The Role of Childhood Infections and Immunizations on Childhood Rhabdomyosarcoma: A Report From the Children's Oncology Group.

BACKGROUND: Rhabdomyosarcoma (RMS) is a rare, highly malignant tumor arising from primitive mesenchymal cells that differentiate into skeletal muscle. Relatively little is known about RMS susceptibility. Based on growing evidence regarding the role of early immunologic challenges on RMS development, we evaluated the role of infections and immunizations on this clinically significant pediatric malignancy. PROCEDURE: RMS cases (n = 322) were enrolled from the third trial coordinated by the Intergroup Rhabdomyosarcoma Study Group. Population-based controls (n = 322) were pair matched to cases on race, sex, and age. The following immunizations were assessed: diphtheria, pertussis, and tetanus (DPT); measles, mumps, and rubella; and oral polio vaccine. We also evaluated if immunizations were complete versus incomplete. We examined selected infections including chickenpox, mumps, pneumonia, scarlet fever, rubella, rubeola, pertussis, mononucleosis, and lung infections. Conditional logistic regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for maternal education and total annual income. RESULTS: Incomplete immunization schedules (OR = 5.30, 95% CI: 2.47-11.33) and incomplete DPT immunization (OR = 1.56, 95% CI: 1.06-2.29) were positively associated with childhood RMS. However, infections did not appear to be associated with childhood RMS. CONCLUSIONS: This is the largest study of RMS to date demonstrating a possible protective effect of immunizations against the development of childhood RMS. Further studies are needed to validate our findings. Our findings add to the growing body of literature, suggesting a protective role of routine vaccinations in childhood cancer and specifically in childhood RMS.

Family history of cancer and risk of pediatric and adolescent Hodgkin lymphoma: A Children's Oncology Group study.

Family history of lymphoid neoplasm (LN) is a strong and consistently observed Hodgkin lymphoma (HL) risk factor, although it has been only marginally examined in pediatric/adolescent patients. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL cases diagnosed at 0-14 years at Children's Oncology Group institutions in 1989-2003. Detailed histories were captured by structured telephone interviews with parents of 517 cases and 783 controls. Epstein-Barr virus (EBV) RNA detection was performed for 355 available case tumors. Two analytic strategies were applied to estimate associations between family cancer history and pediatric/adolescent HL. In a standard case-control approach, multivariate conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs). In a reconstructed cohort approach, each relative was included as a separate observation, and multivariate proportional hazards regression was used to produce hazard ratios (HRs) and 95% CIs. Using the latter, pediatric/adolescent HL was associated with a positive family history (HR = 1.20, 95% CI: 1.06-1.36), particularly early-onset cancers (HR = 1.30, 95% CI: 1.06-1.59) and those in the paternal lineage (HR = 1.38, 95% CI: 1.16-1.65), with a suggested association for LN in first-degree relatives (HR = 3.61, 95% CI: 0.87-15.01). There were no discernable patterns for EBV+ versus EBV- HL. The clustering of LN within pedigrees may signal shared genetic susceptibility or common environmental exposures. Heritable genetic risk variants have only recently begun to be discovered, however. These results are consistent with other studies and provide a compelling rationale for family-based studies to garner information about genetic susceptibility to HL.

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 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.

Allergies, atopy, immune-related factors and childhood rhabdomyosarcoma: a report from the Children's Oncology Group.

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.

Maternal and birth characteristics and childhood rhabdomyosarcoma: a report from the Children's Oncology Group.

PURPOSE: Previous assessments of childhood rhabdomyosarcoma have indicated maternal and birth characteristics may be associated with tumor development; however, much work remains to identify novel and confirm suspected risk factors. Our objective was to evaluate the associations between maternal and birth characteristics and childhood rhabdomyosarcoma. METHODS: This case-control study included 322 cases and 322 pair-matched controls. Cases were enrolled in a trial run by the Intergroup Rhabdomyosarcoma Study Group. Population-based controls were identified using random digit dialing and were individually matched to cases on race, sex, and age. Families of the case and control subjects participated in a telephone interview, which captured information on maternal characteristics (birth control use, number of prenatal visits, anemia, and abnormal bleeding during pregnancy) and birth characteristics [birth weight, preterm birth, and type of delivery (vaginal vs. cesarean)]. 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 rhabdomyosarcoma are embryonal (n = 215) and alveolar (n = 66), we evaluated effect heterogeneity of these exposures. RESULTS: The only characteristic that was associated with childhood rhabdomyosarcoma, and statistically significant, was abnormal vaginal bleeding during pregnancy (OR 1.75, 95% CI 1.12-2.74). Birth control use (OR 1.45, 95% CI 0.96-2.18), anemia during pregnancy (OR 1.27, 95% CI 0.81-1.99), and preterm birth (OR 2.51, 95% CI 0.74-8.49) were positively associated with childhood rhabdomyosarcoma, but were not statistically significant. Low birth weight [adjusted odds ratios (aOR) 4.46, 95% CI 1.41-14.1] and high birth weight (aOR 2.41, 95% CI 1.09-5.35) were strongly associated with alveolar rhabdomyosarcoma. However, these factors did not display significant effect heterogeneity between histologic types (p > 0.15 for all characteristics). CONCLUSIONS: Overall, we found little evidence that these maternal and birth characteristics are strongly associated with childhood rhabdomyosarcoma.

Parental military service, agent orange exposure, and the risk of rhabdomyosarcoma in offspring.

OBJECTIVE: To evaluate the role of parental military service-related exposures and rhabdomyosarcoma (RMS) risk in offspring using data from a large case-control study of childhood RMS. STUDY DESIGN: Cases (n = 319) were enrolled from the third trial run by the Intergroup Rhabdomyosarcoma Study Group. Population-based controls (n = 319) were pair-matched to cases on race, sex, and age. Conditional logistic regression was used to evaluate parental military service-related exposures and their associations with childhood RMS by generating aORs and 95% CIs. Statistical significance was defined as P < .05. RESULTS: There were no significant associations between parental military service and childhood RMS. The strongest association was with maternal military service; however, this association was attenuated and did not remain significant after adjusting for covariates (aOR = 2.75, 95% CI 0.71, 10.62). An elevated effect estimate was found when assessing paternal exposure to Agent Orange (AO) and childhood RMS but was not statistically significant (aOR = 1.72, 95% CI 0.55, 5.41). CONCLUSIONS: We found little evidence that parental military service of AO exposure influences the risk of RMS in offspring. These findings are notable in light of the continuing controversies surrounding the intergenerational effects of AO exposure.

Prenatal X-ray exposure and rhabdomyosarcoma in children: a report from the children's oncology group.

The association between antenatal diagnostic X-ray exposure and risk of rhabdomyosarcoma in children was assessed in a national case-control study of 319 rhabdomyosarcoma cases and 319 matched controls. Data were collected by telephone interviews of subjects' parents. Overall, an odds ratio (OR) of 1.9 [95% confidence interval (CI), 1.1-3.4] was found for any X-ray examination of the mother during pregnancy. Risk was greatest for X-ray exposure during the first trimester (OR, 5.7; 95% CI, 1.2-27.8) and was also increased for the third trimester (OR, 2.0; 95% CI, 0.9-4.6), whereas second trimester exposure was not associated with increased risk. A nonsignificant increase in risk was found for any X-rays of the abdomen, pelvis, chest, or back. Increased risk was significantly associated with "other" X-ray exposures (relative risk, 2.9; 95% CI, 1.1-7.7), primarily composed of dental X-rays. The association was strongest between embryonal rhabdomyosarcoma and first trimester exposure (relative risk, 10.5; 95% CI, 1.5-458.4). This observation regarding embryonal rhabdomyosarcoma, and our previous report of an increased frequency of major malformations in rhabdomyosarcoma are compatible with findings from animal studies in which Ptc heterozygous knockout mice exhibited an increased risk of radiation-induced development defects and of spontaneously occurring embryonal rhabdomyosarcoma.

Predictors of colorectal cancer screening in diverse primary care practices.

BACKGROUND: To explain why rates of colorectal cancer (CRC) screening including fecal occult blood testing (FOBT), flexible sigmoidoscopy (FS), colonoscopy (CS), and barium enema (BE), are low, this study assessed determinants of CRC screening from medical records. METHODS: Data were abstracted from patients aged > or =64 years selected from each clinician from 30 diverse primary care practices (n = 981). Measurements included the rates of annual FOBT, ever receiving FOBT, ever receiving FS/CS/BE under a combination variable, endoscopy/barium enema (EBE). RESULTS: Over five years, 8% had received annual FOBT, 53% had ever received FOBT and 22% had ever received EBE. Annual FOBT was negatively associated with female gender, odds ratio (OR) = .23; 95% confidence interval = .12-.44 and positively associated with routinely receiving influenza vaccine, OR = 2.55 (1.45-4.47); and more office visits: 3 to <5 visits/year, OR = 2.78 (1.41-5.51), and > or =5 visits/year, OR = 3.35 (1.52-7.42). Ever receiving EBE was negatively associated with age > or =75 years, OR = .66 (.46-.95); being widowed, OR = .59 (.38-.92); and positively associated with more office visits: 3 to <5 visits/year, OR = 1.83 (1.18-2.82) and > or =5 visits/year, OR = 2.01 (1.14-3.55). CONCLUSION: Overall CRC screening rates were low, but were related to the number of primary care office visits. FOBT was related to immunization status, suggesting the possible benefit of linking these preventive services.

Family history of cancer and childhood rhabdomyosarcoma: a report from the Children's Oncology Group and the Utah Population Database.

Relatively little is known about the epidemiology and factors underlying susceptibility to childhood rhabdomyosarcoma (RMS). To better characterize genetic susceptibility to childhood RMS, we evaluated the role of family history of cancer using data from the largest case-control study of RMS and the Utah Population Database (UPDB). RMS cases (n = 322) were obtained from the Children's Oncology Group (COG). Population-based controls (n = 322) were pair-matched to cases on race, sex, and age. Conditional logistic regression was used to evaluate the association between family history of cancer and childhood RMS. The results were validated using the UPDB, from which 130 RMS cases were identified and matched to controls (n = 1300) on sex and year of birth. The results were combined to generate summary odds ratios (OR(s) ) and 95% confidence intervals (CI). Having a first-degree relative with a cancer history was more common in RMS cases than controls (OR(s) = 1.39, 95% CI: 0.97-1.98). Notably, this association was stronger among those with embryonal RMS (OR(s) = 2.44, 95% CI: 1.54-3.86). Moreover, having a first-degree relative who was younger at diagnosis of cancer (<30 years) was associated with a greater risk of RMS (OR(s) = 2.37, 95% CI: 1.34-4.18). In the largest analysis of its kind, we found that most children diagnosed with RMS did not have a family history of cancer. However, our results indicate an increased risk of RMS (particularly embryonal RMS) in children who have a first-degree relative with cancer, and among those whose relatives were diagnosed with cancer at <30 years of age.

Secular trends in response rates for controls selected by random digit dialing in childhood cancer studies: a report from the Children's Oncology Group.

Since the mid-1990s, epidemiologists have anecdotally reported difficulty in recruiting controls using random digit dialing (RDD), but few empirical data have been published. From 1982 to 2003, epidemiologists from the Children's Oncology Group conducted 17 case-control studies using RDD controls. Data for calculating RDD and field response rates were available from eight and 13 of these studies, respectively. Over the period of analysis, the contact rate declined 2.5% per year (95% confidence interval (CI): -3.4, -1.6; p = 0.001), from above 90% in the 1980s to 63-69% in the most recent studies. The response rate (the product of the contact and cooperation rates) showed a decline parallel to that of the contact rate (-2.4% per year, 95% CI: -3.2, -1.6; p < 0.001), from above 80% in the 1980s to 50-67% after the mid-1990s. Field response rates appeared to have declined modestly. The overall response rate (the product of the RDD response and field response rates) paralleled that of the RDD response rate and decreased 2.4% per year (95% CI: -2.7, -2.0; p < 0.001). The current low response rates for RDD indicate a substantial potential for selection bias and a need to seek alternative sources of controls.

Antibody responses to Epstein-Barr virus-encoded latent membrane protein-1 (LMP1) and expression of LMP1 in juvenile Hodgkin's disease.

A large group of juvenile Hodgkin's disease patients (n = 242, mean age 11.7 years, 75% [n = 181] seropositive) was evaluated for anti-Epstein-Barr virus (EBV) antibody responses and the presence of EBV-encoded EBER-RNA and latent membrane protein-1 (LMP1)-protein expression in the tumor. The molecular diversity of anti-EBV antibody responses in Hodgkin's disease patients with EBV-positive and-negative tumors was studied by enzyme-linked immunosorbent assay (ELISA) and immunoblot. Using purified recombinant LMP1 protein as antigen, the presence of antibodies to LMP1 was related to expression of LMP1 in the tumor cells and specific EBV-serological patterns. Antibodies to LMP1 were detected in 30% of the EBV-seropositive Hodgkin's disease patients. The presence of antibodies to LMP1 was not associated with a distinct anti-EBV antibody diversity profile (ELISA), but a significantly higher percentage of patients with antibodies to LMP1 had antibodies to ZEBRA and viral capsid antigen (VCA)-p18 (Immunoblot). Significantly more patients with an EBV-positive tumor had detectable antibody responses to LMP1, but the presence of antibodies to LMP1 did not reflect the expression of LMP1 protein in the tumor cells. Interestingly, all patients with the strongest antibody responses to LMP1 had EBV-negative tumors, suggesting immunological selection in vivo.