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.

Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.

Little is known about the etiology of intracranial germ cell tumors (iGCTs), although international incidence data suggest that the highest incidence rates occur in Asian countries. In this analysis, we used 1992–2010 data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program to determine whether rates of iGCT were also high in Asian/Pacific Islanders living in the United States. Frequencies, incidence rates and survival rates were evaluated for the entire cohort and for demographic subgroups based on sex, age category (0–9 and 10–29 years), race (white, black, and Asian/Pacific Islander), and tumor location (pineal gland vs. other) as sample size permitted. Analyses were conducted using SEER*Stat 8.1.2. We observed a significantly higher incidence rate of iGCT in Asian/Pacific Islanders compared with whites (RR = 2.05, 95 % CI 1.57–2.64, RR = 3.04, 95 % CI 1.75–5.12 for males and females, respectively) in the 10–29 year age group. This difference was observed for tumors located both in the pineal gland and for tumors in other locations. Five-year relative survival differed by demographic and tumor characteristics, although these differences were not observed in comparisons limited to cases treated with radiation. Increased incidence rates of iGCT in individuals of Asian descent in the SEER registry are in agreement with data from the International Agency for Research on Cancer, where Japan and Singapore were among the countries with highest incidence. The increased incidence in individuals of Asian ancestry in the United States suggests that underlying genetic susceptibility may play a role in the etiology of iGCT.

An infectious origin for pediatric Hodgkin lymphoma (HL) has long been suspected and Epstein-Barr virus (EBV) has been implicated in a subset of cases. Increased HL incidence in children with congenital and acquired immunodeficiencies, consistent associations between autoimmune diseases and adult HL and genome-wide association and other genetic studies together suggest immune dysregulation is involved in lymphomagenesis. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL diagnosed in 1989-2003 at 0-14 years at Children's Oncology Group institutions. Parents of 517 cases and 784 controls completed telephone interviews, including items regarding medical histories. Tumor EBV status was determined for 355 cases. Using conditional logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for risk of HL. Cases were more likely to have had an infection>1 year prior to HL diagnosis (OR=1.69, 95% CI: 0.98-2.91); case siblings were also more likely to have had a prior infection (OR=2.04, 95% CI: 1.01-4.14). Parental history of autoimmunity associated with increased EBV+ HL risk (OR=2.97, 95% CI: 1.34-6.58), while having a parent (OR=1.47, 95% CI: 1.01-2.14) or sibling (OR=1.62, 95% CI: 1.11-2.36) with an allergy was associated with EBV - HL. These results may indicate true increased risk for infections and increased risk with family history of autoimmune and allergic conditions that varies by tumor EBV status, or they may be attributable to inaccurate recall. In addition to employing biomarkers to confirm the role of immune-modulating conditions in pediatric HL, future studies should focus on family based designs.

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.

Many of the genetic variants identified via genome-wide association studies (GWAS) appear to have larger parameter estimates for younger onset cancers compared with adult onset cancers. We used data from the National Human Genome Research Institute (NHRGI) Catalog of Published GWAS to test the hypothesis that the magnitude of the parameter estimates is larger in younger onset compared to adult onset cancers. We found that the odds ratios in individuals categorized as childhood or young adult cancers were significantly higher than the odds ratios in individuals with adult cancers. The presence of larger effect sizes may mean that the variants associated with younger onset cancers explain a greater proportion of the population attributable risk estimates than the SNPs associated with adult onset cancers, which could improve early detection, treatment, and/or prevention. © 2013 Wiley Periodicals, Inc.

BACKGROUND Hepatoblastoma is a rare pediatric liver tumor that has significantly increased in incidence over the last several decades. The International Agency for Research on Cancer (IARC) recently classified hepatoblastoma as a tobacco-related cancer. Parental alcohol use has shown no association. We examined associations between parental tobacco and alcohol use around the time of pregnancy and hepatoblastoma in a large case-control study. METHODS Maternal interviews were completed for 383 cases diagnosed in the United States during 2000-2008. Controls (n = 387) were identified through U.S. birth registries and frequency-matched to cases on birth weight, birth year, and region of residence. We used unconditional logistic regression to calculate ORs and 95% confidence intervals (CI) for associations between parental smoking and maternal drinking and offspring hepatoblastoma. RESULTS We found no association between hepatoblastoma and maternal smoking at any time (OR, 1.0; 95% CI, 0.7-1.4), within the year before pregnancy (OR, 1.1; 95% CI, 0.8-1.6), early in pregnancy (OR, 1.0; 95% CI, 0.7-1.6), or throughout pregnancy (OR, 0.9; 95% CI, 0.5-1.6). We observed marginally positive associations between hepatoblastoma and paternal smoking in the year before pregnancy (OR, 1.4; 95% CI, 1.0-2.0) and during pregnancy (OR, 1.4; 95% CI, 0.9-2.0). Maternal alcohol use was not associated with hepatoblastoma. CONCLUSION Our results do not provide evidence for an etiologic relationship between maternal smoking or drinking and hepatoblastoma, and only weak evidence for an association for paternal smoking in the year before pregnancy. IMPACT Our study provides limited support for hepatoblastoma as a tobacco-related cancer; however, it remains wise to counsel prospective parents on the merits of smoking cessation.

BACKGROUND: Collection of high-quality DNA is essential for molecular epidemiology studies. Methods have been evaluated for optimal DNA collection in studies of adults; however, DNA collection in young children poses additional challenges. Here, we have evaluated predictors of DNA quantity in buccal cells collected for population-based studies of infant leukemia (N = 489 mothers and 392 children) and hepatoblastoma (HB; N = 446 mothers and 412 children) conducted through the Children's Oncology Group. DNA samples were collected by mail using mouthwash (for mothers and some children) and buccal brush (for children) collection kits and quantified using quantitative real-time PCR. Multivariable linear regression models were used to identify predictors of DNA yield.\n\nRESULTS: Median DNA yield was higher for mothers in both studies compared with their children (14 μg vs. <1 μg). Significant predictors of DNA yield in children included case-control status (β = -0.69, 50% reduction, P = 0.01 for case vs. control children), brush collection type, and season of sample collection. Demographic factors were not strong predictors of DNA yield in mothers or children in this analysis.\n\nCONCLUSIONS: The association with seasonality suggests that conditions during transport may influence DNA yield. The low yields observed in most children in these studies highlight the importance of developing alternative methods for DNA collection in younger age groups.