MYC copy number and mRNA expression in chronic lymphocytic leukemia patients exposed to ionizing radiation due to the Chornobyl NPP accident.

Some clinical and biological features indicating an unfavorable course of the disease were found in ionizing radiation (IR) - related chronic lymphocytic leukemia (CLL) patients. The MYC proto-oncogene is considered to contribute to CLL pathogenesis. Increased MYC copy number is associated with poor prognosis in CLL. AIM: To investigate the frequency of MYC gene copy number amplification in IR-exposed CLL patients and relate the findings to the MYC mRNA levels, the presence of unfavourable prognosis mutations (TP53, SF3B1, NOTCH1), and patient`s outcome. MATERIALS AND METHODS: The analysis of MYC copy number was carried out by real-time quantitative polymerase chain reaction (PCR) in 70 IR-exposed CLL patients. The MYC mRNA expression was measured by real-time quantitative reverse transcription PCR. RESULTS: Increased MYC gene copy number was present in 5.7% of cases. There was a statistically significant association between increased MYC copy number and increased MYC mRNA (p < 0.014). Additionally, somatic deletion in MYC locus was found in one patient. Most of patients (80%) with detected MYC aberrations were previously untreated, suggesting that these lesions might occur early in the course of the disease. The MYC aberrations were found mutually exclusive with high risk TP53 and SF3B1 mutations, while one case was identified, where MYC amplification and NOTCH1 mutation coincided simultaneously. Regarding clinical outcome, the MYC aberrations were associated with a shorter time to first treatment (3 vs 25 months, p = 0.008) as well as reduced overall survival (60 vs 139 months). CONCLUSION: Our data suggest that MYC aberrations might be an early event in IR-related CLL and contribute to aggressive disease development in the absence of high risk TP53 and SF3B1 mutations.

Usefulness of cancer-free survival in estimating the lifetime attributable risk of cancer incidence from radiation exposure.

Risk projection models estimating the lifetime cancer risk from radiation exposure are generally based on exposure dose, age at exposure, attained age, gender and study-population-specific factors such as baseline cancer risks and survival rates. Because such models have mostly been based on the Life Span Study cohort of Japanese atomic bomb survivors, the baseline risks and survival rates in the target population should be considered when applying the cancer risk. The survival function used in the risk projection models that are commonly used in the radiological protection field to estimate the cancer risk from medical or occupational exposure is based on all-cause mortality. Thus, it may not be accurate for estimating the lifetime risk of high-incidence but not life-threatening cancer with a long-term survival rate. Herein, we present the lifetime attributable risk (LAR) estimates of all solid cancers except thyroid cancer, thyroid cancer, and leukemia except chronic lymphocytic leukemia in South Korea for lifetime exposure to 1 mGy per year using the cancer-free survival function, as recently applied in the Fukushima health risk assessment by the World Health Organization. Compared with the estimates of LARs using an overall survival function solely based on all-cause mortality, the LARs of all solid cancers except thyroid cancer, and thyroid cancer evaluated using the cancer-free survival function, decreased by approximately 13% and 1% for men and 9% and 5% for women, respectively. The LAR of leukemia except chronic lymphocytic leukemia barely changed for either gender owing to the small absolute difference between its incidence and mortality. Given that many cancers have a high curative rate and low mortality rate, using a survival function solely based on all-cause mortality may cause an overestimation of the lifetime risk of cancer incidence. The lifetime fractional risk was robust against the choice of survival function.

Optimisation of chemotherapy and radiotherapy for untreated Hodgkin lymphoma patients with respect to second malignant neoplasms, overall and progression-free survival: individual participant data analysis.

BACKGROUND: Efficacy and the risk of severe late effects have to be well-balanced in treatment of Hodgkin lymphoma (HL). Late adverse effects include secondary malignancies which often have a poor prognosis. To synthesise evidence on the risk of secondary malignancies after current treatment approaches comprising chemotherapy and/or radiotherapy, we performed a meta-analysis based on individual patient data (IPD) from patients treated for newly diagnosed HL. OBJECTIVES: We investigated several questions concerning possible changes in the risk of secondary malignancies when modifying chemotherapy or radiotherapy (omission of radiotherapy, reduction of the radiation field, reduction of the radiation dose, use of fewer chemotherapy cycles, intensification of chemotherapy). We also analysed whether these modifications affect progression-free survival (PFS) and overall survival (OS). SEARCH METHODS: We searched MEDLINE and Cochrane CENTRAL trials databases comprehensively in June 2010 for all randomised trials in HL since 1984. Key international trials registries were also searched. The search was updated in March 2015 without collecting further IPD (one further eligible study found) and again in July 2017 (no further eligible studies). SELECTION CRITERIA: We included randomised controlled trials (RCTs) for untreated HL patients which enrolled at least 50 patients per arm, completed recruitment by 2007 and performed a treatment comparison relevant to our objectives. DATA COLLECTION AND ANALYSIS: Study groups submitted IPD, including age, sex, stage and the outcomes secondary malignant neoplasm (SMN), OS and PFS as time-to-event data. We meta-analysed these data using Petos method (SMN) and Cox regression with inverse-variance pooling (OS, PFS) for each of the five study questions, and performed subgroup and sensitivity analyses to assess the applicability and robustness of the results. MAIN RESULTS: We identified 21 eligible trials and obtained IPD for 16. For four studies no data were supplied despite repeated efforts, while one study was only identified in 2015 and IPD were not sought. For each study question, between three and six trials with between 1101 and 2996 participants in total and median follow-up between 6.7 and 10.8 years were analysed. All participants were adults and mainly under 60 years. Risk of bias was assessed as low for the majority of studies and outcomes. Chemotherapy alone versus same chemotherapy plus radiotherapy. Omitting additional radiotherapy probably reduces secondary malignancy incidence (Peto odds ratio (OR) 0.43, 95% confidence interval (CI) 0.23 to 0.82, low quality of evidence), corresponding to an estimated reduction of eight-year SMN risk from 8% to 4%. This decrease was particularly true for secondary acute leukemias. However, we had insufficient evidence to determine whether OS rates differ between patients treated with chemotherapy alone versus combined-modality (hazard ratio (HR) 0.71, 95% CI 0.46 to 1.11, moderate quality of evidence). There was a slightly higher rate of PFS with combined modality, but our confidence in the results was limited by high levels of statistical heterogeneity between studies (HR 1.31, 95% CI 0.99 to 1.73, moderate quality of evidence). Chemotherapy plus involved-field radiation versus same chemotherapy plus extended-field radiation (early stages) . There is insufficient evidence to determine whether smaller radiation field reduces SMN risk (Peto OR 0.86, 95% CI 0.64 to 1.16, low quality of evidence), OS (HR 0.89, 95% C: 0.70 to 1.12, high quality of evidence) or PFS (HR 0.99, 95% CI 0.81 to 1.21, high quality of evidence). Chemotherapy plus lower-dose radiation versus same chemotherapy plus higher-dose radiation (early stages). There is insufficient evidence to determine the effect of lower-radiation dose on SMN risk (Peto OR 1.03, 95% CI 0.71 to 1.50, low quality of evidence), OS (HR 0.91, 95% CI 0.65 to 1.28, high quality of evidence) or PFS (HR 1.20, 95% CI 0.97 to 1.48, high quality of evidence). Fewer versus more courses of chemotherapy (each with or without radiotherapy; early stages). Fewer chemotherapy courses probably has little or no effect on SMN risk (Peto OR 1.10, 95% CI 0.74 to 1.62), OS (HR 0.99, 95% CI 0.73 to1.34) or PFS (HR 1.15, 95% CI 0.91 to 1.45).Outcomes had a moderate (SMN) or high (OS, PFS) quality of evidence. Dose-intensified versus ABVD-like chemotherapy (with or without radiotherapy in each case). In the mainly advanced-stage patients who were treated with intensified chemotherapy, the rate of secondary malignancies was low. There was insufficient evidence to determine the effect of chemotherapy intensification (Peto OR 1.37, CI 0.89 to 2.10, low quality of evidence). The rate of secondary acute leukemias (and for younger patients, all secondary malignancies) was probably higher than among those who had treatment with standard-dose ABVD-like protocols. In contrast, the intensified chemotherapy protocols probably improved PFS (eight-year PFS 75% versus 69% for ABVD-like treatment, HR 0.82, 95% CI 0.7 to 0.95, moderate quality of evidence). Evidence suggesting improved survival with intensified chemotherapy was not conclusive (HR: 0.85, CI 0.70 to 1.04), although escalated-dose BEACOPP appeared to lengthen survival compared to ABVD-like chemotherapy (HR 0.58, 95% CI 0.43 to 0.79, moderate quality of evidence).Generally, we could draw valid conclusions only in terms of secondary haematological malignancies, which usually occur less than 10 years after initial treatment, while follow-up within the present analysis was too short to record all solid tumours. AUTHORS' CONCLUSIONS: The risk of secondary acute myeloid leukaemia and myelodysplastic syndrome (AML/MDS) is increased but efficacy is improved among patients treated with intensified chemotherapy protocols. Treatment decisions must be tailored for individual patients. Consolidating radiotherapy is associated with an increased rate of secondary malignancies; therefore it appears important to define which patients can safely be treated without radiotherapy after chemotherapy, both for early and advanced stages. For early stages, treatment optimisation methods such as use of fewer chemotherapy cycles and reduced field or reduced-dose radiotherapy did not appear to markedly affect efficacy or secondary malignancy risk. Due to the limited amount of long-term follow-up in this meta-analysis, further long-term investigations of late events are needed, particularly with respect to secondary solid tumours. Since many older studies have been included, possible improvement of radiotherapy techniques must be considered when interpreting these results.

Clinical characteristics of chronic lymphocytic leukemia occurring in chornobyl cleanup workers.

The recently demonstrated radiation-induction of chronic lymphocytic leukemia (CLL) raises the question as to whether the amount of radiation exposure influences any of the clinical characteristics of the disease. We evaluated the relationship between bone marrow radiation doses and clinical characteristics and survival of 79 CLL cases diagnosed during 1986-2006 in a cohort of 110 645 male workers who participated in the cleanup work of the Chornobyl nuclear accident in Ukraine in 1986. All diagnoses were confirmed by an independent International Hematology Panel. Patients were followed up to the date of death or end of follow-up on 31 October 2010. The median age at diagnosis was 57 years. Median bone marrow dose was 22.6 milligray (mGy) and was not associated with time between exposure and clinical diagnosis of CLL (latent period), age, peripheral blood lymphocyte count or clinical stage of disease in univariate and multivariate analyses. Latent period was significantly shorter among those older at first exposure, smokers and those with higher frequency of visits to the doctor prior to diagnosis. A significant increase in the risk of death with increasing radiation dose was observed (p = 0.03, hazard ratio = 2.38, 95% confidence interval: 1.11,5.08 comparing those with doses ≥22 mGy to doses <22 mGy). After adjustment for radiation dose, survival of CLL cases was significantly shorter among those with younger age at first exposure, higher peripheral blood lymphocyte count, more advanced clinical stage of disease and older age at diagnosis (all p < 0.05). This is the first study to examine association between bone marrow radiation doses from the Chornobyl accident and clinical manifestations of the CLL in Chornobyl cleanup workers. The current study provides new evidence on the association of radiation dose and younger age at first radiation exposure at Chornobyl with shorter survival after diagnosis. Future studies are necessary with more cases in order to improve the statistical power of these analyses and to determine their significance. Copyright © 2016 John Wiley & Sons, Ltd.

Chronic Lymphocytic Leukemia in Chornobyl Cleanup Workers.

This paper describes the chronic lymphocytic leukemia (CLL) incidence in a cohort of 110,645 (enlarged later to 152,520) male Ukrainian cleanup workers of the Chornobyl (Chernobyl) accident who were exposed to a range of radiation doses over the 1986-1990 time period. The standardized incidence rates are presented for a 27-y period after the exposure. For 2007-2012 period, the authors have identified the incident CLL cases in an enlarged cohort of 152,520 persons by linkage of the cohort file with the Ukrainian National Cancer Registry (NCRU). CLL data for the previous period (1987-2006) were identified in a frame of the Ukrainian-American leukemia study in the original cohort of 110,645 male clean-up workers. A significant CLL incidence excess was shown for the entire study period 1987-2012, with more prominent levels for the earliest years (1987-1996) when the standardized incidence rate (SIR) value was estimated to be 3.61 with 95% confidence interval from 2.32 to 4.91. In 2007-2012, the CLL incidence decreased substantially but still exceeded the national level although not significantly. In parallel, the several studies were performed at the National Research Center for Radiation Medicine (NRCRM) to explore if any clinical and cytogenetic features of CLL existed in the clean-up workers. The clinical study included 80 exposed and 70 unexposed CLL cases. Among the major clinical differences of the CLL course in the clean-up workers were a shorter period of white blood cells (WBC) doubling (10.7 vs. 18.0; p<0.001), frequent infectious episodes, lymphoadenopathy and hepatosplenomegaly (37 vs. 16), higher expression for CD38, and lower expression for ZAP-70 antigen.

Mortality among military participants at the 1957 PLUMBBOB nuclear weapons test series and from leukemia among participants at the SMOKY test.

Health effects following low doses of ionizing radiation are uncertain. Military veterans at the Nevada test site (NTS) during the SMOKY atmospheric nuclear weapons test in 1957 were reported to be at increased risk for leukemia in 1979, but this increase was not evaluated with respect to radiation dose. The SMOKY test was one of 30 tests in 1957 within the PLUMBBOB test series. These early studies led to public laws where atomic veterans could qualify for compensation for presumptive radiogenic diseases. A retrospective cohort study was conducted of 12219 veterans at the PLUMBBOB test series, including 3020 at the SMOKY nuclear test. Mortality follow-up was through 2010 and observed causes of death were compared with expected causes based on general population rates. Radiation dose to red bone marrow was based on individual dose reconstructions, and Cox proportional hazards models were used to evaluate dose response for all leukemias other than chronic lymphocytic leukemia (non-CLL leukemia). Vital status was determined for 95.3% of the 12 219 veterans. The dose to red bone marrow was low (mean 3.2 mGy, maximum 500 mGy). Military participants at the PLUMBBOB nuclear test series remained relatively healthy after 53 years and died at a lower rate than the general population. In contrast, and in comparison with national rates, the SMOKY participants showed significant increases in all causes of death, respiratory cancer, leukemia, nephritis and nephrosis, and accidents, possibly related in part to lifestyle factors common to enlisted men who made up 81% of the SMOKY cohort. Compared with national rates, a statistically significant excess of non-CLL leukemia was observed among SMOKY participants (Standardized Mortality Ratio = 1.89, 95% 1.24-2.75, n = 27) but not among PLUMBBOB participants after excluding SMOKY (SMR = 0.87, 95% 0.64-1.51, n = 47). Leukemia risk, initially reported to be significantly increased among SMOKY participants, remained elevated, but this risk diminished over time. Despite an intense dose reconstruction, the risk for leukemia was not found to increase with increasing levels of radiation dose to the red bone marrow. Based on a linear model, the estimated excess relative risk per mGy is -0.05 (95% CI -0.14, 0.04). An explanation for the observed excess of leukemia remains unresolved but conceivably could be related to chance due to small numbers, subtle biases in the study design and/or high tobacco use among enlisted men. Larger studies should elucidate further the possible relationship between fallout radiation, leukemia and cancer among atomic veterans.

Childhood CT scans and cancer risk: impact of predisposing factors for cancer on the risk estimates.

To investigate the role of cancer predisposing factors (PFs) on the associations between paediatric computed tomography (CT) scan exposures and subsequent risk of central nervous system (CNS) tumours and leukaemia. A cohort of children who underwent a CT scan in 2000-2010 in 23 French radiology departments was linked with the national childhood cancers registry and national vital status registry; information on PFs was retrieved through hospital discharge databases. In children without PF, hazard ratios of 1.07 (95% CI 0.99-1.10) for CNS tumours (15 cases) and 1.16 (95% CI 0.77-1.27) for leukaemia (12 cases) were estimated for each 10 mGy increment in CT x-rays organ doses. These estimates were similar to those obtained in the whole cohort. In children with PFs, no positive dose-risk association was observed, possibly related to earlier non-cancer mortality in this group. Our results suggest a modifying effect of PFs on CT-related cancer risks, but need to be confirmed by longer follow-up and other studies.

Secondary acute lymphoblastic leukemia is an independent predictor of poor prognosis.

Compared to secondary acute myeloid leukemia, secondary acute lymphoblastic leukemia (sALL) is poorly characterized. We utilized data from the Surveillance, Epidemiology, and End Results (SEER) 13 database to further elucidate patient characteristics and prognostic factors in sALL. Cases of adult de novo acute lymphoblastic leukemia (ALL) and sALL in patients with primary breast, rectum, cervix, or ovarian cancers or lymphoma with a latency period of at least 12 months were identified within the SEER 13 database. Survival in sALL and de novo ALL were compared after propensity matching based on age, gender, race, ALL subtype, and year of diagnosis. 4124 cases of de novo ALL and 79 cases of sALL were identified. sALL patients were older at diagnosis (median 62 years vs. 44 years; p<0.01). Overall survival (OS) in sALL was lower than de novo ALL (median 8 months vs. 11 months), 1 year OS: 35% vs. 47% (p=0.05), 2 year OS: 16% vs. 31% (p<0.01), and 5 year OS: 7% vs. 21% (p<0.01). Multivariate analysis revealed sALL as an independent predictor of worsened survival (adjusted HR 1.54; 95% CI 1.16-2.04, p<0.01) after propensity matching.

Simulation-extrapolation method to address errors in atomic bomb survivor dosimetry on solid cancer and leukaemia mortality risk estimates, 1950-2003.

Analyses of the Life Span Study (LSS) of Japanese atomic bombing survivors have routinely incorporated corrections for additive classical measurement errors using regression calibration. Recently, several studies reported that the efficiency of the simulation-extrapolation method (SIMEX) is slightly more accurate than the simple regression calibration method (RCAL). In the present paper, the SIMEX and RCAL methods have been used to address errors in atomic bomb survivor dosimetry on solid cancer and leukaemia mortality risk estimates. For instance, it is shown that using the SIMEX method, the ERR/Gy is increased by an amount of about 29 % for all solid cancer deaths using a linear model compared to the RCAL method, and the corrected EAR 10(-4) person-years at 1 Gy (the linear terms) is decreased by about 8 %, while the corrected quadratic term (EAR 10(-4) person-years/Gy(2)) is increased by about 65 % for leukaemia deaths based on a linear-quadratic model. The results with SIMEX method are slightly higher than published values. The observed differences were probably due to the fact that with the RCAL method the dosimetric data were partially corrected, while all doses were considered with the SIMEX method. Therefore, one should be careful when comparing the estimated risks and it may be useful to use several correction techniques in order to obtain a range of corrected estimates, rather than to rely on a single technique. This work will enable to improve the risk estimates derived from LSS data, and help to make more reliable the development of radiation protection standards.

A prognostic model of therapy-related myelodysplastic syndrome for predicting survival and transformation to acute myeloid leukemia.

INTRODUCTION/BACKGROUND: We evaluated the characteristics of a cohort of patients with myelodysplastic syndrome (MDS) related to therapy (t-MDS) to create a prognostic model. PATIENTS AND METHODS: We identified 281 patients with MDS who had received previous chemotherapy and/or radiotherapy for previous malignancy. Potential prognostic factors were determined using univariate and multivariate analyses. RESULTS: Multivariate Cox regression analysis identified 7 factors that independently predicted short survival in t-MDS: age ≥ 65 years (hazard ratio [HR], 1.63), Eastern Cooperative Oncology Group performance status 2-4 (HR, 1.86), poor cytogenetics (-7 and/or complex; HR, 2.47), World Health Organization MDS subtype (RARs or RAEB-1/2; HR, 1.92), hemoglobin (< 11 g/dL; HR, 2.24), platelets (< 50 × 10(9)/dL; HR, 2.01), and transfusion dependency (HR, 1.59). These risk factors were used to create a prognostic model that segregated patients into 3 groups with distinct median overall survival: good (0-2 risk factors; 34 months), intermediate (3-4 risk factors; 12 months), and poor (5-7 risk factors; 5 months) (P < .001) and 1-year leukemia-free survival (96%, 84%, and 72%, respectively, P = .003). This model also identified distinct survival groups according to t-MDS therapy. CONCLUSION: In summary, we devised a prognostic model specifically for patients with t-MDS that predicted overall survival and leukemia-free survival. This model might facilitate the development of risk-adapted therapeutic strategies.

The risk of childhood leukaemia following exposure to ionising radiation--a review.

Since the early years of follow-up of the Japanese atomic-bomb survivors, it has been apparent that childhood leukaemia has a particular sensitivity to induction by ionising radiation, the excess relative risk (ERR) being expressed as a temporal wave with time since exposure. This pattern has been generally confirmed by studies of children treated with radiotherapy. Case-control studies of childhood leukaemia and antenatal exposure to diagnostic x-rays, a recent large cohort study of leukaemia following CT examinations of young people, and a recent large case-control study of natural background γ-radiation and childhood leukaemia have found evidence of raised risks following low-level exposure. These findings indicate that an ERR/Sv for childhood leukaemia of ~50, which may be derived from risk models based upon the Japanese atomic-bomb survivors, is broadly applicable to low dose or low dose-rate exposure circumstances.

A reanalysis of curvature in the dose response for cancer and modifications by age at exposure following radiation therapy for benign disease.

PURPOSE: To assess the shape of the dose response for various cancer endpoints and modifiers by age and time. METHODS AND MATERIALS: Reanalysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by cancer endpoint (stomach, pancreas, lung, leukemia, all other). RESULTS: There are statistically significant (P<.05) excess risks for all cancer and for lung cancer and borderline statistically significant risks for stomach cancer (P=.07), and leukemia (P=.06), with excess relative risks Gy(-1) of 0.024 (95% confidence interval [CI] 0.011, 0.039), 0.559 (95% CI 0.221, 1.021), 0.042 (95% CI -0.002, 0.119), and 1.087 (95% CI -0.018, 4.925), respectively. There is statistically significant (P=.007) excess risk of pancreatic cancer when adjusted for dose-response curvature. General downward curvature is apparent in the dose response, statistically significant (P<.05) for all cancers, pancreatic cancer, and all other cancers (ie, other than stomach, pancreas, lung, leukemia). There are indications of reduction in relative risk with increasing age at exposure (for all cancers, pancreatic cancer), but no evidence for quadratic variations in relative risk with age at exposure. If a linear-exponential dose response is used, there is no significant heterogeneity in the dose response among the 5 endpoints considered or in the speed of variation of relative risk with age at exposure. The risks are generally consistent with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers. CONCLUSIONS: There are excess risks for various malignancies in this data set. Generally there is a marked downward curvature in the dose response and significant reduction in relative risk with increasing age at exposure. The consistency of risks with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.

Integrating informative priors from experimental research with Bayesian methods: an example from radiation epidemiology.

Informative priors can be a useful tool for epidemiologists to handle problems of sparse data in regression modeling. It is sometimes the case that an investigator is studying a population exposed to two agents, X and Y, where Y is the agent of primary interest. Previous research may suggest that the exposures have different effects on the health outcome of interest, one being more harmful than the other. Such information may be derived from epidemiologic analyses; however, in the case where such evidence is unavailable, knowledge can be drawn from toxicologic studies or other experimental research. Unfortunately, using toxicologic findings to develop informative priors in epidemiologic analyses requires strong assumptions, with no established method for its utilization. We present a method to help bridge the gap between animal and cellular studies and epidemiologic research by specification of an order-constrained prior. We illustrate this approach using an example from radiation epidemiology.

Leukemia risk associated with chronic external exposure to ionizing radiation in a French cohort of nuclear workers.

Leukemia is one of the earliest cancer effects observed after acute exposure to relatively high doses of ionizing radiation. Leukemia mortality after external exposure at low doses and low-dose rates has been investigated at the French Atomic Energy Commission (CEA) and Nuclear Fuel Company (AREVA NC) after an additional follow-up of 10 years. The cohort included radiation-monitored workers employed for at least one year during 1950-1994 at CEA or AREVA NC and followed during 1968-2004. Association between external exposure and leukemia mortality was estimated with excess relative risk (ERR) models and time-dependent modifying factors were investigated with time windows. The cohort included 36,769 workers, followed for an average of 28 years, among whom 73 leukemia deaths occurred. Among the workers with a positive recorded dose, the mean cumulative external dose was 21.7 mSv. Results under a 2-year lag assumption suggested that the risk of leukemia (except chronic lymphatic leukemia) increased significantly by 8% per 10 mSv. The magnitude of the association for myeloid leukemia was larger. The higher ERR/Sv for doses received 2-14 years earlier suggest that time since exposure modifies the effect. The ERR/Sv also appeared higher for doses received at exposure rates ≥20 mSv per year. These results are consistent with those found in other studies of nuclear workers. However, confidence intervals are still wide. Further analyses should be conducted in pooled cohorts of nuclear workers.

H-ferritin overexpression promotes radiation-induced leukemia/lymphoma in mice.

H-ferritin (HF) is a core subunit of the iron storage protein ferritin and is related to the pathogenesis of malignant diseases. HF overexpression is present in human hematologic malignancies, suggesting that HF overexpression may contribute to the development of hematologic cancers. However, in vivo evidence that HF is directly linked to hematologic tumorigenesis has not yet been shown. In this study, we show that transgenic (tg) mice overexpressing the human HF gene (hHF-tg) developed aggressive radiation-induced thymic lymphoma/leukemia (TL) compared with wild-type (WT) mice, providing evidence that HF overexpression promotes leukemia/lymphomagenesis. Fractionated X-irradiation of hHF-tg mice caused a higher incidence and earlier onset of TL compared with WT mice. Immunological and pathological features of TLs were similar in both groups. However, proliferative activity of hHF-tg lymphoma cells was higher than that of WT lymphoma cells, and microarray analyses revealed that some leukemia/lymphoma-related genes were differentially expressed in hHF-tg TLs compared with WT TLs. To investigate whether cell damage induced by irradiation is related to leukemia/lymphomagenesis, we evaluated apoptotic levels in the thymus and bone marrow (BM) of hHF-tg and WT groups after fractionated X-irradiation. Apoptosis was augmented in the hHF-tg BM, but not in the thymus, compared with the WT BM, suggesting a possible linkage between increased BM apoptosis by HF overexpression and accelerated radiation-induced TL development. Our findings indicate that HF overexpression is closely related to the development of leukemia/lymphoma, which could have implications for the prevention of malignant hematologic diseases.

[Mortality study among veterans with dosimeter monitoring during the French nuclear tests in the Pacific]. / Étude de mortalité des vétérans ayant bénéficié d'une surveillance dosimétrique lors des essais nucléaires français dans le Pacifique.

BACKGROUND: A mortality study was carried out in a cohort of veterans present on the sites of the French nuclear experiments center in the Pacific (CEP) from 1966 to 1996, and for whom external dosimeter monitoring recordings were available. METHODS: The cohort included 32,550 veterans having had at least one dosimetry recording. Current vital status was collected from the National Register of Identification of Physical People and causes of death data from the national causes of death database. Total mortality and mortality by cause were compared with mortality of the French population using standardized mortality ratios (SMR). To test the effect of a dosimeter recording higher than the threshold (0.2 mSv), i.e., no null dosimetry, the mortality of veterans was compared inside the cohort, using standardized ratios and Poisson regression models. RESULTS: The mortality analysis was performed among 26,524 men, of whom 8% had had at least one non-null dosimeter. Five thousand four hundred and ninety-two (21%) veterans died before December 31, 2008 and causes were available for nearly 97% of these deaths. Comparing the mortality between the cohort and the French population highlighted a deficit of mortality, for all causes, by cancer and for radiation-induced pathologies; these results were related to the "healthy worker effect". The data showed that all causes mortality and cancer mortality of the cohort of veterans with no null dosimeter were not different from those of other veterans, but also showed an excess of hematological malignancies in this sub-population: this excess was significant in the regression model (RR=1.82; CI 95% [1.6-2.0]). CONCLUSION: Among veterans with an external dosimeter monitoring recording, presence on the sites of CEP from 1966 to 1996 does not constitute a factor of increased mortality compared with the national population. However, an increased risk was observed for mortality by hematological malignancies among veterans with no null dosimetry. This result is in line with studies on veterans present during nuclear experiments abroad.

Ionizing radiation and leukemia mortality among Japanese Atomic Bomb Survivors, 1950-2000.

This paper provides the first comprehensive report on mortality by type of leukemia among the Japanese atomic bomb survivors in the Life Span Study (LSS). Analyses include 310 deaths due to leukemia during the period 1950-2000 among 86,611 people in the LSS. Poisson regression methods were used to evaluate associations between estimated bone marrow dose and leukemia mortality. Attention was given to variation in the radiation dose-leukemia mortality association by time since exposure, age at exposure, city and sex. The excess relative rate per gray of acute myeloid leukemia was best described by a quadratic dose-response function that peaked approximately 10 years after exposure. Acute lymphatic leukemia and chronic myeloid leukemia mortality were best described by a linear dose-response function that did not vary with time since exposure. Adult T-cell leukemia was not associated with estimated bone marrow dose. Overall, 103 of the 310 observed leukemia deaths were estimated to be excess deaths due to radiation exposure. In the most recent decade of observation (1991-2000), the estimated attributable fraction of leukemia deaths among those survivors exposed to >0.005 Gy was 0.34, suggesting that the effect of the atomic bombings on leukemia mortality has persisted in this cohort for more than five decades.