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Acute promyelocytic leukemia (APL) comprises approximately 5-10% of childhood acute myeloid leukemia (AML) cases in the US. While variation in this percentage among other populations was noted previously, global patterns of childhood APL have not been thoroughly characterized. In this comprehensive review of childhood APL, we examined its geographic pattern and the potential contribution of environmental factors to observed variation. In 142 studies (spanning >60 countries) identified, variation was apparent-de novo APL represented from 2% (Switzerland) to >50% (Nicaragua) of childhood AML in different geographic regions. Because a limited number of previous studies addressed specific environmental exposures that potentially underlie childhood APL development, we gathered 28 childhood cases of therapy-related APL, which exemplified associations between prior exposures to chemotherapeutic drugs/radiation and APL diagnosis. Future population-based studies examining childhood APL patterns and the potential association with specific environmental exposures and other risk factors are needed.

BackgroundB-cell lymphomas are a diverse group of hematological neoplasms with differential etiology and clinical trajectories. Increased insights in the etiology and the discovery of prediagnostic markers have the potential to improve the clinical course of these neoplasms.MethodsWe investigated in a prospective study global gene expression in peripheral blood mononuclear cells of 263 incident B-cell lymphoma cases, diagnosed between 1 and 17 years after blood sample collection, and 439 controls, nested within two European cohorts.ResultsOur analyses identified only transcriptomic markers for specific lymphoma subtypes; few markers of multiple myeloma (N = 3), and 745 differentially expressed genes in relation to future risk of chronic lymphocytic leukemia (CLL). The strongest of these associations were consistently found in both cohorts and were related to (B-) cell signaling networks and immune system regulation pathways. CLL markers exhibited very high predictive abilities of disease onset even in cases diagnosed more than 10 years after blood collection.ConclusionsThis is the first investigation on blood cell global gene expression and future risk of B-cell lymphomas. We mainly identified genes in relation to future risk of CLL that are involved in biological pathways, which appear to be mechanistically involved in CLL pathogenesis. Many but not all of the top hits we identified have been reported previously in studies based on tumor tissues, therefore suggesting that a mixture of preclinical and early disease markers can be detected several years before CLL clinical diagnosis.

Multiple follicular lymphoma (FL) susceptibility single-nucleotide polymorphisms in the human leukocyte antigen (HLA) class I and II regions have been identified, including rs6457327, rs3117222, rs2647012, rs10484561, rs9268853 and rs2621416. Here we validated previous expression quantitative trait loci results with real-time reverse transcription quantitative PCR and investigated protein expression in B-lymphoblastoid cell lines and primary dendritic cells using flow cytometry, cell-based enzyme-linked immunosorbent assay and western blotting. We confirmed that FL-protective rs2647012-linked variants, in high linkage disequilibrium with the extended haplotype DRB1*15:01-DQA1*01:02-DQB1*06:02, correlate with increased HLA-DQB1 expression. This association remained significant at the protein level and was reproducible across different cell types. We also found that differences in HLA-DQB1 expression were not related to changes in activation markers or class II, major histocompatibility complex, transactivator expression, suggesting the role of an alternative regulatory mechanism. However, functional analysis using RegulomeDB did not reveal any relevant regulatory candidates. Future studies should focus on the clinical relevance of increased HLA-DQB1 protein expression facilitating tumor cell removal through increased immune surveillance.

Benzene exposure causes acute myeloid leukemia and hematotoxicity, shown as suppression of mature blood and myeloid progenitor cell numbers. As the leukemia-related aneuploidies monosomy 7 and trisomy 8 previously had been detected in the mature peripheral blood cells of exposed workers, we hypothesized that benzene could cause leukemia through the induction of these aneuploidies in hematopoietic stem and progenitor cells. We measured loss and gain of chromosomes 7 and 8 by fluorescence in situ hybridization in interphase colony-forming unit-granulocyte-macrophage (CFU-GM) cells cultured from otherwise healthy benzene-exposed (n=28) and unexposed (n=14) workers. CFU-GM monosomy 7 and 8 levels (but not trisomy) were significantly increased in subjects exposed to benzene overall, compared with levels in the control subjects (P=0.0055 and P=0.0034, respectively). Levels of monosomy 7 and 8 were significantly increased in subjects exposed to

A population-based case-control study of lymphomas in England collected height and weight details from 699 non-Hodgkin's lymphoma (NHL) cases and 914 controls. Obesity, defined as a body mass index (BMI) over 30 kg m(-2) at five years before diagnosis,, was associated with an increased risk of NHL (OR = 1.5, 95% CI 1.1-2.1). The excess was most pronounced for diffuse large B-cell lymphoma (OR = 1.9, 95% CI 1.3-2.8). Genetic variants in the leptin (LEP 19G > A, LEP -2548G > A) and leptin receptor genes (LEPR 223Q > R), previously shown to modulate NHL risk, as well as a polymorphism in the energy regulatory gene adiponectin (APM1 276G>T), were investigated. Findings varied with leptin genotype, the risks being decreased with LEP 19AA (OR = 0.7, 95% CI 0.5-1.0) and increased with LEP -2548GA (OR = 1.3, 95% CI 1.0-1.7) and -2548AA (OR = 1.4, 95% CI 1.0-1.9), particularly for follicular lymphoma. These genetic findings, which were independent of BMI, were stronger for men than women.

Although relatively rare, leukemias place a considerable financial burden on society and cause psychologic trauma to many families. Leukemia is the most common cancer in children. The causes of leukemia in adults and children are largely unknown, but occupational and environmental factors are strongly suspected. Genetic predisposition may also play a major role. Our aim is to use molecular epidemiology and toxicology to find the cause of leukemia and develop biomarkers of leukemia risk. We have studied benzene as a model chemical leukemogen, and we have identified risk factors for susceptibility to benzene toxicity. Numerous studies have associated exposure to benzene with increased levels of chromosome aberrations in circulating lymphocytes of exposed workers. Increased levels of chromosome aberrations have, in turn, been correlated with a heightened risk of cancer, especially for hematologic malignancy, in two recent cohort studies in Europe. Conventional chromosome analysis is laborious, however, and requires highly trained personnel. Further, it lacks statistical power, as only a small number of cells can be examined. The recently developed fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR)-based technologies have allowed the detection of specific chromosome aberrations. These techniques are far less time consuming and are more sensitive than classical chromosomal analysis. Because leukemias commonly show a variety of specific chromosome aberrations, detection of these aberrations by FISH and PCR in peripheral blood may provide improved biomarkers of leukemia risk.

Benzene is a recognized hematotoxin and leukemogen, but its mechanisms of action in humans are still uncertain. To provide insight into these processes, we carried out a cross-sectional study of 44 healthy workers currently exposed to benzene (median 8-hr time-weighted average; 31 ppm), and unexposed controls in Shanghai, China. Here we provide an overview of the study results on peripheral blood cells levels and somatic cell mutation frequency measured by the glycophorin A (GPA) gene loss assay and report on peripheral cytokine levels. All peripheral blood cells levels (i.e., total white blood cells, absolute lymphocyte count, platelets, red blood cells, and hemoglobin) were decreased among exposed workers compared to controls, with the exception of the red blood cell mean corpuscular volume, which was higher among exposed subjects. In contrast, peripheral cytokine levels (interleukin-3, interleukin-6, erythropoietin, granulocyte colony-stimulating factor, tissue necrosis factor-alpha) in a subset of the most highly exposed workers (n = 11) were similar to values in controls (n = 11), suggesting that benzene does not affect these growth factor levels in peripheral blood. The GPA assay measures stem cell or precursor erythroid cell mutations expressed in peripheral red blood cells of MN heterozygous subjects, identifying NN variants, which result from loss of the GPA M allele and duplication of the N allele, and N phi variants, which arise from gene inactivation. The NN (but not N phi) GPA variant cell frequency was elevated in the exposed workers compared with controls (mean +/- SD, 13.9 +/- 8.4 mutants per million cells versus 7.4 +/- 5.2 per million cells, (respectively; p = 0.0002), suggesting that benzene produces gene-duplicating but not gene-inactivating mutations at the GPA locus in bone marrow cells of exposed humans. These findings, combined with ongoing analyses of benzene macromolecular adducts and chromosomal aberrations, will provide an opportunity to comprehensively evaluate a wide range of early biologic effects associated with benzene exposure in humans.

An overall hypothesis for benzene-induced leukemia is proposed. Key components of the hypothesis include a) activation of benzene in the liver to phenolic metabolites; b) transport of these metabolites to the bone marrow and conversion to semiquinone radicals and quinones via peroxidase enzymes; c) generation of active oxygen species via redox cycling; d) damage to tubulin, histone proteins, topoisomerase II, other DNA associated proteins, and DNA itself; and e) consequent damage including DNA strand breakage, mitotic recombination, chromosome translocations, and aneuploidy. If these effects take place in stem or early progenitor cells a leukemic clone with selective advantage to grow may arise, as a result of protooncogene activation, gene fusion, and suppressor gene inactivation. Epigenetic effects of benzene metabolites on the bone marrow stroma, and perhaps the stem cell itself, may then foster development and survival of the leukemic clone. Evidence for this hypothesis is mounting with the recent demonstration that benzene induces gene-duplicating mutations in human bone marrow and chromosome-specific aneuploidy and translocations in peripheral blood cells. If this hypothesis is correct, it also potentially implicates phenolic and quinonoid compounds in the induction of "spontaneous" leukemia in man.

Fluorescence in situ hybridization (FISH) is a powerful new technique that allows numerical chromosome aberrations (aneuploidy) to be detected in interphase cells. In previous studies, FISH has been used to demonstrate that the benzene metabolites hydroquinone and 1,2,4-benzenetriol induce aneuploidy of chromosomes 7 and 9 in cultures of human cells. In the present study, we used an interphase FISH procedure to perform cytogenetic analyses on the blood cells of 43 workers exposed to benzene (median = 31 ppm, 8-hr time-weighted average) and 44 matched controls from Shanghai, China. High benzene exposure (> 31 ppm, n = 22) increased the hyperdiploid frequency of chromosome 9 (p < 0.01), but lower exposure (< or = 31 ppm, n = 21) did not. Trisomy 9 was the major form of benzene-induced hyperdiploidy. The level of hyperploidy in exposed workers correlated with their urinary phenol level (r = 0.58, p < 0.0001), a measure of internal benzene dose. A significant correlation was also found between hyperdiploidy and decreased absolute lymphocyte count, an indicator of benzene hematotoxicity, in the exposed group (r = -0.44, p = 0.003) but not in controls (r = -0.09, p = 0.58). These results show that high benzene exposure induces aneuploidy of chromosome 9 in nondiseased individuals, with trisomy being the most prevalent form. They further highlight the usefulness of interphase cytogenetics and FISH for the rapid and sensitive detection of aneuploidy in exposed human populations.

In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical reasons. Computer modeling offers a reasonable alternative, but the variability and complexity of biological systems pose unique challenges in model building and adjustment. Recent tools from population pharmacokinetics, Bayesian statistical inference, and physiological modeling can be brought together to solve these problems. As an example, we modeled the distribution and metabolism of benzene in humans. We derive statistical distributions for the parameters of a physiological model of benzene, on the basis of existing data. The model adequately fits both prior physiological information and experimental data. An estimate of the relationship between benzene exposure (up to 10 ppm) and fraction metabolized in the bone marrow is obtained and is shown to be linear for the subjects studied. Our median population estimate for the fraction of benzene metabolized, independent of exposure levels, is 52% (90% confidence interval, 47-67%). At levels approaching occupational inhalation exposure (continuous 1 ppm exposure), the estimated quantity metabolized in the bone marrow ranges from 2 to 40 mg/day.

The principal conclusions and opportunities that can be drawn from this conference are as follows. The meeting demonstrated the large communication gap that still exists between most epidemiologists and laboratory scientists. This problem could be overcome if epidemiologists worked closely with laboratory scientists at the outset of any project so that a better understanding could be built between them. Epidemiologists need simple, well-characterized, reproducible assays that can be applied to hundreds or thousands of people. Most laboratory scientists have little interest in running large numbers of assays, but wish to continually refine their methods so that they stay on the "cutting edge" of basic research. This problem could be overcome if the new laboratory technology could be transferred to contract laboratories or small companies. Problems of technology transfer therefore need to be addressed. Current and new biomarkers need to be better validated in the field and by studying animal models. More information on the background expression of biomarkers in the general population is needed (i.e. what is the normal range?). Ethical issues, such as the possibility that biomarkers of susceptibility could be used to exclude people from the workplace, need to be addressed.

The glycophorin A (GPA) assay is a human mutation assay that is potentially useful for large epidemiological studies. The assay is rapid and requires a minimal amount of blood, which can be stored before analysis. The data presented here were collected from workers exposed to styrene in a boat manufacturing plant. This study was the first to apply the GPA assay to an occupationally exposed population. Subjects with a mean styrene exposure of 30 ppm had a higher frequency of GPA N phi variant cells than subjects with mean exposure of 1 ppm, but the subjects differed in respect to smoking and age distribution. Results indicate that the original 1-W-1 version of the assay may not be suitable for studies of small numbers of exposed subjects due to variability and artifacts. The newer BR6 version, however, has much lower variability and shows promise for use in the occupational setting.

Ingestion of arsenic, both from water supplies and medicinal preparations, is known to cause skin cancer. The evidence assessed here indicates that arsenic can also cause liver, lung, kidney, and bladder cancer and that the population cancer risks due to arsenic in U.S. water supplies may be comparable to those from environmental tobacco smoke and radon in homes. Large population studies in an area of Taiwan with high arsenic levels in well water (170-800 micrograms/L) were used to establish dose-response relationships between cancer risks and the concentration of inorganic arsenic naturally present in water supplies. It was estimated that at the current EPA standard of 50 micrograms/L, the lifetime risk of dying from cancer of the liver, lung, kidney, or bladder from drinking 1 L/day of water could be as high as 13 per 1000 persons. It has been estimated that more than 350,000 people in the United States may be supplied with water containing more than 50 micrograms/L arsenic, and more than 2.5 million people may be supplied with water with levels above 25 micrograms/L. For average arsenic levels and water consumption patterns in the United States, the risk estimate was around 1/1000. Although further research is needed to validate these findings, measures to reduce arsenic levels in water supplies should be considered.

This paper describes four assays that detect somatic gene mutations in humans: the hypoxanthine-guanine phosphoribosyl transferase assay, the glycophorin A assay, the HLA-A assay, and the sickle cell hemoglobin assay. Somatic gene mutation can be considered a biomarker of carcinogenesis, and assays for somatic mutation may assist epidemiologists in studies that attempt to identify factors associated with increased risks of cancer. Practical aspects of the use of these assays are discussed.

The metabolism of two of benzene's phenolic metabolites, phenol and hydroquinone, by peroxidase enzymes has been studied in detail. Studies employing horseradish peroxidase and human myeloperoxidase have shown that in the presence of hydrogen peroxide phenol is converted to 4,4'-diphenoquinone and other covalent binding metabolites, whereas hydroquinone is converted solely to 1,4-benzoquinone. Surprisingly, phenol stimulates the latter conversion rather than inhibiting it, an effect that may play a role in the in vivo myelotoxicity of benzene. Indeed, repeated coadministration of phenol and hydroquinone to B6C3F1 mice results in a dramatic and significant decrease in bone marrow cellularity similar to that observed following benzene exposure. A mechanism of benzene-induced myelotoxicity is therefore proposed in which the accumulation and interaction of phenol and hydroquinone in the bone marrow and the peroxidase-dependent formation of 1,4-benzoquinone are important components. This mechanism may also be responsible, at least in part, for benzene's genotoxic effects, as 1,4-benzoquinone has been shown to damage DNA and is shown here to induce multiple micronuclei in human lymphocytes. Secondary activation of benzene's phenol metabolites in the bone marrow may therefore play an important role in benzene's myelotoxic and carcinogenic effects.

A Morel-Lavallée lesion (MLL) is a posttraumatic soft-tissue injury characterized by an accumulation of blood, lymph, and other physiologic breakdown products between subcutaneous tissue and underlying fascia. It was first described as occurring over the proximal lateral thigh, but it has since been documented at various anatomic locations. Diagnosis is typically made by careful physical examination and a radiographic analysis, most commonly with magnetic resonance imaging (MRI). Recently, musculoskeletal ultrasound (US) has been recognized as a useful adjunct to and potential replacement for MRI in the diagnosis and monitoring of an MLL. We present a case report of a patient with an MLL of the knee. We obtained magenetic resonance (MRI) and US images at the time of diagnosis, and follow-up US images during convalescence. By doing so, we were able to identify several key sonographic findings of an MLL at this location and compare them with MRI. Although there have been several published reports to date that describe the use of musculoskeletal US in the diagnosis of MLL, this is the first of which we are aware that does so at the knee. [ABSTRACT FROM AUTHOR]