, one hundred and nine children were sampled. The incidence density of thrombocytopenia was 1 per 57.9 (95% confidence interval [CI] 50.3-66.8) CWHyears. Thrombocytopenia was higher in children with WHO Stage III/IV, lower in children on zidovudine, and had no association with use of lamivudine or nevirapine, CD4 þ suppression, age, and nutrition status. Thrombocytopenia was independently associated with 2.2-fold higher mortality (95% CI 1.62-3.08). The incidence density of thrombocytosis was 1 per 11.4 (95% CI 10.7-12.1) CWH-years. Thrombocytosis was associated with higher CD4 þ cell count, younger age, and use of lamivudine or nevirapine, and did not impact survival.Conclusions: Platelet count is a clinically valuable biomarker of HIV clinical progression and mortality. Laboratory studies are necessary to elucidate the mechanisms of T/T.

Introduction: Langerhans Cell Histiocytosis (LCH) is an inflammatory myeloid neoplastic disorder. Patients with recurrent or refractory LCH are at increased risk of mortality and long-term morbidity. The standard of care for high-risk LCH patients who are refractory to vinblastine/prednisone or who relapse is very high dose While mostly cytarabine/cladribine. While effective, this strategy also has very high treatment-related mortality. Clofarabine is a nucleoside analog with efficacy in other myeloid malignancies. Case reports have suggest that is has activity in LCH and other histiocytic disorders at moderate doses. The purpose of this study was to report the efficacy and toxicity profile of a restrospective cohort of patients with histiocytic disorders treated with clofarabine. Methods: Medical records were retrospectively reviewed for 26 pediatric patients with histiocytic disorders who were treated with clofarabine. Twenty-one of these patients had LCH and had failed at least one prior systemic therapy, while the remaining 5 patients had other histiocytic disorders (JXG, Rosai-Dorfman disease or mixed histiocytic disease). Patients were treated for a minimum of 6 months of with clofarabine (25 mg/m2/day x 5 days every 28 days), were reassessed for response at the end of therapy and monitored for relapse or progression post-treatment. Results: All patients in this series started treatment under the age of 18 years old (median=1.5 years; range: 0.3-16.3). Patients with LCH had received a median of 3 prior treatments (range:1-5). A majority of the patients (n = 17, 65%) were received all clofarabine infusions in an outpatient clinic. The most common adverse event was fever requiring hospital admission (n = 18; 69%), followed by Grade 3 neutropenia (n = 12; 46%), and intractable nausea/vomiting (n = 7; 27%). Additional adverse events included Grade 3 anemia, Grade 2 dehydration, Grade 3 cytopenias, and Grade 3 infection. Overall survival was 100%. LCH patients who completd 6-months of clofarabine had an 85% overall response (33% complete response, 52% partial response); 10% progressed on therapy and 5% had stable disease. Relapse occurred in 5 (28%) patients with LCH after completion of treatment (median time to relapse=22 months; range: 1-42). The odds of relapse was approximately 4-times greater in LCH patients with CNS involvement (n=16) compared to those without (n=4), and also in those with high risk disease (n=5) relative to standard risk (n=10). One of the patients who experienced disease recurrence received an additional 12 cycles of clofarabine and is currently doing well with no active disease. Conclusions: Clofarabine may be an effective and relatively safe salvage therapy for LCH and other histiocytic disorders. Future prospective trials for patients with refractory histiocytic disorders will directly compare efficacy and toxicity relative to other current salvage strategies with cytotoxic nucleoside analogs or targeted inhibitors. Disclosures No relevant conflicts of interest to declare.

Introduction: Langerhans cell histiocytosis (LCH) is a disease characterized by inflammatory lesions including pathologic CD207+ dendritic cells. Clinically, LCH is highly variable ranging from single lesions to highly aggressive, disseminated disease involving multiple organs and requiring intensive chemotherapy. Recent data support a model of pathogenesis in which activating somatic mutations in MAPK pathway genes arise in myeloid DC precursors. However, little is known about genetic susceptibility to this condition. Therefore, we conducted a genome-wide association study to characterize the role of inherited genetic variants on disease risk. Methods: We utilized a case-parent trio approach, which is immune to the effects of population stratification bias. Specifically, this allows for the inclusion of individuals regardless of genetic ancestry. LCH case-parent trios (n=134) were recruited from Texas Children's Cancer Center. Genotyping was performed using the Illumina Omni-5 Quad BeadChip. Genetic ancestry was determined using the bioinformatics algorithm STRUCTURE. To inform this algorithm, a set of 12,898 autosomal ancestry informative markers specifically identified to infer population substructure was extracted from the study trios. Estimated genomic ancestral proportions were then used to classify each study participant as either of European ancestry, Amerindian ancestry, or of African ancestry. For the association analysis, we focused on the role of common variants (i.e., minor allele frequency ≥5%). The association analysis was conducted utilizing the PREMIM-EMIM algorithm, an established, multinomial log-likelihood approach for assessing case-parent trios GWAS data. This method allows for the inclusion of "incomplete" trios (e.g., mother-case duos). We applied a genome-wide statistical significance cutoff of p<1.0x10-5. Results: In this GWAS, LCH cases were predominantly male (54%), and based on the genetic ancestry analysis, 60% were of European ancestry, 36% Amerindian ancestry, and 4% African ancestry. Among the 343 individuals included in the analysis, 1,672,105 SNPs autosomal SNPs were assessed and an overview of the results is displayed using a Manhattan plot. We identified five potential inherited genomic regions associated with LCH susceptibility. The strongest associations between inherited SNPs and childhood LCH were seen in SMAD6 on chromosome 15 (p-value = 2.38x10-7) and in ECE1 on chromosome 1 (p-value = 2.15x10-6). Conclusions: In this genome-wide assessment of the role of inherited genetic variation on the risk of LCH, we identified SNPs with significant effects in genes implicated in diverse pathways including embryogenesis and cellular division. Among the proteins encoded by the regions identified, SMAD6and ECE1 have both been reported to impact ERK activation, a critical feature of LCH pathogenesis. These findings support potential for inherited genetic variants to influence risk of developing LCH. Disclosures Allen: NovImmune: Consultancy, Other: unpaid; Roche: Consultancy, Other: unpaid.