Rachel K. Fonstad

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.

Neonatal medical exposures and characteristics of low birth weight hepatoblastoma cases: A report from the Children's Oncology Group

Hepatoblastoma is a malignancy of young children. Low birth weight is associated with significantly increased risk of hepatoblastoma and neonatal medical exposures are hypothesized as contributors. This study represents the largest case–control study of hepatoblastoma to date and aimed to define the role of neonatal exposures in hepatoblastoma risk among low birth weight children.

Congenital abnormalities and hepatoblastoma: a report from the Children's Oncology Group (COG) and the Utah Population Database (UPDB).

Beckwith–Wiedemann Syndrome (BWS) and familial adenomatous polyposis (FAP) are known to predispose to hepatoblastoma (HB). A case–control study was conducted through the Childrens 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.

Exogenous hormone use, reproductive history and risk of adult myeloid leukaemia

Background:A hormonal aetiology is one explanation for the lower incidence of myeloid leukaemia in women compared with men.Methods:In this population-based case–control study, we evaluated associations between exogenous hormone use and reproductive history and myeloid leukaemia, overall and by disease subtype.Results:We observed a suggestive association between oral contraceptive use and acute myeloid leukaemia (odds ratio=0.55, 95% confidence interval=0.32–0.96). Hormone replacement therapy and reproductive factors were not associated with risk.Conclusion:Despite the biological plausibility for a role of oestrogen in leukaemogenesis, other aetiologic factors are likely to explain the differing incidence rates in males and females.

Abstract 2537: Infectious, autoimmune, and allergic diseases and risk of Hodgkin lymphoma in children and adolescents: A Children's Oncology Group (COG) study.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Relatively little research has been devoted to understanding the causes of Hodgkin lymphoma (HL) in children. HL diagnosed at 1 year prior to HL diagnosis, and EBV+ cases were more likely to report prior sore throats (including strep throat, scarlet fever, tonsillitis; OR=2.19, 95% CI: 1.06-4.53) and infectious mononucleosis (OR=9.10, 95% CI: 0.81-102.3). Case siblings were also more likely to have had an infection prior to HL diagnosis (OR=2.04, 95% CI: 1.01-4.14). In index children, autoimmune (OR=0.46, 95% CI: 0.16-1.38) and allergic (OR=1.22, 95% CI: 0.93-1.59) diseases identified >1 year before HL diagnosis were not associated with HL overall or by EBV status or subtype. There were no notable associations for autoimmune or allergic diseases in parents or siblings. These results may indicate a true increased risk for infections and lack of association with history of conditions imparting immune dysregulation, or they may be attributable to inaccurate recall. Future studies should employ biomarkers to understand differences in immune function preceding pediatric HL. Supported by NIH Grants R01 CA047473 and K05 CA157439, and Childrens Cancer Research Fund, Minneapolis, MN. Citation Format: Amy M. Linabery, Erik B. Erhardt, Rachel K. Fonstad, Seymour Grufferman, Richard F. Ambinder, Greta R. Bunin, Julie A. Ross, Logan G. Spector. Infectious, autoimmune, and allergic diseases and risk of Hodgkin lymphoma in children and adolescents: A Childrens Oncology Group (COG) study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2537. doi:10.1158/1538-7445.AM2013-2537 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Abstract 2291: Incidence of intracranial germ cell tumors by race in the United States, 1992-2009: A potential link with autoimmune encephalitis?.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Pediatric germ cell tumors (GCTs) are rare and heterogeneous tumors that are grouped together due to their presumed common cell of origin, the primordial germ cell (PGC). GCTs typically occur in the testes or ovaries; however, abnormal prenatal PGC migration along with lack of apopotosis can result in tumors in extragonadal locations, including the central nervous system (intracranial and intraspinal GCTs; iGCTs). Little is known about the etiology of iGCTs, although international incidence data suggest that the highest incidence occurs in Asian countries. Autoimmune encephalitis (AE) is a paraneoplastic event characterized by abnormal behavior, seizures, and movement disorders; a number of case reports find AE in conjunction with GCT. We note with interest that a recent registry based study in California reported the highest incidence of AE in Asians. In this analysis, we used 1992-2009 data from the National Cancer Institutes Surveillance, Epidemiology and End Results (SEER) Program to determine whether the increased rates of iGCT observed in Asian countries was also seen in Asian/Pacific Islanders living in the United States. Methods: Frequencies and incidence 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, American Indian/Alaskan Native and Asian/Pacific Islander), and tumor location (pineal gland vs. other) as sample size permitted. Analyses were conducted using SEER*Stat 7.1.0. Results: Two peaks in incidence were observed, the first before age 1 year in both sexes and the second at age 10 years for females and age 18 years for males. We observed a significantly higher incidence rate of iGCT in Asian/Pacific Islanders compared with whites (RR=1.98, 95% CI 1.51-2.56 for males and RR=3.21, 95% CI 1.99-5.05 for females) 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. Conclusions: The increased rates of iGCT we observed in individuals of Asian descent in the SEER registry are in agreement with data from the International Agency for Research on Cancer, where the highest incidence rates were observed in Japan, Singapore, and the Maori population of New Zealand. The explanation for these rate differences has not been investigated to date; however, the increased incidence in individuals of Asian ancestry in the United States suggests that genetic susceptibility may play a role in etiology. The higher frequency of AE in Asians and the co-occurrence with GCT in case reports is also intriguing. It is possible that AE could be triggered by PGCs abnormally present in the cranio-spatial axis prior to GCT diagnosis, and it will be of interest to determine whether a diagnosis of AE precedes iGCT. These differences in incidence patterns by race and the possible link with AE merit further investigation. Citation Format: Jenny N. Poynter, Rachel Fonstad, Jakub Tolar, Logan G. Spector, Julie A. Ross. Incidence of intracranial germ cell tumors by race in the United States, 1992-2009: A potential link with autoimmune encephalitis?. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2291. doi:10.1158/1538-7445.AM2013-2291