Purpose: To evaluate the proportion of BRCA1 / 2 mutations in patients with serous and endometrioid cancer of the ovary, fallopian tube, and peritoneum in Russia, to evaluate the percentage of germinal and somatic mutations, to identify the spectrum of mutations in BRCA1 / 2 genes, to evaluate clinical and morphological features of the BRCA-associated ovarian cancer (OC).Patients and methods: The study enrolled patients of 18 years and older with newly diagnosed serous and endometrioid cancer of the ovary, fallopian tube, and peritoneum. Biological material (blood, tumor tissue) was collected, followed by molecular genetic analysis. The method of mutations detecting in the blood were: allele-specific PCR, high-resolution melting (HRM), Sanger sequencing method. Advanced genetic testing included the use of generation sequencing (NGS) and multiplex amplification of ligated probes (MLPA). The collection of clinical data, family history, clinical and morphological characteristics of the tumor was performed.Results: 500 patients were included in the study, the evaluation of BRCA1 / 2 mutations was performed in 496 patients (99,2 %). The frequency of BRCA1 / 2 mutations in the Russian patient population was 28,4 % (n = 141 / 496). The incidence of germinal mutations was 23,5 % (n = 117 / 141), and somatic — 4,8 % (n = 24 / 141). Frequent mutations in the Russian population were identified in 50 % of cases. When analyzing the ethnicity of patients in the Russian Federation BRCA-associated OC was most common in Russian (83,6 %, n = 118 / 141), Ukrainian (4,2 %, n = 6 / 141) and Tatar (3,5 %, n = 5 / 141) women. A family history of cancer was detected in 44 % of patients (n = 62 / 141) with BRCA1 / 2 mutations.Conclusions: Due to the high frequency of germinal and somatic BRCA1 / 2 mutations in the Russian patients it is recommended to conduct the advanced testing methods not only in blood samples but also in tumor tissue.

Purpose of the study. Study of the characteristics of human papillomavirus (HPV) infection, comparison of HPV status, molecular and genetic parameters of HPV high risk (HR) with the clinical and morphological characteristics of cervical cancer. Materials and methods. The study included 240 patients with morphologically verified cervical cancer stages I–III, in whom the presence of HPV DNA of 14 genotypes was examined before treatment; upon detection, viral load (VL), the presence and degree of DNA integration into the genome of the host cell were examined. Results. A number of statistically significant associative relationships have been identified between the molecular and genetic parameters of HPV infection and clinical and morphological indicators of the tumor process, in particular the relationship of HPV-negative CC with age and stage of the disease; HPV infection with several genotypes and HPV genotype – with the histological type of tumor; VL – with age, stage and histological type of tumor. Significant associative connections have been established between the molecular genetic parameters of the virus itself: genotype and level of VL, genotype and integration of HPV DNA into the host genome, as well as a negative linear correlation between VL and the degree of integration. Conclusion. The obtained data on the relationship between the molecular and genetic parameters of HPV infection and traditional prognostic factors can become the basis for further research on the development of prognostic models for the purpose of personalizing multimodal treatment programs.

The aim of research is to analyze available scientific data for the study of the relationship between carcinoma of the lower uterine segment and traditional prognostic factors for the stage 1 uterine corpus cancer, and to assess its prognostic significance related to the treatment outcomes and the feasibility of adjuvant radiotherapy in cases with the disease poor prognosis. Search for the data of concern in electronic databases with the use of keywords and analysis of Russian and English translated data published between 1987 and 2024. The tumor in the lower segment occurs in 3-27.8% of endometrial cancer of the uterus body and, due to the anatomical features of the structure, blood supply, and lymphatic drainage, can be considered as a potential prognostic factor. According to limited studies data, a tumor lesion in the lower segment has not been associated with other clinical and morphological prognostic factors, and it does not affect the relapse-free survival in patients. Other researchers demonstrate the relationship between a lesion in the lower segment and the myometrium deep invasion, lymphovascular space invasion, and metastatic involvement of lymph nodes, however, they have not found any they have not impacted on treatment outcomes. However, a wide range of studies has demonstrated that the lower segment lesions are independent and poor prognostic factors. The factors significantly correlate with traditional prognostic factors and reduce both overall and recurrence-free survival. Therefore, it may be justified to consider postoperative radiotherapy for patients with a low or intermediate risk of disease progression, despite the absence of evidence of lymph node involvement. Analysis of the found research data has revealed the potential for further research into the impact of tumors in the lower segment of the uterus on patients with stage I endometrioid cancer. This could help identify new prognostic factors and determine whether adjuvant radiation therapy is appropriate for this group of patients.

Chronic radiation exposure in the body may lead to the development of oxidative stress associated with many diseases. Plasma malondialdehyde (MDA) is a common marker of oxidative stress. The aim of the work was to analyze the level of MDA in the blood of female residents of radioactive contamination areas of Kaluga and Bryansk regions 28-30 years after the Chernobyl accident in the assessment of pathologies in women's health. The dependence of MDA index on age, the value of the average accumulated effective dose (AAED) for 1986-2016, the presence of benign diseases of the organs of the female reproductive system and thyroid gland was investigated. MDA concentration was determined by the Temirbulanov method in frozen plasma samples of 455 women (384 – radioactively contaminated territories; 71 – healthy, Obninsk (control)). In two age groups (<=37 years, 120 people and >37 years, 264 people) the level of MDA in sick and healthy women living in contaminated areas was evaluated. Statistical analysis was performed using GraphPad Prism 8.0.1, MedCalc 14.8.1 software package. AUC (Area Under Curve), an indicator of marker efficacy, was calculated. No significant differences were found between MDA concentrations in control and healthy female residents of polluted areas; no correlations of MDA content with AAED were found. MDA level in the group of women >37 years old was significantly higher compared to <=37 years old and significantly higher in patients compared to healthy individuals in both age subgroups. The intensity of lipid peroxidation is comparable in different pathologies of female reproductive system, thyroid gland, or their combinations. In the groups <=37 years and >37 years the AUC is 0.730 (p<0.0001, CI 0.653-0.798) and 0.666 (p<0.0001, CI 0.609-0.719), respectively. Determination of plasma MDA levels has the potential to identify healthy residents of radioactively contaminated areas and individuals for whom comprehensive screening is required.

A review of domestic and foreign literature was carried out. Statistical analysis of the available literature showed that at present, despite the improvement of screening programs around the world, there is a steady increase in the incidence and mortality of cervical cancer in women of reproductive age with a high percentage of patients with advanced forms, whose proportion is 32 %. The percentage of deaths during the year since the verification of the disease in 2020 was 12.6 %. In the structure of mortality in the Russian population, malignant diseases occupy the second ranking place, accounting for 13.6 % after diseases of the cardiovascular system – 43.9 %. Diseases of the female reproductive system account for 18.2 %. At the same time, cervical cancer in the overall structure of oncological morbidity occupies the 4th ranking place, and among the organs of the reproductive system – the 2nd place – 13.3 %, yielding to breast cancer (47.8 %). These figures reflect the lack of implemented programs aimed at reducing the incidence of cervical cancer.

Purpose of the study. Analysis of contemporary literature sources dedicated to the study of characteristics of high oncogenic risk human papillomavirus (HPV), associative links of the virus’s molecular-genetic parameters with the clinical and morphological characteristics of invasive cervical cancer (ICC).Materials and methods. A literature search was conducted in electronic databases including the National Center for Biotechnology Information Search database (PubMed/Medline), ResearchGate, Scopus, Web of Science, Cancer Tomorrow, Global cancer observatory, Cochrane Library, eLIBRARY, DisserCat. The search covered the period from 1990 to 2022 and utilized keywords in Russian and their English translations: cervical cancer, high oncogenic risk HPV, HPV status, HPV genotype, multiple infections, DNA integration, viral load. More than 120 full-text sources were studied, in which the analysis of possible correlations between the parameters of human papillomavirus infection and the clinical and morphological characteristics of cervical cancer was carried out. In review included data from 57 publications. Results. According to most authors, more than 88 % of patients with invasive ICC are HPV-infected. The etiological structure is dominated by HPV 16 (70–72 %), 18 (13–15 %), and 45 (5–7 %) types. Non-detection of HPV HR in cervical cancer is associated, including with a false negative result of the study.The literature analysis showed the presence of an association between HPV status and age, morphological form of the tumor, viral load, high oncogenic risk HPV genotype, presence of deep stromal invasion, and metastatic involvement of lymph nodes. With regard to such molecular genetic parameters of HPV HR as viral load and HPV DNA integration, associative relationship with prognostic important clinical indicators of cervical tumor – the stage of the disease, the loco-regional prevalence of the tumor process, the histological type of tumor – remains the subject of discussion.Conclusion. Many publications report a correlative link between HPV status and high oncogenic risk HPV genotype with such an important factor affecting ICC treatment outcomes as the morphological form of the tumor. Ambiguous conclusions on the presence of an association between a number of molecular-genetic parameters of HPV infection with the main prognostic factor – stage of the disease (due to the heterogeneity of samples, the use of different test systems, and the insufficiently complete account of the main parameters of HPV infection, especially data on viral DNA integration), make it advisable to conduct further research on a representative group of patients with homogeneous diagnostic protocols to determine the most complete spectrum of parameters of high oncogenic risk HPV. In addition, the conducted literature analysis showed the promise of searching for predictors of the effectiveness of specialized treatment of patients with ICC among such HPV infection parameters as HPV status, high oncogenic risk HPV genotype, and the significantly associated physical status of viral DNA.

The article offers the latest view on possibilities of diagnostic algorithm to identify vaginal cancer (VC), rare tumor of the woman’s reproductive system. The algorithm is described as a consensus of leading expert in imaging diagnostics, as well as oncogynecologysts, investigating diagnostic challenges and vaginal cancer therapies. The article sets forth the principal trends in using imaging methods, their role and possibilities for staging VC, planning and assessing the efficacy of applied therapy, on-going surveillance over patients, who have undergone specialized anti-cancer treatment

The article offers the latest view on possibilities of diagnostic algorithm to identify cervical cancer (CC), one of the most incidental tumor of the woman’s reproductive system. The algorithm is described as a consensus of leading expert in imaging diagnostics, as well as oncogynecologysts, investigating diagnostic challenges and cervical cancer therapies. The article sets forth the principal trends in using imaging methods, their role and possibilities for staging CC, planning and assessing the efficacy of applied therapy, on-going surveillance over patients, who have undergone specialized anti-cancer treatment.

(1) Background: There are no reliable and widely available markers of functional iron deficiency (FID) in cancer. The aim of the study was to evaluate the role of transferrin (Tf) as a marker of cancer of the ovary (CrO) and related FID. (2) Methods: The study groups consisted of 118 patients with CrO and 69 control females. Blood serum iron status was determined on a Beckman Coulter AU (USA) analyzer. Tf quantification was performed by immunoturbidimetry. The relative contents of apo- and holo-Tf (iron-free and iron-saturated Tf, respectively) were determined in eight patients and a control female by immunochromatographic analysis based on the use of monoclonal single-domain antibodies (nanobodies). (3) Results: Four groups of patients with different iron statuses were selected according to ferritin and transferrin saturation values: absolute iron deficiency (AID) (n = 42), FID (n = 70), iron overload (n = 4), normal iron status (n = 2). The groups differed significantly in Tf values (p < 0.0001). Lower values of Tf were associated with FID. Furthermore, FID is already found in the initial stages of CrO (26%). Immunosorbents based on nanobodies revealed the accumulation of apo-Tf and the decrease in holo-Tf in patients with CrO. (4) Conclusions: Tf may be a promising tool for diagnosing both CrO and associated FID.

The technology for construction and application of flexible dosimetric assemblies with LiF:Mg,Ti microcrystals (sizes of about 0.1 mm) for off-line measurements of the spatial distribution of the absorbed dose inside organs at risk (rectum, urethra, vagina) at high dose rate brachytherapy in oncoginecology has been developed. The transfer from the usage of luminescent dosimeters LiF:Mg,Ti with macro sizes (more than 1 mm) to microdosimetrs with sizes of about 0.1 mm, in combination with the developed protocols of dose estimations using mini-aliquots (10 mg) of lu-minescent microdosimeters, provided possibility to increase the accuracy of dose measurements in the therapeutic dose range at high dose rate brachytherapy of gynecological malignancies. The developed technology of intracavitary dosimetry at a high dose rate brachytherapy (Ir-129 source) in oncogynecology was tested in the clinic (25 patients). It was found that, as a rule, the measured doses were in a good agreement with the calculated doses in the areas of interest. However, in four cases (16% of all patients) there was an excess of the measured local absorbed doses over the calculated ones (from 0.6 to 1 Gy) in the urethra and rectum (in the organs of maximum calculated doses). These cases may be considered as a basis for monitoring of the patients’ condition in the post-therapeutic period. However, the values of maximal dose were within acceptable dose range, as recommended by GEC-ESTRO. The developed technology of «in vivo» dosimetry allows to adjust the dosimetrical plans at multifractional high dose rate brachytherapy. The results of clinical approbation of the developed technology of «in vivo» dosimetry show the importance of this technology as an essential element of dosimetric assurance of the quality of high dose rate brachytherapy in oncogynecology.

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.

Radio- and chemoresistance of cancer stem cells (CSCs) is considered as one of the possible causes of adverse results of chemoradiotherapy for various malignancies, including cervical cancer. However, little is known about quantitative changes in the CSC subpopulation in the course of treatment and mechanisms for individual response of CSCs to therapy. The purpose of the study was to evaluate the association of radiation response of cervical CSCs with clinical and morphological parameters of disease and features of human papillomavirus (HPV) infection. The proportion of CD44+CD24low CSCs was determined by flow cytometry in cervical scrapings from 55 patients with squamous cell carcinoma of uterine cervix before treatment and after fractionated irradiation at a total dose of 10 Gy. Real-time PCR assay was used to evaluate molecular parameters of HPV DNA. Post-radiation increase in the CSC proportion was found in 47.3% of patients. Clinical and morphological parameters (stage, status of lymph node involvement, and histological type) were not significantly correlated with radiation changes in the CSC proportion. Single- and multifactor analyses revealed two independent indicators affecting the radiation response of CSCs: initial proportion of CSCs and physical status of HPV DNA (R = 0.86, p = 0.001 for the multiple regression model in the whole).

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.

Улучшение качества жизни больных раком шейки матки после лучевой и химиолучевой терапииМкртчян Л.С., Иванов С.А., Кулиева Г.З.К., Замулаева И

The proportion of CD44 + CD24 low 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 (<3%) than that in other patients ( p =0.001). The CSC proportion increased by on average 3% after irradiation in patients with complete integration of HPV 16/18 DNA and decreased by 3.8 % in patients with partial integration or no integration ( p =0.03).

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<0.002 for the model in the whole). The proportion of cancer stem cells before the treatment did not have prognostic significance.

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.

e13111 Background: First large Russian ovarian cancer observational study was conducted in 2014-2018. Methods: A total of 500 patients in 29 sites in Russia with newly diagnosed ovarian, peritoneal and fallopian tube cancer was enrolled (NCT02122588). The primary objective was to describe treatment approaches in the first line treatment. 141 patients (pts) with BRCA1/2 mutations (BRCA1/2mt) detected by NGS in blood and tissue were observed prospectively during at least 2 years. Results: Rate of BRCA1/2 mutations in Russian population is high – 28.4% (141 from 496 available for any testing). 77.6% (388/500) underwent biomarkers blood testing prior to treatment. CA-125 was positive in 99.7% (387/388), 15.2% (59/388) of pts had positive CA19-9, CA72-4 - in 2.3% (9/388). Positive CEA was presented in 15.2% (59/388). This marker was detected more frequently in BRCA2mt pts subgroup (28.0% (7/25)) than in BRCA1mt pts: 9.0% (8/90) (p = 0.05). 26.6% (133/500) of all study population had an oncology family history; 44.0% (62/141) BRCA1/2mt pts had relatives with oncological diseases and 19.7% (70/355) in BRCA wild type pts (p = 0.0001). 98.6% (139/141) of BRCA1/2mt pts received first line therapy. Objective response rate was registered in 79.8% (111/139) pts. Progression after platinum based regimens was observed in 53.6% (59/110) BRCA1mt pts and 44.8% (13/29) BRCA2mt pts. 35.6 % (21/59) of BRCA1mt pts had platinum-refractory and platinum-resistant relapses, while 15.4% in BRCA2mt subgroup (2/13) (p = 0.64). Platinum-sensitive relapses were in 64.4% (38/59) BRCA1mt pts and 84.6% BRCA2mt (11/13) (p = 0,64). Median PFS in BRCA1/2mt pts was 25.5 months. Among BRCA1/2mt pts underwent cytoreduction median PFS in subgroup without visible residual tumor was 36.4 months and in subgroup with residual tumor < 1 cm 15.3 months. Conclusions: In this large-scale prospective non-interventional study diagnostics and treatment approaches in Russian ovarian cancer pts were evaluated and high frequency of BRCA1/2mt was observed. Pts with BRCA1/2mt had better prognosis and most of them had platinum-sensitive relapses after first line chemotherapy that allowed platinum-based regimen rechallenge.