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We analyzed associations of polymorphic markers of DNA repair genes (XRCC1, ERCC2), cell cycle control genes (TP53, MDM2, and CDKN1A), methylation of promoter region, and mutation 5382insC of BRCA1 gene in ovarian cancer with effectiveness of platinumbased chemotherapy assessed by the median of progression-free survival time for markers of DNA repair genes and by relapse risk for all studied markers. An increase in the median of progression-free survival time for carriers of the Gln allele (р=0.025) and Gln/Gln genotype (р=0.022) of the Gln399Arg XRCC1 was observed during the 19-months period after chemotherapy. In carriers of C/C genotype of 5382insC mutation of BRCA1 gene (n=6), no relapses were observed (р=0.035), while 17 of 49 patients without this mutation developed relapses. Of 14 patients with BRCA1 gene function inactivation due to promoter methylation or the presence of the C/C genotype of 5382insC, one relapse was observed (p=0.033). Multivariate analysis revealed an association of markers of the XRCC1, TP53, MDM2 genes, BRCA1 gene inactivation, and type of surgery with the risk of relapse during the follow-up period up to 19 months after the end of chemotherapy (р≤0.0007).

Mutations in the gene DHH are an extremely rare cause of disorders of sex development 46,XY (DSD,46XY). The article describes the clinical cases of two unrelated patients with gonadal dysgenesis 46,XY with female phenotype. By using a next generation sequencing method, in both cases the same biallelic variant substitution c. 419T>G in the DHH gene was revealed. Taking into account the data on the role of DHH in the formation of the nervous system, the diagnosis of minifascicular polyneuropathy at the preclinical stage was confirmed in both cases. These cases demonstrate the value of using NGS, which allows simultaneous analysis of a wide range of candidate genes in DSD and the diagnosis of comorbidities before the development of the clinical picture. These are the first descriptions of patients with mutations in the DHH gene in the Russian population.

We studied the association of polymorphic markers of cell cycle control genes (Arg72Pro of the TP53 gene, T(-410)G of the MDM2 gene, and Ser31Arg of the CDKN1A gene) in ovarian cancer and progression-free survival following platinum-based chemotherapy. Tumor tissue samples obtained from 49 patients who had undergone chemotherapy were examined. Patients received standard platinum-based chemotherapy and were observed until disease progression. Polymorphic markers of genes were evaluated by PCR-RFLP and real-time PCR. In patients carrying the G allele of the T(-410)G marker of the MDM2 gene, a decreasing trend was observed in median progression-free survival. An increase in the median progression-free survival was observed in carriers of the Pro allele of the TP53 gene (p=0.045). Furthermore, a stronger association was noted with carriers of the minor Pro/Pro homozygous genotype relative to the Arg/Arg genotype (p=0.007). In the subgroup of patients who underwent optimal or complete cytoreductive surgery, carriage of the minor Arg allele of the Ser31Arg marker (CDN1A gene) was associated with a decrease in the median progression-free survival time (p=0.004).

Introduction. Most pelvic tumors originate from reproductive organs. Even using the up-to-date imaging techniques, radiologists experience difficulties in determining the source of the lesion since a wide range of tumors look similar to each other on the distorted backdrop of pelvic anatomy, large invasive formations, and an active inflammatory reaction of the pelvic peritoneum.Aim: to evaluate “pitfalls” in the preoperative noninvasive diagnosis of female pelvic tumors by applying the clinical diagnostic tools.Materials and methods. Four rare clinical cases were analyzed; all of them posed difficulties in interpreting the diagnostic examination due to their atypical characteristics. There were 2 cases of ovarian cancer, initially identified by an experienced team of radiologists as benign pelvic pathology. Also, there were fibroids with degeneration, marked proliferative activity, and a massive inflammatory reaction of the peritoneum – that was diagnosed as a malignant ovarian tumor. Tumor biopsies were examined using morphological and immunohistochemical methods (with the р16, Ki-67, p53, CD 117, S 100, CD 34 markers). Immunohistochemical (IHC) studies were performed with formalin-fixed paraffin materials using the avidin-biotin-peroxidase method. Antibodies to estrogen receptor (ER), progesterone receptor (PR), cytokeratin 7 (CK7), cytokeratin 20 (CK20) and Wilms tumor protein 1 (WT1) were also used.Results. A thorough analysis of the clinical picture and a joint multidisciplinary discussion (gynecologist, oncologist, radiologist, etc.) made it possible to avoid diagnostic errors.Conclusion. These observations demonstrate the difficulties of differential diagnosis between ovarian metastases of uterine cancer and primary multiple ovarian and uterine cancer, as well between leiomyosarcoma and uterine myoma with high mitotic activity. Obviously, the change in diagnosis calls for a change in the treatment strategy.

The aim of the work is to conduct a systematic analysis of the available research results on the possibility of using menopausal hormone therapy (MHT) in patients who successfully completed the treatment of endometrial cancer (EC). Materials and methods. The review includes data from foreign articles published in PubMed and Medline, and domestic works published on elibrary.ru over the past 40 years. Results. The results obtained allow us to consider MHT as an independent method of medical rehabilitation for women who have undergone EC. A clear patient profile should be established, allowing the use of this method, with strict adherence to health monitoring. Conclusion Patients who have successfully completed the treatment of EC require the creation of special rehabilitation conditions in the interests of maintaining health and quality of life and should be under the close attention of the doctor. Argumented approaches to the appointment of MHT in such patients will avoid complications associated with estrogen deficiency after surgery, radiation with or without systemic (cytostatic) treatment methods.

Mutations in the gene DHH are an extremely rare cause of disorders of sex development 46,XY (DSD,46XY). The article describes the clinical cases of two unrelated patients with gonadal dysgenesis 46,XY with female phenotype. By using a next generation sequencing method, in both cases the same biallelic variant substitution c. 419Tgt;G in the DHH gene was revealed. Taking into account the data on the role of DHH in the formation of the nervous system, the diagnosis of minifascicular polyneuropathy at the preclinical stage was confirmed in both cases. These cases demonstrate the value of using NGS, which allows simultaneous analysis of a wide range of candidate genes in DSD and the diagnosis of comorbidities before the development of the clinical picture. These are the first descriptions of patients with mutations in the DHH gene in the Russian population.

to investigate the frequency of the types of fallopian tubal secretory cell expansion (SCE) in diseases of the reproductive organs and to determine the immunophenotype and biological role of the cells in the early stages of the pathogenesis of high-grade ovarian serous carcinomas (HGOSC).The investigation enrolled 287 patients with extraovarian diseases and ovarian serous tumors varying in grade, whose fallopian tubes were morphologically and immunohistochemically examined using p53, Ki-67, PAX2, Bcl-2, beta-catenin, and ALDH1 markers. The material was statistically processed applying the Mann-Whitney test and χ2 test.The rate of secretory cell proliferation (SCP) (more than 10 consecutive secretory cells) and that of secretory cell overgrowth (SCO) (more than 30 consecutive secretory cells) increase with age in all investigated reproductive system diseases. The rate of SCP in the corpus fimbriatum of the patients with HGOSC was 5.9 times higher than that in those with extraovarian disease (p0.01); when comparing the same patient groups, that of SCO was 3.4 times higher (p0.05). The immunohistochemical characteristics of the investigated lesions (in scores) were as follows: PAX2 was expressed in the intact epithelium (2.8), in SCP (1.3), in SCO (1.2), in serous tubal intraepithelial carcinoma (STIC) (1.0), and in HGOSC (0.9); Bcl-2 was in the intact epithelium (2.2), in SCP (2.1), STIC (0.9), and in HGOSC (0.6), β-catenin was in the intact epithelium (0.5), in SCP (2.85), in SCO (2.95), in STIC (0.6), and in HGOSC (0.5); ALDH1 was in the intact epithelium (0.5), in SCP (2.91), in SCO (2.92), in STIC (1.2), and in HGOSC (0.6). There were statistically significant differences with a 95% confidence interval (p0.05) for: 1) PAX2 between the intact epithelium and pathology (fallopian tube lesions and HGOSC); 2) Bcl-2 between the intact epithelium and SCE (SCP and SCO) and between SCE and HGOSC; 3) beta-catenin between the intact epithelium and SCE (SCP and SCO) and between SCE and HGOSC; 4) ALDH1 between the intact epithelium and SCE, between and SCE and STIC, and between STIC and HGOSC.SCE was shown to be an independent intraepithelial lesion. The incidence of this abnormality increased with age and significantly differed in the patients with fallopian tubal lesions in extraovarian diseases from that in those with malignant ovarian serous tumors (by 5.3 times), while these groups showed a three-fold difference in SCO. Thus, SCP may serve as a more sensitive marker for the early stages of the pathogenesis of ovarian serous carcinoma. The studied types of SCE demonstrated multiple molecular events (loss of PAX2 expression and increased Bcl-2, beta-catenin, and ALDH1 expressions), some of which underwent considerable changes, by increasing the severity of a pathological process (loss of ALDH1, and beta-catenin, and bcl-2 expressions). Thus, therapeutic exposure in the early stages of pathogenesis may have a few points of application and just several molecules can serve as independent markers for early pathological changes in the fallopian tubal epithelium.Цель исследования - изучить частоту возникновения вариантов экспансии секреторных клеток эпителия маточной трубы при патологии органов репродуктивной системы, определить их иммунофенотип и биологическую роль на ранних этапах патогенеза серозных карцином яичника высокой степени злокачественности (СКЯВСЗ). Материал и методы. В исследование включены 287 пациенток с экстраяичниковой патологией и серозными опухолями яичника разной степени злокачественности, маточные трубы которых исследованы морфологически и иммуногистохимически (с маркерами р53, Ki-67, PAX2, Вcl-2, β-catenin, ALDH1). Статистическая обработка материала выполнена с использованием критериев Манна-Уитни и χ2. Результаты. Частота возникновения пролиферации секреторных клеток - ПСК (более 10 секреторных клеток подряд) и разрастания секреторных клеток - РСК (более 30 секреторных клеток подряд) возрастает с возрастом при всех изученных патологиях репродуктивной системы. В фимбриальном отделе частота ПСК в маточных трубах пациенток СКЯВСЗ в 5,9 раза выше, чем у пациенток с экстраяичниковой патологией (p0,01), частота РСК при сопоставлении тех же групп была в 3,4 раза выше (p0,05). Иммуногистохимическая характеристика изученных поражений была следующей (в баллах): экспрессия PAX2 составила в нормальном эпителии 2,8, в ПСК 1,3, в РСК 1,2, в серозной трубной интраэпителиальной карциноме (СТИК) 1,0, в СКЯВСЗ 0,9, экспрессия Вcl-2 составила в нормальном эпителии 2,2, в ПСК 2,1, в СТИК 0,9, в СКЯВСЗ 0,6, экспрессия β-catenin составила в нормальном эпителии 0,5, в ПСК 2,85, в РСК 2,95, в СТИК 0,6, в СКЯВСЗ 0,5, экспрессия ALDH1 составила в нормальном эпителии 0,5, в ПСК 2,91, в РСК 2,92, в СТИК 1,2, в СКЯВСЗ 0,6. Статистически значимые различия с доверительным интервалом 95% (p0,05) выявлены: 1) в отношении PAX2 между нормальным эпителием и патологией (поражениями маточной трубы и СКЯВСЗ); 2) в отношении Вcl-2 между нормальным эпителием и экспансией секреторных клеток (ПСК и РСК), а также между экспансией секреторных клеток и СКЯВСЗ; 3) в отношении β-catenin между нормальным эпителием и экспансией секреторных клеток (ПСК и РСК), а также между экспансией секреторных клеток и СКЯВСЗ; 4) в отношении ALDH1 между нормальным эпителием и экспансией секреторных клеток, между экспансией секреторных клеток и СТИК, а также между СТИК и СКЯВСЗ. Заключение. Показано, что пролиферация секреторных клеток является самостоятельным интраэпителиальным поражением. Частота данной патологии увеличивалась с возрастом, а также достоверно различалась у больных с поражением маточных труб при экстраяичниковой патологии от таковой у пациенток со злокачественными серозными опухолями яичника (в 5,3 раза), при этом уровень разрастания секреторных клеток в данных группах больных различался в 2 раза. Таким образом, пролиферация секреторных клеток может служить более чувствительным маркером ранних этапов патогенеза серозной карциномы яичника. Для изученных типов экспансии секреторных клеток продемонстрированы множественные молекулярные события (утрата экспрессии PAX2, усиление экспрессии Вcl-2, β-catenin и ALDH1), некоторые из которых претерпевали значительные изменения с усилением тяжести патологического процесса (утрата экспрессии ALDH1, β-catenin, Вcl-2). Таким образом, терапевтическое воздействие на ранних этапах патогенеза может иметь несколько точек приложения и сразу несколько молекул могут служить независимыми маркерами ранних патологических изменений эпителия маточной трубы.

to study the incidence of fallopian tube lesions (secretory cell proliferations (SCP), p53 signature, serous tubal intraepithelial lesions (STIL), and serous tubal intraepithelial carcinomas (STIC) in ovarian epithelial tumors and to propose their pathogenetic association with a certain histotype of the ovarian tumor.The investigation enrolled 136 patients with ovarian epithelial tumors, whose fallopian tubes were morphologically and immunohistochemically (IHC) examined using p53, Ki-67, and PAX2. Statistical analysis was carried out applying the Mann-Whitney test and χ(2) test.Lesions meeting the STIC criteria were found in 14.7% of cases (only in ovarian serous carcinoma (OSC)), those suspecting STICs were in 25.7%, and those without signs of STICs were in 59.6%. IFC examination diagnosed STIC in 10% of cases (only in OSC), STIL in 13.3%, p53 signature in 11.7% (only in serous tumors), and the normal/reactively changed tubal epithelium in 65%. The incidence of STILs correlated with the malignant potential of serous tumors significantly (p0.05). There were significant differences in the incidence of STILs in patients with different histotypes of ovarian carcinomas (p0.05). PAX2-negative SCP was detected in 75% of OSC, 60% of serous borderline tumors, and 40% of serous cystadenomas. The differences in the incidence of SCP between serous tumors of varying grade, between serous tumors and non-serous carcinomas, between OSC and non-serous carcinomas were significant (p0.05).The investigation has shown that IHC examination should be used for the accurate diagnosis of STILs. It has also provided evidence for the pathogenetic association between STIC and high-grade OSC and revealed significant differences in the incidence of other fallopian tubal intraepithelial lesions in serous cystadenomas, borderline tumors, and OSC, in different ovarian carcinomas. The findings may suggest that the earliest stage in the pathogenesis of OSC is the development of SCP, followed by the formation of p53 signatures that may further give rise to STIL, and finally STC (due to the acquisition of additional mutations).Цель исследования - изучить частоту возникновения поражений маточной трубы (разрастаний секреторных клеток (РСК), p53-signature, серозных трубных интраэпителиальных поражений (СТИП), серозных трубных интраэпителиальных карцином (СТИК) при эпителиальных опухолях яичника) и высказать предположение об их патогенетической связи с определенным гистотипом опухоли яичника. Материал и методы. В исследование включены 136 пациенток с эпителиальными опухолями яичника, маточные трубы которых исследованы морфологически и иммуногистохимически (ИГХ) (р53, Ki-67, PAX2). Статистическая обработка материала выполнена с использованием критериев Манна-Уитни и χ2. Результаты. Поражения, соответствующие критериям СТИК, выявлены в 14,7% случаев (только при серозной карциноме яичника - СКЯ), подозрительные в отношении СТИК - в 25,7% случаев, не имеющие признаков СТИК - в 59,6%. После ИГХ-исследования СТИК диагностирована в 10% случаев (только при СКЯ), СТИП - в 13,3%, р53-signature - в 11,7% (только при серозных опухолях), нормальный/с реактивными изменениями трубный эпителий - в 65% случаев. Частота возникновения интраэпителиальных поражений маточной трубы достоверно коррелировала со злокачественным потенциалом серозных опухолей (p0,05). Достоверные различия в частоте возникновения интраэпителиальных поражений маточной трубы выявлены среди пациенток с карциномами яичника разных гистотипов (p0,05). PAX2-негативные РСК диагностированы при 75% СКЯ, 60% серозных пограничных опухолей, 40% серозных цистаденом. Достоверно значимыми были различия во встречаемости РСК между серозными опухолями различной степени злокачественности, серозными опухолями и несерозными карциномами, СКЯ и несерозными карциномами (p0,05). Заключение. Показано, что для точной диагностики интраэпителиальных поражений маточной трубы необходимо применение ИГХ-исследования. Подтверждена патогенетическая связь между СТИК и СКЯ высокой степени злокачественности и выявлены значимые различия во встречаемости других интраэпителиальных поражений маточной трубы при серозных цистаденомах, пограничных опухолях и СКЯ, при различных карциномах яичника. На основании полученных результатов можно предположить, что наиболее ранним этапом в патогенезе СКЯ является развитие РСК, далее образуются р53-signature, которые в дальнейшем могут дать начало развитию СТИП и, наконец, СТИК (при приобретении дополнительных мутаций).

Cell cultures isolated from endometriosis lesions by enzymatic dissociation consisted of fibroblast-like cells expressing CD90, CD73, and CD105; cell viability in these cultures was >90%, but this parameter decreased by passage 3. Zero passage cultures contained 10-25% epithelial cells expressing cytokeratin-7, but by passage 2, the cultures became more homogeneous and epithelial cells disappeared. The proportion of proliferating cells and population doubling level increased from passage 1 to passage 3. The cultures from the endometrium were induced to adipogenic and osteogenic differentiation in vitro. The cultures derived from ectopic endometrium have properties of multipotent mesenchymal stromal cells that exhibited in vitro similarities and differences from cell cultures from eutopic endometrium, which allows using this cell model for the search and testing of new drugs and technologies aimed at suppression of the growth and spread of endometriosis lesions.

The purpose of the study is to explore and systematize the endoscopic features of colorectal endometriosis and to evaluate the role of colonoscopy in its diagnosis.Were analyzed 320 diagnostic colonoscopies performed during the period from March 2011 till November 2012 in patients admitted to the hospital with a diagnosis of "infiltrative form of external endometriosis".Among all the identified cases of intestinal endometriosis (n = 67) pathological process was localized more often in the upper section of the rectum ampullar - 38 (56.7%), less often were revealed lesions of lower ampullar section of rectum and anal canal in 5 (7.4%). In 6 (8.9%) cases were detected multifocal lesions of the intestine. Authentic signs of colorectal endometriosis were detected in lesions of the mucous membrane. These include: polypoid growths above the endometriosis lesion (15 (22.4%)), endometrioid heterotopias in the colon mucosa (7 (10.4%)), the presence of ulceration of the mucous membrane in the projection of endometriosis (4 (5.9%)) geoidal mucosa (3 (4.5%)). Colorectal endometriosis can be systematized according to the following endoscopic criteria: localization of the pathological focus, growth, the presence of mucosal lesions.

Rare cases of lethal outcomes after surgical operations on the liver were analyzed which were caused by invasion of helminth Opisthorchis felineus. It was shown that prolonged and massive invasion, in the absence of specific treatment, can result in failure of the compensatory potencies of the liver. It occurs mainly due to activation of the pathogenic flora in the bile tree against the background of the intraductal hypertension characteristic of opisthorchiasis. Destructive purulent cholangitis, cholangitic abscesses in the liver and suppuration of opisthorchiasis cysts can develop. The direct cause of death was progressing hepatic insufficiency. The postoperative lethality among patients with opisthorchiasis cysts of the liver was 5.7%, with liver abscesses--12.5%. The external drainage of the biliary tree in patients with this pathology and intraportal infusions reduce lethality and the number of specific postoperative complications.