<p>Background: Racial and ethnic disparities in incidence and outcomes for childhood B-cell acute lymphoblastic leukemia (B-ALL) are well established. While genome-wide association studies (GWASs) among children of European (EUR) genetic ancestry have identified robust risk loci, comparable studies in children of African (AFR) genetic ancestry do not exist. Here we report on results from the first GWAS of B-ALL exclusive to AFR children.</p>

<p>The generalizability of clinical trial outcomes hinges upon the equitable access and enrollment of diverse patient populations. Yet, disparities persist that may influence enrollment patterns. In neuroblastoma, the impact of ethnicity, socioeconomic status (SES), distance to care, and age at diagnosis on enrollment in therapeutic trials remains underexplored. We aimed to investigate these factors in neuroblastoma patients to identify potential disparities in clinical trial participation. We utilized the Childhood Cancer Research Network data, selecting neuroblastoma cases from 2008-2015, excluding those &amp;gt;21 years old or with incomplete data. We focused on factors influencing enrollment in therapeutic trials (ANBL0032, ANBL0421, ANBL0531, ANBL0532, ANBL0621, ANBL0931, ANBL1021, ANBL1221, ANBL1232). Key predictors examined were ethnicity, age at diagnosis, SES (via Yost Index), and distance to care from home to treatment hospital. We employed Poisson regression to calculate adjusted risk ratios (aRR) and 95% confidence intervals for trial participation. Analyzing 3,148 neuroblastoma cases from the CCRN registry, the ethnic composition was as follows: 68% were non-Hispanic White, 14% Hispanic, and 10% NH Black and SES distribution was even across quintiles. Age at diagnosis was a significant factor in trial enrollment: children &amp;gt;2 years were 94% more likely to enroll than those under 2 years (p &amp;lt; 0.001). Race, ethnicity, SES, and distance to care showed no significant effect on enrollment, all with non-significant p-values. In CCRN, neuroblastoma patient's age at diagnosis was a determinant in therapeutic trial enrollment, providing insight into design strategies to encourage trial participation. While common barriers like race, ethnicity, SES, and distance to care did not impact enrollment in our cohort, the significant role of age highlights an area where focused efforts can ensure that all age groups have equitable access to the potential benefits of therapeutic trials.</p>

<p>Some evidence suggests that pediatric sarcomas have both shared and distinct genetic profiles; however, large-scale efforts to characterize germline genetic susceptibility across these malignancies are limited by their rarity. We evaluated the role of common and rare variants in the genetic etiology of the more frequent pediatric sarcomas: osteosarcoma (OS); Ewing sarcoma (ES); and rhabdomyosarcoma (RMS), subcategorized into embryonal (ERMS) and alveolar (ARMS).</p>

<p>We evaluated whether socioeconomic status (SES), race/ethnicity, and their interaction were associated with the presentation of advanced stage at diagnosis in embryonal tumors. Children 0 to 19 years of age diagnosed with embryonal tumors between 2006 and 2018 were identified from the US Surveillance, Epidemiology, and End Results program database specialized with Census Tract SES/Rurality. SES quintile was derived from a composite index for census tracts. We performed logistic regression to estimate odds ratios (ORs) and 95% confidence intervals by SES and race/ethnicity, adjusting for sex, age, and diagnosis year. Overall, no significant associations were found between either SES or race/ethnicity and the risk of presenting with advanced stage at diagnosis, although patterns of risk reductions were observed in atypical teratoid/rhabdoid tumors and embryonal rhabdomyosarcoma with increasing SES. In the stratified analysis, decreased odds of presenting with advanced-stage embryonal rhabdomyosarcoma were observed for Hispanics with higher SES (OR: 0.24, 95% Confidence Interval: 0.08-0.75) compared with Hispanics with lower SES. Future studies incorporating individual-level SES, cancer-specific staging information, and potential demographic, clinical, epidemiological, and genetic risk factors are warranted to confirm our findings.</p>

10026Background: Childhood cancer survivors are at high risk for developing subsequent breast cancer with higher mortality than females in the general population wit...

Acute leukemias, mainly consisting of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), comprise a major diagnostic group among hematologic cancers. Due to the early age at onset of ALL, particularly, it has long been suspected that acute leukemias of childhood may have an in utero origin. This supposition has motivated many investigations seeking direct proof of prenatal leukemogenesis, in particular, twin and “backtracking studies”. The suspected in utero origin has also focused on gestation as a critical window of risk, resulting in a rich literature on prenatal risk factors for pediatric acute leukemias. In this narrative review, we recount the circumstantial and direct evidence for an in utero origin of childhood acute leukemias.

<p>Background: We examined association between late stage diagnosis and individual- and community-level characteristics among pediatric Hodgkin lymphoma (HL) and rhabdomyosarcoma (RMS) patients. Methods: We obtained Children’s Oncology Group (COG) data from 1999-2021 including summary stage (local (L), regional (R), distant (D)), tumor subtype, demographics, and ZIP code at diagnosis. We linked ZIP codes to county-level redlining scores (C,D=greatest redlining), Child Opportunity Index (COI), and measures of segregation (racial dissimilarity indices (DI)). Logistic regressions calculated odds ratios for late stage diagnosis, and by race within tumor subtype. Results: 5,933 HL and 2,800 RMS patients were included. Late stage diagnosis of HL was correlated with Black race (ORDistant(D) vs regional/local(R&amp;L)=1.38 [1.13-1.68]), being uninsured (ORD vs R&amp;L=1.38 [1.09-1.75]), and subtype (Nodular sclerosis vs Other HL: ORD vs R&amp;L=1.64 [1.34-2.01], Untyped: ORD vs R&amp;L=1.30 [1.04-1.63]). Late stage rhabdomyosarcoma was correlated with bilingual households (ORDistant/regional(D&amp;R) vs local(L)=2.66 [1.03-6.91]) and tumor type (Alveolar vs Embryonal ORD vs R&amp;L=6.16 [5.00-7.58]. Community-level factors associated with late stage HL were greater Black (OR80-100%=1.83; 95% CI=1.11-3.02) and Hispanic (OR60-79%=1.30; 95%CI=1.05-1.60) DI. Late stage diagnosis for RMS was associated with more redlined census tracts within counties (OR=1.54; 95% CI =1.02-2.35) and low/very low COI (OR=1.21; 95% CI=1.02-1.45). Conclusion: Novel markers of community deprivation, such as redlining and racial segregation, likely affect cancer outcomes for children with HL and RMS in this first disparities study using COG registries. Impact: The interplay of multilevel risk factors provides important consideration for efforts to improve early detection of pediatric cancer diagnosis.</p>

Introduction: Children with congenital heart defects (CHD) have shorter life expectancy than the general population. Previous studies also suggest that patients with CHD have higher risk of cancer. This study aims to describe cancer-related mortality among patients with a history of CHD interventions using the Pediatric Cardiac Care Consortium (PCCC), a large US cohort of such patients. Methods: We performed a retrospective cohort study of individuals (<21 years) who underwent interventions for CHD in the PCCC from 1982 to 2003. Patients surviving their first intervention were linked to the National Death Index through 2020. Multivariable models assessed risk of cancer-related death, adjusting for age, sex, race, and ethnicity. Patients with/without genetic abnormalities (mostly Down syndrome [DS]) were considered separately, due to expected differential risk in cancer. Results: Among the 57,601 eligible patients in this study, cancer was the underlying or contributing cause of death for 208; with 20% among those with DS. Significantly increased risk of cancer-related death was apparent among patients with DS compared to the non-genetic group (aHR: 3.63, 95% confidence interval [CI]: 2.52–5.24, p <.001). For the group with non-genetic abnormalities, the highest association with cancer-related death compared to those with mild CHD was found among those with more severe CHD (severe two-ventricle aHR: 1.82, 95% CI: 1.04–3.20, p =.036, single-ventricle aHR: 4.68, 95% CI: 2.77–7.91, p <.001). Conclusions: Patients with more severe forms of CHD are at increased risk for cancer-related death. Despite our findings, we are unable to distinguish whether having CHD raises the risk of cancer or reduces survival.

<p>Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire‐based and three registry‐based case‐control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire‐based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry‐based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46‐4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81‐4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50‐11.89). Effect sizes were generally larger in registry‐based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire‐ and registry‐based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.</p>

<h2>ABSTRACT</h2><h3>BACKGROUND</h3><p>Regionalization of congenital heart surgery (CHS) has been proposed to improve post-surgical outcomes by increasing experience in the care of high-risk patients. We sought to determine whether procedure-specific center volume was associated with mortality following infantile CHS up to 3 years following surgery.</p><h3>METHODS</h3><p>We analyzed data from 12,263 infants in the Pediatric Cardiac Care Consortium undergoing CHS between 1982 and 2003 at 46 centers within the United States. We used logistic regression to assess the association between procedure-specific center volume and mortality from discharge to 3 years post-procedure, accounting for clustering at the center level and adjusting for patient age and weight at surgery, chromosomal abnormality, and surgical era.</p><h3>RESULTS</h3><p>We found decreased odds for in-hospital mortality for Norwood procedures (OR = 0.955, 95% CI=0.935-0.976), arterial switch operations (OR=0.924, 95% CI=0.889-0.961), tetralogy of Fallot repairs (OR=0.975, 95% CI=0.956-0.995), Glenn shunts (OR=0.971, 95% CI=0.943-1.000) and ventricular septal defect closures (OR=0.974, 95% CI=0.964-0.985). The association persisted up to three years post-surgery for Norwood procedures (OR=0.971, 95% CI=0.955-0.988), arterial switches (OR=0.929, 95% CI=0.890-0.970), and ventricular septal defect closures (OR=0.986, 95% CI=0.977-0.995); however, after excluding deaths which occurred within the first 90 days of following surgery, we observed no association between center volume and mortality for any of the procedures studied.</p><h3>CONCLUSIONS</h3><p>These findings suggest that procedure-specific center volume is inversely associated with early postoperative mortality for infantile CHS across the complexity spectrum but has no measurable effect on later mortality.</p>

<p>OBJECTIVES/GOALS: We leverage the disparate incidence of Ewing sarcoma (ES) between European (EUR) and African (AFR) ancestry to study ES tumorigenesis in iPSC-derived cells from donors with a range of AFR ancestry via functional / molecular profiling. Integrated multi-omics analysis furthers explore local regulatory networks in pursuit of novel drug targets of ES. METHODS/STUDY POPULATION: In our pilot, eight induced pluripotent stem cell lines were obtained, differentiated into neural crest cells, and then transduced with a lentivirus expressing GFP-2A-EWS/FLI1. We compared wild type (WT) to EWS-FLI1-induced cells and then compared cell survival, gene expression, and EWS-FLI1 binding differences at varying levels of EUR / AFR ancestry admixture. We will build on this pilot data by expanding the number of cell lines and measuring chromatin state. Subsequently we will refine our understanding of the relationships between local ancestry, epigenetic and gene expression changes, and phenotype in tumor progression via integration of multi-omics datasets. Our systems genomics approach will utilize directed local regulatory networks in a Bayesian structure learning framework. RESULTS/ANTICIPATED RESULTS: Induction by EWS-FLI1 resulted in gene expression changes enriched in known ES gene sets. Higher %EUR ancestry correlated with prolonged maintenance of EWS-FLI1. We identified thousands of ancestry-linked changes to gene expression and EWS-FLI1 binding. Eighty of these genes are both differentially expressed and differentially bound based on AFR ancestry admixture level and may be some of the early critical targets that initiate the cascade of molecular changes in ES. We will identify novel drug targets, with potential cross functional use of known drugs. Once we have developed directed local regulatory networks, we will use them to test in silico potential perturbations due to small molecules or novel drugs and predict expression changes. DISCUSSION/SIGNIFICANCE: With a limited number of cell lines, we identify 80 ancestry-linked candidate loci for functional validation through genome engineering. As EWS-FLI1 itself has proven elusive to direct targeting, studying its immediate downstream effects has the potential for establishing new druggable biologic pathways for treatment of ES.</p>

<p>Introduction: Prior work indicates that Hispanic and Black children diagnosed with leukemia may experience a higher risk of death in the period shortly after diagnosis, but no work has examined these disparities taking into account leukemia subtypes and the role socioeconomic status (SES) may play. We investigated reported race/ethnicity (RRE), health insurance status, neighborhood SES, and early death among pediatric acute lymphoblastic leukemia (ALL) patients enrolled on clinical trials. Methods: Using data from the Childhood Cancer Research Network as well as Children’s Oncology Group therapeutic trials, we estimated the associations between RRE (Non-Hispanic [NH] White, NH Black, NH Asian/Pacific Islander [PI], or Hispanic/Native American), health insurance status, neighborhood SES using the Yost Index, and death within 60 days of diagnosis using multivariable logistic regression. All analyses were adjusted for age at diagnosis, sex, and ALL subtype (Standard Risk B-Cell, High Risk B-Cell, Infant ALL, T-Cell). We also estimated associations among non-infant patients diagnosed with B-Cell ALL, additionally adjusting for standard or high-risk disease. All associations were estimated as odds ratios (OR) with 95% confidence intervals (CI). Results: Overall, we analyzed data from 8,634 pediatric ALL cases (7,559 B-Cell; 122 Infant ALL; 953 T-Cell) enrolled across 7 clinical trials (AALL0232, AALL0331, AALL0434, AALL0631, AALL0932, AALL1131, AALL1231). In total, there were 29 deaths within 60 days of diagnosis, including 22 among B-Cell, 4 among infant ALL, and 3 among T-Cell patients. In the full analysis, infant ALL subtype was very strongly associated with early death compared to Standard Risk B-Cell patients (OR: 37.8 [95% CI: 9.22, 137]). We also observed a suggestive association between NH Asian/PI RRE and higher odds of early death compared to NH Whites (OR: 3.10 [95% CI: 0.71, 9.63]), which remained after limiting the analysis to B-Cell patients (OR: 5.63 [95% CI: 1.24, 18.7]). No association was apparent between NH Black or Hispanic/Native American RRE and odds of early death. Neighborhood SES was not significantly associated with early death, though point estimates suggested a potential protective effect of increasing SES. Lack of health insurance was also suggestively associated with greater odds of early death (OR: 2.78 [95% CI: 0.60, 9.47]). Conclusion: Unlike prior work, we observed increased odds of death soon after diagnosis for NH Asian/PI children. Future work incorporating more detailed treatment and cytogenetic subtype information is needed to identify the factors contributing to this disparity.</p>

STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3.

Background: Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk. Procedure: Information on cases (n = 517) diagnosed with HL (ages of 0–14) at Children's Oncology Group Institutions for the period of 1989–2003 was obtained. Control children without a history of cancer (n = 784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including whether their child had been born with a non-chromosomal birth defect. To test the association between birth defects and HL risk, conditional logistic regression was applied to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Results: Children born with any non-chromosomal birth defect were not more likely to be diagnosed with HL at 0–14 years of age (aOR: 0.91; 95% CI: 0.69–1.21). No associations were detected between major or minor birth defects and HL (aOR: 1.34; 95% CI: 0.67–2.67 and aOR: 0.88; 95% CI: 0.57–1.34, respectively). Similarly, no association was observed for children born with any birth defect and EBV-positive HL (aOR: 0.57; 95% CI: 0.25–1.26). Conclusions: Previous assessments of HL in children with non-chromosomal birth defects have been limited. Using data from the largest case–control study of HL in those <15 years of age, we did not observe strong associations between being born with a birth defect and HL risk.

PrEP is an HIV prevention option that could benefit substance-involved women, a high-risk population with low PrEP uptake. Little is known about their interest in PrEP. This qualitative study used in-depth interviews to examine PrEP willingness, barriers, and facilitators among 16 women in outpatient psychosocial substance use treatment, methadone, and/or harm reduction/syringe programs in NYC. All expressed willingness to use PrEP, but only during periods of perceived risk. Women perceived themselves to be at high risk for HIV when engaging in active substance use and/or transactional sex. They perceived themselves to be at low risk and therefore unmotivated to take PrEP when abstinent from these activities. Paradoxically, a major barrier to using PrEP was anticipated interference from substance use and transactional sex, the very same activities that create a perception of risk. Facilitators of PrEP use included perceptions of it as effortless (as opposed to barrier methods during sex) and effective, safe, and accessible. Other barriers included fear of stigma and doubts about adhering daily. Recommendations for best PrEP implementation practices for substance-involved women included tailored and venue-specific PrEP information and messaging, PrEP discussion with trusted medical providers, and on-site PrEP prescription in substance use treatment and harm reduction programs.

Childhood central nervous system tumors (cCNSt) are the most common solid tumors in individuals under 20&nbsp;years old, yet environmental risk factors are not well established. Therefore, we conducted an umbrella review to summarize the current literature on risk factors related to cCNSt. Childhood exposure to ionizing radiation from medical devices was the strongest risk factor. There was evidence of positive associations with several other factors, including maternal age, birth weight, and pesticide exposure. Conversely, maternal folic acid supplementation during pregnancy and having childhood allergic conditions were inversely associated with cCNSt. Few studies assessed associations by cCNSt histological subtypes and none by molecular subtypes. Exposure assessments were limited to data linkages, parental recall via questionnaires, or measurements at diagnosis. Because cCNSt are highly heterogeneous, future research is needed to examine risk factors by molecular and histological subtypes and to apply novel, unbiased exposure assessments.

Background: Black children have lower incidence yet worse survival than White and Latinx children with B-cell acute lymphoblastic leukemia (B-ALL). It is unclear how reported race/ethnicity (RRE) is associated with death in B-ALL after accounting for differentially expressed genes associated with genetic ancestry. Methods: Using Phase 1 and 2 NCI TARGET B-ALL cases (N = 273; RRE-Black = 21, RRE-White = 162, RRE-Latinx = 69, RRE-Other = 9, RRE-Unknown = 12), we estimated proportions of African (AFR), European (EUR), and Amerindian (AMR) genetic ancestry. We estimated hazard ratios (HR) and 95% confidence intervals (95% CI) between ancestry and death while adjusting for RRE and clinical measures. We identified genes associated with genetic ancestry and adjusted for them in RRE and death associations. Results: Genetic ancestry varied within RRE (RRE-Black, AFR proportion: Mean: 78.5%, Range: 38.2%–93.6%; RRE-White, EUR proportion: Mean: 94%, Range: 1.6%–99.9%; RRE-Latinx, AMR proportion: Mean: 52.0%, Range: 1.2%–98.7%). We identified 10, 1, and 6 differentially expressed genes (padjusted <0.05) associated with AFR, AMR, and EUR ancestry proportion, respectively. We found AMR and AFR ancestry were statistically significantly associated with death (AMR each 10% HR: 1.05, 95% CI: 1.03–1.17, AFR each 10% increase HR: 1.03, 95% CI:1.01–1.19). RRE differences in the risk of death were larger in magnitude upon adjustment for genes associated with genetic ancestry for RRE-Black, but not RRE-Latinx children (RRE-Black HR: 3.35, 95% CI: 1.31, 8.53; RRE-Latinx HR: 1.47, 0.88–2.45). Conclusions: Our work highlights B-ALL survival differences by RRE after adjusting for ancestry differentially expressed genes suggesting other factors impacting survival are important.