<h3>Importance</h3><p>Tetralogy of Fallot (TOF) is a surgically repairable form of cyanotic congenital heart disease. Multicenter data for long-term survival following repair are sparse.</p><h3>Objective</h3><p>To evaluate the long-term transplant-free survival of TOF by surgical strategy adjusted for era and patient characteristics.</p><h3>Design, Setting, and Participants</h3><p>Retrospective cohort study enriched with data from the National Death Index and the Organ Procurement and Transplantation Network through 2014. Multicenter cohort from the Pediatric Cardiac Care Consortium (PCCC), a large, US-based clinical registry for interventions for congenital heart disease. The cohort included patients with adequate identifiers for linkage with the National Death Index and the Organ Procurement and Transplantation Network who were enrolled in the PCCC registry between 1982 and 2003 and survived surgical repair of simple TOF. Data were analyzed between September 2015 and April 2018.</p><h3>Exposures</h3><p>We examined patient-associated and surgery-associated risk factors affecting survival.</p><h3>Main Outcomes and Measures</h3><p>We analyzed the transplant-free survival during early (&lt;6 years) and late (≥6 years) phase after TOF surgical repair.</p><h3>Results</h3><p>Of the 3283 patients who survived repair for simple TOF and met the study’s inclusion criteria, 56.4% were male and 43.6% were female. Twenty-five–year survival following TOF repair was 94.5%. Multivariable analysis demonstrated increased risk of early mortality with staged repair (HR, 2.68; 95% CI, 1.59-4.49) and non–valve-sparing operation (HR, 3.76; 95% CI, 1.53-9.19). Presence of a genetic abnormality was associated with increased risk of death both in the early (HR, 3.64; 95% CI, 2.05-6.47) and late postoperative phase (HR, 4.41; 95% CI, 2.62-7.44).</p><h3>Conclusions and Relevance</h3><p>Long-term survival after simple TOF repair is excellent. Staged repair and non–valve-sparing operations were negatively associated with survival in the early postrepair phase but not the late postrepair phase. These data are important for patients with repaired TOF and their caretakers and may guide surgical strategies for optimizing the long-term outcomes of this population.</p>

Osteosarcoma is considered to be the most common primary malignant bone cancer among children and young adults. Previous studies suggest growth spurts and height to be risk factors for osteosarcoma. However, studies on the genetic cause are still limited given the rare occurrence of the disease. In this study, we investigated in a family trio data set that is composed of 209 patients and their unaffected parents and conducted a genome-wide association study (GWAS) to identify genetic risk factors for osteosarcoma. We performed a Bayesian gene-based GWAS based on the single-nucleotide polymorphism (SNP)-level summary statistics obtained from a likelihood ratio test of the trio data, which uses a hierarchically structured prior that incorporates the SNP-gene hierarchical structure. The Bayesian approach has higher power than SNP-level GWAS analysis due to the reduced number of tests and is robust by accounting for the correlations between SNPs so that it borrows information across SNPs within a gene. We identified 217 genes that achieved genome-wide significance. Ingenuity pathway analysis of the gene set indicated that osteosarcoma is potentially related to TP53, estrogen receptor signaling, xenobiotic metabolism signaling, and RANK signaling in osteoclasts.

Background: Congenital heart surgery has improved the survival of patients with even the most complex defects, but the long-term survival after these procedures has not been fully described. Objectives: The purpose of this study was to evaluate the long-term survival of patients (age <21 years) who were operated on for congenital heart defects (CHDs). Methods: This study used the Pediatric Cardiac Care Consortium data, a U.S.-based, multicenter registry of pediatric cardiac surgery. Survival analysis included 35,998 patients who survived their first congenital heart surgery at <21 years of age and had adequate identifiers for linkage with the National Death Index through 2014. Survival was compared to that in the general population using standardized mortality ratios (SMRs). Results: After a median follow-up of 18 years (645,806 person-years), 3,191 deaths occurred with an overall SMR of 8.3 (95% confidence interval [CI]: 8.0 to 8.7). The 15-year SMR decreased from 12.7 (95% CI: 11.9 to 13.6) in the early era (1982 to 1992) to 10.0 (95% CI: 9.3 to 10.8) in the late era (1998 to 2003). The SMR remained elevated even for mild forms of CHD such as patent ductus arteriosus (SMR 4.5) and atrial septal defects (SMR 4.9). The largest decreases in SMR occurred for patients with transposition of great arteries (early: 11.0 vs. late: 3.8; p < 0.05), complete atrioventricular canal (31.3 vs. 15.3; p < 0.05), and single ventricle (53.7 vs. 31.3; p < 0.05). Conclusions: In this large U.S. cohort, long-term mortality after congenital heart surgery was elevated across all forms of CHD. Survival has improved over time, particularly for severe defects with significant changes in their management strategy, but still lags behind the general population.

Advanced parental age has been associated with adverse health effects in the offspring including childhood (0–14 years) acute lymphoblastic leukemia (ALL), as reported in our meta-analysis of published studies. We aimed to further explore the association using primary data from 16 studies participating in the Childhood Leukemia International Consortium. Data were contributed by 11 case–control (CC) studies (7919 cases and 12,942 controls recruited via interviews) and five nested case–control (NCC) studies (8801 cases and 29,690 controls identified through record linkage of population-based health registries) with variable enrollment periods (1968–2015). Five-year paternal and maternal age increments were introduced in two meta-analyses by study design using adjusted odds ratios (OR) derived from each study. Increased paternal age was associated with greater ALL risk in the offspring (OR CC 1.05, 95% CI 1.00–1.11; OR NCC 1.04, 95% CI 1.01–1.07). A similar positive association with advanced maternal age was observed only in the NCC results (OR CC 0.99, 95% CI 0.91–1.07, heterogeneity I 2 = 58%, p = 0.002; OR NCC 1.05, 95% CI 1.01–1.08). The positive association between parental age and risk of ALL was most marked among children aged 1–5 years and remained unchanged following mutual adjustment for the collinear effect of the paternal and maternal age variables; analyses of the relatively small numbers of discordant paternal-maternal age pairs were not fully enlightening. Our results strengthen the evidence that advanced parental age is associated with increased childhood ALL risk; collinearity of maternal with paternal age complicates causal interpretation. Employing datasets with cytogenetic information may further elucidate involvement of each parental component and clarify underlying mechanisms.

The Inaugural Symposium on Childhood Cancer Health Disparities was held in Houston, Texas, on November 2, 2016. The symposium was attended by 109 scientists and clinicians from diverse disciplinary backgrounds with interests in pediatric cancer disparities and focused on reviewing our current knowledge of disparities in cancer risk and outcomes for select childhood cancers. Following a full day of topical sessions, everyone participated in a brainstorming session to develop a working strategy for the continued expansion of research in this area. This meeting was designed to serve as a springboard for examination of childhood cancer disparities from a more unified and systematic approach and to enhance awareness of this area of need.

Background: Studies have reported increased risks of pediatric acute lymphoblastic leukemia (ALL) among children born by cesarean delivery (CD). However, no previous study has examined the impact of CD on risk of infant leukemia specifically. Methods: 443 infants diagnosed with acute leukemia, including both ALL and acute myeloid leukemia (AML), were identified at Children's Oncology Group institutions between January 1996 and December 2006. 324 controls frequency matched by year of birth were identified though random digit dialing and random selection from US birth registries. Using interview data and, for a subset of participants, medical record data, we analyzed CD overall and by indications that likely resulted in pre-labor CD (PLCD) or emergency CD (ECD). Odds ratios (OR) and 95% confidence intervals (CI) for risk of ALL and AML were estimated using multivariable unconditional logistic regression models, adjusted for year of birth, birth weight, and maternal race. Results: We observed an increased point estimate for the association between CD and ALL (OR and CI: 1.52 [1.02, 2.25]). We did not observe an association between CD and AML (OR and CI: 1.02 [0.64, 1.62]). In analyses of indication for CD, we observed elevated effect estimates for the associations of both PLCD and ECD and infant ALL. Conclusions: Our analysis suggests an increased risk of infant ALL following CD, including both PLCD and ECD. Altered microbiota colonization may be involved, but clear biological mechanisms have yet to be determined. Impact: This study provides the first in-depth examination of CD and infant leukemia.

The associations between childhood acute lymphoblastic leukemia (ALL) and several factors related to early stimulation of the immune system, that is, farm residence and regular contacts with farm animals (livestock, poultry) or pets in early childhood, were investigated using data from 13 case–control studies participating in the Childhood Leukemia International Consortium. The sample included 7847 ALL cases and 11,667 controls aged 1–14 years. In all studies, the data were obtained from case and control parents using standardized questionnaires. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression adjusted for age, sex, study, maternal education, and maternal age. Contact with livestock in the first year of life was inversely associated with ALL (OR = 0.65, 95% CI: 0.50, 0.85). Inverse associations were also observed for contact with dogs (OR = 0.92, 95% CI: 0.86, 0.99) and cats (OR = 0.87, 95% CI: 0.80, 0.94) in the first year of life. There was no evidence of a significant association with farm residence in the first year of life. The findings of these large pooled and meta‐analyses add additional evidence to the hypothesis that regular contact with animals in early childhood is inversely associated with childhood ALL occurrence which is consistent with Greaves’ delayed infection hypothesis.

Some cancer predisposing germline mutations cause overt birth defects and congenital anomalies. Others are clinically silent and can only be suspected by the presence of increased cancer incidence in family members. A new study shows that long-term monitoring of families may be needed to discover previously unsuspected underlying cancer predisposing mutations.

Overall survival of patients with osteosarcoma (OS) has improved little in the past three decades, and better models for study are needed. OS is common in large dog breeds and is genetically inducible in mice, making the disease ideal for comparative genomic analyses across species. Understanding the level of conservation of intertumor transcriptional variation across species and how it is associated with progression to metastasis will enable us to more efficiently develop effective strategies to manage OS and to improve therapy. In this study, transcriptional profiles of OS tumors and cell lines derived from humans (n ¼ 49), mice (n ¼ 103), and dogs (n ¼ 34) were generated using RNA sequencing. Conserved intertumor transcriptional variation was present in tumor sets from all three species and comprised gene clusters associated with cell cycle and mitosis and with the presence or absence of immune cells. Further, we developed a novel gene cluster expression summary score (GCESS) to quantify intertumor transcriptional variation and demonstrated that these GCESS values associated with patient outcome. Human OS tumors with GCESS values suggesting decreased immune cell presence were associated with metastasis and poor survival. We validated these results in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas. Our results suggest that quantification of immune cell absence and tumor cell proliferation may better inform therapeutic decisions and improve overall survival for OS patients. Significance: This study offers new tools to quantify tumor heterogeneity in osteosarcoma, identifying potentially useful prognostic biomarkers for metastatic progression and survival in patients.

Recent projections for the USA estimate that 6590 patients are diagnosed annually with acute lymphocytic leukemia (ALL) and 19,950 with acute myeloid leukemia (AML), while approximately 1430 patients die from ALL and 10,430 from AML (Siegel et al., CA Cancer J Clin 66(1):7-30, 2016). Together these forms of acute leukemia represent about 1.6% of all newly diagnosed cancers and 2.0% of all cancer deaths in the USA (Siegel et al., CA Cancer J Clin 66(1):7-30, 2016). Advances in the understanding of immunology and molecular/genetic features of the acute leukemias along with laboratory improvements in immunophenotyping and cytogenetic characterization have led to the recognition of molecularly defined subtypes of ALL and AML, targeted therapeutics, and recognition of distinct prognostic groups. The most recent World Health Organization (WHO) classification of hematopoietic malignancies considers three major categories of acute leukemia: AML and related myeloid precursor neoplasms, precursor lymphoid neoplasms (encompassing the entities previously known as ALL), and acute leukemias of ambiguous lineage (World Health Organization classification of tumours of haematopoietic and lymphoid tissues, 4th ed. Lyon: International Agency for Research on Cancer, 2008). Consistent with classifications used in cancer registries, to date most epidemiologic investigations have considered all acute leukemias combined or the broad categories of ALL and AML, although an increasing number of studies, especially those of genetic risk factors, examine cases by molecular subtype. Traditionally pediatric acute leukemias, defined either as those diagnosed at 0-14 or 0-19 years of age, have been studied separately from that in adults.

The etiology of childhood cancers remains largely unknown, especially regarding environmental and behavioral risk factors. Unpacking the association between socioeconomic status (SES) and incidence may offer insight into such etiology. We tested associations between SES and childhood cancer incidence in a population-based case-cohort study (source cohort: Minnesota birth registry, 1989-2014). Cases, ages 0-14 years, were linked from the Minnesota Cancer Surveillance System to birth records through probabilistic record linkage. Controls were 4:1 frequency matched on birth year (2,947 cases and 11,907 controls). We tested associations of individual-level (maternal education) and neighborhood-level (census tract composite index) SES using logistic mixed models. In crude models, maternal education was positively associated with incidence of acute lymphoblastic leukemia (odds ratio (OR) = 1.10, 95% confidence interval (CI): 1.02, 1.19), central nervous system tumors (OR = 1.12, 95% CI: 1.04, 1.21), and neuroblastoma (OR = 1.15, 95% CI: 1.02, 1.30). Adjustment for established risk factors-including race/ethnicity, maternal age, and birth weight-substantially attenuated these positive associations. Similar patterns were observed for neighborhood-level SES. Conversely, higher maternal education was inversely associated with hepatoblastoma incidence (adjusted OR = 0.70, 95% CI: 0.51, 0.98). Overall, beyond the social patterning of established demographic and pregnancy-related exposures, SES is not strongly associated with childhood cancer incidence.

Background: Since 1975, childhood cancer incidence rates have gradually increased in theUnited States; however, few studies have conducted analyses across time to unpack this temporal rise. The aim of this studywas to test the hypothesis that increasing cancer incidence rates are due to secular trends in pregnancy characteristics that are established risk factors for childhood cancer incidence including older maternal age, higher birthweight, and lower birth order.We also consid- ered temporal trends in sociodemographic characteristics including race/ethnicity and poverty. Procedure:We conducted a time series county-level ecologic analysis using linked population- based data from Surveillance, Epidemiology, and EndResults cancer registries (1975–2013), birth data from the National Center for Health Statistics (1970–2013), and sociodemographic data from theUSCensus (1970–2010).We estimated unadjusted and adjusted average annual percent changes (AAPCs) in incidence of combined (all diagnoses) and individual types of cancer among children, ages 0–4 years, from Poisson mixed models. Results: There was a statistically significant unadjusted temporal rise in incidence of combined childhood cancers (AAPC = 0.71%; 95% CI = 0.55–0.86), acute lymphoblastic leukemia (0.78%; 0.49–1.07), acute myeloid leukemia (1.86%; 1.13–2.59), central nervous system tumors (1.31%; 0.94–1.67), and hepatoblastoma (2.70%; 1.68–3.72). Adjustment for county-level maternal age reduced estimated AAPCs between 8% (hepatoblastoma) and 55% (combined).However, adjust- mentfor other county characteristics did not attenuate AAPCs, andAAPCsremained significantly above0%in models fully adjusted for county-level characteristics. Conclusion: Although rising maternal age may account for some of the increase in childhood cancer incidence over time, other factors, not considered in this analysis, may also contribute to temporal trends.

Background: Since 1975, childhood cancer incidence rates have gradually increased in theUnited States; however, few studies have conducted analyses across time to unpack this temporal rise. The aim of this studywas to test the hypothesis that increasing cancer incidence rates are due to secular trends in pregnancy characteristics that are established risk factors for childhood cancer incidence including older maternal age, higher birthweight, and lower birth order.We also consid- ered temporal trends in sociodemographic characteristics including race/ethnicity and poverty. Procedure:We conducted a time series county-level ecologic analysis using linked population- based data from Surveillance, Epidemiology, and EndResults cancer registries (1975–2013), birth data from the National Center for Health Statistics (1970–2013), and sociodemographic data from theUSCensus (1970–2010).We estimated unadjusted and adjusted average annual percent changes (AAPCs) in incidence of combined (all diagnoses) and individual types of cancer among children, ages 0–4 years, from Poisson mixed models. Results: There was a statistically significant unadjusted temporal rise in incidence of combined childhood cancers (AAPC = 0.71%; 95% CI = 0.55–0.86), acute lymphoblastic leukemia (0.78%; 0.49–1.07), acute myeloid leukemia (1.86%; 1.13–2.59), central nervous system tumors (1.31%; 0.94–1.67), and hepatoblastoma (2.70%; 1.68–3.72). Adjustment for county-level maternal age reduced estimated AAPCs between 8% (hepatoblastoma) and 55% (combined).However, adjust- mentfor other county characteristics did not attenuate AAPCs, andAAPCsremained significantly above0%in models fully adjusted for county-level characteristics. Conclusion: Although rising maternal age may account for some of the increase in childhood cancer incidence over time, other factors, not considered in this analysis, may also contribute to temporal trends.

BACKGROUND Over the past two decades the characteristics of women giving birth in the United States and the nature of the births themselves have changed dramatically, with increases in older maternal age, plural births, cesarean deliveries, and conception from infertility treatment. OBJECTIVE To evaluate the risk of severe maternal morbidity by maternal fertility status, and for IVF pregnancies, by oocyte source and embryo state combinations. STUDY DESIGN Women in eight States who underwent in vitro fertilization (IVF) cycles resulting in a live birth during 2004-13 were linked to their infant’s birth certificates; a 10:1 sample of births from non-IVF deliveries were selected for comparison; those with an indication of infertility treatment on the birth certificate were categorized as subfertile, all others were categorized as fertile. IVF pregnancies were additionally categorized by oocyte source (autologous vs donor) and embryo state (fresh vs thawed). Maternal morbidity was identified from the birth certificate, modeled using logistic regression, and reported as adjusted odds ratios and 95% confidence intervals [AOR (95% CI)]. The reference group was fertile women. RESULTS The study population included 1,477,522 pregnancies (1,346,118 fertile, 11,298 subfertile, 80,254 IVF autologous-fresh, 21,964 IVF autologous-thawed, 13,218 IVF donor-fresh and 4,670 IVF donor-thawed pregnancies); 1,420,529 singleton, 54,573 twin, and 2,420 triplet+ pregnancies. Compared to fertile women, subfertile and the four groups of IVF-treated women had increased risks for blood transfusion and 3rd or 4th degree perineal laceration (subfertile, 1.58 [1.23, 2.02] and 2.08 [1.79, 2.43]; autologous-fresh, 1.33 [1.14, 1.54] and 1.37 [1.26, 1.49]; autologous-thawed, 1.94 [1.60, 2.36] and 2.10 [1.84, 2.40]; donor-fresh 2.16 [1.69, 2.75] and 2.11 [1.66, 2.69]; and donor-thawed, 2.01 [1.38, 2.92] and 1.28 [0.79, 2.08]). Also compared to fertile women, the risk of unplanned hysterectomy was increased for IVF-treated women in the autologous-thawed group (2.80, [1.96, 4.00]), donor-fresh group (2.14 [1.33, 3.44], and the donor-thawed group (2.46 [1.33, 4.54]). The risk of ruptured uterus was increased for IVF-treated women in the autologous-fresh group (1.62 [1.14, 2.29]). Among women with a prior birth, the risk of blood transfusion after a vaginal birth was increased for subfertile women (2.91 [1.38, 6.15]), and women in all four IVF groups (autologous-fresh, 1.93 [1.23, 3.01]; autologous-thawed, 2.99 [1.78, 5.02]; donor-fresh, 5.13 [2.39, 11.02]; and donor-thawed, 5.20 [1.83, 14.82]; the risk after a cesarean delivery was increased in the autologous-thawed group (1.74 [1.29, 2.33]) and the donor-fresh group (1.62 [1.07, 2.45]). Unplanned hysterectomy was increased in the autologous-thawed (2.31, [1.43, 3.71]) and donor-thawed groups (2.45 [1.06, 5.67]). CONCLUSIONS The risks of severe maternal morbidity are increased for subfertile and IVF births, particularly in pregnancies that are not from autologous, fresh cycles.

BACKGROUND Male sex is associated with an increased risk of childhood cancer as is high birthweight. Given that sex determination precedes birthweight we conducted a mediation analysis to estimate the direct effect of sex in association with childhood cancer tumor type with birthweight as the mediator. METHODS Cases (n = 12,632) and controls (n = 64,439) (ages 0-14 years) were identified from population-based cancer and birth registries in Minnesota, New York, and Washington states (1970-2014). An inverse odds weighting (IOW) mediation analysis was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) as the measure of association between sex and cancer. RESULTS A significant indirect effect was observed for sex and lymphoid leukemia, mediated by birthweight (indirectOR: 1.03; 95% CI: 1.02-1.04). We observed significant direct effects for male sex and lymphoid leukemia (directOR: 1.16; 95% CI: 1.08-1.25), Hodgkin lymphoma (directOR: 1.48; 95% CI: 1.22-1.81), Burkitt lymphoma (directOR: 5.02; 95% CI: 3.40-7.42), other non-Hodgkin lymphoma (directOR: 1.42; 95% CI: 1.18-1.70), intracranial embryonal tumors (directOR: 1.49; 95% CI: 1.26-1.76), hepatoblastoma (directOR: 1.90; 95% CI: 1.40-2.59), and rhabdomyosarcoma (directOR: 1.47; 95% CI: 1.19-1.81). There were also inverse associations for extracranial GCTs (directOR: 0.41; 95% CI: 0.26-0.63) and thyroid carcinoma (directOR: 0.35; 95% CI: 0.25-0.50). CONCLUSION Significant direct effects for sex and numerous childhood cancer types suggests sex-specific factors such as differences in gene expression from the autosomes or the X chromosome, rather than birthweight, may underlie sex differences in tumor risk.