To investigate prognostic factors in pediatric and young adult patients with localized osteosarcoma that could predict the development of subsequent pulmonary metastases and lead to an ability to risk-stratify therapy. We performed a systematic review of the literature published since January 1990 to establish common evidence-based prognostic factors. Methods. PubMed and Embase searches (Jan 1990–Aug 2018) were performed. Two reviewers independently selected papers for patients with localized osteosarcoma with subsequent metastatic development and then reviewed for quality of methods and prognostic factors. Results. Database searches yielded 216 unique results. After screening, 27 full-text articles were studied in depth, with 9 items fulfilling predetermined inclusion and exclusion criteria. Age, tumor location, tumor size/volume, and histologic response carried independent prognostic value in the majority of the studies. Conclusions. Several prognostic factors seemed to be consistent amongst the studies, but the heterogeneity and smaller sizes of the study populations made pooling of results difficult. Standardization of larger patient populations and consistent definitions/cutoffs for prognostic factors are needed to further assess for consistent prognostic factors and potential predictive models to be developed.

While substantial advances in the identification of cytogenomic subtypes of childhood acute lymphoblastic leukemia (ALL) have been made in recent decades, epidemiologic research characterizing the etiologic heterogeneity of ALL by subtype has not kept pace. The purpose of this review is to summarize the current literature concerning subtype-specific epidemiologic risk factor associations with ALL subtype defined by immunophenotype (e.g. B-cell vs T-cell) and cytogenomics (including gross chromosomal events characterized by recurring numerical and structural abnormalities, along with cryptic balanced rearrangements, and focal gene deletions). In case-control analyses investigating non-genetic risk factors, home paint exposure is associated with hyperdiploid, MLL-rearranged, and ETV6-RUNX1 subtypes, yet there are few differences in risk factor associations between T- and B-ALL. While the association between maternal smoking and ALL overall has been null, maternal smoking is associated with an increasing number of gene deletions among cases. GWAS-identified variants in ARID5B have been the most extensively studied and are strongly associated with hyperdiploid B-ALL. GATA3 single nucleotide variant rs3824662 shows a strong association with Ph-like ALL (OR=3.14). However, there have been relatively few population-based studies of adequate sample size to uncover risk factors that may define etiologic heterogeneity between and within the currently defined cytogenomic ALL subtypes.

<h3>Importance</h3><p>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.</p><h3>Objective</h3><p>To compare the incidence of childhood cancers among children conceived in vitro with those conceived naturally.</p><h3>Design, Setting, and Participants</h3><p>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.</p><h3>Exposure</h3><p>In vitro fertilization.</p><h3>Main Outcomes and Measures</h3><p>Cancer diagnosed in the first decade of life.</p><h3>Results</h3><p>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.</p><h3>Conclusions and Relevance</h3><p>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.</p>

<p>Introduction: Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. Historical studies have found an association between ALL incidence with higher socioeconomic status (SES), though newer findings are contradictory for this association. Nevertheless, it has been well established that inferior outcomes in pediatric ALL are associated with lower SES. We sought to identify if specific ALL disease characteristics at diagnosis are associated with SES to determine if underlying biology plays a role in the known association between inferior outcomes and lower SES.</p>

Objectives Previously published studies on parental occupational exposure to extremely low-frequency magnetic fields (ELF-MF) and risk of acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in their offspring were inconsistent. We therefore evaluated this question within the Childhood Leukemia International Consortium. Methods We pooled 11 case–control studies including 9723 childhood leukaemia cases and 17 099 controls. Parental occupational ELF-MF exposure was estimated by linking jobs to an ELF-MF job-exposure matrix (JEM). Logistic regression models were used to estimate ORs and 95% CIs in pooled analyses and meta-analyses. Results ORs from pooled analyses for paternal ELF-MF exposure >0.2 microtesla (µT) at conception were 1.04 (95% CI 0.95 to 1.13) for ALL and 1.06 (95% CI 0.87 to 1.29) for AML, compared with ≤0.2 µT. Corresponding ORs for maternal ELF-MF exposure during pregnancy were 1.00 (95% CI 0.89 to 1.12) for ALL and 0.85 (95% CI 0.61 to 1.16) for AML. No trends of increasing ORs with increasing exposure level were evident. Furthermore, no associations were observed in the meta-analyses. Conclusions In this large international dataset applying a comprehensive quantitative JEM, we did not find any associations between parental occupational ELF-MF exposure and childhood leukaemia.

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.

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

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

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

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

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

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

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