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.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Little is known about the etiology of hepatoblastoma. We aimed to confirm the results of a previous study evaluating the association between parental occupational exposures and hepatoblastoma. In our case-control study, we identified cases (n=383) from the Children's Oncology Group and controls from birth certificates (n=387), which were frequency matched to cases on year and region of birth, sex, and birth weight. Occupational exposure in the year before and during the index pregnancy was collected through maternal interview and analyzed using unconditional logistic regression. The odds of both paternal and maternal "Likely" exposure to paints was elevated among cases compared with controls (paternal odds ratio (OR): 1.71, 95% confidence interval (CI): 1.04, 2.81; maternal OR: 3.29, 95% CI: 0.32, 33.78) after adjustment for matching factors and the confounding factors of maternal race (maternal only) and household income. In addition, paternal exposure to other chemicals was also elevated when adjusting for matching factors only (OR: 1.53, 95% CI: 1.02, 2.30). The results of our study provide further evidence of an association between parental occupation and hepatoblastoma. These results warrant further investigation of the etiologically relevant timing of occupational exposure to fumes and chemicals related to hepatoblastoma.

PURPOSE: History of fetal loss including miscarriage and stillbirth has been inconsistently associated with childhood (0-14 years) leukemia in subsequent offspring. A quantitative synthesis of the inconclusive literature by leukemia subtype was therefore conducted., METHODS: Eligible studies (N=32) were identified through the screening of over 3500 publications. Random-effects meta-analyses were conducted on the association of miscarriage/stillbirth history with overall (AL; 18,868 cases/35,685 controls), acute lymphoblastic (ALL; 16,150 cases/38,655 controls), and myeloid (AML; 3042 cases/32,997 controls) leukemia. Sensitivity and subgroup analyses by age and ALL subtype, as well as meta-regression were undertaken., RESULTS: Fetal loss history was associated with increased AL risk [Odds Ratio (OR) 1.10, 95% Confidence Intervals (CI) 1.04-1.18]. The positive association was seen for ALL (OR 1.12, 95%CI 1.05-1.19) and for AML (OR 1.13, 95%CI 0.91-1.41); for the latter the OR increased in sensitivity analyses. Notably, stillbirth history was significantly linked to ALL risk (OR 1.33, 95%CI 1.02-1.74), but not AML. By contrast, the association of ALL and AML with previous miscarriage reached marginal significance. The association of miscarriage history was strongest in infant ALL (OR 2.34, 95%CI 1.19-4.60)., CONCLUSIONS: In this meta-analysis involving >50,000 children, we found noteworthy associations by indices of fetal loss, age at diagnosis, and leukemia type; namely, of stillbirth with ALL and miscarriage history with infant ALL. Elucidation of plausible underlying mechanisms may provide insight into leukemia pathogenesis and indicate monitoring interventions prior to and during pregnancy.

Background: The presence of a congenital anomaly is associated with increased childhood cancer risk, likely due to large effects of Down syndrome and chromosomal anomalies for leukemia. Less is known about associations with presence of non-chromosomal anomalies. Methods: Records of children diagnosed with cancer at &lt;20 years of age during 1984-2013 in Washington State cancer registries were linked to their birth certificates (N = 4,105). A comparison group of children born in the same years was identified. Congenital anomalies were assessed from birth records and diagnosis codes in linked hospital discharge data. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for cancer, and for specific cancer types in relation to the presence of any anomaly and specific anomalies. Results: Having any congenital anomaly was associated with an increased risk of childhood cancer (OR: 1.46, 95% CI 1.28-1.65). Non-chromosomal anomalies were also associated with increased childhood cancer risk overall (OR: 1.35; 95% CI: 1.18-1.54), and with increased risk of several cancer types, including neuroblastoma, renal, hepatoblastoma, soft-tissue sarcoma, and germ cell tumors. Increasing number of non-chromosomal anomalies was associated with a stronger risk of childhood cancer (OR for 3+ anomalies: 3.11, 95% CI: 1.54-6.11). Although central nervous system (CNS) anomalies were associated with CNS tumors (OR: 6.05, 95% CI 2.75-13.27), there was no strong evidence of other non-chromosomal anomalies being specifically associated with cancer occurring in the same organ system or anatomic location. Conclusions: Non-chromosomal anomalies increased risk of several cancer types. Additionally, we found that increasing number of non-chromosomal anomalies was associated with a stronger risk of cancer. Pooling similar data from many regions would increase power to identify specific associations in order to inform molecular studies examining possible common developmental pathways in the etiologies of birth defects and cancer.

BackgroundInfant leukaemia (IL) is extremely rare with fewer than 150 cases occurring each year in the United States. Little is known about its causes. However, recent evidence supports a role of de novo mutations in IL aetiology. Parental age has been associated with several adverse outcomes in offspring, including childhood cancers. Given the role of older parental age in de novo mutations in offspring, we carried out an analysis of parental age and IL. MethodsWe evaluated the relationship between parental age and IL in a case-control study using registry data from New York, Minnesota, California, Texas, and Washington. Records from 402 cases {[}219 acute lymphoblastic leukaemia (ALL), 131 acute myeloid leukaemia (AML), and 52 other] and 45392 controls born during 1981-2004 were analysed. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by logistic regression. Estimates were adjusted for infant sex, birth year category, maternal race, state, and mutually adjusted for paternal or maternal age, respectively. ResultsInfants with mothers' age 40years had an increased risk of developing AML (OR 4.80, 95% CI 1.80, 12.76). In contrast, paternal age <20 was associated with increased risk of ALL (OR 3.69, 95% CI 1.62, 8.41). ConclusionThis study demonstrates increased risk of infant ALL in relation to young paternal age. Given record linkage, there is little concern with recall or selection bias, although data are lacking on MLL gene status and other potentially important variables. Parent of origin effects, de novo mutations, and/or carcinogenic exposures may be involved in IL aetiology.

BACKGROUND The long-term outcomes of patients undergoing interventions for congenital heart disease (CHD) remain largely unknown. We linked the Pediatric Cardiac Care Consortium (PCCC) with the National Death Index (NDI) and the United Network for Organ Sharing Dataset (UNOS) registries to study mortality and transplant occurring up to 32 years postintervention. The objective of the current analysis was to determine the sensitivity of this linkage in identifying patients who are known to have died or undergone heart transplant. METHODS AND RESULTS We used direct identifiers from 59 324 subjects registered in the PCCC between 1982 and 2003 to test for completeness of case ascertainment of subjects with known vital and heart transplant status by linkage with the NDI and UNOS registries. Of the 4612 in-hospital deaths, 3873 were identified by the NDI as "true" matches for a sensitivity of 84.0% (95% CI, 82.9-85.0). There was no difference in sensitivity across 25 congenital cardiovascular conditions after adjustment for age, sex, race, presence of first name, death year, and residence at death. Of 455 known heart transplants in the PCCC, there were 408 matches in the UNOS registry, for a sensitivity of 89.7% (95% CI, 86.9-92.3). An additional 4851 deaths and 363 transplants that occurred outside the PCCC were identified through 2014. CONCLUSIONS The linkage of the PCCC with the NDI and UNOS national registries is feasible with a satisfactory sensitivity. This linkage provides a conservative estimate of the long-term death and heart transplant events in this cohort.

We read with interest the article by Pasquali et al1 exploring opportunities and challenges toward an integrated data network for congenital heart disease research. We fully agree with the authors’ conclusion that there is a need for additional integration and collaboration to understand and improve the outcomes for patients with congenital heart disease. A particular gap that needs to be addressed is the lack of long-term and longitudinal outcomes for this population. To achieve this goal, it is important to …

OBJECTIVE: To evaluate the risk of maternal morbidity due to IVF, plurality, and maternal age. DESIGN: Longitudinal case-control cohort study MATERIALS AND METHODS: IVF cycles from the Society for Assisted Reproductive Technology Clinic Online Reporting System were linked to birth certificates of singletons and twins in CA (2004-09), and PA, MI, NY, TX (2004-10) (IVF births); a 10:1 sample of non-IVF births were controls. Maternal morbidity was identified from six items on the birth certificate (see below). Using logistic regression, the risk of each morbidity was modeled by maternal age, IVF versus non-IVF conception, and plurality (twin versus singleton), separately for each mode of delivery. Parity was included in the model for perineal laceration. RESULTS: The study population included 53,053 IVF births (37,193 singletons and 15,860 twin births) and 576,880 non-IVF control births (567,856 singletons and 9,024 twin births). Regardless of mode of delivery, older maternal age was associated with an increased risk of unplanned hysterectomy and unplanned operations; twin pregnancy with blood transfusion, admission to intensive care, and unplanned operations; and IVF pregnancy with blood transfusion. Women with vaginal IVF births were at increased risk for unplanned hysterectomy, unplanned operations, and 3rd or 4th degree perineal lacerations. Cesarean twin births were at increased risk of unplanned hysterectomy. CONCLUSIONS: The risks of maternal morbidity at delivery are increased with IVF, twin pregnancy, and older maternal age. (Table Presented).

BackgroundRhabdomyosarcoma (RMS) is a rare, highly malignant tumor\narising from primitive mesenchymal cells that differentiate into\nskeletal muscle. Relatively little is known about RMS susceptibility.\nBased on growing evidence regarding the role of early immunologic\nchallenges on RMS development, we evaluated the role of infections and\nimmunizations on this clinically significant pediatric malignancy.\nProcedureRMS cases (n = 322) were enrolled from the third trial\ncoordinated by the Intergroup Rhabdomyosarcoma Study Group.\nPopulation-based controls (n = 322) were pair matched to cases on race,\nsex, and age. The following immunizations were assessed: diphtheria,\npertussis, and tetanus (DPT); measles, mumps, and rubella; and oral\npolio vaccine. We also evaluated if immunizations were complete versus\nincomplete. We examined selected infections including chickenpox, mumps,\npneumonia, scarlet fever, rubella, rubeola, pertussis, mononucleosis,\nand lung infections. Conditional logistic regression models were used to\ncalculate an odds ratio (OR) and 95% confidence interval (CI) for each\nexposure, adjusted for maternal education and total annual income.\nResultsIncomplete immunization schedules (OR= 5.30, 95% CI: 2.47-11.33)\nand incomplete DPT immunization (OR = 1.56, 95% CI: 1.06-2.29) were\npositively associated with childhood RMS. However, infections did not\nappear to be associated with childhood RMS.\nConclusionsThis is the largest study of RMS to date demonstrating a\npossible protective effect of immunizations against the development of\nchildhood RMS. Further studies are needed to validate our findings. Our\nfindings add to the growing body of literature, suggesting a protective\nrole of routine vaccinations in childhood cancer and specifically in\nchildhood RMS. (C) 2016 Wiley Periodicals, Inc.

Background: Coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) are rare in children (<18 years). We report indications and outcomes of CABG or PCI from a large North American registry of pediatric cardiac centers. Methods: Cohort study from the Pediatric Cardiac Care Consortium (PCCC) for CABG or PCI between 1982 and 2007. Data included age at time of procedure, primary diagnosis, indication, and in-hospital mortality. Long term outcomes were assessed using PCCC follow up data supplemented by data from the United Network for Organ Sharing (UNOS) and the National Death Index (NDI) for a subgroup with adequate identifiers (n=65). Results: We identified 110 coronary revascularization procedures: 19 were performed in infants (CABG 18, PCI 1) and 91 in children (CABG 75, PCI 16). The majority of patients had surgical heart diseases (n=80) including congenital coronary artery abnormalities (n=33), history of arterial switch operation (n=20) or operation at risk for coronary artery injury (n=24). There were 14 in-hospital deaths. Follow-up using the UNOS and NDI identified 10 transplants (OHT) and 10 deaths respectively. The Kaplan Meier plot of the transplant free survival for the cohort submitted to the UNOS and NDI is presented in the Figure with 10-year transplant free survival of 69% (95% CI: 58%- 81%). Conclusions: Coronary revascularization procedures can be performed in children for a variety of indications with acceptable mid-term transplant-free survival.

Background: With today's advancements in surgical or transcatheter interventions about 90% of infants with congenital heart diseases (CHD) are expected to reach adulthood. However, the long term altered history of patients surviving interventions for CHD remains largely unknown. We aim to study mortality patterns in the cohort registered in the Pediatric Cardiac Care Consortium (PCCC) after undergoing interventions for CHD between 1982 and 2003. The PCCC is the longest registry for pediatric cardiac interventions in the world containing data from surgical and transcatheter procedures from 27 U.S. states. Methods: We linked the PCCC dataset with the National Death Index (NDI) using direct identifiers to determine vital status of individuals with repaired or palliated CHD. The identifiers included first name, middle name, last name, day, month and year of birth, state residence at birth and sex. A total of 59,324 subjects registered in the PCCC as having undergone an intervention for CHD up to April 2003 (date of implementation of HIPAA rules) had sufficient identifiers and were submitted for linkage with the NDI. This number includes also 4,655 inhospital deaths recorded in the PCCC registry. After linking with the NDI, these records are assigned by NDI a probabilistic score based on the NDI algorithm and are identified as true or false matches. We tested for completeness of case ascertainment of subjects with known vital status based on their last admission in a PCCC center. Results and Conclusions: Of the 4,655 known deaths submitted to the NDI, 3,906 were identified as “true” matches, 381 as undetermined matches and 368 deaths had no match. Based on these numbers the sensitivity of the PCCC-NDI match is within the range of 82.8% to 85.0% [95% confidence interval]. There was no difference in sensitivity across 48 congenital cardiovascular conditions after adjustment for age, sex, year and state of death. An additional 3,722 deaths were identified through 12/31/2012 that occurred outside the PCCC. These events provide a conservative estimate of deaths that forms the basis for estimating the long term survival of this cohort.

Background: Results from case-control studies have shown an increased risk of acute lymphoblastic leukaemia (ALL) in young children born by caesarean delivery, and prelabour caesarean delivery in particular; however, an association of method of delivery with childhood leukaemia subtypes has yet to be established. We therefore did a pooled analysis of data to investigate the association between childhood leukaemia and caesarean delivery. Methods: We pooled data from 13 case-control studies from the Childhood Leukemia International Consortium done in nine countries (Canada, Costa Rica, Egypt, France, Germany, Greece, Italy, New Zealand, and the USA) for births from 1970-2013. We analysed caesarean delivery overall and by indications that probably resulted in prelabour caesarean delivery or emergency caesarean delivery. We used multivariable logistic regression models, adjusted for child's birthweight, sex, age, ethnic origin, parental education, maternal age, and study, to estimate odds ratios (ORs) and 95% CIs for the risk of ALL and acute myeloid leukaemia (AML) in children aged 0-14 years at diagnosis. Findings: The studies provided data for 8780 ALL cases, 1332 AML cases, and 23 459 controls, of which the birth delivery method was known for 8655 (99%) ALL cases, 1292 (97%) AML cases, and 23 351 (>99%) controls. Indications for caesarean delivery were available in four studies (there were caesarean deliveries for 1061 of 4313 ALL cases, 138 of 664 AML cases, and 1401 of 5884 controls). The OR for all indications of caesarean delivery and ALL was 1·06 (95% CI 0·99-1·13), and was significant for prelabour caesarean delivery and ALL (1·23 [1·04-1·47]; p=0·018). Emergency caesarean delivery was not associated with ALL (OR 1·02 [95% CI 0·81-1·30]). AML was not associated with caesarean delivery (all indications OR 0·99 [95% CI 0·84-1·17]; prelabour caesarean delivery 0·83 [0·54-1·26]; and emergency caesarean delivery 1·05 [0·63-1·77]). Interpretation: Our results suggest an increased risk of childhood ALL after prelabour caesarean delivery. If this association is causal, maladaptive immune activation due to an absence of stress response before birth in children born by prelabour caesarean delivery could be considered as a potential mechanism. Funding: National Cancer Institute.

STUDY QUESTION How do the assisted reproductive technology (ART) outcomes of women presenting for ART after cancer diagnosis compare to women without cancer?SUMMARY ANSWER The likelihood of a live birth after ART among women with prior cancer using autologous oocytes is reduced and varies by cancer diagnosis but is similar to women without cancer when donor oocytes are used.WHAT IS KNOWN ALREADY Premenopausal patients faced with a cancer diagnosis frequently present for fertility preservation.STUDY DESIGN, SIZE, DURATION Population-based cohort study of women treated with ART in NY, TX and IL, USA.PARTICIPANTS/MATERIALS, SETTING, METHODS Women with their first ART treatment between 2004 and 2009 were identified from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database and linked to their respective State Cancer Registries based on name, date of birth and social security number. Years were rounded, i.e. year 1 = 6–18 months before treatment. This study used reports of cancer from 5 years, 6 months prior to treatment until 6 months after first ART treatment. Women who only presented for embryo banking were omitted from the analysis. The likelihood of pregnancy and of live birth with ART using autologous oocytes was modeled using logistic regression, with women without prior cancer as the reference group, adjusted for woman's age, parity, cumulative FSH dosage, infertility diagnosis, number of diagnoses, number of ART cycles, State of residency and year of ART treatment. Results of the modeling are reported as adjusted odds ratios (AORs) and (95% confidence intervals).MAIN RESULTS AND THE ROLE OF CHANCE The study population included 53 426 women; 441 women were diagnosed with cancer within 5 years prior to ART cycle start. Mean (±SD) age at cancer diagnosis was 33.4 ± 5.7 years; age at start of ART treatment was 34.9 ± 5.8 for women with cancer compared with 35.3 ± 5.3 years for women without cancer (P = 0.03). Live birth rates among women using autologous oocytes differed substantially by cancer status (47.7% without cancer versus 24.7% with cancer, P < 0.0001), and cancer diagnosis (ranging from 53.5% for melanoma to 14.3% for breast cancer, P < 0.0001. The live birth rates among women using donor oocytes did not vary significantly by cancer status (60.4% for women with any cancer versus 64.5% for women without cancer), or by cancer diagnosis (ranging from 57.9% for breast cancer to 63.6% for endocrine cancer). Women with breast cancer make up about one-third of all cancers in this cohort. Among women with breast cancer, 2.8% of the 106 women who underwent ART within 6 months of being diagnosed with cancer used donor oocytes compared with 34.8% of the 46 women who received ART treatment a longer time after being diagnosed with cancer (P < 0.0001). We conjecture that the former group were either unaware that they had cancer or decided to undergo ART therapy prior to cancer treatment. However, their live birth rate was only 11.7% compared with 28.8%, the overall live birth rate for all women with cancer using autologous oocytes (P < 0.0001). The live birth rate for women diagnosed with breast cancer more than 6 months before ART (23.3%) did not differ significantly from the overall live birth rate for cancer (P = 0.49). If this difference is substantiated by a larger study, it would indicate a negative effect of severe recent illness itself on ART success, rather than the poor outcome being only related to the destructive effects of chemotherapies on ovarian follicles. Alternatively, because of the short time difference between cancer diagnosis and ART treatment, these pre-existing cancers may have been detected due to the increased medical surveillance during ART therapy. In women who only used autologous oocytes, women with prior cancers were significantly less likely to become pregnant and to have a live birth than those without cancer (adjusted odds ratio (AOR): 0.34, [95% confidence interval (CI): 0.27, 0.42] and 0.36 [0.28, 0.46], respectively). This was also evident with specific cancer diagnoses: breast cancer (0.20 [0.13, 0.32] and 0.19 [0.11, 0.30], respectively), cervical cancer (0.36 [0.15, 0.87] and 0.33 [0.13, 0.84], respectively) and all female genital cancers (0.49 [0.27, 0.87] and 0.47 [0.25, 0.86], respectively). Of note, among women with cancer who became pregnant, their likelihood of having a live birth did not differ significantly from women without cancer (85.8 versus 86.7% for women using autologous oocytes, and 85.3 versus 86.9% for women using donor oocytes).LIMITATIONS, REASONS FOR CAUTION Women may not have been residents of the individual States for the entire 5-year pre-ART period, and therefore some cancers may not have been identified through this linkage. As a result, the actual observed number of cancers may be an underestimate. In addition, the overall prevalence is low due to the age distributions. Also, because we restricted the pre-ART period to 5 years prior, we would not have identified women who were survivors of early childhood cancers (younger than age 13 years at cancer diagnosis), or who had ART more than 5 years after being diagnosed with cancer. Additional analyses are currently underway evaluating live birth outcomes after embryo banking among women with cancer prior to ART, cycles which were excluded from the analyses in this paper. Future studies are planned which will include more States, as well as linkages to vital records to obtain information on spontaneous conceptions and births, to further clarify some of the issues raised in this analysis.WIDER IMPLICATIONS OF THE FINDINGS Since the live birth rates using donor oocytes were not reduced in women with a prior cancer, but were reduced with autologous cycles, this suggests that factors acting in the pre- or peri-conceptional periods may be responsible for the decline.STUDY FUNDING/COMPETING INTERESTS The study was funded by grant R01 CA151973 from the National Cancer Institute, National Institutes of Health, USA. B.L. is a research consultant for the Society for Assisted Reproductive Technology. All other authors report no conflict of interest.

Rheumatology laboratory tests are often inappropriately ordered in situations for which they are of low diagnostic utility. We surveyed pediatricians to investigate reasons for ordering these tests. The response rate was 15.3% (93/609). The most commonly ordered tests were antinuclear antibody (ANA), anti-double-stranded DNA (dsDNA) antibody, and rheumatoid factor (RF). Of the 89% (83/93) who ordered an ANA, 86% ordered it for correct/possibly correct reasons; of the 73% (68/93) who ordered RF, 80% did so for correct/possibly correct reasons; and among the 59% (54/92) who had ordered anti-dsDNA antibody, 34% ordered it for correct reasons. A positive relationship was seen between years since residency completion and correct use of ANA. However, positive associations were not seen between measures of pediatric rheumatology experience and correct use of other tests. Interventions are needed to improve pediatricians' utilization of rheumatology tests.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor in many countries, with metastatic disease responsible for most patient deaths. This study compares the prevalence of metastatic OS at diagnosis across countries to inform the critical question of whether diagnostic delay or tumor biology drives metastases development prior to diagnosis. PROCEDURE: A literature search of the PubMed database was conducted to compare the prevalence of metastatic disease at the time of OS diagnosis between countries. A pooled prevalence with 95% confidence intervals was calculated for each study meeting inclusion criteria. Studies were grouped for analysis based on human development index (HDI) scores. RESULTS: Our analysis found an 18% (95% confidence interval [CI]: 15%, 20%) average global pooled proportion of metastasis at OS diagnosis. The average prevalence of metastasis at diagnosis increased as HDI groupings decreased, with very high HDI, high HDI, and medium/low HDI groups found to be 15% (95% CI: 13%, 17%), 20% (95% CI: 14%, 28%), and 31% (95% CI: 15%, 52%), respectively. CONCLUSIONS: Our evidence suggests there is a biological baseline for metastatic OS at diagnosis, which is observed in countries with very high HDI. In countries with medium/low HDI, where there are more barriers to accessing healthcare, the higher prevalence of metastasis may result from treatment delay or an artificial prevalence inflation due to patients with less severe symptoms not presenting to clinic. Additional research in countries with medium/low HDI may reveal that earlier detection and treatment could improve patient outcomes in those countries.