Aim of the study – use of the phenomenon of thermo stimulated luminescence in natural microcrystals of sea salt (NaCl) in the range of therapeutic doses in order to develop a method for off line intracavitary «in vivo» dosimetry of patients at high dose-rate brachytherapy of prostate cancer with a 192Ir source. Samples of aliquots with natural microcrystals (a fraction with a size of about 100 m) of sea salt were used in the study. Measurements were carried out using a Harshaw 3500 device, which is a thermoluminescent reader. Irradiation of samples to construct the calibration dependences was carried out by a standard 90Sr/90Y source providing the dose rate of 2.99 mGy/s. It was established, that: (1) there is a linear dose dependence of luminescence intensity from studied microcrystals in the range of therapeutic absorbed doses from 1 to 20 Gy with an error in measuring the luminescence intensity of the studied microcrystal samples of less than 5%; (2) it was revealed that fading (decrease in microdosimeter readings over time) does not exceed 5% 5 days after irradiation; (3) clinical testing of «in vivo» dosimetry method using sea salt microcrystals for high dose-rate brachytherapy of prostate cancer shows that the results of measurements of absorbed doses in the organ at risk (rectum) using studied natural NaCl crystals are consistent, within the limits of error, with the results of measurements by synthetic LiF:Mg,Ti crystals (with intracavitary placement in the organ at risk and simultaneous irradiation both assemblies of these microcrystals). It was concluded that the use of the studied sea salt microcrystals is promising for «in vivo» dosimetry in application to 192Ir high dose-rate brachytherapy of prostate cancer.

Phosphonic acids labeled with beta-emitting radionuclides are promising radiopharmaceutical drugs for palliative therapy of bone metastases. Currently, the possibility of using a new osteotropic compound N,N,N’,N’-ethylenediaminetetrakis (methylene phosphonic acid) with lutetium-177 (177Lu-EDTMP) is being studied. The aim of the work is to develop a compartment mathematical model of the kinetics of 177Lu labeled osteotropic radiopharmaceutical drugs in the body of laboratory animals and calculate their pharmacokinetic and dosimetric characteristics based on it. To assess the stability of 177Lu-EDTMP in vivo, the characteristics of the distribution of free lutetium in the form of 177LuCl3 were also studied. To identify the model parameters and calculate the characteristics of radiopharmaceutical drugs, quantitative data on the bio-distribution of 177Lu-EDTMP and 177LuCl3 in the body of intact Wistar rats were used. A compartment model of kinetics has been developed and two approaches to the identification of its transport constants have been proposed – through the residual functional and using approximation by monoexponential functions. According to pharmacokinetic modeling, it was found that 177Lu-EDTMP is deposited in bone tissues (up to 55% of the administered dose). The calculated value of the apparent volume of distribution of 177Lu-EDTMP is approximately 200 times greater than the volume of blood plasma, the values of biological half-lives from bone tissues are 10-20 times higher than from internal organs. The excretion of 177Lu-EDTMP from the body occurs mainly through renal clearance. Comparative modeling with 177LuCl3 revealed high resistance of 177Lu-EDTMP in vivo. The highest values of absorbed doses are formed in the skeleton and kidneys with minimal radiation load on other internal organs and blood. The results obtained indicate the prospects for further studies of 177Lu-EDTMP and the possibility of its clinical application for the treatment of skeletal metastases.

Metallothioneins are a special group of low-molecular-weight proteins with metal-binding properties, which make them promising chelators for the development of targeted radiopharmaceuticals, as well as with technetium-99m. The aim of this work is to study the biodistribution of 99mTc-metallothionein conjugate (99mTc-MT) in intact mice in comparison with unbound technetium-99m (Na99mTcO4). Low uptake of 99mTc-MT in the thyroid gland (1.20 ± 0.30

Carcinoembryonic antigen (CEA) is widely used to evaluate the effectiveness of treatment in patients with rectal cancer.The aim of the studywas to investigate whether the CEA levels measured before and after neoadjuvant chemoradiotherapy (nCRT) can be used to predict pathological complete response (pCR) in patients with locally advanced rectal cancer.Material and methods.179 patients with locally advanced rectal cancer were treated with nCRT followed by surgical treatment. The serum CEA level was measured before and 610 weeks after the completion of nCRT. Preand post nCRT CEA levels were compared with pCR. The factors associated with pCR were studied.Results.pCR after nCRT was achieved in 12 % (22/179) patients. The incidence of pCR was higher in patients with normal (<5 ng/mL) pre-treatment CEA level (20 %vs8 %, p=0.019). In patients with the elevated pre-treatment CEA level (> 5 ng/mL), there were no significant differences in the incidence of pCR between cases with normalization and without normalization of CEA level after treatment (p=0.08). The maximum likelihood of pCR determined by the ROC curve was <2.8 ng/mL with pre-treatment CEA (31 %) and <1.8 ng/mL with post-treatment CEA (23 %). Well differentiated tumors (G1) had higher likelihood of pCR (46%) in patients with low pre-treatment CEA (<2.8 ng/mL).Conclusion.Low CEA before and after nCRT is a predictor of pCR. Well differentiated tumors increase the probability of pCR after nCRT.

The purpose of the study was to evaluate the prognostic significance of carcinoerembryonic antigen in patients with rectal cancer and correlate its baseline with the degree of therapeutic pathomorphosis after neoadjuvant chemoradiotherapy.Materials and methods. An estimate of the informative value of carcinoerembryonic antigen (CEA) indices in 179 patients with colorectal cancer determined before and after preoperative chemoradiotherapy (CRT) in SOD 50 Gy.Results. Analysis of the results presented in the study showed that in all patients, CRT caused a significant decrease in the level of CEA (–71%) 10 weeks after its end (p < 0.001). In the course of the pathomorphological study, after the neoadjuvant treatment, the first degree of tumor pathomorphism was recorded in 4.5% of patients, II – 38.5%, III – 45%, IV – 12% (the degree of pathomorphosis is not related to the clinical stage and the degree of differentiation of colorectal cancer). It was revealed that patients with III and IV degrees of therapeutic pathomorphosis initially had a CEA level lower, in comparison with patients with grade I-II. Clinical progression of the disease is diagnosed in 24% of cases (43/179). It was noted that in patients with the IV degree of therapeutic pathomorphism of the tumor, no recurrence of the rectal cancer was detected in either case.Conclusion. The results of the study showed that the problem of individual prediction of the effectiveness of combined treatment of the rectal cancer remains very relevant, rather complicated and yet not completely solved. However, it can be assumed that the use of such an indicator as CEA in monitoring patients after the treatment, can serve as a criterion for the sensitivity of colorectal cancer to CRT. Initially low antigen level can be considered as a positive factor of tumor response to ongoing treatment and disease-free survival of patients with locally advanced rectal cancer.

This paper is a short review of literature data and results of our own investigation into the adaptive response (AR). It was aimed at the analysis of the AR induction, its formation, some mechanisms, its expansion, and universality. It is supposed that a lot of mechanisms, a high variability degree, the absence of this phenomenon in some individuals, as well as dependence on many situations make the AR induction not predictable. Perhaps AR induction is not a universal phenomenon in practice, as it was supposed earlier.

В статье представлен обзор данных литературы (с включением в него результатов собственных исследований) по индукции адаптивного ответа (АО), его формированию, некоторым механизмам, распространенности, универсальности. Предполагается, что множественность механизмов, высокая вариабельность проявлений, отсутствие способности к АО при ряде условий делает развитие АО практически непредсказуемым. Предполагается также, что индукция АО не является столь универсальным феноменом, как это считалось ранее.

The genome damage (frequency of cells with micronuclei and chromosome aberrations), concentration of reactive oxygen forms (ROS), markers of lymphocytes activation, expression of proliferation (CD69, Ki67) and proapoptotic antigen (CD95), as well as the ability to adaptive response have been investigated in blood lymphocytes of healthy donors and patients with prostate gland cancer. The influence of hormone-therapy on lymphocytes properties and connection between the parameters studied with the effectiveness of treatment, which was estimated by the level of prostate specific antigen (PSA), have been investigated. It was discovered that the genome damage to the patients with prostate gland cancer lymphocytes does not differ from control. The increase of the ROS level and decrease of radiosensitivity (irradiation of isolated lymphocytes in vitro at a dose of 1 Gy) are observed but they are insignificant. The content of the cells expressing CD69 and CD95 markers doesn't change but the expression of proliferative activity marker Ki67 in cells decreases. Radiosensitivity of lymphocytes in patients with prostate gland cancer correlates with the CD95 markers expression--a higher radio sensitivity points to their predisposition to apoptotic death. The expression of the markers studied depends on the oxidative status--a high ROS level suppresses their expression. The hormone therapy applied before radiotherapy leads to the increase in radiosensitivity and decrease in ROS. As the MN test shows, the ability to adaptive response of the lymphocytes in patients with prostate gland cancer is increased as compared with lymphocytes of healthy donors but it is insignificant; moreover, hormones do not influence the ability to the adaptive response. The high oxidative status further the formation of the adaptive response. We suppose that the discovered correlation between the initial, before treatment, frequency of lymphocytes with micronuclei and treatment effectiveness, namely, the decreased number of damaged cells associated with the treatment efficiency, is very important for the treatment prognosis. The results obtained can be very important for the experimental justification and understanding a possible use of blood lymphocytes for the additional diagnostics of prostate gland cancer and prognosis for its successful treatment.

В лимфоцитах периферической крови здоровых людей и больных раком предстательной железы (РПЖ) изучали поврежденность генома (частоту клеток с микроядрами и аберрациями хромосом), концентрацию активных форм кислорода (АФК), экспрессию маркеров активации (CD69), пролиферации (Ki67) и проапоптотического антигена CD95 Т-лимфоцитов, адаптивную способность. Исследовали также влияние гормонотерапии на свойства лимфоцитов и связь изученных показателей с эффективностью лечения, которую оценивали по уровню содержания в крови простатспецифического антигена (ПСА). Было обнаружено, что поврежденность генома при РПЖ не отличается от контроля, наблюдаются снижение радиочувствительности (облучение лимфоцитов в условиях in vitro в дозе 1 Гр) и повышение концентрации АФК, но эти изменения статистически незначимы. Содержание клеток, экспрессирующих маркеры CD69 и CD95, при РПЖ не изменяется, снижается экспрессия маркера пролиферативной активности Ki67. Радиочувствительность лимфоцитов при РПЖ коррелирует с экспрессией маркера CD95: при более высокой радиочувствительности этих клеток можно предполагать предрасположенность их к апоптотической гибели. Введение гормонов, курс которых проводят перед лучевой терапией, приводит к увеличению радиочувствительности лимфоцитов при РПЖ, снижению содержания АФК. Адаптивная способность лимфоцитов крови при РПЖ возрастает статистически незначимо, на нее гормоны не влияют, но высокий оксидативный статус способствует формированию адаптивного ответа. Для прогноза лечения представляется очень важным обнаруженная нами корреляционная связь между исходной (до начала лечения) частотой клеток с МЯ и эффективностью лечения: чем меньше поврежденных клеток, тем выше эффективность лечения. Полученные результаты могут иметь значение для экспериментального обоснования и понимания возможности использования лимфоцитов крови для дополнительной диагностики РПЖ и прогноза успеха его лечения.

On the blood lymphocytes of prostate cancer (PCa) patients before and during radiotherapy: DNA damage by DNA commet assay (DNA double strand breaks - DSB); the frequency of cells with micronuclei (MN) with cytokinetic cytochalasin block; the adaptive response induction by the additional irradiation of PHA stimulated lymphocytes in the doses of 0.05 and 1.0 Gy 24 h and 48 h after stimulation were studied. Changes of these parameters with the decreasing of prostate specific antigen (PSA) have been compared. PSA decreasing is an adequate of the radiotherapy efficiency. It was shown that in oncological patients the DSB level and the frequency of cells with MN have been increased. During radiotherapy (in 3 months) the DNA DSB level and the frequency of cells with MN is enhancing. The degree and direction change of these parameters coincide. It was discovered the significant correlations between the enhancing of DNA DSB level and the cell frequency with MN during therapy and degree of the PSA level decreasing. Then it was shown that when the cell frequency with MN before treatment is higher the radiotherapy efficiency is worse. These results can have great significance for the evaluation of the prognosis of the treatment efficiency. The investigation of lymphocytes for the adaptive response ability has shown that in the patients with the pronounced adaptive response before radiotherapy the decrease of PSA level during treatment was not significant (in mean 3.5-3.6 ng/ml); when the adaptive response is absent or the phenomenon of enhanced radiosensitivity was observed the PSA level (in the most cases) was decreased very essential (in mean 0.07 ng/ml). We can suppose that prognosis of the treatment efficiency of the prostate cancer patients with the pronounced adaptive response in blood lymphocytes will be worse.

У лимфоцитов крови больных раком предстательной железы (РПЖ) до и во время лучевого лечения изучали: поврежденность ДНК методом ДНК-комет (двунитевые разрывы ДНК – ДР ДНК); частоту клеток с микроядрами (МЯ) при использовании цитокинетического блока цитохалазином В; индукцию адаптивного ответа при дополнительном облучении ФГА стимулированных лимфоцитов в дозах 0.05 и 1.0 Гр через 24 и 48 ч после стимуляции. Изменения этих показателей сравнивали со степенью снижения уровня простатспецифического антигена (ПСА), что является адекватным критерием эффективности лечения. Обнаружено, что в лимфоцитах онкологических больных повышен выход ДР разрывов ДНК и частота клеток с МЯ. При проведении лучевой терапии (в течение 3 мес) уровень ДР ДНК и частота клеток с МЯ возрастают. Степень и направленность изменения этих показателей совпадают. Были обнаружены достоверные корреляционные зависимости между степенью увеличения выхода ДР ДНК и частоты клеток с МЯ во время лечения и степенью снижения уровня ПСА. Показано, что чем выше исходная частота лимфоцитов с МЯ (до лечения), тем хуже эффективность лечения. Эти результаты могут иметь большое значение для определения прогноза эффективности лечения. Исследование способности лимфоцитов к индукции адаптивного ответа показало, что у больных с выраженным адаптивным ответом до лечения отмечается менее значительное снижение уровня ПСА во время лечения (в среднем до 3.5–3.6 нг/мл); при отсутствии адаптивного ответа или индукции повышенной радиочувствительности уровень ПСА в большинстве случаев снижается весьма существенно (в среднем до 0.07 нг/мл). Можно полагать, что прогноз эффективности лечения больных РПЖ с адаптивным ответом будет хуже.

Individual radiosensitivity of prostate malignant tumor cells were estimated in blood of 122 patients in accordance with the level of prostate-specific antigen. Estimation has been performed in dynamics (before and after 3, 6, 12, 18, 24, 30 and 36 months) after radiation (external beam radiotherapy with total dose 70 Gy, brachytherapy with clinical dose 140-170 Gy) and hormone-radiation therapy. It was detected the differences of prostate tumors in the radioresistance. Levels of antigen at all times of detection in patients with relative radioresistant tumors (39 patients) were higher then in patients with radiosensitive tumors (81 patients). The number of persons with clinically unfavorable clinical prognosis in the group of patients with relative radioresistant tumors were registered 2 times more often then in group with radiosensitive timorous (35.9% vs. 16.0%). The ratio of patients with radiosensitive and relative radioresistant tumors depends on the method of treatment. It is supposed that after neoadjuvant hormone therapy tumour becomes more radiosensitive.

Индивидуальная радиочувствительность злокачественной опухоли предстательной железы оценена в крови 122 больных по уровню простатического специфического антигена (ПСА) в динамике в течение 36 мес после лучевого (дистанционная лучевая терапия в суммарной очаговой дозе 70 Гр, брахитерапия в дозе 140–170 Гр) и гормонолучевого лечения. Опухоли предстательной железы различаются по степени радиочувствительности. Показатели ПСА на всех сроках обследования у больных с менее радиочувствительными опухолями (39 человек) достоверно выше, чем у больных с более радиочувствительными (81 человек). Число лиц с неблагоприятным прогнозом клинического течения заболевания в группе больных с менее радиочувствительными опухолями регистрируется в 2 раза чаще, чем с более радиочувствительными (35.9% против 16.0% соответственно). Радиочувствительность опухолей зависит от метода лечения. Делается предположение, что после неоадъювантной гормонотерапии опухоль становится наиболее радиочувствительной.