Publications by authors named "Logan G Spector"

154 Publications

Therapeutic Leukapheresis in Pediatric Leukemia: Utilization Trend and Early Outcomes in a US Nationwide Cohort.

J Pediatr Hematol Oncol 2021 May 5. Epub 2021 May 5.

Division of Pediatric Hematology/Oncology Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology Biostatistics Core, Masonic Cancer Center Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN.

Leukapheresis (LA) in pediatric leukemia is performed for leukostasis, a life-threatening emergency in the setting of extremely increased blast cell counts. The authors aimed to assess the epidemiology of pediatric leukemia who received LA. The authors reviewed US nationally representative admission records of patients aged less than 20 years in the Kids' Inpatient Database for the years 2000, 2003, 2006, 2009, 2012, and 2016. Incidence of new leukemia cases who underwent LA were calculated for the years 2009, 2012, and 2016. Cox and logistic regression analyses were performed to ascertain the risk factors for adverse outcomes. There were 526 admissions for pediatric patients with acute lymphoblastic leukemia (ALL) (n=328), acute myeloid leukemia (AML) (n=124), or chronic myeloid leukemia (CML) (n=74) who underwent LA over the study period. The incidence of leukemia cases that required LA was lower in 2016 than in 2009 or 2012 (1.4%, 2.2%, and 2.7%, respectively; P=0.001). In-hospital mortality was higher in AML than ALL (hzard ratio, 3.2; 95% confidence interval, 1.1-9.1). None with CML died during admission. This first population-based study of LA in pediatric leukemia showed a decreased utilization of LA over recent years. The higher inpatient mortality in AML, as compared with ALL or CML, warrant further investigations.
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http://dx.doi.org/10.1097/MPH.0000000000002140DOI Listing
May 2021

Cesarean Section Is Associated with an Increased Risk of Acute Lymphoblastic Leukemia and Hepatoblastoma in Children from Minnesota.

Cancer Epidemiol Biomarkers Prev 2021 Apr 9;30(4):736-742. Epub 2021 Feb 9.

Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.

Background: In recent decades, Cesarean section (C-section) rates have increased. C-section is hypothesized to negatively impact the developing immune system by altering activation of the hypothalamic-pituitary-adrenal axis and the infant microbiome, among other mechanisms, thereby potentially modulating childhood cancer risk.

Methods: Using linked birth and cancer registry data from Minnesota (1976-2014), we included individuals ages 0-14 at diagnosis with one of 19 cancers. Cases and controls were frequency matched by birth year. We used logistic regression to estimate ORs and 95% confidence intervals (95% CI) as the measure of association between C-section and cancer. We assessed sex-C-section interactions for each cancer and conducted stratified analyses in acute lymphoblastic leukemia (ALL) for birth year, age at diagnosis, and maternal race.

Results: There were 3,166 cases and 20,589 controls. One third ( = 1,174) of controls born during 2004-2014 were delivered via C-section compared with 42.2% of cases ( = 285). C-section was associated with ALL ( = 819; OR: 1.20; 95% CI: 1.01-1.43) and hepatoblastoma ( = 50; OR: 1.89; 95% CI: 1.03-3.48), particularly among females (ALL OR: 1.34; 95% CI: 1.04-1.72; hepatoblastoma OR: 3.87; 95% CI: 1.30-11.57). The risk of ALL was highest during 2005-2014 (OR: 1.62; 95% CI: 1.11-2.34) and among children ages 1-5 years (OR: 1.28; 95% CI: 1.02-1.61).

Conclusions: C-section was associated with an increased risk of ALL and hepatoblastoma.

Impact: These associations require investigation to determine causality and rule out confounding by indication or reverse causality. The mechanisms underlying these associations may depend on neonatal immune system processes altered during C-section deliveries.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1406DOI Listing
April 2021

Sex differences in expression of immune elements emerge in children, young adults and mice with osteosarcoma.

Biol Sex Differ 2021 Jan 6;12(1). Epub 2021 Jan 6.

Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, MN, USA.

Background: Males < 40 years old are more likely to be diagnosed with and die from osteosarcoma (OS). The underlying mechanisms may depend on sex differences in immune response.

Methods: We used SEER data to estimate survival differences between males and females aged < 40 years at OS diagnosis. In NCI TARGET-OS cases, we determined sex differences in gene expression, conducted Gene Set Enrichment Analysis (GSEA), and applied the LM22 signature to identify biologic sex differences. We compared sex differences in gene expression profiles in TARGET-OS to those observed in Sleeping Beauty (SB) transposon mutagenesis accelerated Trp53-mutant mouse-OS and healthy adult osteoblasts.

Results: Males had worse 17-year overall survival than females (SEER p < 0.0001). From 87 TARGET-OS cases, we observed 1018 genes and 69 pathways that differed significantly by sex (adjusted p < 0.05). Pathway and gene lists overlapped with those from mice (p = 0.03) and healthy osteoblasts (p = 0.017), respectively. Pathways that differed significantly by sex were largely immune-based and included the PD-1/PD-L1 immunotherapy pathway. We observed sex differences in M2 macrophages (LM22; p = 0.056) and M1-M2 macrophage transition (GSEA; p = 0.037) in TARGET-OS. LM22 trends were similar in mice. Twenty-four genes differentially expressed by sex in TARGET-OS had existing cancer therapies.

Conclusions: Sex differences in OS gene expression were similar across species and centered on immune pathways. Identified sex-specific therapeutic targets may improve outcomes in young individuals with OS.
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http://dx.doi.org/10.1186/s13293-020-00347-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789366PMC
January 2021

Major birth defects and cancer.

BMJ 2020 12 2;371:m4464. Epub 2020 Dec 2.

Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, GA, USA.

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http://dx.doi.org/10.1136/bmj.m4464DOI Listing
December 2020

Trends in paediatric central nervous system tumour incidence by global region from 1988 to 2012.

Int J Epidemiol 2021 Mar;50(1):116-127

Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

Background: Central nervous system (CNS) tumours comprise 20% of childhood cancers worldwide. Whether childhood CNS tumour incidence has increased over time across geographic regions remains to be explored.

Methods: We identified CNS cancers in the Cancer in Five Continents (CI5) data and estimated age standardized incidence rates (ASRs; cases/million children) and 95% confidence intervals (95% CI), male-to-female incidence rate ratios (IRR; 95% CI) and average annual percent change in incidence (AAPC; 95% CI) by geographic region for children aged 0-19 years where data were available using Poisson regression and generalized estimating equations (GEE). Cancers included: astrocytic tumours, medulloblastoma, ependymal, oligodendroglial and mixed glioma, glioma of uncertain origin, and other embryonal tumours. Geographic regions were defined using the United Nations geoscheme.

Results: There were 56 468 CNS cancers included in the study. ASRs were highest for astrocytic tumours globally in 2012 (ASR: 5.83; 95% CI: 5.68-5.99). Globally, all cancers exhibited a male excess in incidence. Regionally, only medulloblastoma had a consistently elevated male-to-female IRR at 1.4-2.2. Globally, incidence decreased for astrocytic tumours in GEE models (AAPC: -1.66; 95% CI: -3.04 to -0.26) and increased for medulloblastoma (AAPC 0.66; 95% CI: 0.19-1.14), ependymal tumours (AAPC: 1.49; 95% CI: 1.49; 95%: 0.69-2.30), glioma of uncertain origin (AAPC: 4.76; 95% CI: 1.17-1.14) and other embryonal tumours (AAPC: 3.58; 95% CI: 2.03-5.15). Regional variation in incidence trends was observed. Countries moving from lower to higher Human Development Index (HDI) over time did not appear to drive observed incidence trends.

Conclusions: Epidemiologic and molecular studies on underlying mechanisms for changes in the global incidence of CNS tumours are necessary.
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http://dx.doi.org/10.1093/ije/dyaa176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938516PMC
March 2021

Nearly Half of Germline Variants Predicted To Be Pathogenic in Patients With Osteosarcoma Are De Novo: A Report From the Children's Oncology Group.

JCO Precis Oncol 2020 2;4. Epub 2020 Oct 2.

Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN.

Purpose: To ascertain the prevalence of recurrent de novo variants among 240 pediatric patients with osteosarcoma (OS; age < 20 years) unselected for family history of cancer.

Methods: The identification of de novo variants was implemented in 2 phases. In the first, we identified genes with a rare (minor allele frequency < 0.01) de novo variant in > 1 of the 95 case-parent trios examined by whole-exome sequencing (WES) who passed quality control measures. In phase 2, 145 additional patients with OS were evaluated by targeted sequencing to identify rare de novo variants in genes nominated from phase 1. Recurrent rare variants identified from phase 1 and 2 were verified as either de novo or inherited by Sanger sequencing of affected patients and their parents. Categorical and continuous data were analyzed using Fisher exact test and t tests, respectively.

Results: Among 95 case-parent trios who underwent WES, we observed 61 de novo variants in 60 genes among 47 patients, with identified as the only gene with a pathogenic or likely pathogenic (P/LP) de novo variant in more than one case-parent trio. Among all 240 patients with OS, 13 (5.4%) harbored a P/LP germline variant, of which 6 (46.2%) were confirmed to be de novo.

Conclusion: Apart from , we did not observe any other recurrent de novo P/LP variants in the case-parent trios, suggesting that new mutations in other genes are not a frequent cause of pediatric OS. That nearly half of P/LP variants in our sample were de novo suggests universal screening for germline P/LP variants among pediatric patients with OS should be considered.
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http://dx.doi.org/10.1200/PO.20.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608506PMC
October 2020

Comparative analysis of genome-wide DNA methylation identifies patterns that associate with conserved transcriptional programs in osteosarcoma.

Bone 2020 Oct 27:115716. Epub 2020 Oct 27.

Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul 55108, USA; Institute of Health Informatics, University of Minnesota, Minneapolis, MN 55455, USA; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota, UDS Institute for Engineering in Medicine, Minneapolis, MN 55455, USA.

Osteosarcoma is an aggressive tumor of the bone that primarily affects young adults and adolescents. Osteosarcoma is characterized by genomic chaos and heterogeneity. While inactivation of tumor protein p53 (TP53) is nearly universal other high frequency mutations or structural variations have not been identified. Despite this genomic heterogeneity, key conserved transcriptional programs associated with survival have been identified across human, canine and induced murine osteosarcoma. The epigenomic landscape, including DNA methylation, plays a key role in establishing transcriptional programs in all cell types. The role of epigenetic dysregulation has been studied in a variety of cancers but has yet to be explored at scale in osteosarcoma. Here we examined genome-wide DNA methylation patterns in 24 human and 44 canine osteosarcoma samples identifying groups of highly correlated DNA methylation marks in human and canine osteosarcoma samples. We also link specific DNA methylation patterns to key transcriptional programs in both human and canine osteosarcoma. Building on previous work, we built a DNA methylation-based measure for the presence and abundance of various immune cell types in osteosarcoma. Finally, we determined that the underlying state of the tumor, and not changes in cell composition, were the main driver of differences in DNA methylation across the human and canine samples. SIGNIFICANCE: Genome wide comparison of DNA methylation patterns in osteosarcoma across two species lays the ground work for the exploration of DNA methylation programs that help establish conserved transcriptional programs in the context of varied mutational landscapes.
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http://dx.doi.org/10.1016/j.bone.2020.115716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076342PMC
October 2020

Racial and ethnic disparities in survival of children with brain and central nervous tumors in the United States.

Pediatr Blood Cancer 2021 01 24;68(1):e28738. Epub 2020 Sep 24.

Division of Health Policy and Management, University of Minnesota, Minneapolis, Minnesota.

Background: Despite improvements in overall survival for pediatric cancers, treatment disparities remain for racial/ethnic minorities compared to non-Hispanic Whites; however, the impact of race on treatment outcomes for pediatric brain and central nervous system (CNS) tumors in the United States is not well known.

Methods: We included 8713 children aged 0-19 years with newly diagnosed primary brain and CNS tumors between 2000 and 2015 from the Census Tract-level SES and Rurality Database developed by Surveillance, Epidemiology, and End Results (SEER) Program. We used chi-square tests to assess differences in sociodemographic, cancer, and treatment characteristics by race/ethnicity and Kaplan-Meier curves and Cox proportional hazards models to examine differences in 10-year survival, adjusting for these characteristics.

Results: Among 8713 patients, 56.75% were non-Hispanic White, 9.59% non-Hispanic Black, 25.46% Hispanic, and 8.19% from "other" racial/ethnic groups. Median unadjusted survival for all pediatric brain tumors was 53 months, but varied significantly by race/ethnicity with a median survival of 62 months for non-Hispanic Whites, 41 months for non-Hispanic Blacks, and 40 months for Hispanic and other. Multivariable analyses demonstrated minority racial groups still had significantly higher hazard of death than non-Hispanic Whites; Hispanic (adjusted hazard ratio [aHR] 1.25 [1.18-1.31]); non-Hispanic Black (aHR 1.12 [1.04-1.21]); other (aHR 1.22 [1.12-1.32]). Results were consistent when stratified by tumor histology.

Conclusion: We identified disparities in survival among racial/ethnic minorities with pediatric brain and CNS tumors, with Hispanic patients having the highest risk of mortality. Eliminating these disparities requires commitment toward promoting heath equity and personalized cancer treatment.
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http://dx.doi.org/10.1002/pbc.28738DOI Listing
January 2021

Racial and Ethnic Differences in Sarcoma Incidence Are Independent of Census-Tract Socioeconomic Status.

Cancer Epidemiol Biomarkers Prev 2020 Nov 14;29(11):2141-2148. Epub 2020 Sep 14.

Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.

Background: Epidemiologic analyses of sarcoma are limited by the heterogeneity and rarity of the disease. Utilizing population-based surveillance data enabled us to evaluate the contribution of census tract-level socioeconomic status (CT-SES) and race/ethnicity on sarcoma incidence rates.

Methods: We utilized the Surveillance, Epidemiology, and End Results program to evaluate associations between CT-SES and race/ethnicity on the incidence rates of sarcoma. Incidence rate ratios and 99% confidence intervals were estimated from quasi-Poisson models. All models were stratified by broad age groups (pediatric: <20 years, adult: 20-65 years, older adult: 65+ years) and adjusted for sex, age, and year of diagnosis. Within each age group, we conducted analyses stratified by somatic genome (fusion-positive and fusion-negative sarcomas) and for subtypes with >200 total cases. A value less than 0.01 was considered statistically significant.

Results: We included 55,415 sarcoma cases in 35 sarcoma subtype-age group combinations. Increasing CT-SES was statistically significantly associated with 11 subtype-age group combinations, primarily in the older age group strata (8 subtypes), whereas malignant peripheral nerve sheath tumors in adults were associated with decreasing CT-SES. Nearly every sarcoma subtype-age group combination displayed racial/ethnic disparities in incidence that were independent of CT-SES.

Conclusions: We found race/ethnicity to be more frequently associated with sarcoma incidence than CT-SES. Our findings suggest that genetic variation associated with ancestry may play a stronger role than area-level SES-related factors in the etiology of sarcoma.

Impact: These findings provide direction for future etiologic studies of sarcomas.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641997PMC
November 2020

Germline Genetic Risk Stratification in ALL? GATA Get More Information.

J Natl Cancer Inst 2021 Apr;113(4):353-354

Division of Hematology/Oncology, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA.

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http://dx.doi.org/10.1093/jnci/djaa139DOI Listing
April 2021

Associations of Socioeconomic Status, Public vs Private Insurance, and Race/Ethnicity With Metastatic Sarcoma at Diagnosis.

JAMA Netw Open 2020 08 3;3(8):e2011087. Epub 2020 Aug 3.

Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis.

Importance: Approximately 10% to 30% of patients with sarcoma present with detectable metastases at diagnosis. However, the extent to which presentation with metastases is due to delayed diagnosis vs other factors remains unclear.

Objective: To evaluate whether socioeconomic status, insurance status, or race/ethnicity were associated with the presence of metastases at diagnosis of sarcoma.

Design, Setting, And Participants: This cross-sectional study used data from the population-based Surveillance, Epidemiology, and End Results program. Adult and pediatric patients with an initial diagnosis of soft-tissue and bone sarcoma between 2001 and 2015 were stratified by age group (pediatric, <20 years; adult, 20-65 years; older adult, >65 years) and sarcoma subtype. Statistical analyses were performed between August 2019 and January 2020.

Exposures: Surveillance, Epidemiology, and End Results Census tract-level socioeconomic status index, insurance status, and race/ethnicity.

Main Outcomes And Measures: The odds of presenting with metastases at diagnosis were calculated.

Results: A total of 47 337 patients with first primary malignant sarcoma were included (24 343 male patients [51.4%]), with 29 975 non-Hispanic White patients (63.3%), 5673 non-Hispanic Black patients (12.0%), 7504 Hispanic patients (15.8%), and 4185 American Indian-Alaskan Native and Asian Pacific Islander patients (8.8%). Liposarcoma in adults was the only subtype and age group combination that demonstrated a significant trend in incidence across socioeconomic status levels (odds ratio, 0.85; 99% CI, 0.76-0.96; P = .001). However, compared with having non-Medicaid insurance, having Medicaid or no insurance in adults was associated with an increased odds of metastases at diagnosis for 6 of the 8 sarcoma subtypes evaluated; osteosarcoma and Ewing sarcoma were the only 2 subtypes in adults for which metastases were not associated with insurance status. In addition, there was an increased risk of presenting with metastases among non-Hispanic Black adults diagnosed with leiomyosarcoma (odds ratio, 1.87; 99% CI, 1.41-2.48) and unclassified sarcomas (odds ratio, 1.65; 99% CI, 1.01-2.67) compared with non-Hispanic White adults that was independent of socioeconomic and insurance status.

Conclusions And Relevance: These findings suggest that delayed access to care is associated with advanced stage at diagnosis for several soft-tissue sarcoma subtypes in adults, whereas other factors may be associated with the metastatic progression of osteosarcoma and Ewing sarcoma, as well as the racial disparities observed with metastatic leiomyosarcoma and unclassified sarcomas.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.11087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414392PMC
August 2020

Body mass index associated with childhood and adolescent high-risk B-cell acute lymphoblastic leukemia risk: A Children's Oncology Group report.

Cancer Med 2020 09 24;9(18):6825-6835. Epub 2020 Jul 24.

Division of Hematology/Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

Background: Obesity is a risk factor for many adulthood cancers, but its role in childhood, adolescent, and young adult (AYA) cancer is unknown. Childhood and AYA acute lymphoblastic leukemia (ALL) incidence and obesity prevalence have shown concurrent increases. We sought to identify whether obesity may be a risk factor for childhood and AYA ALL.

Methods: Characteristics from individuals with ALL, aged 2-30 years, diagnosed 2004-2017 and treated on Children's Oncology Group (COG) protocols with available pre-treatment anthropometric data (N = 4726) were compared to National Health and Nutrition Examination Survey controls (COG AALL17D2). Body mass index (BMI) was defined using standard CDC definitions. Multivariate conditional logistic regression assessed associations between BMI and ALL with additional analyses stratified by sex and race/ethnicity.

Results: Among cases (72% high-risk (HR) B-ALL, 28% T-ALL), 5% had underweight, 58% normal weight, 17% overweight, and 20% obesity. Underweight (OR 2.11, 95% CI 1.56-2.85) and obesity (OR 1.32, 95% CI 1.15-1.53) were associated with B-ALL diagnosis. Specifically, obesity was associated with B-ALL among males (OR 1.57, 95% CI 1.30-1.91) and Hispanic children (OR 1.78, 95% CI 1.39-2.29). Obesity was also associated with central nervous system (CNS) involvement.

Conclusion: Pre-treatment obesity is associated with HR B-ALL among males and Hispanics, as well as with CNS involvement, suggesting common physiology between obesity and leukemogenesis. An association between underweight and ALL was confirmed, likely due to cancer-associated wasting. These results have important public health implications for obesity prevention and treatment in children and adolescents to reduce cancer risk.
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http://dx.doi.org/10.1002/cam4.3334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520304PMC
September 2020

Race, ethnicity, and socioeconomic differences in incidence of pediatric embryonal tumors in the United States.

Pediatr Blood Cancer 2020 09 16;67(9):e28582. Epub 2020 Jul 16.

Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minnesota, Minneapolis.

Background: The etiology of childhood cancers and its social patterning remains largely unknown. Accounting for socioeconomic status (SES) when exploring the association between race/ethnicity and cancer incidence is necessary to better understand such etiology. We aimed to investigate differences in the incidence of embryonal tumors (ETs) by SES and race/ethnicity in the United States using population-based registries of the Surveillance, Epidemiology, and End Results (SEER) Program.

Procedure: Children with ETs aged 0-19 years diagnosed between 2000 and 2015 were ascertained from the census tract-level SEER database. SES was measured using a tract-level composite index. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) by SES quintile and race/ethnicity were estimated using multivariable Poisson regression models.

Results: The majority of tumors had lower incidence among nonwhite children compared with non-Hispanic (NH) white children, after controlling for SES. NH blacks had a higher incidence of Wilms tumor than NH whites (IRR: 1.26; 95% CI, 1.13-1.39). There was an increasing linear trend (P = 0.0001) across increasing SES quintile for embryonal rhabdomyosarcoma after controlling for race/ethnicity. Effect modification by race/ethnicity of the relationship between SES and tumor incidence was observed for several groups. Hispanics had a significant, linear trend (P = 0.0005) in the incidence of Wilms tumor, while Asian/Pacific Islanders experienced a significant inverse trend (P = 0.0002).

Conclusions: Results from this study suggest differences in the incidence of several ETs by race/ethnicity and that these differences may be modified by SES. Investigation of potential risk factors that are socially patterned is warranted.
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http://dx.doi.org/10.1002/pbc.28582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674242PMC
September 2020

Childhood cancer incidence among specific Asian and Pacific Islander populations in the United States.

Int J Cancer 2020 12 13;147(12):3339-3348. Epub 2020 Jul 13.

Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.

Despite the vast genetic and environmental diversity in Asia, individuals of Asian and Pacific Islander (API) descent are often combined into a single group for epidemiologic analyses within the U.S. We used the Surveillance, Epidemiology and End Results (SEER) Detailed Asian/Pacific Islander Database to calculate incidence rates for discrete groups among children aged 0 to 19 years. Due to sample size constraints we pooled incidence among regional groups based on countries of origin: East Asians (Chinese, Japanese, Korean), Southeast (SE) Asians (Vietnamese, Laotian, Cambodian), Asian Indian/Pakistani, Oceanians (Guamanian, Samoan, Tongan) and Filipinos. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were calculated comparing each API regional group to Non-Hispanic Whites (NHW) and East Asians. Finally, we calculated the correlation between incidence of cancer in specific API ethnicities in SEER and in originating countries in the Cancer Incidence in Five Continents. Incidence rates among API regional groups varied. Acute lymphoblastic leukemia (ALL) was lower in children of SE Asian descent (IRR 0.65, 95% CI 0.44, 0.96) compared to NHW. Acute myeloid leukemia (AML) was more common among children from Oceania compared to NHW (IRR 3.88, 95% CI 1.83, 8.22). East Asians had higher incidence rates than SE Asians but lower rates compared to children from Oceania. Correlation of some incidence rates between US-based API ethnicities and originating countries were similar. The variation observed in childhood cancer incidence patterns among API groups may indicate differences in underlying genetics and/or patterns of exposure.
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http://dx.doi.org/10.1002/ijc.33153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736474PMC
December 2020

Cancer Progress and Priorities: Childhood Cancer.

Cancer Epidemiol Biomarkers Prev 2020 06;29(6):1081-1094

Department of Pediatrics, Division of Epidemiology & Clinical Research, University of Minnesota, Minneapolis, Minnesota.

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http://dx.doi.org/10.1158/1055-9965.EPI-19-0941DOI Listing
June 2020

Cancer diagnostic profile in children with structural birth defects: An assessment in 15,000 childhood cancer cases.

Cancer 2020 Aug 29;126(15):3483-3492. Epub 2020 May 29.

Department of Medicine, Baylor College of Medicine, Houston, Texas.

Background: Birth defects are established risk factors for childhood cancer. Nonetheless, cancer epidemiology in children with birth defects is not well characterized.

Methods: Using data from population-based registries in 4 US states, this study compared children with cancer but no birth defects (n = 13,111) with children with cancer and 1 or more nonsyndromic birth defects (n = 1616). The objective was to evaluate cancer diagnostic characteristics, including tumor type, age at diagnosis, and stage at diagnosis.

Results: Compared with the general population of children with cancer, children with birth defects were diagnosed with more embryonal tumors (26.6% vs 18.7%; q < 0.001), including neuroblastoma (12.5% vs 8.2%; q < 0.001) and hepatoblastoma (5.0% vs 1.3%; q < 0.001), but fewer hematologic malignancies, including acute lymphoblastic leukemia (12.4% vs 24.4%; q < 0.001). In age-stratified analyses, differences in tumor type were evident among children younger than 1 year and children 1 to 4 years old, but they were attenuated among children 5 years of age or older. The age at diagnosis was younger in children with birth defects for most cancers, including leukemia, lymphoma, astrocytoma, medulloblastoma, ependymoma, embryonal tumors, and germ cell tumors (all q < 0.05).

Conclusions: The results indicate possible etiologic heterogeneity in children with birth defects, have implications for future surveillance efforts, and raise the possibility of differential cancer ascertainment in children with birth defects.

Lay Summary: Scientific studies suggest that children with birth defects are at increased risk for cancer. However, these studies have not been able to determine whether important tumor characteristics, such as the type of tumor diagnosed, the age at which the tumor is diagnosed, and the degree to which the tumor has spread at the time of diagnosis, are different for children with birth defects and children without birth defects. This study attempts to answer these important questions. By doing so, it may help scientists and physicians to understand the causes of cancer in children with birth defects and diagnose cancer at earlier stages when it is more treatable.
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http://dx.doi.org/10.1002/cncr.32982DOI Listing
August 2020

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma.

JAMA Oncol 2020 05;6(5):724-734

Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, United Kingdom.

Importance: Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear.

Objective: To investigate the germline genetic architecture of 1244 patients with osteosarcoma.

Design, Setting, And Participants: Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019.

Main Outcomes And Measures: The frequency of rare pathogenic or likely pathogenic genetic variants.

Results: Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 × 10-18). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53.

Conclusions And Relevance: In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.
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http://dx.doi.org/10.1001/jamaoncol.2020.0197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082769PMC
May 2020

Age-, sex- and disease subtype-related foetal growth differentials in childhood acute myeloid leukaemia risk: A Childhood Leukemia International Consortium analysis.

Eur J Cancer 2020 05 9;130:1-11. Epub 2020 Mar 9.

Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Clinical Epidemiology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden. Electronic address:

Aim: Evidence for an association of foetal growth with acute myeloid leukaemia (AML) is inconclusive. AML is a rare childhood cancer, relatively more frequent in girls, with distinct features in infancy. In the context of the Childhood Leukemia International Consortium (CLIC), we examined the hypothesis that the association may vary by age, sex and disease subtype using data from 22 studies and a total of 3564 AML cases.

Methods: Pooled estimates by age, sex and overall for harmonised foetal growth markers in association with AML were calculated using the International Fetal and Newborn Growth Consortium for the 21st Century Project for 17 studies contributing individual-level data; meta-analyses were, thereafter, conducted with estimates provided ad hoc by five more studies because of administrative constraints. Subanalyses by AML subtype were also performed.

Results: A nearly 50% increased risk was observed among large-for-gestational-age infant boys (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.03-2.14), reduced to 34% in boys aged <2 years (OR: 1.34, 95% CI: 1.05-1.71) and 25% in boys aged 0-14 years (OR: 1.25, 95% CI: 1.06-1.46). The association of large for gestational age became stronger in boys with M0/M1subtype (OR: 1.80, 95% CI: 1.15-2.83). Large birth length for gestational age was also positively associated with AML (OR: 1.38, 95% CI: 1.00-1.92) in boys. By contrast, there were null associations in girls, as well as with respect to associations of decelerated foetal growth markers.

Conclusions: Accelerated foetal growth was associated with AML, especially in infant boys and those with minimally differentiated leukaemia. Further cytogenetic research would shed light into the underlying mechanisms.
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http://dx.doi.org/10.1016/j.ejca.2020.01.018DOI Listing
May 2020

Field Application of Digital Technologies for Health Assessment in the 10,000 Families Study.

Cancer Epidemiol Biomarkers Prev 2020 04 4;29(4):744-751. Epub 2020 Mar 4.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.

Background: We field tested new-to-market portable, digital applications to assess hearing, pulmonary, and cognitive function to determine the feasibility of implementing these applications across a range of age groups in the pilot phase of the 10,000 Families Study (10KFS), a new Minnesota family-based prospective cohort study.

Methods: We followed manufacturer recommended protocols for audiometry (SHOEBOX Inc), spirometry (NuvoAir), and the digital clock drawing test (dCDT; Digital Cognition Technologies Inc).

Results: These digital devices were low cost and readily implemented in a 2.5-hour health fair visit with minimal training (2-3 hours) of study staff. To date, we have performed these measurements on 197 eligible 10KFS participants during an in-person clinic visit. A total of 37 children (age 4-17 years), 107 adults (18-64 years), and 53 seniors (≥65 years) were eligible to undergo hearing and pulmonary assessments. Children were less likely to successfully complete the hearing test (76%) compared with adults (86%) and seniors (89%). However, successful completion of the pulmonary assessment was high across all groups: 100% of children and seniors and 98% of adults. The dCDT was performed among those over the age of 40, and completion rates were 92% for those aged 41-64 and 94% for those ≥65 years.

Conclusions: Our field testing indicates these digital applications are easy and cost-effective to implement in epidemiologic studies.

Impact: Digital applications provide exciting opportunities to collect data in population studies. Issues related to data privacy, data access, and reproducibility of measurements need to be addressed before deploying digital applications in epidemiologic studies.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0858DOI Listing
April 2020

Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome.

Blood 2019 10;134(15):1227-1237

Department of Paediatric and Adolescent Oncology, University of Manchester, Manchester, United Kingdom.

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.
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http://dx.doi.org/10.1182/blood.2018890764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788009PMC
October 2019

Survival Differences Between Males and Females Diagnosed With Childhood Cancer.

JNCI Cancer Spectr 2019 Jun 11;3(2):pkz032. Epub 2019 May 11.

Division of Epidemiology & Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN.

Background: Males have worse survival for childhood cancer, but whether this disparity exists among all childhood cancer types is undescribed.

Methods: We estimated sex differences in survival for 18 cancers among children (0-19 years) in Surveillance, Epidemiology, and End Results 18 (2000-2014). We used Kaplan-Meier survival curves (log-rank values) to characterize sex differences in survival and Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between sex and death for each cancer type. We used an inverse odds weighting method to determine whether the association between sex and death was mediated by stage of disease for solid tumors.

Results: Males had worse overall survival and a higher risk of death for acute lymphoblastic leukemia (HR = 1.24, 95% CI = 1.12 to 1.37), ependymoma (HR = 1.36, 95% CI = 1.05 to 1.77), neuroblastoma (HR = 1.28, 95% CI = 1.09 to 1.51), osteosarcoma (HR = 1.29, 95% CI = 1.08 to 1.53), thyroid carcinoma (HR = 3.25, 95% CI = 1.45 to 7.33), and malignant melanoma (HR = 1.97, 95% CI = 1.33 to 2.92) (all log-rank values < .02). The association between sex and death was mediated by stage of disease for neuroblastoma (indirect HR = 1.12, 95% CI = 1.05 to 1.19), thyroid carcinoma (indirect HR = 1.24, 95% CI = 1.03 to 1.48), and malignant melanoma (indirect HR = 1.28, 95% CI = 1.10 to 1.49). For these six tumors, if male survival had been as good as female survival, 21% of male deaths and 13% of total deaths after these cancer diagnoses could have been avoided.

Conclusions: Consideration of molecular tumor and clinical data may help identify mechanisms underlying the male excess in death after childhood cancer for the aforementioned cancers.
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http://dx.doi.org/10.1093/jncics/pkz032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580869PMC
June 2019

Birth Defects and Cancer in Childhood-Dual Diseases of Development.

JAMA Oncol 2019 Aug;5(8):1105-1107

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill.

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http://dx.doi.org/10.1001/jamaoncol.2019.1207DOI Listing
August 2019

Risk Factors for Development of Canine and Human Osteosarcoma: A Comparative Review.

Vet Sci 2019 May 25;6(2). Epub 2019 May 25.

Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN 55108, USA.

Osteosarcoma is the most common primary tumor of bone. Osteosarcomas are rare in humans, but occur more commonly in dogs. A comparative approach to studying osteosarcoma has highlighted many clinical and biologic aspects of the disease that are similar between dogs and humans; however, important species-specific differences are becoming increasingly recognized. In this review, we describe risk factors for the development of osteosarcoma in dogs and humans, including height and body size, genetics, and conditions that increase turnover of bone-forming cells, underscoring the concept that stochastic mutational events associated with cellular replication are likely to be the major molecular drivers of this disease. We also discuss adaptive, cancer-protective traits that have evolved in large, long-lived mammals, and how increasing size and longevity in the absence of natural selection can account for the elevated bone cancer risk in modern domestic dogs.
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http://dx.doi.org/10.3390/vetsci6020048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631450PMC
May 2019

A comparison of risk factors for metastasis at diagnosis in humans and dogs with osteosarcoma.

Cancer Med 2019 06 21;8(6):3216-3226. Epub 2019 Apr 21.

Division of Pediatric Epidemiology and Clinical Research, School of Medicine, University of Minnesota, Minneapolis, Minnesota.

Background: Canine osteosarcoma (OS) is a relevant spontaneous model for human OS. Identifying similarities in clinical characteristics associated with metastasis at diagnosis in both species may substantiate research aimed at using canine OS as a model for identifying mechanisms driving distant spread in the human disease.

Methods: This retrospective study included dog OS cases from three academic veterinary hospitals and human OS cases from the Surveillance, Epidemiology, and End Results program. Associations between clinical factors and metastasis at diagnosis were estimated using logistic regression models.

Results: In humans, those with trunk tumors had higher odds of metastasis at diagnosis compared to those with lower limb tumors (OR = 2.38, 95% CI: 1.51, 3.69). A similar observation was seen in dogs with trunk tumors compared to dogs with forelimb tumors (OR = 3.28, 95% CI 1.36, 7.50). Other associations were observed in humans but not in dogs. Humans aged 20-29 years had lower odds of metastasis at diagnosis compared to those aged 10-14 years (OR = 0.67, 95% CI: 0.47, 0.96); every 1-cm increase in tumor size was associated with a 6% increase in the odds of metastasis at diagnosis (95% CI: 1.04, 1.08); compared to those with a white, non-Hispanic race, higher odds were observed among those with a black, non-Hispanic race (OR: 1.51, 95% CI: 1.04, 2.16), and those with a Hispanic origin (OR 1.35, 95% CI: 1.00, 1.81).

Conclusion: A common mechanism may be driving trunk tumors to progress to detectable metastasis prior to diagnosis in both species.
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http://dx.doi.org/10.1002/cam4.2177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558582PMC
June 2019

Trends in International Incidence of Pediatric Cancers in Children Under 5 Years of Age: 1988-2012.

JNCI Cancer Spectr 2019 Mar 9;3(1):pkz007. Epub 2019 Apr 9.

Background: Pediatric cancer incidence has been steadily increasing over the last several decades with the largest increases reported in infants. Few evaluations have looked at international pediatric cancer incidence trends in the youngest children. The aim of this analysis was to evaluate trends in cancer incidence in children under 5 years of age, overall and by type, using data from () from 1988 to 2012 (CI5 volumes VII-XI).

Methods: Rates of cancers in children ages 0-4 years were extracted from registries available in from 1988 to 2012. To overcome small numbers in individual registries, numerators and denominators were aggregated within regions corresponding to the United Nations' geoscheme. Average annual percent change (AAPC) was estimated using Poisson regression.  Robust standard errors were used in all models to correct for overdispersion in some regions, and 95% Wald confidence intervals and values were reported. The top five cancers by increasing AAPC were ranked within each region.

Results: Overall, in children under 5 years, increasing incidence was seen in multiple regions for acute lymphoblastic leukemia, acute myeloid leukemia, ependymal tumors, neuroblastoma, and hepatoblastoma. Hepatoblastoma had the largest AAPC in 11 out of 15 regions and showed an increase in all regions except southern Asia. Astrocytic tumors were the only cancer that decreased over the time period.

Conclusions: We evaluated 25 years of cancer incidence in children ages 0-4 years and observed increases in incidence for hepatoblastoma, leukemia, neuroblastoma, and ependymal tumors. Further etiologic evaluation will be required to explain these increases in incidence.
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http://dx.doi.org/10.1093/jncics/pkz007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455426PMC
March 2019

Association of In Vitro Fertilization With Childhood Cancer in the United States.

JAMA Pediatr 2019 06 3;173(6):e190392. Epub 2019 Jun 3.

Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, East Lansing.

Importance: In vitro fertilization (IVF) is associated with birth defects and imprinting disorders. Because these conditions are associated with an increased risk of childhood cancer, many of which originate in utero, descriptions of cancers among children conceived via IVF are imperative.

Objective: To compare the incidence of childhood cancers among children conceived in vitro with those conceived naturally.

Design, Setting, And Participants: A retrospective, population-based cohort study linking cycles reported to the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System from January 1, 2004, to December 31, 2012, that resulted in live births from September 1, 2004, to December 31, 2013, to the birth and cancer registries of 14 states, comprising 66% of United States births and 75% of IVF-conceived births, with follow-up from September 1, 2004, to December 31, 2014. The study included 275 686 children conceived via IVF and a cohort of 2 266 847 children, in which 10 births were randomly selected for each IVF birth. Statistical analysis was performed from April 1, 2017, to October 1, 2018.

Exposure: In vitro fertilization.

Main Outcomes And Measures: Cancer diagnosed in the first decade of life.

Results: A total of 321 cancers were detected among the children conceived via IVF (49.1% girls and 50.9% boys; mean [SD] age, 4.6 [2.5] years for singleton births and 5.9 [2.4] years for multiple births), and a total of 2042 cancers were detected among the children not conceived via IVF (49.2% girls and 50.8% boys; mean [SD] age, 6.1 [2.6] years for singleton births and 4.7 [2.6] years for multiple births). The overall cancer rate (per 1 000 000 person-years) was 251.9 for the IVF group and 192.7 for the non-IVF group (hazard ratio, 1.17; 95% CI, 1.00-1.36). The rate of hepatic tumors was higher among the IVF group than the non-IVF group (hepatic tumor rate: 18.1 vs 5.7; hazard ratio, 2.46; 95% CI, 1.29-4.70); the rates of other cancers did not differ between the 2 groups. There were no associations with specific IVF treatment modalities or indication for IVF.

Conclusions And Relevance: This study found a small association of IVF with overall cancers of early childhood, but it did observe an increased rate of embryonal cancers, particularly hepatic tumors, that could not be attributed to IVF rather than to underlying infertility. Continued follow-up for cancer occurrence among children conceived via IVF is warranted.
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http://dx.doi.org/10.1001/jamapediatrics.2019.0392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547076PMC
June 2019

Sex ratio among childhood cancers by single year of age.

Pediatr Blood Cancer 2019 06 28;66(6):e27620. Epub 2019 Feb 28.

Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.

Background: The male excess in childhood cancer incidence is well-established; however, the underlying biologic mechanisms remain unknown. Examining the association between male sex and childhood cancer by single year of age and tumor type may highlight important periods of risk such as variation in growth and hormonal changes, which will inform etiologic hypotheses.

Methods: Using data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries (2000-2015), incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated as the measure of association between male sex and childhood cancer by single year of age (0-19).

Results: The IRR for male cancer overall was 1.19 (95% CI, 1.18-1.20) and was similar in magnitude at nearly every year of age. Burkitt lymphoma was strongly associated with male sex (IRRs ≥2 at each year of age). Increased incidence was observed among males for acute lymphoblastic leukemia, Hodgkin and non-Hodgkin lymphomas for nearly all years of age. Medulloblastoma was the only central nervous system tumor with a significant male predominance at nearly every age. Male sex displayed a consistent inverse association with nephroblastoma and thyroid carcinoma over the ages studied.

Conclusions: Male sex was positively associated with most cancers. The higher incidence rates observed in males remained consistent over the childhood and adolescent periods, suggesting that childhood and adolescent hormonal fluctuations may not be the primary driving factor for the sex disparities in childhood cancer. The observed incidence disparities may be due to sex differences in exposures, genetics, or immune responses.
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http://dx.doi.org/10.1002/pbc.27620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472964PMC
June 2019

Parental age and the risk of childhood acute myeloid leukemia: results from the Childhood Leukemia International Consortium.

Cancer Epidemiol 2019 04 15;59:158-165. Epub 2019 Feb 15.

Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Clinical Epidemiology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden. Electronic address:

Background: Parental age has been associated with several childhood cancers, albeit the evidence is still inconsistent.

Aim: To examine the associations of parental age at birth with acute myeloid leukemia (AML) among children aged 0-14 years using individual-level data from the Childhood Leukemia International Consortium (CLIC) and non-CLIC studies.

Material/methods: We analyzed data of 3182 incident AML cases and 8377 controls from 17 studies [seven registry-based case-control (RCC) studies and ten questionnaire-based case-control (QCC) studies]. AML risk in association with parental age was calculated using multiple logistic regression, meta-analyses, and pooled-effect estimates. Models were stratified by age at diagnosis (infants <1 year-old vs. children 1-14 years-old) and by study design, using five-year parental age increments and controlling for sex, ethnicity, birthweight, prematurity, multiple gestation, birth order, maternal smoking and education, age at diagnosis (cases aged 1-14 years), and recruitment time period.

Results: Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) derived from RCC, but not from the QCC, studies showed a higher AML risk for infants of mothers ≥40-year-old (OR = 6.87; 95% CI: 2.12-22.25). There were no associations observed between any other maternal or paternal age group and AML risk for children older than one year.

Conclusions: An increased risk of infant AML with advanced maternal age was found using data from RCC, but not from QCC studies; no parental age-AML associations were observed for older children.
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http://dx.doi.org/10.1016/j.canep.2019.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098424PMC
April 2019