Etiology Of Childhood Leukemia Research Articles

In This Issue

See article, p. 434.Ficlatuzumab is a first-in-class monoclonal antibody that blocks oncogenic MET signaling by blocking its ligand HGF. Here Wang et al. report on the safety and efficacy of ficlatuzumab combination with cytarabine in 17 patients with relapsed/refractory acute myeloid leukemia. Nine of the patients (53%) achieved a complete remission. Progression-free survival was 31.2 months, and median overall survival has not been reached. These outcomes compare favorably to historical data but remain to be validated in larger, randomized trials. Phosphoproteomic analysis identified S6 and MET phosphorylation as molecular correlates of response. Ras and GTPase gene expression signature was higher in prospective responders, whereas prospective nonresponders had elevated interferon and Myc signature.See article, p. 450.Human T-cell leukemia virus type-1 (HTLV-1) infection can progress to adult T-cell leukemia/lymphoma (ATL). To elucidate determinants of HTLV-1–driven oncogenesis, Koya et al. characterize circulating blood cells of healthy donors, HTLV-1 carriers, and patients with ATL by genome sequencing and CITE-seq combined with TCR-seq and BCR-seq. This high-dimensional single-cell analysis identifies Treg phenotype as a hallmark of premalignant clonal outgrowth. As the neoplastic clones progress to ATL, their expansion is accompanied by a proportional expansion of the myeloid compartment and immunosuppressive phenotypes including PD-L1 upregulation. The study delineates a new mechanism of PD-L1 acquisition by protein transfer from ATL to nonmalignant cells.See article, p. 468.Immunologic consequences of cell death contribute to clinical efficacy of certain chemotherapeutics, and identification of immunogenic drugs is essential for their optimal clinical use alone and in combination with immunotherapy. In this work, Gulla et al. have shown that a specific anti–multiple myeloma (MM) immunity occurs upon cell death induced by the proteasome inhibitor bortezomib, leading to immunologic memory and long-term clinical response. Intrinsic activation of STING followed by a viral mimicry state further contributes to the immunogenic effect, and combination of bortezomib with a STING agonist potentiates tumor cell–immune microenvironment interplay. These findings invite a deeper characterization of the immunologic effects of anti-MM agents and inform novel chemo-immunotherapy combinations.See article, p. 484.To obtain insight into the etiology of childhood leukemia, Brandsma et al. determined mutation burden of leukemic blasts and normal hematopoietic stem and progenitor cells (HSPC) from pediatric acute myeloid leukemia (pAML) patients and healthy age-matched controls. Integrating these data with available adult cohorts, they established a baseline of HSPC mutation accrual over the entire human lifespan. A subset of pediatric leukemia cases falling above the baseline harbored more genetic driver events and associated with better survival. The mutation pattern, characteristic of cells with high proliferation and oxidative stress, suggests a more committed progenitor as a cell of origin in this pAML subset.See article, p. 500.While the most frequent drivers of clonal hematopoiesis have been characterized previously, mutations in these genes are not present in about half of clonal hematopoiesis cases. By identifying recurrent mutations in the blood of large numbers of healthy people, Beauchamp et al. discover additional genes likely to drive clonal hematopoiesis and thus regulating hematopoietic stem cell (HSC) expansion. Modeling ZBTB33 mutations in mouse HSCs, the authors observe that the edited cells expand and have a competitive advantage compared with control cells. Cells with Zbtb33 mutations also have altered intron retention, potentially connecting ZBTB33 to RNA splicing, a commonly mutated pathway in clonal hematopoiesis and myelodysplastic syndromes.See article, p. 518.Romine et al. characterize acute myeloid leukemia (AML) sensitivity to BET inhibitors (BETi) by two orthogonal approaches: ex vivo drug screening of genetically defined primary AML samples, and genome-wide CRISPR screens of BETi-sensitive and BETi-resistant cells. Both identify loss of monocytic differentiation regulators as drivers of BETi resistance. BETi-resistant AML cells express low levels of myeloid markers; conversely, forced myeloid differentiation sensitizes AML cells to BETi. CRISPR dropout screens in BETi-resistant cells reveal BCL2 and CDK4/6 as targetable vulnerabilities to overcome BETi resistance. Moreover, monocytic AML refractory to BCL2 inhibition, an unmet clinical challenge, shows preclinical responses to combined Bcl2 and BETi.See article, p. 532.Binding of tyrosine kinase inhibitors (TKI) by plasma proteins, most notably alpha-1-acid glycoprotein (AGP), can dramatically reduce TKI bioavailability and thus clinical potency. In this work, Young et al. characterize AGP impact on staurosporine-derived TKI (STS-TKI) activity against FLT3-mutated acute myeloid leukemia (AML). Under physiologic conditions and drug concentrations, AGP quenches STS-TKI activity to subtherapeutic levels due to high-affinity drug–protein interactions. To overcome this, the authors screen for drugs restoring TKI activity in the presence of AGP, identifying mifepristone. In an in vivo model, mifepristone coadministration restores midostaurin clearance of AML cells. These results suggest a combinatorial approach for unlocking TKI activity to potentiate therapeutic responses in FLT3-mutated AML.

Socio-Demographic and Blood Group Findings in Children with Acute Leukemia: a single cancer center experience

Leukemia is a cancer of white blood cells, in which the bone marrow produces irregular white blood cells. These cells swarm out the solid blood cells. In intense leukemia, the cells are highly irregular, and their number increments quickly. Acute lymphocytic leukemia (ALL) most common childhood malignancy in most parts of the world. The etiology of childhood leukemia is unknown and is probably multifactorial. Leukemia can often be cured. However, the association between this type of cancer and ABO blood group is not established. The present study aimed to identify the association between blood groups and Rh types with childhood leukemia. For this purpose, a quantitative design retrospective study was conducted between the 1st December 2019 and the 30th January 2020 on the records of 100 patients who were under 18 years old with diagnosed leukemia, treated, and followed at the pediatric unit of Hiwa Hospital in Sulaimaniyah. Data on patients’ age, gender, residence, age at diagnosis, and blood group were collected. According to the retrospective analysis, 100 patients who met the diagnosis of ALL and acute myeloid leukemia (AML) were 18 years or younger, most of them had ALL (81%), 85% lived in urban areas, 63% were male, and A+ was the most common blood group (36%). Also, there was no statistically significant association between ABO blood group and diverse autonomous factors with childhood leukemia. ABO blood groups can be used as an effective technique to understand the etiology of hematological malignancies, particularly if they are assessed within the ground of later atomic writing of such hereditary polymorphism.

Is the risk of childhood leukaemia associated with socioeconomic measures in Denmark? A nationwide register-based case-control study.

The aetiology of childhood leukaemia is poorly understood. Knowledge about differences in risk by socioeconomic status (SES) may enhance etiologic insights. We conducted a nationwide register-based case-control study to evaluate socioeconomic differences in the risk of childhood leukaemia in Denmark and to access whether associations varied by different measures of SES, time point of assessment, leukaemia type and age at diagnosis. We identified all cases of leukaemia in children aged 0 to 19 years, born and diagnosed between 1980 and 2013 from the Danish Cancer Registry (N = 1336) and sampled four individually matched controls per case (N = 5330). We used conditional logistic regression models for analysis. Medium and high level of parental education was associated with a higher risk of acute myeloid leukaemia (AML) in the offspring, mainly driven by children diagnosed at ages 0 to 4 years [odds ratio (OR) for high maternal education = 3.07; 95% confidence interval (CI): 1.44-6.55]. We also observed a modestly increased risk for lymphoid leukaemia (LL) in association with higher level of parental education, but only in children diagnosed at ages 5 to 19 years. Higher parental income was associated with an increased risk of LL but not AML among children aged 5 to 19 years at diagnosis (OR for high maternal income = 2.78; 95% CI: 1.32-5.89). Results for neighbourhood SES measures indicated null associations. Bias or under-ascertainment of cases among families with low income or basic education are unlikely to explain the observed socioeconomic differences. Future research addressing explicitly the underlying mechanisms of our results may help to enhance etiologic insights of the disease.

Agricultural crop density in the municipalities of France and incidence of childhood leukemia: An ecological study

BackgroundPesticide exposure is suspected to play a role in the etiology of childhood leukemia (AL). Various sources of exposure have been explored, but few studies have investigated the risk of childhood AL in relation to residential exposure to agricultural pesticides. Since around 50% of France is agricultural land, with marked pesticide use, France is a suitable location to investigate for an association. We aimed to analyze the association between the agricultural crop density in the municipalities of France and the incidence of childhood AL between 1990 and 2014. Methods11,487 cases of AL diagnosed in children aged 0–14 years were registered by the French National Registry of Childhood Hematological Malignancies over 1990–2014. National agricultural census data for 1990, 2000 and 2010 were used to estimate the densities of the most common crops in France. The incidence of AL was estimated in the 35,512 municipalities, by age and gender, and 3 observation periods, and expressed as the standardized incidence ratio (SIR). ResultsWe observed a moderate log-linear association between viticulture density and the incidence of AL, with a 3% increase in SIR for a 10% increase in viticulture density (SIRR = 1.03; 95%CI [1.00–1.06]). The association remained for lymphoblastic AL but not for myeloid AL. The association was stable after stratification by geographic area, age and period, and after adjustment on UV radiation and a French deprivation index. No consistent association was observed for other crop types. DiscussionThis nationwide study shows a moderate increase in incidence of childhood AL in municipalities where viticulture is common. Future individual studies are needed to know whether this observation is confirmed and related to particular use of pesticides.

Genetic polymorphisms of Th2 interleukins, history of asthma or eczema and childhood acute lymphoid leukaemia: Findings from the ESCALE study (SFCE)

BackgroundPrevious studies on the putative role of allergy in the aetiology of childhood leukaemia have reported contradictory results. The present study aimed to analyse the relation between a medical history of asthma or eczema and childhood acute lymphoid leukaemia (ALL) in light of potential candidate gene-environment interactions. MethodsAnalyses were based on a subset of 434 cases of ALL and 442 controls successfully genotyped and of European ancestry children enrolled in a French population-based case-control study conducted in 2003–2004. Information about medical history was obtained during a standardized interview with the mothers. Candidate polymorphisms in genes of the Th2 cytokines IL4, IL10, IL13 and IL4-receptor, were genotyped or imputed. ResultsNone of the variant alleles were directly associated with childhood acute lymphoid leukaemia. A medical history of asthma or eczema was reported more often in the control group (OR = 0.7 [0.5–1.0]). This association was mostly seen in the group of children not carrying the IL13-rs20541 variant allele (Interaction Odds Ratio IOR 1.9, p-interaction = 0.07) and in those carrying the IL10 triple variant haplotype (IOR 0.5, p-interaction = 0.04). No interaction was observed with the candidate polymorphisms in IL4 and IL4R. ConclusionThis study provides a new insight into the relationship between allergic symptoms and childhood acute lymphoid leukaemia, by suggesting this inverse association could be limited to children carrying certain genetic polymorphisms. If confirmed, these results could help better understand the biological mechanisms involved in the development of childhood acute lymphoid leukaemia.

Childhood Leukemia: A Preventable Disease.

In contrast to most pediatric cancers, there is a growing body of literature, nationally and internationally, that has implicated the role of several environmental indoor and outdoor hazards in the etiology of childhood leukemia. For example, exposures to solvents, traffic, pesticides, and tobacco smoke have consistently demonstrated positive associations with the risk of developing childhood leukemia. Intake of vitamins and folate supplementation during the preconception period or pregnancy has been demonstrated to have a protective effect. Despite the strength of these findings, the dissemination of this knowledge to clinicians has been limited. Some children may be more vulnerable than others as documented by the high and increasing incidence of childhood leukemia in Hispanics. To protect children's health, it is prudent to establish programs to alter exposure to those factors with well-established associations with leukemia risk rather than to suspend judgment until no uncertainty remains. This is particularly true because other serious health outcomes (both negative and positive) have been associated with the same exposures. We draw from historical examples to put in perspective the arguments of association versus causation, as well as to discuss benefits versus risks of immediate and long-term preventive actions.

Childhood Leukemia and Primary Prevention

Leukemia is the most common pediatric cancer, affecting 3800 children per year in the United States. Its annual incidence has increased over the last decades, especially among Latinos. Although most children diagnosed with leukemia are now cured, many suffer long-term complications, and primary prevention efforts are urgently needed. The early onset of leukemia-usually before 5 years of age-and the presence at birth of "pre-leukemic" genetic signatures indicate that pre- and postnatal events are critical to the development of the disease. In contrast to most pediatric cancers, there is a growing body of literature-in the United States and internationally-that has implicated several environmental, infectious, and dietary risk factors in the etiology of childhood leukemia, mainly for acute lymphoblastic leukemia, the most common subtype. For example, exposures to pesticides, tobacco smoke, solvents, and traffic emissions have consistently demonstrated positive associations with the risk of developing childhood leukemia. In contrast, intake of vitamins and folate supplementation during the preconception period or pregnancy, breastfeeding, and exposure to routine childhood infections have been shown to reduce the risk of childhood leukemia. Some children may be especially vulnerable to these risk factors, as demonstrated by a disproportionate burden of childhood leukemia in the Latino population of California. The evidence supporting the associations between childhood leukemia and its risk factors-including pooled analyses from around the world and systematic reviews-is strong; however, the dissemination of this knowledge to clinicians has been limited. To protect children's health, it is prudent to initiate programs designed to alter exposure to well-established leukemia risk factors rather than to suspend judgment until no uncertainty remains. Primary prevention programs for childhood leukemia would also result in the significant co-benefits of reductions in other adverse health outcomes that are common in children, such as detriments to neurocognitive development.

Socioeconomic Status and Childhood Leukemia Incidence in Switzerland

Socioeconomic status (SES) discrepancies exist for child and adult cancer morbidity and are a major public health concern. In this Swiss population-based matched case–control study on the etiology of childhood leukemia, we selected the cases from the Swiss Childhood Cancer Registry diagnosed since 1991 and the controls randomly from census. We assigned eight controls per case from the 1990 and 2000 census and matched them by the year of birth and gender. SES information for both cases and controls was obtained from census records by probabilistic record linkage. We investigated the association of SES with childhood leukemia in Switzerland, and explored whether it varied with different definitions of socioeconomic status (parental education, living condition, area-based SES), time period, and age. In conditional logistic regression analyses of 565 leukemia cases and 4433 controls, we found no consistent evidence for an association between SES and childhood leukemia. The odds ratio comparing the highest with the lowest SES category ranged from 0.95 (95% CI: 0.71–1.26; Ptrend = 0.73) for paternal education to 1.37 (1.00–1.89; Ptrend = 0.064) for maternal education. No effect modification was found for time period and age at diagnosis. Based on this population-based study, which avoided participation and reporting bias, we assume the potential association of socioeconomic status and childhood leukemia if existing to be small. This study did not find evidence that socioeconomic status, of Switzerland or comparable countries, is a relevant risk factor or strong confounder in etiological investigations on childhood leukemia.

Race/ethnicity and the risk of childhood leukaemia: a case–control study in California

BackgroundWe conducted a large registry-based study in California to investigate the association between race/ethnicity and childhood leukaemia focusing on two subtypes: acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML).MethodsWe...

SETIL: Italian multicentric epidemiological case-control study on risk factors for childhood leukaemia, non hodgkin lymphoma and neuroblastoma: study population and prevalence of risk factors in Italy.

BackgroundAetiology of childhood leukaemia and childhood neoplasm is poorly understood. Information on the prevalence of risk factors in the childhood population is limited. SETIL is a population based case–control study on childhood leukaemia, conducted with two companion studies on non-Hodgkin Lymphoma (NHL) and neuroblastoma. The study relies on questionnaire interviews and 50 Hz magnetic field (ELF-MF) indoor measurements. This paper discusses the SETIL study design and includes descriptive information.MethodsThe study was carried out in 14 Italian regions (78.3% of Italian population aged 0–10). It included leukaemia, NHL and neuroblastoma cases incident in 0–10 year olds in 1998–2001, registered by the Italian Association of Paediatric Haematology and Oncology (AIEOP) (accrual over 95% of estimated incidence). Two controls for each leukaemia case were randomly sampled from the Local Health Authorities rolls, matched by gender, birthdate and residence. The same controls were used in NHL and neuroblastoma studies. Parents were interviewed at home on: physical agents (ELF-MF and ionizing radiation), chemicals (smoking, solvents, traffic, insecticides), occupation, medical and personal history of children and parents, infectious diseases, immunizations and associated factors. Occupational exposure was collected using job specific modules. ELF-MF was measured in the main rooms (spot measurement) and close to child’s bed (48 hours measurement).ResultsThe study included: 683 leukaemia cases (87% ALL, 13% AnLL), 97 NHL, 155 neuroblastomas, and 1044 controls.ELF-MF long term measurements were obtained for 61.1% of controls and 81.6% of leukaemia cases; 8.8% of controls were exposed at over 0.1 microTesla (μT), 3.5% and 2.1% at respectively over 0.2 and 0.3 μT. 25% of controls’ fathers had smoked over 10 cigarettes/day during the year of conception, varying according to education and region. Maternal smoking was less common (71.4% did not smoke in pregnancy). Maternal passive smoking during pregnancy was reported by 31.2% of controls; the child’s passive smoking for 28.6%.Occupational exposure to solvents was estimated in 18.3% of controls’ fathers and 7.7% of mothers. Contact with public was more frequent among mothers (36.1%) than fathers (23.4%).ConclusionsSETIL represents a data source on exposure of Italian children to a broad array of potential carcinogenic factors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13052-014-0103-5) contains supplementary material, which is available to authorized users.

Maternal reproductive history, fertility treatments and folic acid supplementation in the risk of childhood acute leukemia: the ESTELLE study.

To investigate the potential involvement of fertility treatments and other conditions of becoming pregnant (infertility, getting pregnant on birth control, maternal history of fetal loss) and folic acid supplements in the etiology of childhood leukemia (CL). The ESTELLE study included 747 cases of CL [636 cases of acute lymphoblastic leukemia (ALL) and 100 of acute myeloblastic leukemia (AML)] diagnosed in France in 2010-2011 and 1,421 population controls frequency-matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. The odds ratios (OR) and their 95% confidence intervals were estimated using unconditional regression models adjusted for potential confounders. CL was not associated with difficulty in becoming pregnant [OR 0.9 (0.7-1.2)], in vitro fertilisation [OR 0.6 (0.3-1.5)] or the use of any fertility treatment [OR 0.8 (0.5-1.1)] for the index pregnancy. CL was not significantly associated with becoming pregnant on contraception [OR 1.2 (0.8-1.8)], but a positive association was observed for third generation oral contraception [OR 4.3 (1.2-16.2)]; however, the result is based on small numbers. Folic acid supplementation during pregnancy was not associated with CL, but an inverse borderline association was observed for supplementation initiated in the 3 months preceding pregnancy [OR 0.7 (0.5-1.0)]. In addition, maternal histories of stillbirth and miscarriage were associated with ALL [OR 2.6 (1.1-5.9)] and AML [OR 1.8 (1.1-2.8)], respectively. The findings do not suggest that infertility and fertility treatments are risk factors for CL. They suggest that maternal histories of stillbirth and miscarriage may be more frequent among mothers of CL cases and that folic acid supplementation during preconception may reduce the risk of CL.

Mode of Delivery and Risk of Childhood Leukemia

Childhood infection and immune response have long been suspected in the etiology of childhood leukemia, specifically acute lymphoblastic leukemia (ALL). Normal primary inoculation of the core human microbiome is circumvented by cesarean section (CS) delivery, which is a proposed modulator of both immune response and early-life infection. In this study, we examined CS delivery and the risk of childhood leukemia using data from the California Childhood Leukemia Study (CCLS) case-control study and additive logistic regression models. We observed no association between CS and acute myelogenous leukemia [OR, 0.96; 95% confidence interval (CI), 0.52-1.55]. We observed a suggestive association for ALL and CS (OR, 1.22; 95% CI, 0.97-1.54). When examining common ALL (cALL), defined as ALL with expression of CD10 and CD19 surface antigens and diagnosis occurring between 2 and 5.9 years of age, we found a significant association with CS (OR, 1.44; 95% CI, 1.0-2.06). ALL subjects that are not cALL showed a similar risk as ALL overall (OR, 1.15; 95% CI, 0.91-1.44). Because of previous findings suggesting effect modification, we stratified cALL subjects by Hispanic status. Although we observed no relationship for CS in non-Hispanics (OR, 1.14; 95% CI, 0.72-1.79), we did observe a strong association between cALL and CS in Hispanics (OR, 2.34; 95% CI, 1.23-4.46). Within the CCLS, CS delivery seems to be associated with cALL and Hispanic subjects may be driving the association. Further research combined with investigations into response to early infection and the microbiome is warranted.

The Role of Population Mixing in the Aetiology of Childhood Leukaemia: A Swiss National Cohort Study

Background:Leukaemia is the most important cancer in childhood but little is known about its causes. It has been suggested that early infections might play a role: Kinlen (1988) proposed that childhood leukaemia might be a rare response to a common, yet unidentified, infection. Rapid population influxes into isolated areas (population mixing) could lead to epidemics of the infection in question and a localised increase in incidence of leukaemia. Previous studies investigating the population mixing hypothesis showed heterogeneous results. Aims: The aim of this study is to examine the association between incidence of childhood leukemia and measures of population mixing in a nation-wide cohort study. Methods: We will include Swiss residence aged <20 years during the period 1985-2012. Leukaemia cases will be obtained from the Swiss Childhood Cancer Registry (SCCR) and person time at risk from the Swiss National Cohort (SNC). Outcomes will be any leukaemia, acute lymphocytic leukaemia (ALL), and important cytogenetic subtypes of ALL. We will calculate the following measures of population mixing at community level: (1) Proportion of the population that was not living in the same community 5 years earlier (5-year in-migration)(2) Diversity (Shannon Index) of places of origin of 5-year in-migrants; (3) Change in annual in-migration relative to average in-migration in previous years. We will use Poisson regression to calculate associations between leukaemia incidence and measures of population mixing for communities of residence at diagnosis and also at birth. Significance: Compared to previous studies, this study will measure population mixing with greater spatial and temporal resolution, both at birth and at diagnosis. It should therefore provide new insights into the potential association of childhood leukaemia and population mixing. Understanding the role of infections in the aetiology of childhood leukaemia could open possibilities for prevention.

Genetic Variation in the Extended Major Histocompatibility Complex and Susceptibility to Childhood Acute Lymphoblastic Leukemia: A Review of the Evidence

The enduring suspicion that infections and immunologic response may play a role in the etiology of childhood leukemia, particularly acute lymphoblastic leukemia (ALL), is now supported, albeit still indirectly, by numerous epidemiological studies. The cumulative evidence includes, for example, descriptive observations of a peculiar peak incidence at age 2–5 years for ALL in economically developed countries, clustering of cases in situations of population mixing associated with unusual patterns of personal contacts, associations with various proxy measures for immune modulatory exposures early in life, and genetic susceptibility conferred by variation in genes involved in the immune system. In this review, our focus is the extended major histocompatibility complex (MHC), an approximately 7.6 Mb region that is well-known for its high-density of expressed genes, extensive polymorphisms exhibiting complex linkage disequilibrium patterns, and its disproportionately large number of immune-related genes, including human leukocyte antigen (HLA). First discovered through the role they play in transplant rejection, the classical HLA class I (HLA-A, -B, and -C) and class II (HLA-DR, HLA-DQ, and HLA-DP) molecules reside at the epicenter of the immune response pathways and are now the targets of many disease susceptibility studies, including those for childhood leukemia. The genes encoding the HLA molecules are only a minority of the over 250 expressed genes in the xMHC, and a growing number of studies are beginning to evaluate other loci through targeted investigations or utilizing a mapping approach with a comprehensive screen of the entire region. Here, we review the current epidemiologic evidence available to date regarding genetic variation contained within this highly unique region of the genome and its relationship with childhood ALL risk.

Impact of high electromagnetic field levels on childhood leukemia incidence

The increasing exposure to electromagnetic fields (EMFs) has raised concern, as increased exposure may result in an increased risk of childhood leukemia (CL). Besides a short introduction of CL and EMF, our article gives an evaluation of the evidence of a causal relation between EMF and CL by critically appraising the epidemiological and biological evidence. The potential impact is also estimated by the population attributable risk. The etiology of CL is largely unknown, but is probably multifactorial. EMF may be one of the environmental exposures involved. Three pooled analyses of case-control studies showed a 1.4- to 1.7-fold increased CL risk for extremely low-frequency EMF (ELF-EMF) exposure levels above 0.3 μT. Several biases may have played a role in these studies, but are unlikely to fully explain the increased risk. For effects of radiofrequency ELF evidence is lacking. None of the proposed biological mechanisms by which ELF-EMF might cause CL have been confirmed. The estimated overall population attributable risk was 1.9%, with the highest estimates in Northern America and Brazil (4.2% and 4.1%, respectively). The potential impact of EMF exposure on public health is probably limited, although in some countries exposure might be relatively high and thus might have a more substantial impact. We recommend nationwide surveys to gain more insight into the contemporary exposure levels among children. Reducing exposure from power lines near densely populated areas and schools is advised. Future epidemiological studies should focus on limiting bias.

Parental risk factors of childhood acute leukemia: a case-control study.

Leukemia is the most common cancer in children, accounting for near to half of all childhood cancers. Different risk factors might be effective in the occurrence of this cancer such as parental characteristics. This study was done in West Azarbaijan Province in order to determine the relation between parental characteristics and acute leukemia in children. This matched case-control study was conducted on children less than 15 years affected by acute leukemia from March 20, 2003 to March 20, 2009. Two control groups were selected, one from hospital and the other from the study population. Cases and controls were matched on age and sex. Logistic regression model was used for data analysis. This study was done on 130 patients, 108 (83.1%) were affected by Acute Lymphoblastic Leukemia and 22 (16.9%) by Acute Myeloblastic Leuke-mia. Seventy two of the patients were male (55.4%) and 58 were female (44.6%). There was a statistically significant correlation between acute leuke-mia and variables such as mother's education [OR=4.2, 95% CI: 2.42, 7.34], mother's history of using Oral Contraceptive Pills [OR=1.77, 95% CI: 1.05, 2.82] and parental relationship [OR=2.05, 95% CI: 1.30, 3.23]. It seems that some parental characteristics have an important role in etiology of childhood leukemia.

Exposure to sodium tungstate and Respiratory Syncytial Virus results in hematological/immunological disease in C57BL/6J mice

The etiology of childhood leukemia is not known. Strong evidence indicates that precursor B-cell Acute Lymphoblastic Leukemia (Pre-B ALL) is a genetic disease originating in utero. Environmental exposures in two concurrent, childhood leukemia clusters have been profiled and compared with geographically similar control communities. The unique exposures, shared in common by the leukemia clusters, have been modeled in C57BL/6 mice utilizing prenatal exposures. This previous investigation has suggested in utero exposure to sodium tungstate (Na2WO4) may result in hematological/immunological disease through genes associated with viral defense. The working hypothesis is (1) in addition to spontaneously and/or chemically generated genetic lesions forming pre-leukemic clones, in utero exposure to Na2WO4 increases genetic susceptibility to viral influence(s); (2) postnatal exposure to a virus possessing the 1FXXKXFXXA/V9 peptide motif will cause an unnatural immune response encouraging proliferation in the B-cell precursor compartment. This study reports the results of exposing C57BL/6J mice to Na2WO4in utero via water (15ppm, ad libetum) and inhalation (mean concentration PM5 3.33mg/m3) and to Respiratory Syncytial Virus (RSV) within 2weeks of weaning. Inoculation of C57BL/6J mice with RSV was associated with a neutrophil shift in 56% of 5-month old mice. When the RSV inoculation was combined with Na2WO4-exposure, significant splenomegaly resulted (p=0.0406, 0.0184, 0.0108 for control, Na2WO4-only and RSV-only, respectively) in addition to other hematological pathologies which were not significant. Exposure to Na2WO4 and RSV resulted in hematological/immunological disease, the nature of which is currently inconclusive. Further research is needed to characterize this potential leukemia mouse model.

A precautionary public health protection strategy for the possible risk of childhood leukaemia from exposure to power frequency magnetic fields

BackgroundEpidemiological evidence showing a consistent association between the risk of childhood leukaemia and exposure to power frequency magnetic fields has been accumulating. This debate considers the additional precautionary intervention needed to manage this risk, when it exceeds the protection afforded by the exposure guidelines as recommended by the International Commission on Non-Ionizing Radiation Protection.MethodsThe Bradford-Hill Criteria are guidelines for evaluating the scientific evidence that low frequency magnetic fields cause childhood leukaemia. The criteria are used for assessing the strength of scientific evidence and here have been applied to considering the strength of evidence that exposures to extremely low frequency magnetic fields may increase the risk of childhood leukaemia. The applicability of precaution is considered using the risk management framework outlined in a European Commission (EC) communication on the Precautionary Principle. That communication advises that measures should be proportionate, non-discriminatory, consistent with similar measures already taken, based on an examination of the benefits and costs of action and inaction, and subject to review in the light of new scientific findings.ResultsThe main evidence for a risk is an epidemiological association observed in several studies and meta-analyses; however, the number of highly exposed children is small and the association could be due to a combination of selection bias, confounding and chance. Corroborating experimental evidence is limited insofar as there is no clear indication of harm at the field levels implicated; however, the aetiology of childhood leukaemia is poorly understood. Taking a precautionary approach suggests that low-cost intervention to reduce exposure is appropriate. This assumes that if the risk is real, its impact is likely to be small. It also recognises the consequential cost of any major intervention. The recommendation is controversial in that other interpretations of the data are possible, and low-cost intervention may not fully alleviate the risk.ConclusionsThe debate shows how the EC risk management framework can be used to apply the Precautionary Principle to small and uncertain public health risks. However, despite the need for evidence-based policy making, many of the decisions remain value driven and therefore subjective.

Abstract 1825: Maternal alcohol consumption and childhood acute myeloid leukemia risk

Abstract Background: Leukemia is the most common malignancy in children. The etiology of childhood leukemia is mostly unknown, although some environmental factors such as ionizing radiation and parental alcohol and tobacco use may play a causative role in leukemia. Methods: To investigate the association between parental alcohol consumption and childhood leukemia in a hospital-based case-control study in Korea, histologically-confirmed incident childhood leukemia cases (n=365) aged 0-18 years old were recruited from three teaching hospitals located in Seoul, Korea, between May 2003 and August 2008. Non-cancer controls (n=558) aged 0-18 years old without medical history of childhood cancer were recruited from the Department of Pediatrics of the same hospitals. Controls were frequency-matched to cases by 5-year age intervals and sex (cases: controls=1:1). Leukemia risks were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis adjusted for age, sex, parent's education, and birth weight (<3.25, 3.25-3.70, ≥3.70 kg). In addition to conducting analyses of all childhood leukemia, we calculated histologic subtype-specific ORs for acute lymphoblastic leukemia (ALL; n=200) and acute myeloid leukemia (AML; n=88). Results: Among general characteristics, higher birth weight and parental education were associated with childhood leukemia risk (P<0.05). The proportion of drinking mothers was significantly higher among all leukemia cases than controls (58% vs. 49%: OR=1.4, 95% CI=1.00-1.83), whereas no association was observed for paternal alcohol consumption (87% vs. 83%). When the analysis was restricted to AML cases, the association between maternal drinking and cancer risk became stronger (OR=1.8, 95% CI=1.06-2.90). Drinking frequency of the mothers was also associated with the increased risk. (≥1/month vs. <1/month; OR=1.7, 95% CI=1.10-2.28). Also, drinking duration of more than one year before pregnancy increased the risk of AML (OR=1.7, 95% CI= 1.00-2.85). No association was found between parental alcohol consumption and ALL risk. Conclusion: Our results suggest that maternal alcohol consumption is associated with AML among Korean children. However, larger studies need to be conducted to replicate our findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1825.

Breastfeeding and early infection in the aetiology of childhood leukaemia in Down syndrome

Background:For a child to develop acute leukaemia (AL), environmental exposure may not be sufficient: interaction with a susceptibility factor to the disease, such as Down syndrome (DS), may also be necessary. We assessed whether breastfeeding and early infection were associated with the risk of developing AL in children with DS.Methods:Children with DS in Mexico City, and either with or without AL, were the cases (N=57) and controls (N=218), respectively. Population was divided in children with AL and with acute lymphoblastic leukaemia (ALL) and also in children ⩽6 and >6 years old.Results:Breastfeeding and early infections showed moderate (but not significant) association for AL, whereas hospitalisation by infection during the first year of life increased the risk: odds ratios (confidence interval 95%) were 0.84 (0.43–1.61), 1.70 (0.82–3.52); and 3.57 (1.59–8.05), respectively. A similar result was obtained when only ALL was analysed.Conclusion:We found that breastfeeding was a protective factor for developing AL and ALL, and during the first year of life, infections requiring hospitalisation were related to a risk for developing the disease in those children with DS >6 years of age. These data do not support the Greaves's hypothesis of early infection being protective for developing ALL.