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Individual retrospective dosimetry was developed at A. Tsyb Medical Radiological Research Centre (A. Tsyb MRRC) after the Chernobyl accident for assessment and analysis of radiation effects on people lived in radioactively contaminated settlements in the Kaluga and Bryansk regions. The method was also used in radiation epidemiology case-control studies within frames of international pilot projects. The ob-tained data demonstrated reliable dose-response relationship for thyroid cancer in patients with diag-nosed thyroid cancer, who were children and adolescents at the time of the accident and resided in radi-oactively contaminated areas in the Bryansk region. The dose-response relationship for diagnosed inva-sive breast cancer was found in women, resided in radioactively contaminated settlements since the acci-dent till the first diagnosis of cancer that was established within the period from October 2008 to February 2013. Their age at diagnosis was under 55 years. At the same time, no dose-response relationship for leu-kaemia was found in children under 5 years old at the time of the accident. The individual retrospective dosimetry method has been updated and used in pilot studies for verifying conservative estimates of radi-ation doses to the population exposed to radiation as a result of nuclear tests at the Semipalatinsk nuclear test site, as well as for verifying estimates of external radiation doses to people affected by the accident at the Fukushima Daiichi NPP. The method was also used for estimating individual doses from residual radi-oactivity for the survivors of the Hiroshima and Nagasaki atomic bombings. The long-term collaboration continues under bilateral International Collaboration Agreements between the National Medical Research Radiological Centre and leading research centres in the Republic of Kazakhstan and Japan. Since 2016 researchers and physicians of A. Tsyb MRRC have modi-fied method of stimulated luminescence of natural and synthetic materials and developed innovative technology in vivo dosimetry that has been put into clinical practice for estimating spatial radiation doses distribution in internal organs at risk during the brachytherapy of prostate cancer, gynecologic and recur-rent pelvic tumors, as well as for estimating local radiation dose to the skin of the breast gland with the tumor. The 35-year experience in the development and application of methods for individual retrospective dosimetry after the Chernobyl accident formed the basis for identifying future-pointing trends for the de-velopment of novel applications of stimulated luminescence techniques. Radiation-induced stimulated luminescence dosimetry can be applicable in uncontrolled radiation events; retrospective dosimetry method applicable for neutron beam radiation therapy is under development. The method of in vivo do-simetry is useful in radiation oncology. Now assembled thermoluminiscent micro-sized dosimeters are used for arterial radioembolization. At present, feasibility of using items of clothing and special inserts (buttons, fastenings, etc.), parts of wearable electronic devices as natural dosimeters, as well as the feasi-bility of using luminescent microdosimeters, made of different materials, after exposure to high LET radiation ranged from a fraction of mGy to the dose greater than 60 Gy have been examined. Development of flexible planar microdosimeter assemblies in order to obtain more detailed information about possible discrepancy in distribution of planned and actual radia-tion doses to patients during radiotherapy is considered.

Numerous studies have proven the high resistance of cancer stem cells (CSCs) to a single-dose low-LET ionizing radiation exposure in vitro. These data are the basis for the assumption about the important role of CSCs in cancer recurrence after conventional radiation therapy. However, the patterns and mechanisms of fractionated radiation effects on this population of cells have not been studied enough, and there are only a few publications regarding cervical cancer. Therefore, the purpose of this work is to elucidate the quantitative changes in the CSC population after low-LET radiation exposure using the conventional fractionation regimen in vitro (in cervical cancer cell lines HeLa and SiHa) and in vivo (in cervical scrapings from patients with squamous cell cervical cancer during radiation therapy). Using flow cytometry, the proportion of CSCs was measured in these cell lines after each dose fraction until a cumulative dose of 10 Gy was reached, and in clinical samples of 26 patients before treatment and after irradiation at a cumulative dose of 10 Gy to point A. CSCs were identified in cell cultures by the ability of these cells to pump out the fluorescent dye Hoechst 33 342 and form a side population (SP) and in cervical scrapings by the CD44+CD24low immunophenotype. A statistically significant increase in the proportion of CSCs was found after fractionated irradiation of cervical cell cultures in the range of 2–10 Gy, as compared with the nonirradiated control. High individual variability in the proportion of CD44+CD24low CSCs was detected in cervical scrapings before treatment and after radiation exposure. An irradiation-induced increase in this indicator was observed in 38% of patients; in other patients, a decrease in this indicator was found after irradiation at a cumulative dose of 10 Gy or its preservation at the initial level. A high inverse correlation was observed between the CSC proportion before treatment with its change after irradiation (R = –0.71; p < 0.0001). The results indicate significant individual differences in the response of cervical CSCs to radiation treatment and substantiate the fundamental possibility of further investigation of the prognostic significance of CSC quantitative changes after the first sessions of radiotherapy with regard to the short- and long-term results of treatment.

The presence of virus DNA integration into the cell genome was studied for 47 primary HPV16-positive patients with morphologically verified stage III cervical cancer. By using ROC analysis, the patients were divided into two groups: with and without HPV DNA integration into the host cell genome. The differences between the groups by the histological type, degree of tumor differentiation, and primary response to therapy were statistically insignificant. Virus DNA integration more than 7-fold reduced 5-year relapse-free survival and 1.7-fold reduced overall survival rate in comparison with patients without HPV DNA integration (p=0.0002 and p=0.05, respectively). The relative risk of adverse outcome of the disease in patients with the presence of HPV16 DNA integration increases by 4 times over a period of less than 3 years (р=0.0006) at high AUC level. The probability of earlier progression of the disease in patients with of HPV DNA integration calculated according to the Cox proportional hazards model was 85.5% (hazard ratio 5.96; p=0.002). Thus, the results suggest that the presence of HPV16 DNA integration into the cell genome is an independent factor in predicting clinical outcome of advanced cervical cancer and can serve as an effective criterion for the individual choice of treatment tactics for the patients.

The proportion of CD44+CD24low cancer stem cells (CSC) was determined in cervical scrapings of 41 patients with squamous cell carcinoma of the uterine cervix before treatment and after irradiation in a total focal dose of 10 Gy. The relationship of quantitative changes in the CSC population with such parameters of papillomavirus infection as genotype, viral load, and physical status of HPV DNA (the absence or presence of HPV DNA integration into the cell genome and the degree of integration) was studied. Single- and multi-factor analysis revealed 2 independent indicators affecting the radiation response of CSC: initial number of these cells before treatment and physical status of HPV DNA. The increase in the CSC proportion after radiation exposure was observed 4.5-fold more often in patients with an initially low proportion of CSC (

Prognostic significance of the proportion of cancer stem cells in cervical scrapings from 38 patients with uterine cervical cancer before treatment and after irradiation in a total dose of 10 Gy was assessed for immediate results of radio- and combined chemoradiotherapy evaluated by the degree of tumor regression in 3-6 months after the treatment. Cancer stem cells were detected as cells with CD44+CD24low immunophenotype by flow cytometry. The proportion of cancer stem cells in patients with the complete tumor regression decreased by on average 2.2±1.1% after irradiation, while in patients with partial regression this indicator increased by on average 3.3±2.3% (p=0.03). Multiple regression analysis revealed two independent indicators affecting tumor regression: the stage of the disease (which is quite expected) and change in the proportion of cancer stem cells after the first irradiation sessions (R=0.60, p

The ROS concentration and proliferation activity (Ki67 expression.marker) have been studied in the periphery blood lymphocytes of Moscow and Obninsk citizens, donors, Chernobyl disaster liquidators, inhabitants of the region contaminated after Chernobyl disaster (Klincy) and individuals with prostate cancer. It was shown that ROS concentration in lymphocytes of the liquidators and residents of the polluted region was lowered. But in lymphocytes of patients with tumors the ROS content was higher in comparison with the control. The cell content with Ki67 expression in lymphocytes of the individuals resided in the polluted region and tumor patients was lowered.

The aim of this study is to assess the level of somatic mutagenesis according to the frequency of lymphocytes bearing mutations at the locus of T-cell receptor (TCR) in the residents of the Bryansk region contaminated with radionuclides as a result of the Chernobyl accident. The study was :conducted in 2014 in two regional centers - Klintsy and Novozybkov (average¹³⁷Cs pollution density of 322 and 708 kBq/m²,.respectively). The average frequency of the TCR-mutant cells in the total group of examined residents of the Bryansk region (n = 237) was not significantly different from that in the group of agematched control persons living in un- contaminated areas (n = 146): 3.8 x 10⁻⁴ vs 3.5 x 10⁻⁴, respectively (p = 0.84). However, after separation of examinees into 3 groups depending on age at the start of irradiation (at.the moment of the Chernobyl acci- dent) it was found that the average frequency of the TCR-mutant cells in the persons exposed in utero was 1.6 higher than that in the control group (p = 0.04). Proportion of persons with an increased frequency of the mutant cells (more than the age norm of this indicator) among prenatally exposed population reached 23.8%; which was about.4 times higher than in the control group (p = 0.04). Proportion of persons with an increased frequency of the TCR-mutant cells in group "0-17 years at the start of irradiation", was about 2 times higher than in controls, but this difference was not statistically significant (8.0% vs 4.3%, respectively, p = 0.33). In the third group "18 or more years old at the start of irradiation" we could not register the difference in the average frequency of theTCR mutant cells or the proportion of persons with an increased frequency of these cells in comparison with the age-matched control group. In general, comparison with earlier data shows that age-related regularities of somatic mutagenesis established 15-18 years after the Chernobyl accident persist at a later date (after 28 years in this study).

There was performed a comparative analysis of quantitative load and physical status of human papillomavirus (HPV) type 16 in groups of patients with cervical intraepithelial neoplasia (CIN)--25 people and cervical cancer (CC)--85 people. According to the analysis there were selected criteria appropriate to a combination of adverse factors that characterized HPV- infection and at the same time estimated both quantitative load and physical status of the virus: high viral load (6,5 lg copies of HPV DNA per 100000 cells) in episomal form or low load (6,5 lg copies of HPV DNA per 100000 cells) in integrated form of the virus. According to calculations a relative chance of appearing of CC in CIN patients with unfavorable combination of factors was 7,5 times higher than in other patients.

For the 83 patients with HPV 16-cancer of the cervix (cervical cancer) I-III stages it was performed a comparative analysis of primary tumor response to therapy, the clinical outcome of the disease for 3-5 years after radical treatment and an evaluation of the possible contribution in these rates of the physical status of the virus. It was shown that total tumors regression in the early stages of the observation predominate in patients with "high-integrated" virus DNA (the degree of integration50%) of compared with a group of patients with episomal and "low-integrated" form of the virus, but in a distant periods (3-5 years) in the first group predominate an adverse outcome of disease. This pattern is true for tumors of stage I-III, and for less common--I-II stages. It is assumed that the integration of HPV16 DNA into the cellular genome may serve as an independent predictor of clinical outcome of cervical cancer.

In patients with ovarian cancer, the colony-forming capacity and radiosensitivity of clonogenic tumor cells from the primary node and metastases (ascites) differed considerably.

Real-time polymerase chain reaction procedure was used to evaluate bioptic tumor samples from patients suffering cervical carcinoma (CC) stages I-IV. Out of 110 patients, high-risk human papillomavirus (HPV) infection was identified in 98 (89.1%), HPV type 16--63, HPV type 18--10 and HPV type 45--5. One of genotypes 31.33, 35, 39, 52, 58, 59 was established in 8 and a combination of several genotypes of the virus--12 patients. Frequency of remission in CC patients associated with HPV type 16 who had survived 3 years was significantly higher than in the same category associated with HPV type 18 (p=0.03). Relapse frequency and mortality rates in patients with tumors associated with one of viruses 31.33, 35, 39, 52, 58 or 59 were higher as compared with HPV type 16--associated cases 2 years (p=0.03) or 3 years on (p=0.11), respectively. A similar trend was established for squamous-cell tumors stages 1 and 2 (p=0.07) (p=0.12), respectively. No difference was observed in efficacy of therapy for infection with one or a combination of several genotypes of high-risk HPV. Hence, the genotype of virus is believed to be a factor of prognosis in CC early cancers. However, a definitive conclusion cannot be reached until results of a larger body of evidence and longer follow-up are available.

The association between polymorphisms in genes COMT, HFE that takes part in oxidative stress regulation, and chromosome aberration frequency in lymphocytes was assessed in 278 female residents of radiation polluted regions of Central Russia: Bryansk (322 kBk/m2) and Tula Districts (137Cs - 171 kBk/m2). The C187G, G845A genotyping of HFE and G1947A (H/L) of COMT was done by means of polymerase chain reaction-restriction fragment length polymorphism. Studied population was divided into 3 subgroups by level of chromosome aberrations per cell (0-2, 3-4,5). There was shown statistically significant difference in distribution of COMTand HFE genotypes between the groups. The high frequency of chromosome aberrations (or = 5%) was associated with homozygotes of the high activity COMT G/G and HFE CC. Heterozygotes for G1947A COMT and C187G HFE reveal negative association with the high frequency of chromosome aberrations and correspond to "resistance factors".

Studies with rats and white mice demonstrated that combined radiation injury (CRI) comes to reducing protease activity in small intestine tissues. In liver tissue the activity of cathepsine D increased under the action of new enterosorbent--clay of Kaluga deposit ("CKD"). In blood serum of the damaged animals the amount of histogenic toxins--middle mass molecules (MMM) and oligopeptides decreased after "CKD" administration. An effective fixation and withdrawal of bacteria from the bowl of the affected animals took place. The survival level of mice in 30 days after CRI comprised 20% as compared with 60% in the case of "CK D" administration. It is supposed that the increase of survival after "CKD" administration is the result of enhancement of macrophage detoxification in liver, determined on the increase of activity of cathepsine D (lysosomal protease), elimination of MMM and normalization of gut microflora.

In the period of 2001-2004, frequency of cells bearing mutations at T-cell receptor (TCR) locus was assessed in 553 inhabitants of radiation polluted regions of the Russian Federation and 154 unexposed control persons. The inhabitants were divided into three groups according to age at the moment of the Chernobyl disaster and 137Cs pollution density: 1) in utero, 37-555 kBq/m2; 2) 0-14 years old, 20-555 kBq/m2; 3) 18 and more years old, highest 137Cs density (185 more than 555 kBq/m2). The most intense changes of the TCR-mutant cell frequency were observed in the group of persons exposed to ionizing radiation in utero. The mean frequency of the mutant cells was higher in the first group than in age-matched control group by about 1.5-fold: 4.0 x 10(-4) vs 2.7 x 10(-4) accordingly (p0.0001). Elevation in the mean TCR-mutant cell frequency was less expressed in group of inhabitants aged 0-14 years at the moment of irradiation start: 1.3-fold increase in comparison to age-matched control (3.8 x 10(-4) vs 2.9 x 10(-4), p = 0.0002). It was not found significant differences in mutant cell frequencies between control group and adults consisting in the third group (18 and more years old at the moment of the Chernobyl accident). The changes of the TCR-mutant cell frequency in persons exposed in pre- and postnatal periods differ not only quantitatively, but qualitatively. In the fist case all persons react to irradiation by increasing number of the TCR-mutant cells in some degree. In the second case - only a part of population. Proportion of reacting persons depends on age at the start of irradiation and, perhaps, on dose absorbed. The TCR-mutant frequency was significantly higher in persons with benign tumors of different localizations and nodules in thyroid gland than in persons without this pathology.

In patients with ovarian cancer, the colony-forming capacity and radiosensitivity of clonogenic tumor cells from the primary node and metastases (ascites) differed considerably.

The study was concerned with radiotherapy planning using individual data on tissue volume to be treated. The investigation used criteria based on correlations of TDF, actual volume identified by ultrasound, computed and magnetic resonance tomography and dose fractionation regime. As a result, grave complication rates dropped 3 times including cases of locally advanced tumors, non-traditional dose fractionation and advanced regimens of polychemotherapy.

The introduction of remote afterloading into mixed radiation therapy of uterine body cancer using high activity Co-60 sources promoted improvement of treatment conditions (2, 3). However, the high radio-resistance of adenocarcinomas prompts scientists to search for new methods of treatment. Among them is application of Cf-252 neutron radiation in contact therapy that provides high biological efficiency of neutrons and the absence of oxygen effect in tumors (1, 6, 7, 8, 9). The goal of the study was to investigate the results of endometrial cancer treatment using high activity Cf-252 sources.

The paper is concerned with the consideration of technical potentialities of local UHF-hyperthermia with regard to combined radiotherapy of endometrial cancer. The authors performed comparative analysis of thermoradiotherapy of a tumor and adjacent normal tissues and of combined radiotherapy as an independent method. The results of this investigation have shown that a decrease in a single focal dose per fraction, taking into account the DMF of hyperthermia in thermoradiotherapy, the same therapeutic effect on a tumor being preserved like in radiotherapy, reduces the frequency of radiation reactions of adjacent normal organs and tissues.

The authors presented 5-year results of combined radiation therapy of 217 patients with stage I-II cervical cancer using 60Co high energy sources on the Agat-B unit for intracavitary irradiation. Intracavitary therapy with fractions of 10 and 5 Gy was compared. No significant correlation was found between a therapeutic effect and a fraction value. Nevertheless irradiation of 5 Gy was found more preferable as it was less frequently accompanied by complications of the adjacent organs.