This study investigated cytogenetic damage in peripheral blood lymphocytes of 10 differentiated thyroid cancer patients who received multiple 131I radioiodine (RAI) treatments following total thyroidectomy. Blood samples were collected before the RAI therapy course and 2-3 days after the course for a few selected courses (from 1 to 3) for each patient. The cumulative average number of chromosome aberrations (CAs) per cell and its increment due to a selected RAI course were evaluated using the multiplex fluorescence in situ hybridization method (mFISH). An increase in the number of CAs was observed with the accumulation of RAI activity. The yield of these CAs per unit of accumulated RAI activity was, however, approximately three-fold lower than the respective yield for the incremented number of CAs in a selected course, thus demonstrating the elimination of CAs and/or aberrant cells with time. Biological dosimetry was performed based on the number of all types of CAs and in vitro mFISH calibration curves. With an average administered RAI activity of 3.40 ± 0.39 GBq, the average absorbed blood dose was 0.61 Gy (0.31-0.89:95% CI). Our results demonstrate that one-time administration of such activities of RAI was safe, since the commonly accepted threshold of 2 Gy for the blood dose was not exceeded.

The risk of toxicity attributable to radioiodine therapy (RIT) remains a subject of ongoing research, with a whole-body dose of 2 Gy proposed as a safe limit. This article evaluates the RIT-induced cytogenetic damage in two rare differentiated thyroid cancer (DTC) cases, including the first follow-up study of a pediatric DTC patient. Chromosome damage in the patient's peripheral blood lymphocytes (PBL) was examined using conventional metaphase assay, painting of chromosomes 2, 4, and 12 (FISH), and multiplex fluorescence in situ hybridization (mFISH). Patient 1 (female, 1.6 y.o.) received four RIT courses over 1.1 years. Patient 2 (female, 49 y.o.) received 12 courses over 6.4 years, the last two of which were examined. Blood samples were collected before and 3-4 days after the treatment. Chromosome aberrations (CA) analyzed by conventional and FISH methods were converted to a whole-body dose accounting for the dose rate effect. The mFISH method showed an increase in total aberrant cell frequency following each RIT course, while cells carrying unstable aberrations predominated in the yield. The proportion of cells containing stable CA associated with long-term cytogenetic risk remained mostly unchanged during follow-up for both patients. A one-time administration of RIT was safe, as the threshold of 2 Gy for the whole-body dose was not exceeded. The risk of side effects projected from RIT-attributable cytogenetic damage was low, suggesting a good long-term prognosis. In rare cases, such as the ones reviewed in this study, individual planning based on cytogenetic biodosimetry is strongly recommended.

This paper presents the results of the study of long-term effect of radiation therapy on patients with different types of cancer. The aim of the retrospective study was to evaluate effect of external beam radiation therapy (EBRT) for improving rehabilitation effectiveness. To estimate the effect a cytogenetic analysis of chromosomal aberrations in peripheral blood lymphocytes was performed. The group included patients for whom clarification, confirmation or refutation of the total focal dose (TFD) indicated in the epicrisis after EBRT was required. A group of 25 patients (5 males and 20 females) was examined. The patients had different types of cancer: Hodgkin’s lymphoma, cancer of breast and prostate glands, cervical and uterine cancers, bone cancer and multisite cancer. All examined patients underwent rehabilitation in the department of surgical and conservative treatment of radiation Injuries of A. Tsyb MRRC. For examination patient’s blood lymphocytes were stained followed by fluorescence or light microscopy to image first mitosis cells. To detect aberrations chromosome preparations with stained chromosomes 2, 4, and 12 were subjected to FISH analysis. Chromosomal aberration analysis was also used for dose assessment in accordance with IAEA recommendations. As a result, it was shown that the individual response of patients varies significantly under irradiation schemes comparable in terms of total dose and fractionation. A significant role is played by the factor of the time interval between the end of EBRT and the cytogenetic analysis (∆T). There was a clear excess of the observed frequency of aberrations in the first decade after EBRT compared with the subsequent time. The work did not reveal any dependence between the total frequency of aberrations, as well as its components, on the type of cancer disease. According to the preliminary conclusion, there is a basis for applying obtained estimates of the dose coefficient for retrospective biodosimetry of patients with the diseases listed in the group. The revealed patterns of chromosomal damage induction in blood lymphocytes of cancer patients prove the need for a personalized approach to planning and implementing a radical course of therapy in order to increase its effectiveness and prevent side effects.

The radioiodine therapy is the most well-known branch of radionuclide therapy. The therapy composed of thyroidectomy and iodine-131 radiopharmaceutical is the “gold standard” for treat-ment of differentiated thyroid cancer patients (DTC). Given metastases in lymph nodes such therapy is absolutely exclusive treatment mode. At the same time, despite the targeted effect of radioiodine on pathological foci a side internal exposure of healthy organs and tissues is noted in the course of radioiodine therapy. Therefore, a reliable assessment of the side exposure is nec-essary taking into account the individual characteristics of patients considering that the side dose varies significantly from patient to patient. For this reason, the identification of significance of personal clinic-diagnostic factors determined the side whole body exposure is the vital and im-portant task. In this aspect, the cytogenetic examination of DTC patients by means of the analysis of chromosomal aberrations in peripheral blood lymphocytes is the goal of essential importance. The certain types of chromosomal aberrations are specific radiation markers that unequivocally indicate radiation exposure. Using the frequency of radiation markers the side absorbed dose can be reliably estimated. In the present work, the statistical analysis of the significance of vari-ous clinic-diagnostic factors in relation to the induction of radiation markers in the blood lympho-cytes was performed. For that end the results of the cytogenetic examination of the group com-prised of 38 DTC patients have been used. The examined patients underwent a course of radio-iodine therapy in the department of radionuclide therapy of the A.F. Tsyb MRRC, Obninsk. The slide preparation and cytogenetic analysis were carried out in the laboratory of radiation cytoge-netic of the same Center. The performed analysis of the correlation matrix with respect to the dependence of the increased frequency of stable and unstable markers resulted from a one-time course of radioiodine therapy showed no meaningfulness at the level R>0.3 for all the studied factors. For the absolute value of the frequency of radiation markers, both before and after radioiodine therapy, the meaningful relationship was found at the level R>0.7 for unsta-ble and at the level R>0.8 for stable markers with a total administered activity of radioiodine dur-ing all the previous courses of radioiodine therapy.

Radical surgery is the mainstay for differentiated thyroid cancer, radioiodine therapy followed by the surgery is the “gold standard” treatment modality indicated after the surgery. Radioiodine therapy becomes practically non-alternative treatment for patients with distant metastases. How-ever, orally administered radioiodine may be also absorbed into the bloodstream and can dam-age surrounding normal organs and tissues and cause side effect. To test radioiodine therapy safety side effects of the radionuclide on somatic cells should be accurately assessed. In addi-tion, external beam radiotherapy can also damage adjacent normal organs and tissues and thereby increases radioiodine therapy side effect. It is possible to evaluate patient-specific total radiation dose with the use of cytogenetic assay of chromosome aberrations level in peripheral blood lymphocytes because some types of chromosome aberrations are specific radiation mark-ers clearly indicating that the cells have been exposed to radiation. Radiation absorbed dose can be estimated by the number of the aberrations occurrence frequency, and the value of side radia-tion dose greatly depends on a patient personality. In this case peripheral blood lymphocytes are thought of as a model of somatic and bone marrow cells. The paper present results of application of cytogenetic assay for estimating side effects caused by exposure of adjacent organs and tis-sues to external beam radiotherapy and surrounding somatic cells to radioiodine therapy. Results of statistical analysis of external beam radiotherapy related side effect contribution to the total side effect are present in the paper. The joint group of 43 patients was involved in the study, all patients received radioiodine therapy and 5 of them received also external beam radiotherapy in addition to radioiodine therapy. All patents received radioiodine therapy in the Radionuclide Therapy Department, A. Tsyb MRRC in Obninsk. Cytogenetic assay was carried out in the Radia-tion Cytogenetics Laboratory, A. Tsyb MRRC. Results of the study and examination of regularities of radioiodine therapy and external beam radiotherapy related side effects development make it evident that patients received combining radioiodine therapy and external beam radiotherapy should present special group with the treatment plan different from that for the radioiodine thera-py exposed group. Exposure to external radiation may cause not only significant overestimation but also a false-positive underestimation of the number of radiation-specific markers because of lymphocytes inhibition following exposure to high total radiation dose. Inhibition effect may be a result of overestimating multiple radioiodine therapy administrations to achieve total I-131 activity (Σact) exceeds 1200 mCi. The absolute value of the total focal radiotherapy dose is probably ir-relevant. In general, patients assigned to both radioiodine therapy and external beam radiothera-py require personalized approach to treatment.

Оценка последствий дистанционной лучевой терапии у больных раком лёгкого путём анализа хромосомных аберраций в лимфоцитах крови Хвостунов И.К. 1 , Курсова Л.В. 1 , Севанькаев А.В. 1 , Рагулин Ю.А. 1 , Шепель Н.Н. 1 , Коровчук О.Н. 1 , Пятенко В.С. 1,2, Хвостунова Т

The group of radiation victims who had received radiation injures similar to those of Chernobyl accident victims was evaluated in terms of retrospective cytogenetic biodosimetry in the long term period of from 17 y up to 50 y after irradiation. Based on the existing results of the long-term cytogenetic examination of the victims injured after the Chernobyl accident, an original method was developed. This method of retrospective dose recovery was based on the use of a special computer program, the time elapsed after irradiation and the frequency of atypical chromosomes. Both patient groups were examined using conventional cytogenetic analysis. The new method of a retrospective biodosimetry was tested on the non-Chernobyl group. As a result the multiple regression equations which included frequency atypical chromosomes produced better results because the majority of the estimates of the retrospective doses fell into the 95%-prediction intervals for the reference group of the Chernobyl victims.

The development of hemoblastosis is often associated with the influence of various genotoxic unfavorable factors, in particular, with the effect of ionizing radiation. This article presents a case report of acute myeloid leukemia (AML) in a patient who was involved in the 1986 accident at the Chernobyl Nuclear Power Plant and suffered an acute radiation syndrome of degree II severity. Based on clinical and cytogenetic dosimetry, the average absorbed radiation dose to the whole body was estimated to be 4.3 Gy. During long-term clinical follow-up (27 years), moderate transient instability of hematological parameters was observed: lymphocytosis, leukopenia and thrombocytopenia, which was associated with chronic viral hepatitis C. Further cytogenetic investigations demonstrated a very high frequency of translocations, up to 50 times background values, that persisted over 3 decades. In 2014, the patient was diagnosed and operated on for prostate cancer and received a course of radiotherapy (total fractionated local dose of 35 Gy) in May 2015. From December 2015 through April 2016, the patient experienced general weakness and developed progressive cytopenia. A diagnosis of AML, resulting from a myelodysplastic syndrome, was confirmed by abnormal complex clones detected in 38% of metaphases by the mFISH-method, along with other chromosomal rearrangements. The patient underwent several chemotherapy treatments for AML but eventually died of bilateral pneumonia in March 2017.

The experimental observations demonstrate that different cell lines reveal various shape of dynamic curves for radiation-induced chromosomal instability (RICI). We analyzed our own and published data on RICI for three cell lines, CHO-K1, V79 and TK6, on the basis of the mechanistic RICI model. We demonstrate that all three dynamic curves can be successfully described by the proposed model with partially cell line specific parameters.

This study set out to investigate chromosomal damage in peripheral blood lymphocytes of thyroid cancer patients receiving 131I for thyroid remnant ablation or treatment of metastatic disease. The observed chromosomal damage was further converted to the estimates of whole-body dose to project the adverse side effects. Chromosomal aberration analysis was performed in 24 patients treated for the first time or after multiple courses. Blood samples were collected before treatment and 3 or 4 days after administration of 2–4 GBq of 131I. Both conventional cytogenetic and chromosome 2, 4 and 12 painting assays were used. To account for dose-rate effect, a dose-protraction factor was applied to calculate the whole-body dose. The mean dose was 0.62 Gy (95% CI: 0.44–0.77 Gy) in the subgroup of patients treated one time and 0.67 Gy (95% CI: 0.03–1.00 Gy) in re-treated patients. These dose estimates are about 1.7-fold higher than those disregarding the effect of exposure duration. In re-treated patients, the neglected dose-rate effect can result in underestimation of the cumulative whole-body dose by the factor ranging from 2.6 to 6.8. Elevated frequency of chromosomal aberrations observed in re-treated patients before radioiodine therapy allows estimation of a cumulative dose received from all previous treatments.

Different cell lines demonstrate various dose response for radiation-induced chromosomal instability (RICI). To clarify the origin of differences we analyzed own and published data on RICI for four cell lines, V79, TK6, WTK1 and CHO-K1 on the basis of the mechanistic RICI model. We conclude that observable dose-response shapes, both plateau-like and strong dose dependent behavior, may be jointly explained by the same model of RICI. Mechanistic modeling reveals that a variation of certain set of RICI parameters leads to strong modification of dose-response curve.

The authors present data of prolonged clinical observation of patient underwent relatively uniform radiation exposure (4,3 Gy). Stable RBC and WBC counts within normal ranges were seen over 27 years. Neutrophils count transitory exceeded normal values probably due to exacerbation of chronic diseases in the patient (chronic tonsillitis and chronic bronchitis). Lymphocyte and platelet conts were the least stable: frequent lymphocytosis, lymphopenia and nearly constant (over 27 years) transitory moderate thrombocytopenia. Usually thrombocytopenia was considered as a manifestation of chronic persistent hepatitis. Cytogenetic studies of peripheral lymphocytes cultures via trichromatic FISH-method demonstrated presence of high levels of translocations - that indicates their presence in other cell lines and could be a source of malignant transformation. The discussion section considers various ways of leucosis clone formation. The conclusion stresses that the studied leucemia case is a polyethiologic disease with undoubtfully high contribution of accidental radiation exposure.

The purpose of this study was to compare cytogenetic data in a patient before and after treatment with radioiodine to evaluate the assays in the context of biological dosimetry. We studied a 34-year-old male patient who underwent a total thyroidectomy followed by ablation therapy with (131)I (19.28 GBq) for a papillary thyroid carcinoma. The patient provided blood samples before treatment and then serial samples at monthly intervals during the first year period and quarterly intervals for 5 years and finally 20 years after treatment. A micronucleus assay, dicentric assay, FISH method and G-banding were used to detect and measure DNA damage in circulating peripheral blood lymphocytes of the patient. The results showed that radiation-induced cytogenetic effects persisted for many years after treatment as shown by elevated micronuclei and chromosome aberrations as a result of exposure to (131)I. At 5 years after treatment, the micronucleus count was tenfold higher than the pre-exposure frequency. Shortly after the treatment, micronucleus counts produced a dose estimate of 0.47 ± 0.09 Gy. The dose to the patient evaluated retrospectively using FISH-measured translocations was 0.70 ± 0.16 Gy. Overall, our results show that the micronucleus assay is a retrospective biomarker of low-dose radiation exposure. However, this method is not able to determine local dose to the target tissue which in this case was any residual thyroid cells plus metastases of thyroidal origin.

April 26, 2016 marks 30 years since the Chernobyl accident. As a result of this catastrophic event, more than 200,000 km2 were subjected to levels of radioactive deposits exceeding 37 kBq/m2 of 137Cs, the cut-off level to classify an area as contaminated [ [1] Bernhardsson C. Raaf C.L. Mattsson S. Spatial variability of the dose rate from 137Cs fallout in settlements in Russia and Belarus more than two decades after the Chernobyl accident. J Environ Radioact. 2015; 149: 144-149 Crossref PubMed Scopus (13) Google Scholar ]. As an immediate aftermath of the accident, two fatalities occurred among employees while 134 power plant employees and emergency workers were diagnosed with an acute radiation syndrome resulting in 28 deaths [ [2] UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) Health effects due to radiation from the Chernobyl accident. Annex D of the UNSCEAR 2008: sources and effects of ionizing radiation. Vol II. United Nations, 2011 Google Scholar ]. Following the accident, a significant clean-up operation was undertaken, as well as building the "sarcophagus" – a structure to contain the crippled building. The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) 2008 report summarized effective doses for 530,000 recovery operation workers which were received primarily from external irradiation [ [2] UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) Health effects due to radiation from the Chernobyl accident. Annex D of the UNSCEAR 2008: sources and effects of ionizing radiation. Vol II. United Nations, 2011 Google Scholar ]. The average effective dose was estimated at 120 mSv with recorded doses varying from <10 mSv to >1 Sv, with uncertainties as large as factor of five [ [2] UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) Health effects due to radiation from the Chernobyl accident. Annex D of the UNSCEAR 2008: sources and effects of ionizing radiation. Vol II. United Nations, 2011 Google Scholar ]. Doses to residents of the contaminated areas and evacuees primarily resulted from exposure to short-lived 131I (half-life 8 days) and long-lived 137Cs (half-life 30 years). The UNSCEAR 2008 report also presented thyroid and effective doses for 115,000 evacuees and 6,400,000 inhabitants of the contaminated areas [ [2] UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) Health effects due to radiation from the Chernobyl accident. Annex D of the UNSCEAR 2008: sources and effects of ionizing radiation. Vol II. United Nations, 2011 Google Scholar ] in Belarus, Russian Federation and Ukraine. The particular attention to thyroid dose was motivated by the observed excess incidence of thyroid cancer in individuals who were 18 years or younger at the time of the accident and were exposed to 131I. Average dose to the thyroid among evacuees was estimated at 0.5 Gy ranging from <50 mGy to >5 Gy. For the residents of contaminated areas the average dose was 100 mGy although a small (<1%) proportion of individuals received >1 Gy. As of 2010, there were approximately 7000 reported cases of thyroid cancer in individuals exposed prenatally, as children or adolescents in Ukraine alone [ [3] Tronko M. Shpak V. Bogdanova T. Saenko V. Yamashita V. Epidemiology of thyroid cancer in Ukraine after Chernobyl. in: Tronko M. Bogdanova T. Saenko V. Thomas G.A. Likhtarev I. Yamashita S. Thyroid cancer in Ukraine after Chernobyl. IN-TEX, Nagasaki2014: 39-64 Google Scholar ], and a significant dose–response for the induction of cancer has been reported [ [4] Cardis E. Kesminiene A. Ivanov A. et al. Risk of thyroid cancer after exposure to 131I in childhood. J Natl Cancer Inst. 2005; 18: 724-732 Crossref Scopus (451) Google Scholar ]. While the background annual incidence of thyroid cancer among children 10 years old or younger is 2–4 per million, the crude annual incidence for children in this age group (at time of diagnosis) in Belarus reached approximately 34 per million among girls and 18 among boys during 1991–1995. Notably, the incidence for children born after 1986 who were 10 years or younger at diagnosis agreed with background levels, for 1996–2000 and 2001–2005 periods of observation, thus linking excess thyroid cancer to radiation exposure [ [2] UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) Health effects due to radiation from the Chernobyl accident. Annex D of the UNSCEAR 2008: sources and effects of ionizing radiation. Vol II. United Nations, 2011 Google Scholar ].

The method for retrospective dose assessment based on the analysis of cell distribution by the number of dicentrics and unstable aberrations using a special computer program was earlier developed based on the data about the persons irradiated as a result of the accident at the Chernobyl nuclear power plant. This method was applied for the same purpose for data processing of repeated cytogenetic studies of the patients exposed to γ-, γ-β- or γ-neutron radiation in various situations. As a whole, this group was followed up in more distant periods (17-50 years) after exposure than Chernobyl patients (up to 25 years). The use for retrospective dose assessment of the multiple regression equations obtained for the Chernobyl cohort showed that the equation, which includes computer recovered estimate of the dose and the time elapsed after irradiation, was generally unsatisfactory (r = 0.069 at p = 0.599). Similar equations with recovered estimate of the dose and frequency of abnormal chromosomes in a distant period or with all three parameters as variables gave better results (r = 0.686 at p = 0.000000001 and r = 0.542 at p = 0.000008, respectively).