Review of the Churchill County, NV ALL cluster, 1997-2004

Between 1997 and 2002, 16 cases of acute childhood leukemia were diagnosed in children who either lived in Churchill County, Nevada at the time of diagnosis or had lived in the county before their diagnosis. The cases were characterized as a cluster of like illnesses and the probability of having such a cluster occur by chance was estimated to be very small (approximately one in 2.33×10(8)). This suggested that the cluster could be linked to one or more physical, limnological, chemical, or biological agents. This review discusses the setting in which the cluster took place, the epidemiological investigations carried out by the Nevada Bureau of Health Protection Services, the National Center for Environmental Health Centers for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry, and subsequent investigations supported by a special allocation of federal funds through the US Environmental Protection Agency's Region IX office in San Francisco, CA. This review is meant as background for the papers in this special issue that report results from multi- and interdisciplinary research into environmental and biological factors potentially related to the Churchill County leukemia cluster.     

The scale-invariant spatial clustering of leukemia in San Francisco.

This study tests the hypothesis of scale-invariant self-similar clustering of childhood leukemia cases over the San Francisco spatial area. The spatial distribution of leukemia cases has been investigated over seven scales of observation. A power-law relation of the variance to the mean of aggregates (quadrats) was used to detect possible scale-invariant self-similar clustering. The spatial distribution of leukemia cases (incidence from 1946 to 1964) was well fitted by a power-law function. The follow-up of clustering from the first years of case notification (1946) confirmed a scale-invariant self-similar spatial pattern with a stable power-law slope from 1952 onward. This pattern was shown to pertain specifically to school-age leukemia cases. Younger cases had a random distributional pattern over space. Observation and simulations of the distributional patterns revealed memory-keeping of historical (the pre-1953 era) fractal-like conditions. Based on a comparison of the leukemia fractal dimension with that of the city residential data, it is speculated that the current scale-invariant self-similar spatial clustering of the leukemia cases reflects the onset of the historical fractal patterning of the city residences at a particular time point in the past.     

Perspectives on the causes of childhood leukemia

Acute leukemia is the most common cancer in children but the causes of the disease in the majority of cases are not known. About 80% are precursor-B cell in origin (CD19+, CD10+), and this immunophenotype has increased in incidence over the past several decades in the Western world. Part of this increase may be due to the introduction of new chemical exposures into the child's environment including parental smoking, pesticides, traffic fumes, paint and household chemicals. However, much of the increase in leukemia rates is likely linked to altered patterns of infection during early childhood development, mirroring causal pathways responsible for a similarly increased incidence of other childhood-diagnosed immune-related illnesses including allergy, asthma, and type 1 diabetes. Factors linked to childhood leukemia that are likely surrogates for immune stimulation include exposure to childcare settings, parity status and birth order, vaccination history, and population mixing. In case-control studies, acute lymphoblastic leukemia (ALL) is consistently inversely associated with greater exposure to infections, via daycare and later birth order. New evidence suggests also that children who contract leukemia may harbor a congenital defect in immune responder status, as indicated by lower levels of the immunosuppressive cytokine IL-10 at birth in children who grow up to contract leukemia, as well as higher need for clinical care for infections within the first year of life despite having lower levels of exposure to infections. One manifestation of this phenomenon may be leukemia clusters which tend to appear as a leukemia "outbreak" among populations with low herd immunity to a new infection. Critical answers to the etiology of childhood leukemia will require incorporating new tools into traditional epidemiologic approaches - including the classification of leukemia at a molecular scale, better exposure assessments at all points in a child's life, a comprehensive understanding of genetic risk factors, and an appraisal of the interplay between infectious exposures and the status of immune response in individuals.     

Additional analysis of dendrochemical data of Fallon, Nevada

Previously reported dendrochemical data showed temporal variability in concentration of tungsten (W) and cobalt (Co) in tree rings of Fallon, Nevada, US. Criticism of this work questioned the use of the Mann-Whitney test for determining change in element concentrations. Here, we demonstrate that Mann-Whitney is appropriate for comparing background element concentrations to possibly elevated concentrations in environmental media. Given that Mann-Whitney tests for differences in shapes of distributions, inter-tree variability (e.g., "coefficient of median variation") was calculated for each measured element across trees within subsites and time periods. For W and Co, the metals of highest interest in Fallon, inter-tree variability was always higher within versus outside of Fallon. For calibration purposes, this entire analysis was repeated at a different town, Sweet Home, Oregon, which has a known tungsten-powder facility, and inter-tree variability of W in tree rings confirmed the establishment date of that facility. Mann-Whitney testing of simulated data also confirmed its appropriateness for analysis of data affected by point-source contamination. This research adds important new dimensions to dendrochemistry of point-source contamination by adding analysis of inter-tree variability to analysis of central tendency. Fallon remains distinctive by a temporal increase in W beginning by the mid 1990s and by elevated Co since at least the early 1990s, as well as by high inter-tree variability for W and Co relative to comparison towns.     

The association between Acute Lymphoblastic Leukemia in children and Helicobacter pylori as the marker for sanitation

ABSTRACT: BACKGROUND: Greaves "delayed infection" hypothesis suggested that Acute Lymphoblastic Leukemia (ALL) in children is caused by a lack of exposure to infection in infancy, which may be due higher standards of sanitation. We have conducted an ecologic analysis of the relationship between sanitation, using Helicobacter pylori (H. pylori) as the marker, and the incidence of childhood ALL in 127 cancer registries from 28 countries. RESULTS: There were inverse associations between H. pylori perverse and ALL incidence rates in children. These associations were minor and only significant for ALL incidence rates for all cancer registries. They became non-significant and smaller in magnitude when the population source and/or the GNP per capita were added to the relationship. Furthermore, these results were unchanged when the associations were examined using the Generalized Estimating Equations. CONCLUSIONS: Although the findings showed lower prevalence of H. pylori and improved sanitation is associated with increased incidence of childhood ALL, they do not conclusively support Greaves "delayed infection" hypothesis.     

Spatial Analysis of Childhood Cancer: A Case/Control Study

BackgroundChildhood cancer was the leading cause of death among children aged 1-14 years for 2012 in Spain. Leukemia has the highest incidence, followed by tumors of the central nervous system (CNS) and lymphomas (Hodgkin lymphoma, HL, and Non-Hodgkin’s lymphoma, NHL). Spatial distribution of childhood cancer cases has been under concern with the aim of identifying potential risk factors.ObjectiveThe two objectives are to study overall spatial clustering and cluster detection of cases of the three main childhood cancer causes, looking to increase etiological knowledge.MethodsWe ran a case-control study. The cases were children aged 0 to 14 diagnosed with leukemia, lymphomas (HL and NHL) or CNS neoplasm in five Spanish regions for the period 1996-2011. As a control group, we used a sample from the Birth Registry matching every case by year of birth, autonomous region of residence and sex with six controls. We geocoded and validated the address of the cases and controls. For our two objectives we used two different methodologies. For the first, for overall spatial clustering detection, we used the differences of K functions from the spatial point patterns perspective proposed by Diggle and Chetwynd and the second, for cluster detection, we used the spatial scan statistic proposed by Kulldorff with a level for statistical significance of 0.05.ResultsWe had 1062 cases of leukemia, 714 cases of CNS, 92 of HL and 246 of NHL. Accordingly we had 6 times the number of controls, 6372 controls for leukemia, 4284 controls for CNS, 552 controls for HL and 1476 controls for NHL. We found variations in the estimated empirical D(s) for the different regions and cancers, including some overall spatial clustering for specific regions and distances. We did not find statistically significant clusters.ConclusionsThe variations in the estimated empirical D(s) for the different regions and cancers could be partially explained by the differences in the spatial distribution of the population; however, according to the literature, we cannot discard environmental hazards or infections agents in the etiology of these cancers.     

Evaluation of childhood acute leukemia incidence and underreporting in Brazil by capture–recapture methodology

Background: Population-based cancer registries (PBCR) are important in cancer epidemiology as they provide the basis for monitoring cancer incidence. Childhood acute lymphoblastic leukemia (ALL) is said to have lower incidence in developing countries, which has implications for its pathogenesis, but there are few studies concerning the completeness of cancer registries in developing countries. This study analyzes the number of cases and incidence of childhood acute lymphoblastic leukemia in three different cities in Brazil and estimates underreporting cases and possible PBCR failures. Methods: We evaluated the completeness of PBCR and the incidence rates of childhood ALL from three different Brazilian cities using the two-source capture–recapture method. The sources used were a population-based registry and databases from a diagnosis reference laboratory in 2001 and the Chapman's formula was used to calculate the estimates. Results: The estimated incidence was 5.76, 6.32 and 5.48 per 100,000 inhabitants for Salvador, Recife and Belo Horizonte, respectively. The estimated completeness of childhood ALL in PBCRs was 15.5%, 35.4% and 29.2%, respectively, for Salvador, Recife and Belo Horizonte. Conclusions: There was a high estimated underreporting of childhood leukemia cases in some Brazilian cities. The relationship between information systems and the capture–recapture method application improved epidemiological estimates. Childhood acute lymphoblastic leukemia incidence rates are similar to those of developed countries.     

Strategies for evaluating the environment-public health interaction of long-term latency disease: the quandary of the inconclusive case-control study

Environmental links to disease are difficult to uncover because environmental exposures are variable in time and space, contaminants occur in complex mixtures, and many diseases have a long time delay between exposure and onset. Furthermore, individuals in a population have different activity patterns (e.g., hobbies, jobs, and interests), and different genetic susceptibilities to disease. As such, there are many potential confounding factors to obscure the reasons that one individual gets sick and another remains healthy. An important method for deducing environmental associations with disease outbreak is the retrospective case-control study wherein the affected and control subject cohorts are studied to see what is different about their previous exposure history. Despite success with infectious diseases (e.g., food poisoning, and flu), case-control studies of cancer clusters rarely have an unambiguous outcome. This is attributed to the complexity of disease progression and the long-term latency between exposure and disease onset. In this article, we consider strategies for investigating cancer clusters and make some observations for improving statistical power through broader non-parametric approaches wherein sub-populations (i.e., whole towns), rather than individuals, are treated as the cases and controls, and the associated cancer rates are treated as the dependent variable. We subsequently present some ecological data for tungsten and cobalt from studies by University of Arizona researchers who document elevated levels of tungsten and cobalt in Fallon, NV. These results serve as candidates for future hybrid ecologic case-control investigations of childhood leukemia clusters.     

Exposure to electrical contact currents and the risk of childhood leukemia

The objectives of this study were to examine the association between contact current exposure and the risk of childhood leukemia and to investigate the relationship between residential contact currents and magnetic fields. Indoor and outdoor contact voltage and magnetic-field measurements were collected for the diagnosis residence of 245 cases and 269 controls recruited in the Northern California Childhood Leukemia Study (2000-2007). Logistic regression techniques produced odds ratios (OR) adjusted for age, sex, Hispanic ethnicity, mother's race and household income. No statistically significant associations were seen between childhood leukemia and indoor contact voltage level [exposure ≥90th percentile (10.5 mV): OR = 0.83, 95% confidence interval (CI): 0.45, 1.54], outdoor contact voltage level [exposure ≥90th percentile (291.2 mV): OR = 0.89, 95% CI: 0.48, 1.63], or indoor magnetic-field levels (>0.20 μT: OR = 0.76, 95% CI: 0.30, 1.93). Contact voltage was weakly correlated with magnetic field; correlation coefficients were r = 0.10 (P = 0.02) for indoor contact voltage and r = 0.15 (P = 0.001) for outdoor contact voltage. In conclusion, in this California population, there was no evidence of an association between childhood leukemia and exposure to contact currents or magnetic fields and a weak correlation between measures of contact current and magnetic fields.     

Meningitis in the central Arctic: a 4-year experience.

There were 37 cases of meningitis during a 4-year period among the native and white populations served by the Churchill Health Centre in northern Manitoba, an annual incidence of 128 per 100 000 in the overall population and of 202 per 100 000 among the Inuit. Bacterial meningitis predominated; Neisseria meningitidis and Haemophilus influenzae each accounted for one third of the cases. There were five deaths, and 14 of the survivors had severe sequelae. Therefore, although the doctors and nurses involved in the study had improved access to telecommunication and air transportation services in caring for patients in isolated northern settlements, and despite their efforts to be vigilant for possible cases of meningitis and to begin vigorous treatment early, the incidence, morbidity and mortality of this disease remained relatively high, particularly among the Inuit.     

靖西县2007—2011年流行性腮腺炎流行病学分析

目的为了解靖西县流行性腮腺炎的疫情动态,为制定预防控制措施提供依据。方法采用描述流行病学分析方法对靖西县2007—2011年流行性腮腺炎发病情况进行分析。结果 2007—2011年共报告流行性腮腺炎721例,占法定传染病报告数4.03%,占丙类传染病报告数17.82%,报告年均发病率为23.39/10万。2007—2011年发病率呈上升趋势,其中2011年发病率最高达49.32/10万。全年均有发病,以5—7月为发病高峰,占37.86%,5、6、7月发病数分别占13.73%、11.65%、12.48%。全县19个乡镇都有腮腺炎病例发生,以新靖镇发病率居首位达254.52/10万,其次化峒镇的发病率为183.65/10万。发病主要分布0～15岁年龄组,发病人数占89.65%,以4～8岁年龄组发病人数最多,占45.91%。结论靖西县流行性腮腺炎发病率较高,近年发病呈上升趋势,应采取以腮腺炎疫苗接种为重点的综合性预防控制措施,降低学生和托幼机构儿童的发病率。     

Hypothesis: The risk of childhood leukemia is related to combinations of power-frequency and static magnetic fields

We present a hypothesis that the risk of childhood leukemia is related to exposure to specific combinations of static and extremely-low-frequency (ELF) magnetic fields. Laboratory data from calcium efflux and diatom mobility experiments were used with the gyromagnetic equation to predict combinations of 60 Hz and static magnetic fields hypothesized to enhance leukemia risk. The laboratory data predicted 19 bands of the static field magnitude with a bandwidth of 9.1 μT that, together with 60 Hz magnetic fields, are expected to have biological activity. We then assessed the association between this exposure metric and childhood leukemia using data from a case-control study in Los Angeles County. ELF and static magnetic fields were measured in the bedrooms of 124 cases determined from a tumor registry and 99 controls drawn from friends and random digit dialing. Among these subjects, 26 cases and 20 controls were exposed to static magnetic fields lying in the predicted bands of biological activity centered at 38.0 μT and 50.6 μT. Although no association was found for childhood leukemia in relation to measured ELF or static magnetic fields alone, an increasing trend of leukemia risk with measured ELF fields was found for subjects within these static field bands (P for trend = 0.041). The odds ratio (OR) was 3.3 [95% confidence interval (CI) = 0.4–30.5] for subjects exposed to static fields within the derived bands and to ELF magnetic field above 0.30 μT (compared to subjects exposed to static fields outside the bands and ELF magnetic fields below 0.07 μT). When the 60 Hz magnetic fields were assessed according to the Wertheimer-Leeper code for wiring configurations, leukemia risks were again greater with the hypothesized exposure conditions (OR = 9.2 for very high current configurations within the static field bands: 95% CI = 1.3–64.6). Although the risk estimates are based on limited magnetic field measurements for a small number of subjects, these findings suggest that the risk of childhood leukemia may be related to the combined effects of the static and ELF magnetic fields. Further tests of the hypothesis are proposed. © 1995 Wiley-Liss, Inc.     

Epidemiologic Clues to the Cause of Melanoma

An intensive search found that 146 cases of cutaneous or ocular melanoma had occurred among residents of Lane County, Oregon, from 1958 through 1972. Of these cases, 35 led to death. Countywide, increasing incidence rates were corroborated by increasing death rates for both sexes. Risk of disease was highest in a moist, flat residential area near the intersection of two rivers in the county''s urban portion and in its agricultural area. The incidence pattern strongly suggested local cycles in subcounty units. Although overall melanoma risk was higher in urban areas, an apparent widespread rural epidemic was identified, beginning abruptly in 1965 and lasting several years. If similar geographic and temporal characteristics can be identified in other localities, the search for an etiologic agent could focus on a smaller range of possibilities.     

Spatial and temporal patterns of problem polar bears in Churchill,Manitoba

Human–bear interactions near the town of Churchill, Manitoba occur annually because the Western Hudson Bay polar bear population spends 4–5 months on-land each year when the sea ice melts completely. Significant changes have occurred in the Hudson Bay ecosystem and in the bear population as a result of climate warming; however, how these changes may have influenced human–bear interactions near Churchill is unclear. This study examined the temporal and spatial patterns of 1,487 problem bears captured in the Churchill area from 1970 to 2004. We also examined the relationship between problem bears and environmental variables as well as the Nunavut harvest. The number of individual problem bears caught near Churchill varied from 10 to 90 individuals per year and increased over time. Subadult males comprised 39%, subadult females 23%, adult males 18%, females with young 14%, and solitary females 6% of captures. Bears that became problem individuals were in closer proximity to the Churchill area. Nutritional stress and a northward shift in the distribution of the bears that spend the summer on-land in northeastern Manitoba may account for the increase in problem bear numbers. The date of sea ice freeze-up, which is getting progressively later, was the best predictor explaining the annual variation in the occurrence of problem bears. These results provide an understanding of how a warming climate may directly impact polar bear behaviour. This information may allow wildlife managers to predict relative levels of human–bear interactions and thereby implement effective management strategies to improve human safety and the conservation of polar bears.     

SNP Association Mapping across the Extended Major Histocompatibility Complex and Risk of B-Cell Precursor Acute Lymphoblastic Leukemia in Children

The extended major histocompatibility complex (xMHC) is the most gene-dense region of the genome and harbors a disproportionately large number of genes involved in immune function. The postulated role of infection in the causation of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) suggests that the xMHC may make an important contribution to the risk of this disease. We conducted association mapping across an approximately 4 megabase region of the xMHC using a validated panel of single nucleotide polymorphisms (SNPs) in childhood BCP-ALL cases (n=567) enrolled in the Northern California Childhood Leukemia Study (NCCLS) compared with population controls (n=892). Logistic regression analyses of 1,145 SNPs, adjusted for age, sex, and Hispanic ethnicity indicated potential associations between several SNPs and childhood BCP-ALL. After accounting for multiple comparisons, one of these included a statistically significant increased risk associated with rs9296068 (OR=1.40, 95% CI=1.19-1.66, corrected p=0.036), located in proximity to HLA-DOA. Sliding window haplotype analysis identified an additional locus located in the extended class I region in proximity to TRIM27 tagged by a haplotype comprising rs1237485, rs3118361, and rs2032502 (corrected global p=0.046). Our findings suggest that susceptibility to childhood BCP-ALL is influenced by genetic variation within the xMHC and indicate at least two important regions for future evaluation.     

The Childhood Leukemia International Consortium

Background: Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case–control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene–environment interactions. Objectives: The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene–environment interactions and subtype-specific associations through the pooling of data from independent studies. Methods: By September 2012, CLIC included 22 studies (recruitment period: 1962–present) from 12 countries, totaling approximately 31 000 cases and 50 000 controls. Of these, 19 case–control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child–parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens. Conclusions: CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene–environment interactions and associations among specific leukemia subtypes in different ethnic groups.     

Targeting leukemia stem cells: The new goal of therapy in adult acute myeloid leukemia

The most popular view of hematopoietic cell lineage organization is that of complex reactive or adaptative systems. Leukemia contains a subpopulation of cells that display characteristics of stem cells. These cells maintain tumor growth. The properties of leukemia stem cells indicate that current conventional chemotherapy, directed against the bulk of the tumor, will not be effective. Leukemia stem cells are quiescent and do not respond to cell cycle-specific cytotoxic agents used to treat leukemia and thus contribute to treatment failure. New strategies are required that specifically target this malignant stem cell population.     

Epidemiology of childhood leukemia in the presence and absence of Down syndrome

Down syndrome (DS) is a common congenital anomaly, and children with DS have a substantially higher risk of leukemia. Although understanding of genetic and epigenetic changes of childhood leukemia has improved, the causes of childhood leukemia and the potential role of environmental exposures in leukemogenesis remain largely unknown. Although many epidemiologic studies have examined a variety of environmental exposures, ionizing radiation remains the only generally accepted environmental risk factor for childhood leukemia. Among suspected risk factors, infections, exposure to pesticides, and extremely low frequency magnetic fields are notable. While there are well-defined differences between leukemia in children with and without DS, studies of risk factors for leukemia among DS children are generally consistent with trends seen among non-DS (NDS) children.We provide background on DS epidemiology and review the similarities and differences in biological and epidemiologic features of leukemia in children with and without DS. We propose that both acute lymphoblastic and acute myeloblastic leukemia among DS children can serve as an informative model for development of childhood leukemia. Further, the high rates of leukemia among DS children make it possible to study this disease using a cohort approach, a powerful method that is unfeasible in the general population due to the rarity of childhood leukemia.     

Under-diagnosis and under-ascertainment of cases may be the reasons for low childhood cancer incidence in rural India

Cancer statistics from India revealed that childhood cancer incidence is lesser in rural than urban India. This might be due to under-diagnosis or under-ascertainment of cases or could even be true. With registries able to explicitly measure and appropriately streamline the ascertainment of cases to comply with acceptable standards, it is under-diagnosis that is variable and highly influenced by development of or accessibility to specialized centres in or around the registry area. This is reflected implicitly by marked variation in incidence between different populations in India: weighted age standardized rates of all childhood cancers together was the highest (108 per million) in metropolitan areas, followed by other urban (86) and rural (53) areas in that order. A childhood cancer registry focusing on pertinent data collection and specific epidemiological studies is desirable to explain the variations in incidence and outcome of childhood cancers in India.