Amy M. Linabery

Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975-2005.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents aged <20 years; its etiology remains largely unknown. It is believed that embryonal (ERMS) and alveolar rhabdomyosarcoma (ARMS), the most common subtypes, arise through distinct biologic mechanisms. The authors of this report evaluated incidence and survival trends by RMS demographic subgroups to inform future etiologic hypotheses.

Stronger influence of maternal than paternal obesity on infant and early childhood body mass index: the Fels Longitudinal Study

Excessive early childhood adiposity is a prevalent and increasing concern in many parts of the world. Parental obesity is one of the several factors previously associated with infant and early childhood weight, length and adiposity. Parental obesity represents a surrogate marker of the complex interplay among genetic, epigenetic and shared environmental factors, and is potentially modifiable. The relative contributions of maternal and paternal body mass index (BMI) to infant and early childhood growth, as well as the timing of such effects, have not been firmly established.

The Association Between Atopy and Childhood/Adolescent Leukemia: A Meta-Analysis

Atopic disease is hypothesized to be protective against several malignancies, including childhood/adolescent leukemia. To summarize the available epidemiologic evidence, the authors performed a meta-analysis of associations between atopy/allergies, asthma, eczema, hay fever, and hives and childhood/adolescent leukemia, acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML). They searched MEDLINE literature (1952-March 2009) and queried international experts to identify eligible studies. Ten case-control studies were included. Summary odds ratios and 95% confidence intervals were computed via random-effects models. Odds ratios for atopy/allergies were 1.42 (95% confidence interval (CI): 0.60, 3.35) for 3 studies of leukemia overall, 0.69 (95% CI: 0.54, 0.89) for 6 studies of ALL, and 0.87 (95% CI: 0.62, 1.22) for 2 studies of AML, with high levels of heterogeneity detected for leukemia overall and ALL. Inverse associations were observed for ALL and asthma (odds ratio (OR) = 0.79, 95% CI: 0.61, 1.02), eczema (OR = 0.74, 95% CI: 0.58, 0.96), and hay fever (OR = 0.55, 95% CI: 0.46, 0.66) examined separately. Odds ratios for ALL differed by study design, exposure data source, and latency period, indicating that these factors affect study results. These results should be interpreted cautiously given the modest number of studies, substantial heterogeneity, and potential exposure misclassification but are useful in designing future research.

Childhood Cancer Incidence Trends in Association With US Folic Acid Fortification (1986–2008)

OBJECTIVE: Epidemiologic evidence indicates that prenatal vitamin supplementation reduces risk for some childhood cancers; however, a systematic evaluation of population-based childhood cancer incidence trends after fortification of enriched grain products with folic acid in the United States in 1996–1998 has not been previously reported. Here we describe temporal trends in childhood cancer incidence in association with US folic acid fortification. METHODS: Using Surveillance, Epidemiology, and End Results program data (1986–2008), we calculated incidence rate ratios and 95% confidence intervals to compare pre- and postfortification cancer incidence rates in children aged 0 to 4 years. Incidence trends were also evaluated by using joinpoint and loess regression models. RESULTS: From 1986 through 2008, 8829 children aged 0 to 4 years were diagnosed with malignancies, including 3790 and 3299 in utero during the pre- and postfortification periods, respectively. Pre- and postfortification incidence rates were similar for all cancers combined and for most specific cancer types. Rates of Wilms tumor (WT), primitive neuroectodermal tumors (PNETs), and ependymomas were significantly lower postfortification. Joinpoint regression models detected increasing WT incidence from 1986 through 1997 followed by a sizable decline from 1997 through 2008, and increasing PNET incidence from 1986 through 1993 followed by a sharp decrease from 1993 through 2008. Loess curves indicated similar patterns. CONCLUSIONS: These results provide support for a decrease in WT and possibly PNET incidence, but not other childhood cancers, after US folic acid fortification.

Genetic variants modify susceptibility to leukemia in infants: A Children's Oncology Group report

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.

ARID5B and IKZF1 variants, selected demographic factors, and childhood acute lymphoblastic leukemia: A report from the Children's Oncology Group

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.

Comparability and Representativeness of Control Groups in a Case-Control Study of Infant Leukemia: A Report From the Children's Oncology Group

Traditionally, controls in US pediatric cancer studies were selected through random digit dialing. With declining participation and lack of nonparticipant information, random digit dialing (RDD) controls may be substandard. Birth certificate (BC) controls are an alternative, because they are population based and include data from nonparticipants. The authors examined controls collected by random digit dialing and birth certificates for a Childrens Oncology Group case-control study of infant leukemia in 1995-2006. Demographic variables were used to assess differences in RDD and BC controls and their representativeness. RDD and BC controls did not differ significantly with regard to maternal variables (age, race, education, marital status, alcohol during pregnancy) or child variables (sex, gestational age, birth weight), but they varied in smoking during pregnancy (22% RDD controls, 12% BC controls) (P = 0.05). The studys combined control group differed significantly from US births: Mothers of controls were more likely to be older (29.8 vs. 27.2 years), white (84% vs. 59%), and married (85% vs. 67%) and to have >16 years of education (37% vs. 25%). Control children were more often full term (88% vs. 81%) and heavier (3,436 vs. 3,317 g). Finally, participating BC mothers were likely to be older and to have more education than nonparticipants. Thus, the studys control groups were comparable but differed from the population of interest.

Infant leukemia and congenital abnormalities: A Children's Oncology Group study†

Leukemia in infants is rare and has not been well studied apart from leukemia in older children. Differences in survival and the molecular characteristics of leukemia in infants versus older children suggest a distinct etiology, likely involving prenatal factors.

Exposure to Medical Test Irradiation and Acute Leukemia Among Children With Down Syndrome: A Report From the Children's Oncology Group

OBJECTIVE. The etiology of acute childhood leukemia is not well understood, particularly among children with Down syndrome, in whom a 10- to 20-fold increased risk of leukemogenesis has been reported compared with children without Down syndrome. We explored the association between medical test irradiation, a postulated leukemogenic agent, and acute leukemia among children with Down syndrome. PATIENTS AND METHODS. Children with Down syndrome (controls) were frequency matched on age to children with Down syndrome and leukemia (cases) diagnosed at ages 0 to 19 years during the period 1997–2002 at participating Childrens Oncology Group institutions in North America. Telephone interviews were completed with mothers of 158 cases (n = 97 acute lymphoblastic leukemia and n = 61 acute myeloid leukemia) and 173 controls. Paternal interviews were completed with 275 fathers and 40 mothers serving as surrogates. Three irradiation exposure periods were examined: preconception, in utero, and postnatal. Multivariate unconditional logistic regression models were constructed to evaluate the associations of interest, resulting in odds ratios and 95% confidence intervals. RESULTS. There was little evidence that maternal or paternal preconception irradiation exposure, intrauterine exposure, or postnatal exposure contributes to leukemogenesis in children with Down syndrome. Overall, no evidence for an effect of any periconceptional exposure was observed. Similar results were observed among acute lymphoblastic leukemia and acute myeloid leukemia cases analyzed separately. CONCLUSIONS. This was the first study, to our knowledge, to examine such an association among this unique patient population. The results do not provide evidence of a positive association between ionizing radiation exposure and acute leukemia among children with Down syndrome. The absence of an association should be encouraging for concerned parents of children with Down syndrome who undergo a series of diagnostic radiographs in the course of their standard care.

Infectious, autoimmune and allergic diseases and risk of Hodgkin lymphoma in children and adolescents: A Children's Oncology Group study

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 Childrens 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.