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1.  Assisted reproductive technology use and outcomes among women with a history of cancer† 
How do the assisted reproductive technology (ART) outcomes of women presenting for ART after cancer diagnosis compare to women without cancer?
The likelihood of a live birth after ART among women with prior cancer using autologous oocytes is reduced and varies by cancer diagnosis but is similar to women without cancer when donor oocytes are used.
Premenopausal patients faced with a cancer diagnosis frequently present for fertility preservation.
Population-based cohort study of women treated with ART in NY, TX and IL, USA.
Women with their first ART treatment between 2004 and 2009 were identified from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database and linked to their respective State Cancer Registries based on name, date of birth and social security number. Years were rounded, i.e. year 1 = 6–18 months before treatment. This study used reports of cancer from 5 years, 6 months prior to treatment until 6 months after first ART treatment. Women who only presented for embryo banking were omitted from the analysis. The likelihood of pregnancy and of live birth with ART using autologous oocytes was modeled using logistic regression, with women without prior cancer as the reference group, adjusted for woman's age, parity, cumulative FSH dosage, infertility diagnosis, number of diagnoses, number of ART cycles, State of residency and year of ART treatment. Results of the modeling are reported as adjusted odds ratios (AORs) and (95% confidence intervals).
The study population included 53 426 women; 441 women were diagnosed with cancer within 5 years prior to ART cycle start. Mean (±SD) age at cancer diagnosis was 33.4 ± 5.7 years; age at start of ART treatment was 34.9 ± 5.8 for women with cancer compared with 35.3 ± 5.3 years for women without cancer (P = 0.03). Live birth rates among women using autologous oocytes differed substantially by cancer status (47.7% without cancer versus 24.7% with cancer, P < 0.0001), and cancer diagnosis (ranging from 53.5% for melanoma to 14.3% for breast cancer, P < 0.0001. The live birth rates among women using donor oocytes did not vary significantly by cancer status (60.4% for women with any cancer versus 64.5% for women without cancer), or by cancer diagnosis (ranging from 57.9% for breast cancer to 63.6% for endocrine cancer). Women with breast cancer make up about one-third of all cancers in this cohort. Among women with breast cancer, 2.8% of the 106 women who underwent ART within 6 months of being diagnosed with cancer used donor oocytes compared with 34.8% of the 46 women who received ART treatment a longer time after being diagnosed with cancer (P < 0.0001). We conjecture that the former group were either unaware that they had cancer or decided to undergo ART therapy prior to cancer treatment. However, their live birth rate was only 11.7% compared with 28.8%, the overall live birth rate for all women with cancer using autologous oocytes (P < 0.0001). The live birth rate for women diagnosed with breast cancer more than 6 months before ART (23.3%) did not differ significantly from the overall live birth rate for cancer (P = 0.49). If this difference is substantiated by a larger study, it would indicate a negative effect of severe recent illness itself on ART success, rather than the poor outcome being only related to the destructive effects of chemotherapies on ovarian follicles. Alternatively, because of the short time difference between cancer diagnosis and ART treatment, these pre-existing cancers may have been detected due to the increased medical surveillance during ART therapy. In women who only used autologous oocytes, women with prior cancers were significantly less likely to become pregnant and to have a live birth than those without cancer (adjusted odds ratio (AOR): 0.34, [95% confidence interval (CI): 0.27, 0.42] and 0.36 [0.28, 0.46], respectively). This was also evident with specific cancer diagnoses: breast cancer (0.20 [0.13, 0.32] and 0.19 [0.11, 0.30], respectively), cervical cancer (0.36 [0.15, 0.87] and 0.33 [0.13, 0.84], respectively) and all female genital cancers (0.49 [0.27, 0.87] and 0.47 [0.25, 0.86], respectively). Of note, among women with cancer who became pregnant, their likelihood of having a live birth did not differ significantly from women without cancer (85.8 versus 86.7% for women using autologous oocytes, and 85.3 versus 86.9% for women using donor oocytes).
Women may not have been residents of the individual States for the entire 5-year pre-ART period, and therefore some cancers may not have been identified through this linkage. As a result, the actual observed number of cancers may be an underestimate. In addition, the overall prevalence is low due to the age distributions. Also, because we restricted the pre-ART period to 5 years prior, we would not have identified women who were survivors of early childhood cancers (younger than age 13 years at cancer diagnosis), or who had ART more than 5 years after being diagnosed with cancer. Additional analyses are currently underway evaluating live birth outcomes after embryo banking among women with cancer prior to ART, cycles which were excluded from the analyses in this paper. Future studies are planned which will include more States, as well as linkages to vital records to obtain information on spontaneous conceptions and births, to further clarify some of the issues raised in this analysis.
Since the live birth rates using donor oocytes were not reduced in women with a prior cancer, but were reduced with autologous cycles, this suggests that factors acting in the pre- or peri-conceptional periods may be responsible for the decline.
The study was funded by grant R01 CA151973 from the National Cancer Institute, National Institutes of Health, USA. B.L. is a research consultant for the Society for Assisted Reproductive Technology. All other authors report no conflict of interest.
PMCID: PMC4677965  PMID: 26577302
oncofertility; assisted reproduction; cohort study; cancer among women; live births; breast cancer
2.  In‐Hospital Vital Status and Heart Transplants After Intervention for Congenital Heart Disease in the Pediatric Cardiac Care Consortium: Completeness of Ascertainment Using the National Death Index and United Network for Organ Sharing Datasets 
The long‐term outcomes of patients undergoing interventions for congenital heart disease (CHD) remain largely unknown. We linked the Pediatric Cardiac Care Consortium (PCCC) with the National Death Index (NDI) and the United Network for Organ Sharing Dataset (UNOS) registries to study mortality and transplant occurring up to 32 years postintervention. The objective of the current analysis was to determine the sensitivity of this linkage in identifying patients who are known to have died or undergone heart transplant.
Methods and Results
We used direct identifiers from 59 324 subjects registered in the PCCC between 1982 and 2003 to test for completeness of case ascertainment of subjects with known vital and heart transplant status by linkage with the NDI and UNOS registries. Of the 4612 in‐hospital deaths, 3873 were identified by the NDI as “true” matches for a sensitivity of 84.0% (95% CI, 82.9–85.0). There was no difference in sensitivity across 25 congenital cardiovascular conditions after adjustment for age, sex, race, presence of first name, death year, and residence at death. Of 455 known heart transplants in the PCCC, there were 408 matches in the UNOS registry, for a sensitivity of 89.7% (95% CI, 86.9–92.3). An additional 4851 deaths and 363 transplants that occurred outside the PCCC were identified through 2014.
The linkage of the PCCC with the NDI and UNOS national registries is feasible with a satisfactory sensitivity. This linkage provides a conservative estimate of the long‐term death and heart transplant events in this cohort.
PMCID: PMC5015299  PMID: 27506544
cohort study; congenital heart disease; mortality; sensitivity and specificity; transplant; Epidemiology
3.  Home pesticide exposures and risk of childhood leukemia: Findings from the Childhood Leukemia International Consortium 
Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, we pooled individual level data from 12 case-control studies in the Childhood Leukemia International Consortium (CLIC). Exposure data were harmonized into compatible formats. Pooled analyses were undertaken using multivariable unconditional logistic regression. The odds ratio (ORs) for acute lymphoblastic leukaemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39 (95% confidence interval (CI) 1.25, 1.55) (using (2,785 cases, 3635 controls), 1.43 (95% CI 1.32, 1.54) (5,055 cases, 7,370 controls) and 1.36 (95% CI 1.23, 1.51) (4,162 cases 5,179 controls), respectively. Corresponding ORs for risk of acute myeloid leukaemia (AML) were 1.49 (95% CI 1.02, 2.16) (173 cases, 1,789 controls), 1.55 (95% CI 1.21, 1.99) (344 cases, 4,666 controls) and 1.08 (95% CI 0.76, 1.53) (198 cases, 2,655 controls) respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukaemia types, time periods and pesticide types may be explained by similar exposure patterns and effects across the time periods in ALL and AML, participants’ exposure to multiple pesticides, or recall bias. Although some recall bias is likely, until a better study design can be found to investigate associations between home pesticide use and childhood leukaemia in an equally large sample, it would appear prudent to limit the use of home pesticides before and during pregnancy, and during childhood.
PMCID: PMC4572913  PMID: 26061779
pesticide; acute lymphoblastic leukemia acute myeloid leukemia; childhood; pooled analysis; case-control study
4.  Cancer in Women after Assisted Reproductive Technology 
Fertility and sterility  2015;104(5):1218-1226.
To evaluate the risk of cancer after assisted reproductive technology (ART) therapy.
Longitudinal cohort of New York, Texas, and Illinois residents between 2004-09, treated with ART, and whose cycles were reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System (SART CORS).
Not applicable
Cycles of 113,226 women, including 53,859 women without prior ART treatment, were linked to their respective Cancer Registries. Standardized incidence ratios (SIR) and their 95% confidence intervals were calculated, comparing the observed to expected cancer cases based on age-specific cancer rates in the general population of each State. Among the cohort of women without prior ART therapy, hazard ratios (HR) and 95% confidence intervals were calculated for treatment parameters and reproductive history factors.
Main Outcome Measures
Diagnosis of cancer, as reported to the State Cancer Registry
Mean follow-up was 4.87 years; among women without prior ART, 450 women developed 460 cancers. Women treated with ART had significantly lower risks for all cancers (for all women: SIR 0.78, 0.73-0.83; and women without prior ART: SIR 0.75, 0.68-0.82), breast cancer, and all female genital cancers; nonsignificant lower risks for endocrine and uterine cancer; and nonsignificant higher risks for melanoma and ovarian cancer. Among women without prior ART, there were no significant increased HRs by parity, number of cycles, cumulative FSH dosage, or cycle outcome.
These results suggest no greater risks for developing cancer after nearly 5 years of follow-up compared to the general population, and to other women treated with ART.
These results suggest no greater short-term risks for developing cancer compared to the general population, and to other women treated with ART.
PMCID: PMC4630138  PMID: 26271227
cancer risk; assisted reproductive technology; pregnancy outcome; fertility
5.  Family history of cancer and risk of pediatric and adolescent Hodgkin lymphoma: A Children's Oncology Group study 
International journal of cancer  2015;137(9):2163-2174.
Family history of lymphoid neoplasms (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 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.
PMCID: PMC4833396  PMID: 25940226
Hodgkin lymphoma; children; family cancer history; genetic predisposition
6.  Invited Commentary: Childhood Acute Lymphoblastic Leukemia and Allergies: Biology or Bias? 
American Journal of Epidemiology  2012;176(11):979-983.
Previous epidemiologic studies have shown an inverse association between a personal history of atopy/allergies, both overall and among asthma, eczema, and hay fever investigated separately, and childhood acute lymphoblastic leukemia (ALL) with some consistency; however, in most of these studies, exposure data were collected by maternal interview. Now, in a population-based and records-based study in this issue of the Journal (Am J Epidemiol. 2012;176(11):970–978), Chang et al. report an increased risk for allergic conditions across different etiologic time periods, calling the former paradigm into doubt. A review of the basic biology literature shows that proposed mechanisms support either a positive or an inverse association. In light of this ambiguity, it is epidemiology's turn to determine the direction of association.
PMCID: PMC3571240  PMID: 23171875
child; hypersensitivity; leukemia
7.  Prenatal Tobacco Exposure and Cotinine in Newborn Dried Blood Spots 
Pediatrics  2014;133(6):e1632-e1638.
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.
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.
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.
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.
PMCID: PMC4035592  PMID: 24819573
cotinine; dried blood spot testing; newborn
8.  Parental occupational paint exposure and risk of childhood leukemia in the offspring: Findings from the Childhood Leukemia International Consortium 
Cancer causes & control : CCC  2014;25(10):1351-1367.
It has been suggested that parental occupational paint exposure around the time of conception or pregnancy increases the risk of childhood leukemia in the offspring.
We obtained individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium (CLIC). Occupational data were harmonized to a compatible format. Meta-analyses of study-specific odds ratios (ORs) were undertaken, as well as pooled analyses of individual data using unconditional logistic regression.
Using individual data from fathers of 8,185 cases and 14,210 controls, the pooled OR for paternal exposure around conception and risk of acute lymphoblastic leukaemia (ALL) was 0.93 (95% confidence interval (CI) 0.76, 1.14). Analysis of data from 8,156 ALL case mothers and 14,568 control mothers produced a pooled OR of 0.81 (95% CI 0.39, 1.68) for exposure during pregnancy. For acute myeloid leukaemia (AML), the pooled ORs for paternal and maternal exposure were 0.96 (95% CI 0.65, 1.41) and 1.31 (95% CI 0.38, 4.47) respectively, based on data from 1,231 case and 11,392 control fathers and 1,329 case and 12,141 control mothers. Heterogeneity among the individual studies ranged from low to modest.
Null findings for paternal exposure for both ALL and AML are consistent with previous reports. Despite the large sample size, results for maternal exposure to paints in pregnancy were based on small numbers of exposed. Overall, we found no evidence that parental occupational exposure to paints increases the risk of leukemia in the offspring, but further data on home exposure are needed.
PMCID: PMC4845093  PMID: 25088805
paint; parental occupation; leukemia; childhood; pooled analysis; meta-analysis
9.  Parental occupational pesticide exposure and the risk of childhood leukemia in the offspring: Findings from the Childhood Leukemia International Consortium 
International journal of cancer  2014;135(9):2157-2172.
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 five years or more and those with T cell ALL which raises interesting questions on possible mechanisms.
PMCID: PMC4845098  PMID: 24700406
pesticide; occupation; leukemia; childhood; pooled analysis; meta-analysis
10.  Maternal exposure to household chemicals and risk of infant leukemia: A report from the Children's Oncology Group1 
Cancer causes & control : CCC  2011;22(8):1197-1204.
Utilizing data from the largest study to date, we examined associations between maternal preconception/prenatal exposure to household chemicals and infant acute leukemia.
We present data from a Children's Oncology Group case-control study of 443 infants (<1 year of age) diagnosed with acute leukemia (including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML)) between 1996-2006 and 324 population controls. Mothers recalled household chemical use one month before and throughout pregnancy. We used unconditional logistic regression adjusted for birth year, maternal age, and race/ethnicity to calculate odds ratios (ORs) and 95% confidence intervals (CIs).
We did not find evidence for an association between infant leukemia and eight of nine chemical categories. However, exposure to petroleum products during pregnancy was associated with AML (OR=2.54; 95% CI:1.40-4.62) and leukemia without mixed lineage leukemia (MLL) gene rearrangements (“MLL-”) (OR=2.69; 95% CI: 1.47-4.93). No associations were observed for exposure in the month before pregnancy.
Gestational exposure to petroleum products was associated with infant leukemia, particularly AML and MLL- cases. Benzene is implicated as a potential carcinogen within this exposure category, but a clear biological mechanism has yet to be elucidated.
PMCID: PMC4836386  PMID: 21691732
epidemiology; infants; leukemia; chemical; prenatal
11.  Childhood Acute Lymphoblastic Leukemia and Indicators of Early Immune Stimulation: A Childhood Leukemia International Consortium Study 
American Journal of Epidemiology  2015;181(8):549-562.
The associations between childhood acute lymphoblastic leukemia (ALL) and several proxies of early stimulation of the immune system, that is, day-care center attendance, birth order, maternally reported common infections in infancy, and breastfeeding, were investigated by using data from 11 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980–2010). The sample included 7,399 ALL cases and 11,181 controls aged 2–14 years. The data were collected by questionnaires administered to the parents. Pooled odds ratios and 95% confidence intervals were estimated by unconditional logistic regression adjusted for age, sex, study, maternal education, and maternal age. Day-care center attendance in the first year of life was associated with a reduced risk of ALL (odds ratio = 0.77, 95% confidence interval: 0.71, 0.84), with a marked inverse trend with earlier age at start (P < 0.0001). An inverse association was also observed with breastfeeding duration of 6 months or more (odds ratio = 0.86, 95% confidence interval: 0.79, 0.94). No significant relationship with a history of common infections in infancy was observed even though the odds ratio was less than 1 for more than 3 infections. The findings of this large pooled analysis reinforce the hypothesis that day-care center attendance in infancy and prolonged breastfeeding are associated with a decreased risk of ALL.
PMCID: PMC4850899  PMID: 25731888
breastfeeding; childhood leukemia; day care; infections
12.  A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma 
Cancer discovery  2015;5(9):920-931.
Metastasis is the leading cause of death in osteosarcoma patients, the most common pediatric bone malignancy. We conducted a multi-stage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified a SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P=1.2×10−9, OR 2.43, 95% CI 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. Additionally, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib, and had lowered Nfib expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis, and that NFIB is an osteosarcoma metastasis susceptibility gene.
PMCID: PMC4560660  PMID: 26084801
osteosarcoma; metastasis; genome-wide association study
13.  Immune-related conditions and acute leukemia in children with Down syndrome: A Children's Oncology Group report 
Children with Down syndrome (DS) have unique immune profiles and increased leukemia susceptibility.
Mothers of 158 children with DS diagnosed with acute leukemia at 0-19 years in 1997-2002 and 173 children with DS but no leukemia were interviewed. Associations were evaluated via multivariable unconditional logistic regression.
No associations were detected for asthma, eczema, allergies, or hypothyroidism. Diabetes mellitus associated with leukemia (odds ratio=9.23, 95% confidence interval: 2.33-36.59), however most instances occurred concurrent with or after the leukemia diagnosis.
Conclusions and Impact
Children with DS who develop leukemia have increased diabetes risk, likely due to treatment and underlying susceptibility factors.
PMCID: PMC4323733  PMID: 25499068
epidemiology; children; Down syndrome; diabetes mellitus; leukemia
14.  Parental tobacco and alcohol use and risk of hepatoblastoma in offspring: A report from the Children’s Oncology Group 
Hepatoblastoma (HB) is a rare pediatric liver tumor that has significantly increased in incidence over the last several decades. The International Agency for Cancer Research (IARC) recently classified HB 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 HB in a large case-control study.
Maternal interviews were completed for 383 cases diagnosed in the U.S. 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 employed unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between parental smoking and maternal drinking and offspring HB.
We found no association between HB 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 HB 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 HB.
Our results do not provide evidence for an etiological relationship between maternal smoking or drinking and HB, and only weak evidence for an association for paternal smoking in the year before pregnancy.
Our study provides limited support for HB as a tobacco-related cancer; however, it remains wise to counsel prospective parents on the merits of smoking cessation.
PMCID: PMC4188411  PMID: 23950215
hepatoblastoma; alcohol; smoking; childhood cancer
15.  An exploratory analysis of mitochondrial haplotypes and allogeneic hematopoietic cell transplantation (HCT) outcomes 
Certain mitochondrial haplotypes (mthaps) are associated with disease, possibly through differences in oxidative phosphorylation and/or immunosurveillance. We explored whether mthaps are associated with allogeneic HCT outcomes. Recipient (n=437) and donor (n=327) DNA was genotyped for common European mthaps (H, J, U, T, Z, K, V, X, I, W, K2). HCT outcomes for mthap matched siblings (n=198), all recipients, and all donors were modeled using relative risks (RR) and 95% confidence intervals and compared to mthap H, the most common. Siblings with I and V were significantly more likely to die within 5 years (RR=3.0; 1.2–7.9 and 4.6; 1.8–12.3, respectively). W siblings experienced higher aGVHD II–IV events (RR=2.1; 1.1–2.4) with no events for K or K2. Similar results were observed for all recipients combined, although J recipients experienced lower GVHD and higher relapse. Patients with I donors had a 2.7 fold (1.2–6.2) increased risk of death in five years, while few patients with K2 or W donors died. No patients with K2 donors and few patients with U donors relapsed. Mthap may be an important consideration in HCT outcomes, although validation and functional studies are needed. If confirmed, it may be feasible to select donors based on mthap to increase positive or decrease negative outcomes.
PMCID: PMC4272903  PMID: 25300867
Mitochondria; HCT; GVHD; polymorphism
16.  Incidence of intracranial germ cell tumors by race in the United States, 1992–2010 
Journal of neuro-oncology  2014;120(2):381-388.
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.
PMCID: PMC4206671  PMID: 25086758
Pediatric cancer; Germ cell tumors; Intracranial; SEER; Incidence
17.  Infectious, autoimmune, and allergic diseases and risk of Hodgkin lymphoma in children and adolescents: A Children’s Oncology Group (COG) 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 cases 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.
PMCID: PMC4107091  PMID: 24523151
Hodgkin lymphoma; children; infections; autoimmune disease; allergies
18.  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 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.
PMCID: PMC4134712  PMID: 24934283
Hepatoblastoma; Beckwith-Wiedemann syndrome; Familial Adenomatous Polyposis; Kidney abnormalities; case-control study; congenital abnormality; congenital anomaly
19.  Barriers and alternatives to pediatric rheumatology referrals: survey of general pediatricians in the United States 
Access to pediatric rheumatology (PR) care is limited, however the impact that limited access to PR has on pediatricians has not been examined. The goal of this study was to investigate barriers to PR referrals and resulting alternative referral patterns among primary pediatricians.
A web-based survey was emailed to primary pediatricians practicing in Minnesota, North Dakota, and South Dakota in order to investigate access to PR care issues. Basic descriptive analysis was performed.
The response rate was 15 % (93/609). 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 six hours away. Ninety-two percent (85/92) had referred a patient to PR at least once, but 89 % (83/93) had experienced a situation in which they considered a referral to PR but ultimately did not. Many had referred to other subspecialists instead: 29 % (24/83) to pediatric infectious disease, 20 % to adult rheumatology, and 12 % to pediatric orthopedics, while 34 % managed the patient themselves. Thirty-five percent (32/60) had referred to an adult rheumatologist, commonly due to decreased travel (44 %), while physician preference was never selected as a reason.
Pediatricians often refer children with possible rheumatic disease to specialists other than PR mainly due to long travel distances. 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 PR care.
PMCID: PMC4517495  PMID: 26215389
Pediatrician; Pediatric rheumatology; Access to care
20.  Case-parent analysis of variation in pubertal hormone genes and pediatric osteosarcoma: a Children’s Oncology Group (COG) study 
Osteosarcoma (OS) is a rare malignant bone tumor with an overall incidence rate of 4.6 cases per million children aged 0-19 years in the United States. While the etiology of OS is largely unknown, its distinctive age-incidence pattern suggests that growth and development is crucial in genesis. Prior studies have suggested that variants in genes in the estrogen metabolism (ESTR) and insulin-like growth factor/growth hormone (IGF/GH) pathways are associated with OS. We examined 798 single nucleotide polymorphisms (SNPs) in 42 genes from these pathways in a case-parent study (229 complete triads and 56 dyads) using buccal cell samples. Relative risks (RR) and 95% confidence intervals (CI) associated with transmitting one or two copies of the variant were estimated using log-linear models. After Bonferroni correction, 1 SNP within the ESTR pathway (rs1415270: RR = 0.50 and 8.37 for 1 and 2 vs. 0 copies, respectively; p = 0.010), and two SNPs in the IGF/GH pathway (rs1003737: RR = 0.91 and 0.0001 for 1 and 2 vs. 0 copies, respectively; p <0.0001 and rs2575352: RR = 2.62 and 0.22 for 1 and 2 vs. 0 copies; p < 0.0001) were significantly associated with OS incidence. These results confirm previous findings that variation in the estrogen metabolism and bone growth pathways influence OS risk and further support a biologically and epidemiologically plausible role in OS development.
PMCID: PMC3508538  PMID: 23205180
Osteosarcoma; case-parent study; growth and development; insulin-like growth factor pathway; estrogen metabolism pathway
21.  Maternal and birth characteristics and childhood rhabdomyosarcoma: a report from the Children’s Oncology Group 
Cancer causes & control : CCC  2014;25(7):905-913.
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.
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.
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 (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).
Overall, we found little evidence that these maternal and birth characteristics are strongly associated with childhood rhabdomyosarcoma.
PMCID: PMC4091713  PMID: 24831857
abnormal vaginal bleeding; epidemiology; rhabdomyosarcoma; soft tissue sarcoma
22.  Family history of cancer and childhood rhabdomyosarcoma: a report from the Children's Oncology Group and the Utah Population Database 
Cancer Medicine  2015;4(5):781-790.
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 (ORs) and 95% confidence intervals (CI). Having a first-degree relative with a cancer history was more common in RMS cases than controls (ORs = 1.39, 95% CI: 0.97–1.98). Notably, this association was stronger among those with embryonal RMS (ORs = 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 (ORs = 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.
PMCID: PMC4430270  PMID: 25809884
Childhood cancer; epidemiology; family history; rhabdomyosarcoma; soft tissue sarcoma
23.  Genetic and nongenetic risk factors for childhood cancer 
The causes of childhood cancer have been systematically studied for several decades, but apart from high-dose radiation and prior chemotherapy there are few or no strong external risk factors. On the other hand, inherent risk factors including birth weight, parental age, and congenital anomalies are consistently associated with most types of pediatric cancer. Rare, highly-penetrant syndromes have long been known to cause a small proportion of cancers but recently the contribution of common genetic variation to etiology has come into focus through genome wide association studies. These have highlighted genes not previously implicated in childhood cancers and, surprisingly, have suggested that common variation explains a larger proportion of childhood cancers than adult. Rare variation and non-Mendelian inheritance, such as through maternal genetic effects or de novo germline mutations, may also contribute to childhood cancer risk but have not been widely examined to date.
PMCID: PMC4384439  PMID: 25435109
Epidemiology; etiology; genome-wide association studies; case-control studies; pediatric cancer
24.  Cancer risk among children with very low birth weight 
Pediatrics  2009;124(1):96-104.
Risk of hepatoblastoma is strongly increased among children with very low birth weight (VLBW: <1,500 grams). Because data on VLBW and other childhood cancers is sparse, we examined the risk of malignancy following VLBW in a large dataset.
We combined case-control datasets created by linking the cancer and birth registries of California, Minnesota, New York, Texas, and Washington states, which comprised 17,672 children diagnosed with cancer at 0-14 years of age and 57,966 randomly selected controls. Unconditional logistic regression was used to examine the association of cancer with VLBW and moderately low birth weights (1,500-1,999g and 2,000-2,499g) compared to moderate/high birth weight (≥2,500) adjusting for sex, gestational age, birth order, plurality, maternal age, maternal race, state, and year of birth.
Most childhood cancers were not associated with low birth weights. However, retinoblastoma and gliomas other than astrocytomas and ependymomas were possibly associated with VLBW, with respective odds ratios (OR) of 2.43 (95% Confidence Interval (CI): 1.00-5.89) and 2.13 (95% CI: 0.71-6.39). Risk of other gliomas was also increased among children weighing 1,500-1,999g at birth (OR = 3.58; 95% CI: 1.98-6.47). For hepatoblastoma the ORs associated with birth weights of 2,000-2,499g, 1,500-1999g, and 350-1,499g were 1.56 (95% CI: 0.81-2.98), 3.37 (95% CI: 1.44-7.88), and 17.18 (95% CI: 7.46-39.54), respectively
These data suggest no association between most cancers and VLBW with the exception of the known association with hepatoblastoma and possible moderately increased risks of other gliomas and retinoblastoma, which may warrant confirmation.
PMCID: PMC2704984  PMID: 19564288
Infant; very low birth weight; cancer; case-control studies; registries
25.  Parental age and risk of childhood cancer: A pooled analysis 
Epidemiology (Cambridge, Mass.)  2009;20(4):475-483.
Few risk factors for childhood cancer are well-established. We investigated whether advancing parental age increases childhood cancer risk.
We assessed the relationship between parental age and childhood cancer in a case-control study using pooled population-based data. Our pooling was based on linked cancer and birth registry records from New York, Washington, Minnesota, Texas, and California. Subjects included 17,672 cancer cases diagnosed at ages 0–14 years during 1980–2004 and 57,966 controls born during 1970–2004. Persons with Down syndrome were excluded. Odds ratios and 95% confidence intervals were calculated by logistic regression for the association between parental age and childhood cancer after adjustment for sex, birth weight, gestational age, birth order, plurality, maternal race, birth year, and state.
Positive linear trends per 5-year maternal age increase were –observed for childhood cancers overall (odds ratio = 1.08 [95% confidence interval = 1.06–1.10]) and 7 of the 10 most frequent diagnostic groups: leukemia (1.08 [1.05–1.11]), lymphoma (1.06 [1.01–1.12]), central nervous system tumors (1.07 [1.03–1.10]), neuroblastoma (1.09 [1.04–1.15]), Wilms’ tumor (1.16 [1.09–1.22]), bone tumors (1.10 [ 1.00–1.20]), and soft tissue sarcomas (1.10 [1.04–1.17]). No maternal age effect was noted for retinoblastoma, germ cell tumors, or hepatoblastoma. Paternal age was not independently associated with most childhood cancers after adjustment for maternal age.
Our results suggest that older maternal age increases risk for most common childhood cancers. Investigation into possible mechanisms for this association is warranted.
PMCID: PMC2738598  PMID: 19373093

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