Objective is to study methylation features of microRNA genes (miR-107, -124a-1/2/3, -125b-1, -127, -130b, -137, -203a, -375) in different breast cancer molecular subtypes.
Materials and Methods. The study comprised 70 patients with verifi ed diagnosis of breast cancer aged from 30 to 70 years . Patients with stages II (51,4%) and III (31,4%) prevailed. Lymph node metastases were observed in 60% of cases. Invasive ductal carcinoma was identifi ed in 72,8% of cases, invasive lobular carcinoma — in 12,8% of cases, 14,4% of patients were diagnosed with other types of cancer. Moderately differentiated breast cancer was detected in the majority of patients (74,2%), 21,4% of patients had poorly differentiated carcinomas, and only 4,4% of patients had well-differentiated tumors. Luminal A subtype is identifi ed in 27,1% of patients; luminal B subtype Her2-negative — in 18,5% of patients; luminal B subtype Her2-positive — in 32,8% of cases, triple-negative — in 14,2% of cases and non-luminal Her2 (+) positive subtype — in 7,1% of cases. Methylation-specifi c polymerase chain reaction was used to examine the methylation profi le of microRNA genes (miR-107, -124a-1/2/3, -125b-1, -127, -130b, -137, -203a, -375) in paired samples of tumor and histologically unchanged breast tissue. The result were processed using standard packages STATISTICA, v.10 and IBM SPSS Statistics, v.21.
Results. During this study it was found that in luminal A breast cancer subtype the frequency of miR-124a-1 and miR- 125b-1 methylation in tumor tissue is increased by 2,3 times (84,2% (n = 16) versus 36,8% (n = 7), p = 0,0069), and by 8 times (42,1% (n = 8) versus 15,8% (n = 1), p = 0,0189), respectively in comparison with an unchanged breast tissue. Signifi cant differences were shown in the frequency of microRNAs miR-124a-1, miR-375 gene methylation in the tumor and histologically unchanged tissue in Her2-negative and Her2-positive luminal B subtype. The frequency of these microRNA methylation in Her2-positive subtype made up 69,5% (16/23) versus 17,3% (4/23), (p = 0,0008) and 43,4% (10/23) versus 13% (3/23), (p = 0,0472) respectively. For Her2-negative cancer these values were: 84,6% (11/13) versus 38,4% (5/13), (p = 0,04) and 69,2% (9/13) versus 23% (3/13), (p = 0,04), respectively.
A high level of miR-124a-3 and miR-125b-1 methylation frequency in Her2-positive B subtype of breast cancer was observed. In triple-negative subtype miR-125b-1 methylation in tumor tissue was observed in most samples (70% (n = 7), p = 0,0075) and was absent in histologically unchanged tissue.
Conclusion. The study revealed increased levels of methylation of CpG-islands of promoter regions of all microRNA, which indicates their potential diagnostic signifi cance. Frequency of miR-375 methylation is reliably increased in a tumor in triple-negative subtype in comparison with luminal B Her2-negative subtype of breast cancer. A high percentage of methylation of 6 microRNA (miR-124a-1, miR-375, miR-124a-3, miR-125b-1, miR-127, miR-130b) was found in Her2-positive luminal B subtype.
Keywords: breast cancer, microRNA gene methylation.
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Objective of the study — is to carry out a systematic analysis of the data available in current literature on the clinical signifi cance of LAG3 and GITR molecules in breast cancer.
Materials and Methods. The review comprises the data obtained from foreign and Russian academic articles found in PubMed on the subject published over the past 10 years.
Results of the study. Methods that act on immune checkpoints using targeted immunotherapy have been actively introduced into oncologic practice over the past decade. This made it possible to change the prognosis for many patients with various types of cancer, including in particular melanoma, lung cancer, renal cell carcinoma. CTLA-4 (CD152) and PD-1 are the most studied inhibitory receptors of regulatory T-cells and a wide range of immunotherapy medicines (ipilimumab, nivolumab, pembrolizumab and etc.), which allowed to improve the results of the treatment of patients even with disseminated cancer, were created on their basis. This necessitates further research of the role of other molecules expressed on regulatory cells such as LAG-3 and GITR in the identifi cation of molecular mechanisms of the generation of an effective immune response in cancer patients. This article concerns the results of the research on the subject of the signifi cance of LAG3 and GITR molecules in breast cancer.
Keywords: immune checkpoint, LAG3, GITR, breast cancer.
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Objective of the study is to analyze the literature data on genetic and epigenetic disorders of the BRCA1 suppressor gene in ovarian tumors, on the possibilities of their use for diagnosis and therapy.
Materials and Methods. The review comprises analysis of the articles presented in PubMed database.
Results. The presence of genetic (mutations) and epigenetic (promoter hypermethylation) disorders of BRCA1 gene is a distinctive feature of high-grade epithelial ovarian tumors (HGEOC). The defi ciency of BRCA1 functions that occurs in a tumor cell as a consequence of these disorders, is accompanied by a decrease/loss of the ability to repair double-strand DNA breaks and by genetic instability. Germinal BRCA1 mutations are a risk factor for high-grade epithelial ovarian cancer (HGEOC) formation and a predictive marker for their therapy with DNA-damaging drugs. Their incidence is from 9 to 18% of all epithelial ovarian tumors and depends on the ethnicity of the mutation carriers. The incidence of somatic mutations and BRCA1 promoter hypermethylation makes up 10-12% and 10-15% respectively. Data on the possibility of using both somatic mutations and BRCA1 promoter hypermethylation as a predictive marker for the therapy of sporadic high-grade epithelial ovarian tumors (HGEOC) with-DNA-damaging preparations are contradictory, which is apparently associated with the absence of unifi ed and correct method of their determination.
Conclusion. Genetic and epigenetic gene BRCA1 disorders detected by molecular biology techniques can be potentially used as diagnostic, prognostic or predictive markers. However, diversity of mutations revealed recently due to using of new techniques and stricter and increased requirements for the correct determination of the level of BRCA1 promoter hypermethylation necessitate the expansion of DNA-diagnostic testing for comprehensive detection for BRCA1-defi cient tumours.
Keywords: high-grade epithelial ovarian tumors, BRCA1 gene, mutations, promoter hypermethylation.
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Immature ovarian teratoma (IOT) — is a rare histological variant of germline ovarian tumors, which makes up about 1% of all teratomas and 35,6% of all malignant germline ovarian tumors. These neoplasms are more prevalent among girls, in 60% of cases patients with germline tumors are under 20 years old, therewith, the younger the patient, the higher the likelihood of malignant tumor diagnosis is [1, 2, 3]. This article presents a clinical observation of immature teratoma in a young woman who underwent treatment at gynecology department of a municipal hospital. Errors in diagnosis and determination of treatment strategy are outlined. The feasibility of examination and treatment of patients with immature teratomas at specialized cancer treatment centers is demonstrated.
Keywords: immature teratoma, ovaries, alpha-fetorpotein, germline tumors.
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Objective of the study is to summarize the literature data on the liver resection in recurrent ovarian granulosa cell tumors (GCT), compare them with our own results, to determine the feasibility of liver resection in recurrent ovarian granulosa cell tumors (GCT).
Materials and Methods. A retrospective analysis of medical records of patients, who had undergone treatment at Federal State Budgetary Institution “N.N. Blokhin National Medical Research Center of Oncology” of the Ministry of Healthcare of the Russian Federation for the period from 2003 to 2020, was carried out. Inclusion criteria were morphologically verifi ed ovarian granulosa cell tumor, recurrence with liver involvement and with the possibility of liver resection, the fi ndings of instrumental examination.
Results. 9 patients with recurrent ovarian granulosa cell tumors (GCT) of adult type with liver involvement were included into the study retrospectively, two of them had undergone anatomical liver resection, the rest — atypical resection (n=7). Five patients had received chemotherapy just prior to resection. More than one metastasis had been diagnosed in 3 patients. Liver spread had been, at a minimum, the second recurrence of ovarian granulosa cell tumor (GCT) in all the cases. 5 patients had required performing of en bloc diaphragm resection with liver resection. Intervention on extrahepatic metastases had been carried out in 7 cases. One case had been coded as R1 resection , and another case — as R2.
Reactive hydrothorax had been identifi ed in all patients with diaphragm resection (N = 5). In one case — in combination with pneumothorax, that had required drainage of the pleural space. Histological examination had revealed post-treatment pathologic changes of Grade I in 1 patient of 5 who had received preoperative (neoadjuvant) chemotherapy.
Post-operative examination including ultrasound imaging of the abdomen and pelvis had been performed every three months, and monitoring of inhibin B level in blood serum — one month after the resection, and later — every three months. Median time to progression (MTTP) made up 15 months, median overall survival (MOS) reached 56 months. Two patients after liver resection underwent repeat surgical intervention for the recurrence of ovarian granulosa cell tumor (GCT).
Conclusion. According to international literature sources that reported on a total of 18 patients who had undergone liver resection for recurrent ovarian granulosa cell tumor (GCT), surgical treatment in similar clinical situations is justifi ed. It permits to mitigate symptoms of the disease at a low postoperative complication rate, as well as to achieve satisfactory long-term outcomes — at the time of publication of the reports — 12 patients lived for 10 to 168 months, in 6 patients long-term results were not conclusively tracked and investigated. In our study (n = 9) 5-year overall survival was 45,7%, median overall survival — 56 months, that is consistent with international literature data. Postoperative examination with mandatory inhibin B level control is indicated for an early detection of recurrence. The development of novel, more effective systemic treatment regimens that can be used both as stand-alone treatment method and as supplementary treatment option after surgical intervention for recurrent ovarian granulosa cell tumor (GCT) is required.
Keywords: granulosa cell tumor, recurrence, liver involvement, liver resection, inhibin B.
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A tumor derived from cells of Wolffi an duct — is extremely rare and insuffi ciently studied, with uncertain malignant potential. Immunohistochemical diagnosis is rather used to exclude other pathology, whereas the genetic aberrations presently don’t have an explicit pattern. Due to the small number of observations there are no standards of surgical and adjuvant treatment, also no algorithm of surgical staging has been developed. This article presents a clinical observation of the tumor of probable Wolffi an origin, diagnosed in a 46-year-old patient with recurrent disease occurred 14 months after organ preservation surgery.
Keywords: tumor of Wolffi an origin, FATWO, tumors of uncertain malignant potential.
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Objective of the study is to carry out a multiple factor analysis of the clinical data and of 5-year results of the treatment to determine the indications for adjuvant radiation therapy in patients of “low risk” group with stage IA endometrial cancer with myometrial invasion of more than 5 mm.
Materials and Methods. Analysis comprises the clinical data of the patients with “low risk” stage IA G1-2 endometrial cancer who underwent treatment at Federal State Budgetary Institution “Russian Research Center of Radiography (X-ray) and Radiology” of the Ministry of Healthcare of the Russian Federation, State Healthcare Institution “Lipetsk Regional Oncological Dispensary” and Regional State Budgetary Healthcare Institution “Altai Regional Oncological Dispensary” in 2009-2015.
Results. The work presents a systematic multiple factor analysis of the treatment of patients with stage IA endometrial cancer with myometrial invasion of more than 5 mm at cancer treatment centers and institutions of different regions of the Russian Federation. It was found that patients with stage IA endometrial cancer of relatively low risk of progression with myometrial invasion of more than 5 mm comprise clinically and morphologically quite heterogeneous group, and a unifi ed approach to adjuvant treatment of these patients cannot be based exclusively on the fi ndings of a standard postoperative morphologic examination.
Conclusion. To resolve the issue of adjuvant treatment of patients with stage IA endometrial cancer of relatively low risk of progression with myometrial invasion of more than 5 mm, it is necessary to examine and take account of prognostic value of a number of additional clinical factors — size of the lesion, tumor localization in tubal corners, uterine isthmus involvement, as well as specifi c molecular characteristics of the tumor, opting for adjuvant radiation treatment with an emphasis on endovaginal brachytherapy in case of their identifi cation.
Keywords: endometrial cancer, adjuvant therapy, surgical treatment, chemotherapy, radiation therapy.
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Presence of BRCA1 and BRCA2 gene mutations signifi cantly increases the risk of developing breast and ovarian cancer in a lifetime. Primary diagnosis of ovarian cancer is a challenging issue due to the absence of effective screening programs. Medical and genetic counseling of patients followed by molecular genetic testing permits to choose the optimal strategy for treatment and prevention for patients with breast and ovarian cancer. This paper presents a clinical case of an early detection of ovarian cancer as a result of prophylactic salpingo-oophorectomy in a patient with bilateral metachronous breast cancer and germline 538insC mutation in BRCA1 gene.
Keywords: BRCA1/2 gene mutations, ovarian cancer, breast cancer, genetic counseling.
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Objective of the study is to carry out a systematic analysis of the data available in current literature on the amendments made in the current classifi cations of gynecological malignancies.
Materials and Methods. The overview comprises the comments of the 8th edition of the Union for International Cancer Control (UICC) TNM classifi cation, recent FIGO (The International Federation of Gynecology and Obstetrics) classifi cation revisions as well as foreign articles on this subject.
Results. The main change in the 8th edition of TNM classifi cation of gynecological malignant tumors is the unifi cation of staging for ovarian cancer, fallopian tube cancer and primary peritoneal cancer, whereas in the 7th edition they were staged as separate entities. In addition, the new edition describes the system of prognostic factors for cervical cancer, endometrial cancer and ovarian tumors. If these factors contribute signifi cantly to the prognosis, they can be included into the future intermediate classifi cations.
Conclusion. The main goal of the Union for International Cancer Control (UICC) and the International Federation of Gynecology and Obstetrics (FIGO) continues to be the creation of unifi ed statistical information on the incidence of the disease on a case-by-case basis.
Keywords: FIGO, TNM, staging, gynecologic oncology.
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