Leukemia incidence in the Russian cohort of Chernobyl emergency workers.

Of all potentially radiogenic cancers, leukemia, a type of cancer of the blood, has the highest risk attributable to ionizing radiation. Despite this, the quantitative estimation of radiation risk of a leukemia demands studying very large exposed cohorts, because of the very low level of this disease in unexposed populations and because of the tendency for its radiation risk to decrease with time. At present, the Japanese cohort of atomic bomb survivors is still the primary source of data that allows analysis of radiation-induced leukemia and the underlying dose-response relationship. The second large cohort that would allow to study radiation-induced leukemia is comprised of individuals who were exposed due to the accident of the Chernobyl nuclear power plant in 1986. The objective of the present study was to estimate radiation risks of leukemia incidence among the Russian cohort of Chernobyl emergency workers, for different time periods after the accident. Twenty-five years after the Chernobyl accident and based on the results of the present study, one can conclude that the radiation risk of leukemia incidence derived from the Russian cohort of Chernobyl emergency workers is similar to that derived from the cohort of atomic bomb survivors: The time-averaged excess relative risk per Gray (ERR Gy(-1)) equals 4.98 for the Russian cohort and 3.9 for the life span study (LSS) cohort; excess absolute risk decreases with time after exposure at an annual rate of 9% for the Russian cohort, and of 6.5% for the LSS cohort. Thus, the excess in risk of leukemia incidence in a population due to a single exposure is restricted in time after exposure by the period of about 15 years.

The allometry of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is an acquired neoplastic hematopoietic stem cell (HSC) disorder characterized by the expression of the BCR-ABL oncoprotein. This gene product is necessary and sufficient to explain the chronic phase of CML. The only known cause of CML is radiation exposure leading to a mutation of at least one HSC, although the vast majority of patients with CML do not have a history of radiation exposure. Nonetheless, in humans, significant radiation exposure (after exposure to atomic bomb fallout) leads to disease diagnosis in 3-5 years. In murine models, disease dynamics are much faster and CML is fatal over the span of a few months. Our objective is to develop a model that accounts for CML across all mammals. In the following, we combine a model of CML dynamics in humans with allometric scaling of hematopoiesis across mammals to illustrate the natural history of chronic phase CML in various mammals. We show how a single cell can lead to a fatal illness in mice and humans but a higher burden of CML stem cells is necessary to induce disease in larger mammals such as elephants. The different dynamics of the disease is rationalized in terms of mammalian mass. Our work illustrates the relevance of animal models to understand human disease and highlights the importance of considering the re-scaling of the dynamics that accrues to the same biological process when planning experiments involving different species.

Radiation leukemogenesis: a proteomic approach.

OBJECTIVE: The objectives of this study were to identify protein biomarkers of radiation-induced acute myeloid leukemia (rAML) in CBA/CaJ mice, and to examine the similarities or differences in the patterns of protein-expression profiles among AMLs induced by low linear energy transfer (LET) radiation (e.g., gamma- or x-rays), and high LET radiation (i.e., neutrons). MATERIALS AND METHODS: We used two-dimensional electrophoresis gel in combination with mass spectrometry (MS), i.e., matrix-assisted laser desorption ionization/time-of-flight MS and electrospray ionization-liquid chromatography/tandem mass spectrometry, to identify protein signatures in blood-plasma samples collected from control and rAML mice. There were nine cases of rAML (three cases induced by high LET radiation; six induced by low LET radiation) and eight control mice at similar ages. RESULTS: The results showed differences in the patterns of protein profiles from blood-plasma samples collected from rAML vs control mice. Moreover, our data demonstrated, both qualitatively and quantitatively, differences between the plasma protein profiles obtained from mice with AML induced by low vs high LET radiation. Most of the proteins that were present at greater levels in normal samples than in rAML samples were associated with normal metabolism and growth. Several acute-phase proteins were upregulated in rAML samples. CONCLUSION: The data present, for the first time, evidence for increased expression of clusterin and a loss of gelsolin expression in blood plasma as potential biomarkers of rAML in the CBA/CaJ mouse. Results also indicate that two-dimensional electrophoresis, in combination with MS, is a highly sensitive technique for identification of blood-based biomarkers of rAML.

Acquired radioresistance of hematopoietic progenitors (granulocyte/monocyte colony-forming units) during chronic radiation leukemogenesis.

Protracted exposure of dogs to low daily doses of whole-body gamma-radiation (7.5 cGy/day for duration of life) elicits a high incidence of myeloid leukemia or related myeloproliferative disorders. Under such exposure, vital hematopoietic progenitors [granulocyte/monocyte colony-forming units in agar (CFU-GM)] acquire increased radioresistance along with renewed proliferative capacity at an early phase of evolving myeloid leukemia. To further characterize the expression of acquired radioresistance by CFU-GM, we evaluated the effects of various exposure rates, cumulative radiation doses, and times of exposure and postexposure in several groups of long-lived dogs under two conditions of irradiation: (a) continuous, duration-of-life exposures at dose rates of 0.3-7.5 cGy/day; and (b) discontinuous, fraction-of-life exposures at dose rates of 3.8-26.3 cGy/day, with cumulative doses of 450-3458 cGy and postexposure times of 14-4702 days. Results indicated that (a) under protracted continuous irradiation, the degree of radioresistance expressed by CFU-GM in vitro increased markedly in a biphasic pattern with rising daily rates of exposure; (b) under discontinuous, fraction-of-life exposure regimens, elevated levels of radioresistance were expressed and stably maintained by CFU-GM only following large radiation doses accumulated at high dose rates; and (c) with extended postexposure times, the magnitude of expressed radioresistance appeared to wane. These results continue to support the hypothesis that the acquisition of radioresistance and associated repair functions by vital lineage-committed progenitors, under the strong selective and mutagenic pressure of chronic irradiation, is tied temporally and causally to leukemogenic transformation elicited by radiation exposure.

Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiation: the NSABP experience.

Since 1971, 8,483 women with primary breast cancer participated in seven trials evaluating adjuvant chemotherapy. Leukemia occurred in only three of 2,068 patients treated by operation alone. The cumulative risk was 0.06% after 10 years in those free of metastases or a second primary tumor, and 0.27% in those with tumor. Thus, leukemia is not an important factor in the natural history of breast cancer. Five of 646 women receiving postoperative regional radiation developed leukemia, an overall risk of 1.39 +/- .49% at 10 years. Twenty-seven cases of leukemia (0.5%) and seven of myeloproliferative syndrome (0.1%) were recorded in 5,299 patients who received L-phenylalanine mustard (L-PAM)-containing regimens. The maximum cumulative risk of leukemia in chemotherapy recipients (leukemia of any type and myeloproliferative syndrome) was 1.68 +/- .33% at 10 years following operation. The risk excluding those with myeloproliferative syndrome was 1.29 +/- .28%. The risk of leukemia in patients free of metastases or a second primary was 1.11 +/- .30% at 10 years, and when combined with myeloproliferative syndrome, it was 1.54 +/- .36%; risks not significantly greater than observed following radiation (P = .58 and .29). No cases of leukemia were observed during the 2 years of chemotherapy and none have occurred after the seventh postoperative year. Comparisons with the surveillance, epidemiology, and end results tumor registries (SEER) data indicate an increased relative risk of acute myelogenous leukemia following postoperative regional radiation (P less than .01) and adjuvant chemotherapy (P less than .001). The findings indicate that hematologic disorders are side effects of both radiation and alkylating agents used in the adjuvant treatment of primary breast cancer. The risk of such events is lower than that reported following treatment of other solid tumors and hematologic malignancies by chemotherapy. The benefit from adjuvant chemotherapy for breast cancer exceeds the risk of leukemia. Since chemotherapy is not uniformly beneficial, efforts should be directed toward identifying responders so that only those who will benefit are exposed to the risk.

[P-glycoprotein expression in radiation-associated acute myeloid leukemia].

The article presents findings of the analysis on P-glycoprotein expression of leukemic cells in 52 acute myeloid leukemia (AML) patients. Of these, there were 20 persons exposed to ionizing radiation due to the Chernobyl accident and 32 patients with spontaneous disease. Leukemic cells in patients with radiation-associated AML compared to spontaneous cases more often were P-glycoprotein positive (12/20 vs 9/32, P<0,05). P-glycoprotein overexpression significantly correlated with resistant disease in patients with radiation-associated AML, but was not a prognostic variable for treatment outcome in terms of overall survival.

Leukemia, lymphoma, and multiple myeloma after pelvic radiotherapy for benign disease.

The relationship between exposure to sparsely ionizing radiation and mortality due to cancers of hematopoietic and lymphopoietic tissues was studied among 12,955 women treated for benign gynecological disorders at any of 17 hospitals in New England or New York State and followed for an average of 25 years; 9770 women were treated by radiation (intracavitary 226Ra, external-beam X rays), while 3185 were treated by other methods, including curettage, surgery, and hormones. The average age at treatment was 46.5 years, and the mean dose to active bone marrow among irradiated women was 119 cGy. Forty deaths due to acute, myelocytic, or monocytic leukemia were observed among irradiated women. This number was 70% higher than expected based on U.S. mortality rates [standardized mortality ratio (SMR) = 1.7; 90% confidence interval (CI) 1.3-2.3]. A deficit was recorded among nonirradiated women, based on three observed deaths (SMR = 0.5; 90% CI 0.1-1.2). A well-defined gradient in the SMR with dose among exposed women was not detected. The SMR was highest within 5 years after irradiation but remained elevated even after 30 years. The temporal pattern differed by subtype of leukemia: excess mortality due to chronic myelocytic leukemia occurred almost exclusively within the first 15 years, whereas the SMR for acute leukemia, though also elevated, varied little over time. Cancers of lymphoreticular tissue occurred more often than expected based on U.S. mortality rates, but not appreciably differently for irradiated and nonirradiated women. There was little or no evidence of effects attributable to radiotherapy for chronic lymphocytic leukemia [relative risk (RR) = 1.1; 90% CI 0.5-3.0], Hodgkin's disease (RR = 0.9; 90% CI 0.3-3.2), non-Hodgkin's lymphoma (RR = 0.9; 90% CI 0.6-1.6), or multiple myeloma (RR = 0.6; 90% CI 0.3-1.4). These results corroborate previous findings indicating that acute and myelocytic leukemias are the most prominent malignancies after exposure to sparsely ionizing radiation, occurring in excess shortly after irradiation, and that lymphomas are either not caused by radiation or are induced only rarely.

A case of therapy-related extramedullary acute promyelocytic leukemia.

We report a patient with extramedullary acute promyelocytic leukemia (APL) occurring after radiation therapy for carcinoma of the prostate. To the authors' knowledge, this patient represents the first case of cytogenetically and fluorescence in situ hybridization (FISH) confirmed therapy-related extramedullary APL. In contrast to the majority of previously reported t-APL, this case underwent a very unfavorable course.

Hematopoietic cell crisis: an early stage of evolving myeloid leukemia following radiation exposure.

Under select radiological conditions, chronic radiation exposure elicits a high incidence of myeloproliferative disease, principally myeloid leukemia (ML), in beagles. Previously we demonstrated that for full ML expression, a four-stage preclinical sequence is required, namely (I) suppression, (II) recovery, (III) accommodation, and (IV) preleukemic transition. Within this pathological sequence, a critical early event has been identified as the acquisition of radioresistance by hematopoietic progenitors that serves to mediate a newfound regenerative hematopoietic capacity. As such, this event "sets the stage" for preleukemic progression by initiating progression from preclinical phase I to II. Due to the nature of target cell suppression, the induction of crisis, and the outgrowth of progenitors with altered phenotypes, this preleukemic event resembles the "immortalization" step of the in vitro transformation sequence following induction with either physical and chemical carcinogens. The radiological, temporal, and biological dictages governing this event have been extensively evaluated and will be discussed in light of their role in the induction and progression of chronic radiation leukemia.

Leukemia-associated gene rearrangements in blood mononuclears of subjects in long terms after radiation exposure.

The results of electron microscopy and molecular genetic study of blood mononuclears of 220 clean-up workers after 7-10 years since Chernobyl accident are presented. An increase of lymphocytes with altered ultrastructure of nuclei and membrane has been observed. Structural polymorphism of leukemia associated bcr and rRNA genes has been analyzed using Southern blot hybridization. Allelic polymorphism of bcr gene with allele distribution characteristic of myeloid leukemia and rearrangements of rRNA genes have been revealed in 11,5% of clean-up workers under study.

Cytogenic investigations of serious overexposures to an industrial gamma radiography source.

This paper describes the sequence of events, medical aspects and dose estimations for two radiographers and their driver who were seriously exposed to an iridium-192 industrial radiography source that became detached from its wind-out cable. The men came to medical attention about 1 month later by which time all three were severely leucopenic and one had skin burns on both hands. Doses were estimated by (i) physics calculations combined with their accounts of the event. (ii) the levels of depression of their blood neutrophils, (iii) electron spin resonance on tooth enamel and (iv) blood lymphocyte chromosomal analyses by the conventional dicentric and the fluorescence in situ hybridisation methods. Intercomparison of these methods for estimating doses showed a good level of agreement. In brief, the averaged whole body dose for the most seriously exposed man was about 2.5-3.0 Gy and for the others it was 1.0-2.0 Gy.

[Spontaneous leukosis as a model for an investigation of low and very low physical and physico-chemical effects on oncological process]. / Spontannyi leikoz -- model' dlia izucheniia éffektov malykh i sverkhmalykh doz fizicheskikh i fiziko-khimicheskikh vozdeistvii na opukholevyi protsess.

Kinetic investigation of spontaneous leukosis in AKR mice have been carried in connection with a number of indices: changes in the mass of principal organs of the immune systems (thymus, spleen, lymphatic nodes), liver, alterations of haematological data (the sum of leukocytes, the percentage composition of blood cells, the quantity of undifferentiated cells), changes of physico-chemical conditions in cells (NMR-investigation). The dynamics of some of these indices and also life-spans of animals with leukosis after irradiation with doses 1.2-2.4 cGy (dose-rate 0.6 cGy/day) have been investigated. The enhancement of the frequency of leukosis and shortening the average and maximum life-spans of irradiated mice has been found.

[Markers of the metabolic changes arising as a result of ionizing radiation exposure]. / Markery metabolicheskikh izmenenii, voznikaiushchikh vsledstvie vozdeistviia ioniziruiushchei radiatsii.

Time-related changes have been studied in the content of extracellular DNA, Fe(3+)-transferrin (TF), and Cu(2+)-ceruloplasmin (CP) in the blood plasma and the activity of ribonucleotide reductase (RR) in the tumor cells and spleen of mice during the development of acute lympholeukosis P-388 and after ionizing irradiation. At the initial stages of leucosis P-388, the content of extracellular DNA increases, the TF and CP pools in the blood plasma enlarge, and the RR activity in the tumor cells and spleen of tumoral mice markedly increases. A dose-dependent increase in RR activity was also recorded in the spleen of 5-day-old rats within 15-30 min after irradiation. The causes of these changes and the possibility for these indices to be used in estimating leucosis risk are discussed. Radiation-induced increases in RR activity are discussed in relation to the SOS-response to DNA damage; an increased pool of deoxyribonucleotides is necessary for repair of DNA. The mean contents of extracellular DNA, TF and CP in the blood plasma were obtained from children of different ages degrees of radioactive contamination suffering the consequences of the accident at the Chernobyl' Nuclear Power Station (n = 155). Groups of children have been isolated with increased, sharply decreased, and close to normal levels of extracellular DNA, TF, and CP. The lowered TF pool was observed in children with thyroid glands damaged by incorporated radioactive iodine with the degree of suppression determined by the dose. For most children subject to general irradiation, the TF and CP pools in the blood were higher than in the control, suggesting an adaptive response to irradiation.

[Age-related differences in hematopoietic progenitor cells and the problems of carcinogenesis]. / Vozrastnye razlichiia rodonachal'nykh krovetvornykh kletok i nekotorye problemy kantserogeneza.

In the past years the authors advanced a hypothesis of the "age-associated layers" of parent hemopoietic cells. The hypothesis was based first of all on the differences in the patterns of leukemias and noncancerous diseases (of the hemopoietic tissues) in children and adults. The nature of the changing age-associated characteristics of parent cells remained obscure. Analysis of leukemias and epithelial tumors of radiation nature, formed in the victims to nuclear bomb explosion in Japan in 1945, analysis of leukemias occurring in persons with genetic diseases characterized by the known chromosomal aberrations (Down's syndrome, Louis-Bar syndrome, etc.), studies into the inherited forms of leukemias (chronic lympholeukemia, subleukemic myelosis, etc.--all these conditions are marked by the unstable genetic apparatus and high mutability) allowed the authors to make a conclusion about a kit of active differentiation genes which are replaced in health with age. Cancerous transformation may take place just at the level of those genes in parent cells with an unstable genome, since there appear specific mutation (in contrast to nonspecific ones characterizing the unstable genome) and a cancerous clone.

[The clinical course and histological characteristics of medullary hematopoiesis in acute leukemia in those who worked in the cleanup of the aftermath of the accident at the Chernobyl Atomic Electric Power Station]. / Klinichnyi perebih ta histolohichni osoblyvosti kistkovomozkovoho krovotvorennia pry hostromu leikozi u likvidatoriv naslidkiv avariï na ChAES.

The course is analyzed of myeloblastic leukemia in twelve participants in the elimination of the aftermath of the Chernobyl Atomic Power Plant breakdown. The iliac trepanobiopsies bone-marrow hemopoiesis is studied. A gross depression of normal hemopoiesis has been revealed together with a fibrous transformation of the bone marrow, which fact suggests a profound damage to the hemopoietic micro-surroundings, being a cause of ineffective hemopoiesis, of grave course of the illness, and of failure to respond to cytostatic therapy.

[Problem of radiation-induced leukemia]. / K peobleme radiatsionnogo leikozogeneza.

A case of radiation-induced leukemia has been described in a woman living in the area exposed to radioactive contamination as a result of the disaster at the Chernobyl NPS. Radiation-induced leukemia was diagnosed basing on the cytogenetic changes in the bone marrow and peripheral blood lymphocytes. Cytogenetic changes in the peripheral blood lymphocytes have been recorded in 60 subjects who were evacuated from areas contaminated with isotopes as a result of the disaster.

Effect of ovariectomy on x-ray carcinogenesis in rats.

Tumor induction by fractionated whole-body X-irradiation (400 rad) was studied in spayed Sprague-Dawley rats. Ovariectomy was chosen as an intensifying factor for radiation leukemogenesis. Ovariectomized rats gained more body weight and responded more quickly (but transiently) in the recovery of WBC levels after the last (3rd or 4th) X-irradiation. A total of 26 tumors developed in 21 out of 47 ovariectomized rats, 11 tumors in 6 out of 13 ovariectomized and ovary-grafted rats, and 44 tumors in 25 out of 29 sham-ovariectomized rats during the observation period up to 64 weeks after starting X-irradiation. Eighty per cent of tumors were of mammary gland origin in the latter two groups with intact or grafted ovaries. By contrast, 61.1% of tumors in the spayed rats were derived from the subcutaneous mesenchymal tissue and the hematopoietic tissue. This may imply that some forms of mesenchymal tumors including leukemia are under the suppressive influence of female sex hormones.

32P and acute leukemia: development of leukemia in a patient with hemoglobin Yakima.

In 1954 a then 31-yr-old male was found to have erythrocytosis. Over the ensuing decade he received 72 mCi32P. In 1964 his daughters were found to have erythrocytosis. Further investigation led to the discovery of hemoglobin Yakima, a variant with high oxygen affinity. He received no further therapy and was well until 1975, when he developed the preleukemic syndrome. Within 12 mo. he developed acute nonlymphocytic leukemia accompanied by fetal erythropoiesis. Because the inital discovery of this type of hemoglobinopathy came 27 yr after the introduction of 32P for use in the treatment of polycythemia vera, and because there are now known to be more than 39 different high-oxygen-affinity hemoglobins, we anticipate that more patients such as ours have been exposed to 32P. The exposed population should be cosely followed, since this will likely permit assessment of the risk of 32P-induced leukemia in a nonneoplastic condition.