Maternal occupational pesticide exposure during pregnancy and/or paternal occupational pesticide exposure around conception have been suggested to increase risk of leukemia in the offspring. With a view to providing insight in this area we pooled individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium (CLIC). Occupational data were harmonized to a compatible format. Pooled individual analyses were undertaken using unconditional logistic regression. Using exposure data from mothers of 8,236 cases, and 14,850 controls, and from fathers of 8,169 cases and 14,201 controls the odds ratio (OR) for maternal exposure during pregnancy and the risk of acute lymphoblastic leukemia (ALL) was 1.01 [95% confidence interval (CI) 0.78, 1.30] and for paternal exposure around conception 1.20 (95% 1.06, 1.38). For acute myeloid leukemia (AML), the OR for maternal exposure during pregnancy was 1.94 (CI 1.19, 3.18) and for paternal exposure around conception 0.91 (CI 0.66, 1.24.) based on data from 1,329 case and 12,141 control mothers, and 1,231 case and 11,383 control fathers. Our finding of a significantly increased risk of AML in the offspring with maternal exposure to pesticides during pregnancy is consistent with previous reports. We also found a slight increase in risk of ALL with paternal exposure around conception which appeared to be more evident in children diagnosed at the age of 5 years or more and those with T cell ALL which raises interesting questions on possible mechanisms.

BACKGROUND: The Childhood Cancer Research Network (CCRN) was established within the Children's Oncology Group (COG) in July 2008 to provide a centralized pediatric cancer research registry for investigators conducting approved etiologic and survivorship studies. The authors conducted an ecological analysis to characterize CCRN catchment at >200 COG institutions by demographic characteristics, diagnosis, and geographic location to determine whether the CCRN can serve as a population-based registry for childhood cancer.\n\nMETHODS: During 2009 to 2011, 18,580 US children newly diagnosed with cancer were registered in the CCRN. These observed cases were compared with age-specific, sex-specific, and race/ethnicity-specific expected numbers calculated from Surveillance, Epidemiology, and End Results (SEER) Program cancer incidence rates and 2010 US Census data.\n\nRESULTS: Overall, 42% of children (18,580 observed/44,267 expected) who were diagnosed with cancer at age <20 years were registered in the CCRN, including 45%, 57%, 51%, 44%, and 24% of those diagnosed at birth, ages 1 to 4 years, ages 5 to 9 years, ages 10 to 14 years, and ages 15 to 19 years, respectively. Some malignancies were better represented in the CCRN (leukemia, 59%; renal tumors, 67%) than others (retinoblastoma, 34%). There was little evidence of differences by sex or race/ethnicity, although rates in nonwhites were somewhat lower than rates in whites.\n\nCONCLUSIONS: Given the low observed-to-expected ratio, it will be important to identify challenges and barriers to registration to improve case ascertainment, especially for rarer diagnoses and older age groups; however, it is encouraging that some diagnoses in younger children are fairly representative of the population. Overall, the CCRN is providing centralized, real-time access to cases for research and could be used as a model for other national cooperative groups.

BACKGROUND: Maternal prenatal supplementation with folic acid and other vitamins has been inconsistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Little is known regarding the association with acute myeloid leukemia (AML), a rarer subtype.\n\nMETHODS: We obtained original data on prenatal use of folic acid and vitamins from 12 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980-2012), including 6,963 cases of ALL, 585 cases of AML, and 11,635 controls. Logistic regression was used to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for child's age, sex, ethnicity, parental education, and study center.\n\nRESULTS: Maternal supplements taken any time before conception or during pregnancy were associated with a reduced risk of childhood ALL; odds ratios were 0.85 (95% CI = 0.78-0.92) for vitamin use and 0.80 (0.71-0.89) for folic acid use. The reduced risk was more pronounced in children whose parents' education was below the highest category. The analyses for AML led to somewhat unstable estimates; ORs were 0.92 (0.75-1.14) and 0.68 (0.48-0.96) for prenatal vitamins and folic acid, respectively. There was no strong evidence that risks of either types of leukemia varied by period of supplementation (preconception, pregnancy, or trimester).\n\nCONCLUSIONS: Our results, based on the largest number of childhood leukemia cases to date, suggest that maternal prenatal use of vitamins and folic acid reduces the risk of both ALL and AML and that the observed association with ALL varied by parental education, a surrogate for lifestyle and sociodemographic characteristics.

BACKGROUND: Tobacco smoking by pregnant women is a major public health hazard with both short- and long-term effects on offspring. This study describes the presence and level of the nicotine metabolite cotinine in newborn dried blood spots (DBS) and compares it with the reported maternal smoking recorded on state birth registries. We hypothesize that cotinine in DBS may be a useful measure of newborn in utero tobacco exposure.METHODS: An observational, cross-sectional study of 1414 DBS obtained from California, Michigan, New York, and Washington newborn screening programs was carried out. Cotinine levels in DBS were quantified by liquid chromatography tandem mass spectrometry analysis and compared with maternal smoking as reported in vital statistics data.RESULTS: Cotinine ≥0.3 ng/g was detected in 35% of newborn DBS, including DBS of 29% of newborns whose mothers reportedly did not smoke cigarettes during pregnancy, some of whom were presumably exposed to environmental tobacco smoke. Twelve percent of the newborn DBS had cotinine levels that were ≥9.0 ng/g (equivalent to 6 ng/mL plasma, a level that indicates active smoking of the mother), although 41% of the mothers of these infants reportedly did not smoke.CONCLUSIONS: These data confirm that reported smoking during pregnancy is an imperfect measure of prenatal tobacco smoke exposure. Cotinine assessment in newborns may improve surveillance of tobacco use during pregnancy.

Beckwith-Wiedemann Syndrome (BWS) and familial adenomatous polyposis (FAP) are known to predispose to hepatoblastoma (HB). A case-control study was conducted through the Children's Oncology Group (COG) to study the association of HB with isolated congenital abnormalities. Cases (N = 383) were diagnosed between 2000 and 2008. Controls (N = 387) were recruited from state birth registries, frequency matched for sex, region, year of birth, and birth weight. Data on congenital abnormalities among subjects and covariates were obtained by maternal telephone interview. Odds ratios (OR) and 95% confidence intervals (CI) describing the association between congenital abnormalities with HB, adjusted for sex, birth weight, maternal age and maternal education, were calculated using unconditional logistic regression. There was a significant association of HB with kidney, bladder, or sex organ abnormalities (OR = 4.75; 95% CI: 1.74-13) which appeared to be specific to kidney/bladder defects (OR = 4.3; 95% CI: 1.2-15.3) but not those of sex organs (OR = 1.24; 95% CI: 0.37-4.1). Elevated but non-significant ORs were found for spina bifida or other spinal defects (OR = 2.12; 95% CI: 0.39-11.7), large or multiple birthmarks (OR = 1.33; 95% CI: 0.81-2.21). The results were validated through the Utah Population Database (UPDB), a statewide population-based registry linking birth certificates, medical records, and cancer diagnoses. In the UPDB, there were 29 cases and 290 population controls matched 10:1 on sex and birth year. Consistent with the COG findings, kidney/bladder defects were associated with hepatoblastoma. These results confirm the association of HB with kidney/bladder abnormalities. © 2014 Wiley Periodicals, Inc.

Rhabdomyosarcoma (RMS) is a highly malignant tumor of developing muscle that can occur anywhere in the body. Due to its rarity, relatively little is known about the epidemiology of RMS. Atopic disease is hypothesized to be protective against several malignancies; however, to our knowledge, there have been no assessments of atopy and childhood RMS. Therefore, we explored this association in a case-control study of 322 childhood RMS cases and 322 pair-matched controls. Cases were enrolled in a trial run by the Intergroup Rhabdomyosarcoma Study Group. Controls were matched to cases on race, sex and age. The following atopic conditions were assessed: allergies, asthma, eczema and hives; in addition, we examined other immune-related factors: birth order, day-care attendance and breastfeeding. Conditional logistic-regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for age, race, sex, household income and parental education. As the two most common histologic types of RMS are embryonal (n=215) and alveolar (n=66), we evaluated effect heterogeneity of these exposures. Allergies (OR=0.60, 95% CI: 0.41-0.87), hives (OR = 0.61, 95% CI: 0.38-0.97), day-care attendance (OR=0.48, 95% CI: 0.32-0.71) and breastfeeding for ≥ 12 months (OR=0.36, 95% CI: 0.18-0.70) were inversely associated with childhood RMS. These exposures did not display significant effect heterogeneity between histologic types (p>0.52 for all exposures). This is the first study indicating that atopic exposures may be protective against childhood RMS, suggesting additional studies are needed to evaluate the immune system's role in the development of this tumor.

Background/Purpose:Access to pediatric rheumatology (PR) care is limited. An average of 28 fellows graduate from PR training programs annually, and there are 224 board-certified pediatric rheumatologists in the United States. Eleven states have no pediatric rheumatologist and 24 states have two or fewer. Furthermore, the mean distance to a certified pediatric rheumatologist is 60 miles. The impact that limited access to PR has on general pediatricians has not been studied.Methods:A web-based survey was emailed to general pediatricians practicing in Minnesota (MN), North Dakota (ND), and South Dakota (SD). The email databases were obtained from the MN and ND state medical licensing boards and from the SD chapter of the American Academy of Pediatrics. The goal of the survey was to define barriers to access to PR care and the consequences of limited access. Basic descriptive analysis was performed and responses were summarized.Results:The overall response rate was 15.3% (93/609). Responders were younger than non-responders (mean age 48 yo versus 53 yo, p = 0.0006) and had been in practice a shorter period of time (mean 22 y versus 27 y, p = 0.0051). Forty percent (37/92) of the clinics were urban, 40% (37/92) suburban, and 20% (18/92) rural. Twenty-nine percent (27/92) of respondents' clinics were at least two hours by car from a pediatric rheumatologist, and 9% (8/92) were more than 6 hours away. Ninety-two percent (85/92) had referred a patient to PR at least once, but 89% (83/93) had experienced a situation at least once in which they considered a referral to PR but ultimately did not. Reasons for not referring varied. When asked, “In cases in which you considered a PR referral but did not refer a patient to a pediatric rheumatologist, please indicate your reasons for doing so. (Select all that apply),” many had referred to other subspecialists instead: 29% (24/83) to pediatric infectious disease, 20% (17/83) to adult rheumatology, and 12% (10/83) to pediatric orthopedics, while 34% (28/83) managed the patient themselves. Although not a pre-specified choice in the survey, 9% (3/32) of pediatricians added wait-time as the reason for not referring to PR. Thirty-five percent (32/60) had referred a pediatric patient to an adult rheumatologist, most commonly for distance (47%), while physician preference was never selected as a reason.Conclusion:Pediatricians often refer children with possible rheumatic disease to specialists other than PR due to reasons of distance and wait-time. Referral to adult rheumatologists occurs, but not based on pediatrician preference. These findings suggest that the PR workforce is inadequate to meet demand, at least in the Upper Midwest. Interventions are needed to improve access to care in PR.

Background/Purpose:Rheumatology lab tests are often of low diagnostic utility when ordered by primary care physicians, and may lead to erroneous referrals. No prior studies have investigated pediatricians' reasons for ordering these tests. We surveyed pediatricians in three states of the Upper Midwest regarding their ordering of rheumatology lab tests and reasons for referral to pediatric rheumatology (PR).Methods:A web-based survey was emailed to general pediatricians practicing in Minnesota, North Dakota, and South Dakota. The rheumatology tests queried included antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), rheumatoid factor (RF), anti-citrullinated peptide antibodies (anti-CCP), and HLA-B27. Basic descriptive analysis was performed. Subgroup analysis was performed to assess the relationship between the pediatrician's experience with PR (defined as years since completion of residency training, whether or not the training program had a PR division, time spent in a PR clinic during training and completion of continued medical education focused on PR in the last three years) and the appropriateness of lab tests and PR referrals.Results:The response rate was 15.3% (93/609). Eighty-nine percent (83/93) of the respondents had ordered ANA, for reasons including abnormal joint exam (72%), musculoskeletal (MSK) pain with a normal exam (52%), concern for juvenile idiopathic arthritis (JIA) (47%), rash (41%), concern for systemic lupus erythematosus (39%), fatigue (35%), and fever (35%). Fifty-nine percent (54/92) had ordered anti-dsDNA, and the distribution of reasons paralleled that of ANA. Seventy-three percent (67/92) had ever ordered RF, most commonly for abnormal joint exam (67%), joint pain with a normal exam (60%), concern for JIA (42%), and fever (30%). Only 8% (7/92) had ordered anti-CCP. Forty-two percent (39/92) had ordered HLA-B27, primarily for back pain (59%). Of those who had ever referred a patient to a pediatric rheumatologist, 44% (37/85) did so for a positive ANA of unclear significance, 14% (12/85) for positive RF of unclear significance, and 9% (8/85) for anti-dsDNA of unclear significance. Positive HLA-B27 and anti-CCP were less common referral reasons. Subgroup analysis did not show significant differences between experience level and appropriateness of lab tests and referrals to PR.Conclusion:Inappropriate ordering of rheumatology lab tests with subsequent referral to PR is common among pediatricians in the Upper Midwest and likely elsewhere. The correctness of lab test utilization and referral to PR did not obviously improve with increased experience in PR. New educational interventions are needed to improve general pediatricians' understanding and utilization of rheumatology lab tests and to decrease unnecessary referrals to PR.

Osteosarcoma is the most common primary bone malignancy affecting children and adolescents. Although several genetic predisposing conditions have been associated with osteosarcoma, our understanding of its pathobiology is rather limited. Here we show that, first, an imprinting defect at human 14q32-locus is highly prevalent (87%) and specifically associated with osteosarcoma patients < 30 years of age. Second, the average demethylation at differentially methylated regions (DMRs) in the 14q32-locus varied significantly compared to genome-wide demethylation. Third, the 14q32-locus was enriched in both H3K4-me3 and H3K27-me3 histone modifications that affected expression of all imprinted genes and miRNAs in this region. Fourth, imprinting defects at 14q32 - DMRs are present in triad DNA samples from affected children and their biological parents. Finally, imprinting defects at 14q32-DMRs were also observed at higher frequencies in an Rb1/Trp53 mutationinduced osteosarcoma mouse model. Further analysis of normal and tumor tissues from a Sleeping Beauty mouse model of spontaneous osteosarcoma supported the notion that these imprinting defects may be a key factor in osteosarcoma pathobiology. In conclusion, we demonstrate that imprinting defects at the 14q32 locus significantly alter gene expression, may contribute to the pathogenesis of osteosarcoma, and could be predictive of survival outcomes.

Although leukemia is the most common childhood cancer diagnosis, the subtype, acute myeloid leukemia (AML), is less common and fewer etiologic studies exist. This review summarizes the major risk factors for AML. We searched the literature using PubMed for articles on childhood AML and reviewed 180 articles. While few risk factors are definitive, we identified several with consistent evidence of a possible effect. Thorough analysis of genetic and epigenetic factors is missing from this literature and methodological issues are unresolved. Future studies should more closely examine causal mechanisms, improve exposure measurement, and include analysis using genetic and epigenetic factors.

Interactions between common germline variants in ARID5B and IKZF1 and other known childhood acute lymphoblastic leukemia (ALL) risk factors were queried using biospecimens and data from 770 ALL cases and 384 controls. Case-control comparisons revealed dose-dependent associations between ARID5B rs10821936, ARID5B rs10994982, and IKZF1 rs11978267 and childhood ALL overall, and B lineage and B lineage hyperdiploid ALL examined separately (all allelic odds ratios >1.33, Ptrend≤0.001). No heterogeneity was observed between ORs for males and females (all Pinteraction>0.48). Likewise, no significant genotype-birth weight interactions were detected (all Pinteraction>0.12) among cases. These results indicate similar ALL risk across strata of known risk factors. © 2013 Elsevier Ltd.

BACKGROUND: The mixed lineage leukemia (MLL) gene is commonly rearranged in infant leukemia (IL). Genetic determinants of susceptibility to IL are unknown. Recent genome-wide association studies for childhood acute lymphoblastic leukemia (ALL) have identified susceptibility loci at IKZF1, ARID5B, and CEBPE.\n\nPROCEDURE: We genotyped these loci in 171 infants with leukemia and 384 controls and evaluated associations overall, by subtype [ALL, acute myeloid leukemia (AML)], and by presence (+) or absence (-) of MLL rearrangements.\n\nRESULTS: Homozygosity for a variant IKZF1 allele (rs11978267) increased risk of infant AML [Odds ratio (OR) = 3.9, 95% confidence interval (CI) = 1.8-8.4]; the increased risk was similar for AML/MLL+ and MLL- cases. In contrast, risk of ALL/MLL- was increased in infants homozygous for the IKZF1 variant (OR = 5.1, 95% CI = 1.8-14.5) but the variant did not modify risk of ALL/MLL+. For ARID5B (rs10821936), homozygosity for the variant allele increased risk for the ALL/MLL- subgroup only (OR = 7.2, 95% CI = 2.5-20.6). There was little evidence of an association with the CEBP variant (rs2239633).\n\nCONCLUSION: IKZF1 is expressed in early hematopoiesis, including precursor myeloid cells. Our data provide the first evidence that IKZF1 modifies susceptibility to infant AML, irrespective of MLL rearrangements, and could provide important new etiologic insights into this rare and heterogeneous hematopoietic malignancy.

Background: Hepatoblastoma is a rare childhood liver cancer with an obscure etiology, however it is potentially associated with selected pregnancy events and hepatoblastoma risk in offspring. Methods: Adjusted unconditional logistic regression estimated odds ratios (OR) and corresponding 95% confidence intervals (CI) for self-reported pregnancy events and medication use in a sample of mothers of 383 childhood hepatoblastoma cases and 387 controls. Results: Risk of hepatoblastoma was significantly associated with maternal first trimester weight gain (OR. =. 1.02; 95% CI 1.00, 1.04 per 1. lb increase and nearly significantly with maternal multivitamin use (OR. =. 0.73; 95% CI 0.51, 1.03). Hepatoblastoma was not associated with other maternal weight changes, maternal illness or medication use during pregnancy. Conclusion: We found little evidence that maternal illness or most medication use during pregnancy are associated with hepatoblastoma in offspring. © 2012 Elsevier Ltd.

Background: Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case-control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene-environment interactions. Objectives: The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene-environment interactions and subtype-specific associations through the pooling of data from independent studies. Methods: By September 2012, CLIC included 22 studies (recruitment period: 1962-present) from 12 countries, totaling approximately 31. 000 cases and 50. 000 controls. Of these, 19 case-control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child-parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens. Conclusions: CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene-environment interactions and associations among specific leukemia subtypes in different ethnic groups. © 2013 Elsevier Ltd.

Tobacco use is the major preventable cause of premature death in the United States. Second-hand smoke (SHS) exposure also contributes to a number of premature deaths as well as other negative health outcomes. An accurate assessment of tobacco smoke exposure is critical to understanding these disease processes. The plasma concentration of cotinine, the primary metabolite of nicotine, is widely accepted as a quantitative measure of tobacco and SHS exposure. However, it is not always feasible to collect plasma. Dried blood spots (DBS), which are collected routinely from newborns and often from young children for lead screening, provide an alternative sampling method. We have developed a quantitative high throughput liquid chromatography tandem mass spectrometry method for the analysis of cotinine in DBS. The limit of quantitation was 0.3 ng/g (~ 0.2 ng/ml plasma). Cotinine levels in DBS from 83 smokers and 99 non-smokers exposed to SHS were determined. Plasma cotinine concentrations in these subjects ranged from <0.02 to 443 ng/ml. Cotinine was detected in DBS from 157 subjects, and the correlation between cotinine in plasma and DBS was excellent, 0.992 (P<0.001). We also determined the ratio of trans 3'-hydroxycotinine to cotinine, a measure of nicotine metabolism, in DBS from smokers. This ratio in DBS was well correlated with the ratio in plasma, 0.94 (P<0.001). In a small study, we confirmed the feasibility of using extant DBS collected for lead screening to assess SHS exposure in children.

OBJECTIVES We assessed tobacco smoke exposure (TSE), defined according to detection of cotinine, in dried blood spots collected from children for lead screening. METHODS Dried blood spots collected from a national sample of 1541 Black and White children and submitted to a commercial laboratory for lead analysis were analyzed for cotinine. We used an anonymous administrative data set including information on children's characteristics to conduct univariate and multivariate analyses. RESULTS Cotinine was detected in 61% of dried blood spots; 17% of samples had cotinine levels above 3 nanograms per gram. Median cotinine levels were significantly higher among Black than White children (0.66 ng/g vs 0.30 ng/g) and among Medicaid recipients (0.94 ng/g vs < 0.3 ng/g). In multivariate analyses, significant increases in cotinine levels were associated with Black (vs White) race, older age, Medicaid coverage, higher state smoking rate, and higher average winter temperature. Detectable cotinine levels were significantly associated with higher lead levels. CONCLUSIONS TSE is highly prevalent among children undergoing lead screening, and exposure levels are greater among Black children and children on Medicaid. TSE may contribute to lead exposure. Concurrent lead screening and biological screening for TSE may be a feasible approach to increasing childhood TSE detection.