[show abstract][hide abstract] ABSTRACT: BACKGROUND: Risks of most types of leukemia from exposure to acute high doses of ionizing radiation are well known, but risks associated with protracted exposures, as well as associations between radiation and chronic lymphocytic leukemia (CLL), are not clear.
OBJECTIVES: We estimated relative risks of CLL and non-CLL from protracted exposures to low-dose ionizing radiation.
METHODS: A nested case-control study was conducted in a cohort of 110,645 Ukrainian cleanup workers of the 1986 Chornobyl nuclear power plant accident. Cases of incident leukemia diagnosed in 1986-2006 were confirmed by a panel of expert hematologists/hematopathologists. Controls were matched to cases on place of residence and year of birth. We estimated individual bone marrow radiation doses by the Realistic Analytical Dose Reconstruction with Uncertainty Estimation (RADRUE) method. We then used a conditional logistic regression model to estimate excess relative risk of leukemia per gray (ERR/Gy) of radiation dose.
RESULTS: We found a significant linear dose response for all leukemia [137 cases, ERR/Gy = 1.26 (95% CI: 0.03, 3.58]. There were nonsignificant positive dose responses for both CLL and non-CLL (ERR/Gy = 0.76 and 1.87, respectively). In our primary analysis excluding 20 cases with direct in-person interviews < 2 years from start of chemotherapy with an anomalous finding of ERR/Gy = -0.47 (95% CI: < -0.47, 1.02), the ERR/Gy for the remaining 117 cases was 2.38 (95% CI: 0.49, 5.87). For CLL, the ERR/Gy was 2.58 (95% CI: 0.02, 8.43), and for non-CLL, ERR/Gy was 2.21 (95% CI: 0.05, 7.61). Altogether, 16% of leukemia cases (18% of CLL, 15% of non-CLL) were attributed to radiation exposure.
CONCLUSIONS: Exposure to low doses and to low dose-rates of radiation from post-Chornobyl cleanup work was associated with a significant increase in risk of leukemia, which was statistically consistent with estimates for the Japanese atomic bomb survivors. Based on the primary analysis, we conclude that CLL and non-CLL are both radiosensitive.
Environmental Health Perspectives 01/2013; 121(1):59-65. · 7.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: PURPOSE: To present previously unavailable data on the use of stem cell administration to aid recovery of victims of the Chernobyl disaster. On 26 April 1986, an accident at Unit 4 of the Chernobyl Nuclear Power Plant took place during the planned test of one of the safety systems. The diagnosis of acute radiation syndrome (ARS) was confirmed in 134 individuals exposed to high levels of radiation. There were nine patients heretofore unreported in the scientific literature who underwent intraosseous injections of allogeneic bone marrow cells in Kyiv. CONCLUSIONS: Transplantation was associated with significantly shortened time to recovery of granulocyte and platelet counts in these patients. While current guidelines would certainly include the use of cytokines, these data provide an indication of the effectiveness of stem cell transplant to treat victims of radiation exposure.
International Journal of Radiation Biology 03/2011; 87(8):846-50. · 1.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: After the Chernobyl accident, the Research Center for Radiation Medicine (RCRM) was established in Kiev (Ukraine). Its main task was to maintain a high level of emergency preparedness and be ready to examine and treat patients who suffer as a result of hypothetical radiation accident. Based on the previous experience, this institution's specialists worked out new diagnostic criteria and drug treatment schemata for acute radiation sickness, created a database on 75 patients with this diagnosis and improved educational programmes for medical students and physicians working in the field of radiation medicine. RCRM collaborates fruitfully with western partners through the joint research projects and connects with the World Health Organization's Radiation Emergency Medical Preparedness and Assistance Network centre. Collaboration with Kiev Center for Bone Marrow Transplantation allows RCRM to use aseptic wards having highly filtered air for the treatment of most severely irradiated patients.
[show abstract][hide abstract] ABSTRACT: Leukemia is one of the cancers most susceptible to induction by ionizing radiation, but the effects of lower doses delivered over time have not been quantified adequately. After the Chornobyl (Chernobyl) accident in Ukraine in April 1986, several hundred thousand workers who were involved in cleaning up the site and its surroundings received fractionated exposure, primarily from external gamma radiation. To increase our understanding of the role of protracted low-dose radiation exposure in the etiology of leukemia, we conducted a nested case-control study of leukemia in a cohort of cleanup workers identified from the Chornobyl State Registry of Ukraine. The analysis is based on 71 cases of histologically confirmed leukemia diagnosed in 1986-2000 and 501 age- and residence-matched controls selected from the same cohort. Study subjects or their proxies were interviewed about their cleanup activities and other relevant factors. Individual bone marrow radiation doses were estimated by the RADRUE dose reconstruction method (mean dose = 76.4 mGy, SD = 213.4). We used conditional logistic regression to estimate leukemia risks. The excess relative risk (ERR) of total leukemia was 3.44 per Gy [95% confidence interval (CI) 0.47-9.78, P < 0.01]. The dose response was linear and did not differ significantly by calendar period of first work in the 30-km Chornobyl zone, duration or type of work. We found a similar dose-response relationship for chronic and non-chronic lymphocytic leukemia [ERR = 4.09 per Gy (95% CI < 0-14.41) and 2.73 per Gy (95% CI < 0-13.50), respectively]. To further clarify these issues, we are extending the case-control study to ascertain cases for another 6 years (2001-2006).
Radiation Research 01/2009; 170(6):711-20. · 2.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: There are relatively few data on the risk of leukemia among those exposed to external radiation during cleanup operations after the Chornobyl nuclear accident, and results have not been consistent. To investigate this further, we assembled a cohort of 110,645 male cleanup workers from Ukraine and identified cases of leukemia occurring during the period 1986 to 2000. Detailed interviews were conducted and individual bone marrow doses estimated using a new time-and-motion method known as RADRUE described in companion paper II. For the initial analyses we used a nested case-control approach with a minimum of five controls per case, matched for year of birth, oblast (region) of registration, and residence. All identified cases were reviewed by an international panel of experts; 87 of 111 were confirmed. The dose-response analysis and results are given in companion paper III. As background, we describe herein the design, procedures, outcome of case finding and confirmation, control selection, dose estimation and interviewing of subjects.
Radiation Research 01/2009; 170(6):691-7. · 2.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Ionizing radiation (IR) is a primordial terrestrial and extraterrestrial background
and archetypal environmental stress-factor for the origin of life, evolution
and existence. Psychophysiological norm/pathology dichotomy and borderline
states, and the nature of organism's systems disorders and diseases with respect to
IR effects is a matter of boundaries–thresholds–adaptation–optimization phenomena
and perturbations of organism systems dynamic free-radical/redox
homeostasis where brain/CNS is evolutionary immanently most sensitive and
vulnerable to free-radical/ redox deviations induced by IR. Investigation of IR
effects on the human organism is a unique opportunity for novel theoretical and
experimental insights into themolecular nature of complex inherent mechanisms
and gene–environment interactions underlying human psychophysiology and
pathopsychophysiology in brain aging/neurodegeneration processes, neuropsychiatric,
cognitive /memory disorders, cardiovascular and neuroimmunology
functional deviations, brain laterality, etc. Having in essence free-radical (redox)
nature and mechanisms, IR effects encompass all conceptual, experimental, and
clinical implications and manifestations connected with novel free-radical
paradigm in biology and medicine based on free radicals redox and physiological
ambivalence and complementarity. Possibility for selection on the base of
Chornobyl data systematic cases with variable specific external and internal
exposure characteristics interpreted at molecular level, for targeting and
manipulating molecular machinery, and pertinent subjects group allow to
investigate, conceptualize, and illustrate modeling psychophysiology/ pathopsychophysiology
duality phenomena by IR effects. Multi-lateral, multi-level IR
impact on human body accelerates, enhances, and condenses in time, effect, scale,
and plausibly reflects at all hierarchy level – molecular, cellular, subsystem (axis),
system/organ, whole organism – basic gene–environment interactions including
epigenetics, changing gene expression, stress responses and adaptation, and all
spectrum from normal homeodynamic reactions to pathopsychophysiological
mechanisms. This is also reliable basis for understanding at the molecular level subtle ways for relevant intervention and developing pertinent new biomarkers,
biodosymetry, and countermeasures using IR selective signature in the terms of
state of the art “omics”.
International Journal of Psychophysiology 01/2008; 69:249. · 2.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Studies performed at RCRM have shown that hematopoietic and immune systems’ reconstitution after irradiation depends greatly
on the functional abilities of the stem cells. Subset analysis and expression of CD34+ antigens on bone marrow and peripheral
blood cells were studied in Chernobyl accident clean-up workers including patients with leukemia and myelodysplasia and patients
exposed to the natural levels of irradiation. In myelodysplasia the elevation of early CD34+ cells was detected in bone marrow
and peripheral blood. In leukemia the CD34+117+38- primitive progenitor cell counts were elevated mainly in patients with
proliferation of poorly differentiated cells while in ALL’s the CD34+ counts were smaller. Circulating HSC and progenitors
after radiation exposure in a wide range of doses have are preserved in a number and with proliferation potencies sufficient
for the onset of clonal proliferation. In AML FLT3 mutations are the most abundant single-gene mutations. There is no difference in prevalence of FLT3 mutations in groups of radiation-associated and spontaneous AML cases. LOH/deletions at 5q and/or 7q and 7? tend to be more
frequent in radiation-associated AML cases. Bone marrow and bone tissue microenvironment plays a key role in normal and neoplastic
HSC changes. Differentiation to B-lineage isn’t changed and is associated with B-cell compartment growth.
Keywords: stem cells; radiation; leukemia; Chernobyl
[show abstract][hide abstract] ABSTRACT: THE AIM of the study was to evaluate the frequency of IGHV3-21 gene usage and its clinical significance for patients with B-cell chronic lymphocytic leukemia (CLL) in Ukraine.
Immunoglobulin variable heavy chain (IGHV) gene repertoire was studied in 189 CLL patients using reverse transcribed polymerase chain reaction and direct sequence of amplified products.
IGHV3-21 gene expression was found in 11 cases (5.8%), and its frequency was intermediate between Scandinavian (11.7%) and Mediterranean CLL (2.9%) cohorts. The most of cases (9 of 11) belonged to subset with heterogeneous HCDR3 (heteroHCDR3 subset), and only 2 cases--to subset with classical short ARDANGMDV motif (homHCDR3 subset). Six IGHV3-21 cases were mutated and 5 cases were unmutated. All unmutated cases (all were from heteroHCDR3 subset) had similarity of their HCDR3s with previously published sequences. The differences in overall (OS), progression-free (PFS) and treatment-free survival (TFS) for IGHV3-21 positive patients in comparison with CLL patients expressing the other IGHV genes were statistically insignificant. These survival parameters were comparable also for CLL patients with mutated IGHV3-21 gene usage and expression the others mutated IGHV genes. But remarkable feature of IGHV3-21 expressing patients was high incidence of solid tumors. They have developed in 4 IGHV3-21 positive cases (36.4%) and in 10 cases with expression of the others IGHV genes (5.6%, p=0.0002). Furthermore, in small group of 6 patients with mutated IGHV3-21 gene expression, 3 patients had solid tumors and one underwent Richter transformation. Unmutated IGHV3-21 gene expressed patients had worse OS and PFS in comparison with CLL patients that expressed the others unmutated IGHV genes.
Presented data are in agreement with the opinion about negative prognostic significance of IGHV3-21 gene expression regardless its mutation status. IGHV3-21 expression was associated with development of secondary solid tumors. Revealed high level of homology in heteroHDR3s subset might suggest about possible antigenic influence also, in addition to homHCDR3 subset that was proposed earlier.
[show abstract][hide abstract] ABSTRACT: A study of non-cancer effects was based on the data from the State Chernobyl registry of Ukraine. The relative risks of cardiovascular and cerebrovascular diseases are higher in the groups exposed in 250–700 mGy range as compared with the group exposed under 100 mGy. Neurologic and psychological changes rank second and third in structure of morbidity. Relative risks of mortality from circulation diseases were shown to be increased in recovery operation workers of 1986–1987. A case-control study of 14,731 clean-up workers by means non-threshold multi-factor non-linear model has demonstrated a dose-dependent additive-relative risk of radiation cataract being equal to 3.451 (1.347–5.555) per 1 Gy. Changes of proliferative activity of haemopoietic and stromal progenitor cells of exposed in 1986–1987, wavy variations of cellular and humoral immunity parameters were still detected 15–18 years after the exposure.
International Congress Series 01/2007; 1299:54-59.
[show abstract][hide abstract] ABSTRACT: The article considers the possibility of the use of current infrastructure of specialized population registers of Ukraine to study leukemia and other systemic blood diseases revealed in Chernobyl accident liquidators. Advantage and limitation of such registers in the use are discussed in the article. Ukrainian state register of people who suffered from Chernobyl accident and Ukrainian national cancer registers are the largest population registers in the country, which cover all the territory of Ukraine and contain information on each individual and may serve as source base for epidemiological studies. To solve issues on leukemia and other oncological diseases is recommended to use in complex data of specialized registers of Ukraine. It should be also taken into account necessity of using late registered cases and verifying registered diagnoses.
Likars'ka sprava / Ministerstvo okhorony zdorov'ia Ukrainy 07/2006;
[show abstract][hide abstract] ABSTRACT: The aim of this study was to evaluate significance of VH mutation status for prognosis of B-cell chronic lymphocytic leukemia (B-CLL) patients in comparison with other prognostic markers.
The VH mutation status was evaluated in 43 B-CLL patients by RT-PCR amplification and nucleotide sequencing, and CD38 expression - by two-color FACS analysis. The prognostic influence of VH mutation rate and CD38 expression level was tested by different statistical methods.
The increasing number of advanced cases over the follow-up period, shorter median time from diagnosis to start of second line therapy, worse response to fludarabine treatment, poor survival for early stages B-CLL were found in unmutated versus mutated CLL patients. The significance of CD38 expression for CLL prognosis was revealed as predictor for response for fludarabine treatment and time of progression in advanced stages. The correlation between CD38 expression and VH mutation status was not found.
Simultaneous determination of VH mutation status and CD38 expression may be helpful for prediction of CLL prognosis.
[show abstract][hide abstract] ABSTRACT: The results of multidrug resistance determinants expression analysis on leukemic cells of 56 acute myeloid leukemia (AML) patients by immunophenotyping are presented. Of these, there were 21 persons exposed to ionizing radiation due to the Chemobyl accident with radiation-associated AML and 35 patients with spontaneous leukemia. The aim of this study was to determine if transport proteins (P-glycoprotein, LRP, and MDR1), apoptosis-related proteins (Fas, Bcl-2, Bax, p53, and Bcl-X(L)), and topoisomerase IIalpha expression in AML patients with the history of radiation exposure differed from those in spontaneous AML cases. Leukemic cells in patients with radiation-associated diseases compared to spontaneous AML more often overexpressed antiapoptotic oncoprotein Bcl-2 (12/21 vs. 6/35, p < 0.005) and less often demonstrated expression of Fas receptor (12/21 vs. 30/35, p < 0.05). Moreover, leukemic cells were simultaneously Fas negative and Bcl-2 positive in 4 out of 21 patients exposed to ionizing radiation but none of spontaneous cases had similar phenotype (p < 0.05). Leukemic cells in patients with radiation-associated AML compared to spontaneous cases more often were P-glycoprotein positive (12/20 vs 9/31, p < 0.05). P-glycoprotein overexpression significantly correlated with resistant disease in patients with radiation-associated AML (r = 0.47, p < 0.05), but was not a prognostic variable for the treatment outcome in terms of overall survival. Defects in pathways of drug-induced apoptosis and function of pump, that actively effluxes drugs could contribute significantly to developing drug resistance in radiation-associated AML.
Radiatsionnaia biologiia, radioecologiia / Rossiĭskaia akademiia nauk 01/2006; 46(5):555-62.