![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.

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 hematopoietic cell transplantation (HCT) outcomes. Recipient (n= 437) and donor (n= 327) DNA were genotyped for common European mthaps (H, J, U, T, Z, K, V, X, I, W, and 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 with mthap H, the most common mitochondrial haplotypes. Siblings with I and V were significantly more likely to die within 5 years (RR= 3.0; 95% confidence interval [CI], 1.2 to 7.9; and RR= 4.6; 95% CI, 1.8 to 12.3, respectively). W siblings experienced higher acute graft-versus-host disease (GVHD) grades II to IV events (RR= 2.1; 95% CI, 1.1 to 2.4) with no events for those with 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 to 6.2) increased risk of death in 5 years, whereas 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.

BACKGROUND: Children with Down syndrome have unique immune profiles and increased leukemia susceptibility.\n\nMETHODS: Mothers of 158 children with Down syndrome diagnosed with acute leukemia at 0 to 19 years in 1997 to 2002 and 173 children with Down syndrome but no leukemia were interviewed. Associations were evaluated via multivariable unconditional logistic regression.\n\nRESULTS: No associations were detected for asthma, eczema, allergies, or hypothyroidism. Diabetes mellitus associated with leukemia (OR = 9.23; 95% confidence interval 2.33-36.59); however, most instances occurred concurrent with or after the leukemia diagnosis.\n\nCONCLUSIONS AND IMPACT: Children with Down syndrome who develop leukemia have increased diabetes risk, likely due to treatment and underlying susceptibility factors.

OBJECTIVE\nTo evaluate the risk of cancer after assisted reproductive technology (ART) therapy. \n\nDESIGN\nLongitudinal cohort study. \n\nSETTING\nNot applicable. \n\nPATIENT(S)\nNew York, Texas, and Illinois residents between 2004 and 2009, treated with ART, comprising cycles of 113,226 women, including 53,859 women without prior ART treatment, who were linked to their respective state cancer registries and whose cycles were reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System (SART CORS). \n\nINTERVENTION(S)\nNone. \n\nMAIN OUTCOME MEASURE(S)\nDiagnosis of cancer, as reported to the state cancer registry; standardized incidence ratios (SIR) and their 95% confidence intervals, comparing the observed to expected cancer cases based on age-specific cancer rates in the general population of each state. \n\nRESULT(S)\nAmong the cohort of women without prior ART therapy, hazard ratios (HR) and 95% confidence intervals (CI) were calculated for treatment parameters and reproductive history factors. The mean follow-up period was 4.87 years; among women without prior ART, 450 women developed 460 cancers. Women treated with ART had a statistically significantly lower risk for all cancers (for all women: SIR 0.78; CI, 0.73–0.83; women without prior ART: SIR 0.75; CI, 0.68–0.82), breast cancer, and all female genital cancers; a non-statistically-significant lower risk for endocrine and uterine cancer; and a non-statistically-significant higher risk for melanoma and ovarian cancer. Among women without prior ART, we found no statistically significant increased HR by parity, number of cycles, cumulative follicle-stimulating hormone dosage, or cycle outcome. \n\nCONCLUSION(S)\nWomen initiating ART treatment have no greater risk for developing cancer after nearly 5 years of follow-up compared with the general population and with other women treated with ART.

Genetic syndromes and pediatric cancers are rare, so instances of co-occurrence raise the question of whether the two conditions may be etiologically linked. Clear examples of causal association can be found in the cancer predisposition syndromes. This report contains the results of a systematic literature search using Ovid Medline for co- occurrence of genetic syndromes with 23 types of pediatric cancer. The results reflect known associations as well as many reports of infrequently observed co-occurrences. This compilation may suggest previously overlooked patterns, and the information could be used to identify gene pathways critical in the development of childhood cancers. Pediatr Blood Cancer 2015;62:2071–2075.

Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.

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.

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.

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.