![Figure][1] With the death of Dr. Julie A. Ross, pediatric cancer epidemiology lost one of its leaders. Julie died of cancer on June 19th at the age of 54. A career-long member of the University of Minnesota faculty, Julie was Professor of Pediatrics and the Suzanne Holmes Hodder Chair in

Comment 1278 www.thelancet.com/oncology Vol 16 October 2015 challenge the existing regulatory infrastructure. Would 11 drugs in nine treatment groups, using various companion diagnostics, and for any histology, all be simultaneously approved for expanded indication if confi rmed in a phase 3 trial? What if some drugs are not already commercially available? What should be done about development and approval pathways for multiple incorporated companion diagnostics? Thus, to pre-emptively tackle these issues in preparation for potential future positive type II trials, next-generation regulation must accompany next-generation trials through the integration of next-generation companion diagnostics and the concept of personalised treatment strategies, to continue to advance clinical cancer care. 1 fi rst speculated that acute lymphoblastic leukaemia is indirectly caused by an absence of infection in early life and subsequent fl orid immune response when infections are inevitably encountered. Many lines of evidence address this hypothesis and not all agree. For instance, the rough correlation of acute lymphoblastic leukaemia incidence with national socioeconomic status is consistent with this hypothesis. However, evidence from studies of individuals is less clear about the role of early infection, partly because of the frequent reliance on case-control studies with data for infections collected by maternal interview. Other studies 2 examine proxies for infection, with the largest study of its kind indicating that acute lymphoblastic leukaemia risk is decreased in children with early exposure to day care, where increased transmission of microbes would be expected. Into this ambiguous scientifi c literature comes a study by Jiun-Nong Lin and colleagues in The Lancet Oncology, 3 who report fi ndings from a unique cohort study that uses data from Taiwan's nearly universal National Health Insurance programme to examine the association between enterovirus infection and childhood leukemia. They identifi ed that early enterovirus infections seemed to halve the risk of leukaemia. In view of the general absence of strong, modifi able risk factors for childhood leukaemia, 4 this study is exciting because it alludes to the possibility of inoculation against the most frequent forms of cancer in children. 5 Yet, a crisis of reproducibility exists in biomedical science,

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.

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=1.2x10(-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.

The causes of childhood cancer have been systematically studied for decades, but apart from high-dose radiation and prior chemotherapy there are few strong external risk factors. However, inherent risk factors including birth weight, parental age, and congenital anomalies are consistently associated with most types of pediatric cancer. 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 have suggested that common variation explains a larger proportion of childhood cancers than adult. Rare variation and nonmendelian inheritance may also contribute to childhood cancer risk but have not been widely examined.

BACKGROUND: 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.\n\nMETHODS: 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.\n\nRESULTS: 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.\n\nCONCLUSION: 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.

Background: High birthweight is an established risk factor for childhood leukaemia. Its association with other childhood cancers is less clear, with studies hampered by low case numbers. Methods: We used two large independent datasets to explore risk associations between birthweight and all subtypes of childhood cancer. Data for 16 554 cases and 53 716 controls were obtained by linkage of birth to cancer registration records across five US states, and 23 772 cases and 33 206 controls were obtained from the UK National Registry of Childhood Tumours. US, but not UK, data were adjusted for gestational age, birth order, plurality, and maternal age and race/ethnicity. Results: Risk associations were found between birthweight and several childhood cancers, with strikingly similar results between datasets. Total cancer risk increased linearly with each 0.5 kg increase in birthweight in both the US [odds ratio 1.06 (95% confidence interval 1.04, 1.08)] and UK [1.06 (1.05, 1.08)] datasets. Risk was strongest for leukaemia [USA: 1.10 (1.06, 1.13), UK: 1.07 (1.04, 1.10)], tumours of the central nervous system [USA: 1.05 (1.01, 1.08), UK: 1.07 (1.04, 1.10)], renal tumours [USA: 1.17 (1.10, 1.24), UK: 1.12 (1.06, 1.19)] and soft tissue sarcomas [USA: 1.12 (1.05, 1.20), UK: 1.07 (1.00, 1.13)]. In contrast, increasing birthweight decreased the risk of hepatic tumours [USA: 0.77 (0.69, 0.85), UK: 0.79 (0.71, 0.89) per 0.5 kg increase]. Associations were also observed between high birthweight and risk of neuroblastoma, lymphomas, germ cell tumours and malignant melanomas. For some cancer subtypes, risk associations with birthweight were non-linear. We observed no association between birthweight and risk of retinoblastoma or bone tumours. Conclusions: Approximately half of all childhood cancers exhibit associations with birthweight. The apparent independence from other factors indicates the importance of intrauterine growth regulation in the aetiology of these diseases.

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.

Table S1. Family history of cancer types and risk of childhood RMS.

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.

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. Exposure data were harmonized into compatible formats. Pooled analyses were undertaken using multivariable unconditional logistic regression. The odds ratio (ORs) for acute lymphoblastic leukemia (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 and 3,635 controls), 1.43 (95% CI: 1.32, 1.54) (5,055 cases and 7,370 controls) and 1.36 (95% CI: 1.23, 1.51) (4,162 cases and 5,179 controls), respectively. Corresponding ORs for risk of acute myeloid leukemia (AML) were 1.49 (95% CI: 1.02, 2.16) (173 cases and 1,789 controls), 1.55 (95% CI: 1.21, 1.99) (344 cases and 4,666 controls) and 1.08 (95% CI: 0.76, 1.53) (198 cases and 2,655 controls), respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukemia 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 the associations between home pesticide use and childhood leukemia in an equally large sample, it would appear prudent to limit the use of home pesticides before and during pregnancy, and during childhood.

Background: 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. Procedure: Incident hepatoblastoma cases who were born <2,500g (N=60), diagnosed between 2000 and 2008, were identified through the Children's Oncology Group. Controls were recruited through state birth registries (N=51). Neonatal medical exposures were abstracted from medical records. Subjects from the Vermont Oxford Network were used for further comparisons, as were existing reports on neonatal medical exposures. Results: Case-control comparisons were hindered by poor matching within birth weight strata. Cases were smaller and received more aggressive neonatal treatment compared to controls, and reflected high correlation levels between birth weight and treatments. Similar difficulty was encountered when comparing cases to Vermont Oxford Network subjects; cases were smaller and required more aggressive neonatal therapy. Furthermore, it appears hepatoblastoma cases were exposed to a greater number of diagnostic X-rays than in case series previously reported in the neonatal literature. Conclusions: This study presents the largest case series of hepatoblastoma in <2,500g birth weight infants with accompanying neonatal medical exposure data. Findings confirm that birth weight is highly correlated with exposure intensity, and neonatal exposures are themselves highly correlated, which hampers the identification of a causal exposure among hepatoblastoma cases. Experimental models or genetic susceptibility testing may be more revealing of etiology.

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 5 years or more and those with T cell ALL which raises interesting questions on possible mechanisms.

BACKGROUND: The Childhood Cancer Research Network (CCRN) was established within the Children's Oncology Group (COG) in July 2008 to provide a centralized pediatric cancer research registry for investigators conducting approved etiologic and survivorship studies. The authors conducted an ecological analysis to characterize CCRN catchment at >200 COG institutions by demographic characteristics, diagnosis, and geographic location to determine whether the CCRN can serve as a population-based registry for childhood cancer.\n\nMETHODS: During 2009 to 2011, 18,580 US children newly diagnosed with cancer were registered in the CCRN. These observed cases were compared with age-specific, sex-specific, and race/ethnicity-specific expected numbers calculated from Surveillance, Epidemiology, and End Results (SEER) Program cancer incidence rates and 2010 US Census data.\n\nRESULTS: Overall, 42% of children (18,580 observed/44,267 expected) who were diagnosed with cancer at age <20 years were registered in the CCRN, including 45%, 57%, 51%, 44%, and 24% of those diagnosed at birth, ages 1 to 4 years, ages 5 to 9 years, ages 10 to 14 years, and ages 15 to 19 years, respectively. Some malignancies were better represented in the CCRN (leukemia, 59%; renal tumors, 67%) than others (retinoblastoma, 34%). There was little evidence of differences by sex or race/ethnicity, although rates in nonwhites were somewhat lower than rates in whites.\n\nCONCLUSIONS: Given the low observed-to-expected ratio, it will be important to identify challenges and barriers to registration to improve case ascertainment, especially for rarer diagnoses and older age groups; however, it is encouraging that some diagnoses in younger children are fairly representative of the population. Overall, the CCRN is providing centralized, real-time access to cases for research and could be used as a model for other national cooperative groups.

BACKGROUND: Maternal prenatal supplementation with folic acid and other vitamins has been inconsistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Little is known regarding the association with acute myeloid leukemia (AML), a rarer subtype.\n\nMETHODS: We obtained original data on prenatal use of folic acid and vitamins from 12 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980-2012), including 6,963 cases of ALL, 585 cases of AML, and 11,635 controls. Logistic regression was used to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for child's age, sex, ethnicity, parental education, and study center.\n\nRESULTS: Maternal supplements taken any time before conception or during pregnancy were associated with a reduced risk of childhood ALL; odds ratios were 0.85 (95% CI = 0.78-0.92) for vitamin use and 0.80 (0.71-0.89) for folic acid use. The reduced risk was more pronounced in children whose parents' education was below the highest category. The analyses for AML led to somewhat unstable estimates; ORs were 0.92 (0.75-1.14) and 0.68 (0.48-0.96) for prenatal vitamins and folic acid, respectively. There was no strong evidence that risks of either types of leukemia varied by period of supplementation (preconception, pregnancy, or trimester).\n\nCONCLUSIONS: Our results, based on the largest number of childhood leukemia cases to date, suggest that maternal prenatal use of vitamins and folic acid reduces the risk of both ALL and AML and that the observed association with ALL varied by parental education, a surrogate for lifestyle and sociodemographic characteristics.

BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: 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.

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. © 2014 Wiley Periodicals, Inc.

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.