The frequency of micronuclei (MN) in peripheral blood lymphocytes (PBL) is extensively used as a biomarker of chromosomal damage and genome stability in human populations. Much theoretical evidence has been accumulated supporting the causal role of MN induction in cancer development, although prospective cohort studies are needed to validate MN as a cancer risk biomarker. A total of 6718 subjects from of 10 countries, screened in 20 laboratories for MN frequency between 1980 and 2002 in ad hoc studies or routine cytogenetic surveillance, were selected from the database of the HUman MicroNucleus (HUMN) international collaborative project and followed up for cancer incidence or mortality. To standardize for the inter-laboratory variability subjects were classified according to the percentiles of MN distribution within each laboratory as low, medium or high frequency. A significant increase of all cancers incidence was found for subjects in the groups with medium (RR=1.84; 95% CI: 1.28-2.66) and high MN frequency (RR=1.53; 1.04-2.25). The same groups also showed a decreased cancer-free survival, i.e. P=0.001 and P=0.025, respectively. This association was present in all national cohorts and for all major cancer sites, especially urogenital (RR=2.80; 1.17-6.73) and gastro-intestinal cancers (RR=1.74; 1.01-4.71). The results from the present study provide preliminary evidence that MN frequency in PBL is a predictive biomarker of cancer risk within a population of healthy subjects. The current wide-spread use of the MN assay provides a valuable opportunity to apply this assay in the planning and validation of cancer surveillance and prevention programs.

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The increased cerebrovascular mortality may be due to GH deficiency, or to long-term lack or inadequacy of substitution for other pituitary hormones. The observations that an early onset of pituitary insufficiency and female sex are predictors for a high risk for cerebrovascular mortality merit particular attention when treating this group of patients.

The aim of the present study was to model apparent serum half-lives of polybrominated diphenyl ethers (PBDEs) with 7–10 bromine substituents. Workers with occupational exposure to PBDEs have elevated serum levels of PBDEs, but these substances are also found in the general population and are ubiquitous environmental contaminants. The calculations were based on exposure assessments of rubber workers (manufactured flame-retarded rubber compound) and electronics dismantlers who donated blood during a period with no work-related exposures to PBDEs, and referents without any known occupational exposure (clerks, cleaners, and abattoir workers). The workers had previously been found to have elevated levels of high- and medium-brominated diphenyl ethers compared with the referent populations. We performed nonlinear mixed-effects modeling of kinetics, using data from previous and present chemical analyses. The calculated apparent half-life for decabromodiphenyl ether (BDE-209) was 15 days (95% confidence interval, 11–18 days). The three nona-BDEs and four octa-BDE congeners were found to have half-lives of 18–39 and 37–91 days, respectively. BDE-209 has a short half-life in human blood. Because BDE-209 is commonly present in humans in general, the results of this study imply that humans must be more or less continuously exposed to BDE-209 to sustain the serum concentrations observed. BDE-209 is more readily transformed and/or eliminated than are lower brominated diphenyl ether congeners, and human health risk must be assessed accordingly.

To ascertain the frequency of treatment-related acute myeloid leukemias and myelodysplastic syndromes (t-AML/t-MDS) in an unselected series, we have identified all adult cases analyzed in our department from 1976 to 1993. Further aims were to compare karyotypic features of t-AML/t-MDS with de novo AML/MDS, in our material as well as in 5098 unselected, cytogenetically abnormal, published cases, and to analyze associations between type of prior therapy and karyotype. Among our 372 AML and 389 MDS, 47 (13%) were t-AML and 62 (16%) were t-MDS. Clonal abnormalities were significantly more common in t-AML and t-MDS than in de novo disease (68% vs 50%, P Ͻ 0.05 and 84% vs 45%, P Ͻ 0.001, respectively). Among the available 4230 AML and 1629 MDS (the present series and published cases), 14% were t-AML and 15% were t-MDS. In t-AML/t-MDS, the number of anomalies and the ploidy levels differed significantly from de novo cases, with complex and hypodiploid karyotypes being more common in t-AML/t-MDS. In t-AML, unbalanced changes in general, t(1;3), der(1;7), 3p−, −5, 5q−, −7, 7q−, t(9;11), t(11;19), t(11q23), der(12p), −17, der(17p), −18, and −21 were significantly more frequent than in de novo AML. In t-MDS, −5, −7, 7q−, 13q−, der(17p), and −18 were significantly more common. Type of prior treatment correlated significantly with number of anomalies in t-AML and with ploidy levels in t-AML/t-MDS. The frequencies of several aberrations varied with type of therapy, eg, 5q− was more frequent in radiotherapyassociated t-MDS, monosomy 7 was more common in t-AML and t-MDS after treatment with alkylators, and t(11q23) in t-AML was associated with topoisomerase II inhibitors. Abnormalities significantly more common in de novo disease were +8 as a sole anomaly, balanced changes in general, t(8;21), t(9;22), t(15;17), inv(16), and t(21q22) in AML, and −Y, 5q−, and 20q− as sole anomalies and +8 in MDS. The results emphasize the strong association between previous genotoxic exposure and karyotypic features. Leukemia (2002) IntroductionEver since the mid-1970s, when the first case reports describing chromosomal abnormalities in treatment-related acute myeloid leukemias (t-AML) were published, 1,2 the cytogenetic features of t-AML and of therapy-associated myelodysplastic syndromes (t-MDS) have received much attention. 3,4 To date, two distinct karyotypic patterns that correlate with specific types of chemotherapeutic agents have emerged. Previous chemotherapy (CT) with alkylators (alk) has been strongly linked to the development of t-MDS/t-AML harboring unbal- anced changes, mainly whole or partial losses of chromosomes 5 and 7, often in complex, hypodiploid karyotypes, 5-9 whereas prior CT with DNA topoisomerase II inhibitors (topo II) has been associated with t-AML characterized by, in particular, translocations involving chromosome band 11q23 resulting in MLL gene rearrangements. 4,[10][11][12] It has been debated, but remains to be settled, whether prior radiotherapy (RT) alone or exposure to CT other than alk/topo II may correla...