Introduction. The incidence and mortality of malignant melanoma have increased steadily over the last decades; therefore, the development of novel diagnostic markers for malignant melanoma is of great importance. The purpose of the study was to assess whether the development of melanoma before any treatment is accompanied by the body changes and, in particular, DNA damage in the mononuclear cells of the peripheral blood of patients. Material and Methods. In 93 patients (26 men and 67 women) admitted to the N.N. Petrov National Medical Research Center of Oncology for surgical treatment of stage T1c-2a-b-3a-b4a-bN0-1 cutaneous malignant melanoma, and in 118 healthy people as a comparison group, the level of damage to DNA in peripheral blood mononuclear cells was studied using the “comet” method. All patients were divided into two groups: group 1 included 45 patients (13 men and 32 women) who were examined before a decision on treatment was made and group 2 consisted of 48 patients (13 men and 35 women) who previously underwent excision biopsy for melanoma. Results. The level of DNA damage in peripheral blood mononuclear cells, assessed by the comet assay, was found to be signifcantly higher in patients with melanoma than in the comparison group. Moreover, the increase in the level of DNA damage was similar both in patients with a primary tumor before starting any treatment and in those who previously underwent excision biopsy for melanoma. The relationship between the level of DNA damage in peripheral blood mononuclear cells and the morphological characteristics of the tumor cells was revealed. The Spearman correlation analysis showed that all parameters that determined DNA damage positively correlated with the thickness of melanoma according to the Breslow’s depth, and the percentage of DNA in the comet and the comet tail moment correlated with the stage of the disease. Conclusion. The development of cutaneous melanoma is accompanied by an increase in the level of DNA damage in peripheral blood mononuclear cells. The level of DNA damage in peripheral blood mononuclear cells refects the changes that occur in the patient’s body under the infuence of the tumor process, which may allow using this indicator as an additional criterion for the diagnosis and aggressiveness of melanoma.

This review presents basic data on the hypothalamo-hypophyseal system (HHS) and its main components; the role of age (with the focus on aging) is discussed as a factor linked with changes in the state of the HHS and mediating its involvement in “preparative” predisposition to various major chronic noncommunicable diseases in humans (in particular, such neoplasms as cancer of the breast, endometrium, and prostate; ischemic heart disease as the leading cardiovascular pathology; type 2 diabetes mellitus) with the involvement of this major hormonal-metabolic system via obesity, insulin resistance, and decreased glucose tolerance, as well as the interaction of insulin, insulin-like growth factor 1, and their receptors and effects on the reproductive and hypothalamo-hypophyseal-adrenal system. Data are presented on links between HHS subsystems in stress conditions, impairments to physiological rhythms, and in response to the gender factor. This review presents information on possible measures to prevent the main noncommunicable diseases based on consideration of the role of the HHS and the outcomes of impairments to its functioning. The review also addresses the fact that along with the widely accepted similarity in the hormonal-metabolic factors creating a platform for the development of the main noncommunicable diseases, there are examples of nonsimilarity, a point which requires further research.

The publication of this article is undoubtedly a significant and positive phenomenon, while the initiative of the journal «Problems of Endocrinology» with the introduction of a new section «Oncoendocrinology» should be welcomed and will serve to unite the efforts of specialists of various profiles in the appropriate direction.

Работа посвящена двум медико-биологическим проблемам - семейному диабету (имея в виду наличие случаев сахарного диабета 2-го типа в семье, в том числе в разных поколениях), а также особенностям его связей с основными неинфекционными заболеваниями человека и приурочена к юбилею известнейшего отечественного специалиста (теоретика и врача) в области геронтологии и эндокринологии профессора В. М. Дильмана. Широко признанные труды Владимира Михайловича, основанные на оригинальных идеях и породившие важные практические следствия (включая применение антидиабетических бигуанидов в не использовавшихся до него областях, необходимость устранения метаболической иммунодепрессии, учета изменений с возрастом на уровне гипоталамического порога в различных гомеостатических системах и целого ряда других предложений), как представляется, в течение долгого времени будут питать интеллектуальным материалом и стимулировать к дальнейшему поиску его последователей и специалистов, которым еще предстоит окунуться в область, очерченную В. М. Дильманом и интересовавшую его в течение многих лет. The work discusses the two biomedical problems: family diabetes (bearing in mind the presence of cases of type 2 diabetes mellitus in the family, including its different generations) and the features of relationship of family diabetes with major non-communicable human diseases (NCDs). The paper is timed to the anniversary of the famous - in our country and abroad - expert in the field of gerontology and endocrinology, Professor V. M. Dilman. The widely recognized works of V. M. Dilman, based on original ideas and giving rise to important practical consequences (including the use of antidiabetic biguanides in areas not studied before him, the need to eliminate metabolic immunodepression, to take into account the changes with age at the level of the hypothalamic threshold in various homeostatic systems and a whole number of other essential proposals), which for a long time, as it seems, will stimulate the further scientific search of his followers and specialists, who have yet to get acquainted with the area that attracted Prof. Dilman and interested him for many years.

The study objective is to evaluate the results of using the Petrov Thyroid Cancer Score (PTCS) in 2018 and assess the diagnostic value of the original PTCS and modified PTCS.Materials and methods. PTCS, proposed in the N.N. Petrov National Medical Research Center of Oncology in early 2018, was tested in this institution in 310 patients, 99 of whom underwent surgery, mainly due to suspected malignancy of thyroid nodules or at the request of patients.Results. According to the standard histological evaluation, in 35 cases the process was considered benign (group Д), while in 61 cases — after exclusion of 3 medullary carcinomas — regarded as highly differentiated (according to previous classification) thyroid cancer (group Р). The average values of such components of PCTS as BethesdaScore, TI-RADSScore, ElastoScore and body mass index (BMI) in group Р were significantly higher than in group Д. The sum of the scores of the used four parameters was not only higher in group Р, but also at a magnitude of ≥5.0 (62.3 % of observations in this group) it always corresponded to the diagnosis of thyroid carcinoma. At the same time, a similar histological conclusion was made, in particular, in respect of 14 patients (23 % of the group Р contingent) with the value of the mentioned sum <3.5. Of note, according to the preoperative cytological study, among these 14 cases 11 follicular neoplasms and 3 colloid nodules were found.Conclusion. A high value (≥5.0) of the sum of four selected parameters (3 from PTCS + BMI_Score) indicates an extremely high probability of detecting a tumor process, while in other cases (and not only under the assumption of follicular neoplasia presence), an additional diagnostic methods of research are needed.

A method for assessing the likelihood of finding a differentiated thyroid cancer based on the use of the Petrov Thyroid Cancer Score (PTCS) is proposed. The individual components of the score are divided into 4 groups in terms of their diagnostic significance. PTCS reflects the opinions of specialists working in the different areas of oncology and needs further approbation based on retro- and prospective studies

Clinical trials of metformin efficacy in breast cancer were reviewed in this article. According to some data from cohort and case-controlled studies, the use of metformin with combined therapy of breast cancer improves overall and disease-free survival. Initial data from randomized clinical trials of metformin in adjuvant and neoadjuvant therapy of breast cancer are expected in the nearest future.

Processes important for hormone-mediated carcinogenesis are present on different, even very early, ontogenesis stages. Early shifts in hormone-metabolic status often display opposite correlations with the risk of most common age-associated non-communicable pathologies (namely, hormone-dependent cancers and cardiovascular diseases). Additional known contradiction is the raise of reproductive system tumors incidence in the age associated with lower production of mitogenic hormones. Consequently, one should take into account production of steroids in target tissues themselves, recognize the importance of progenotoxic effect, which, apart from mitogenic function, is characteristic for estrogens and their derivatives, as well as the role of endocrine-genotoxic switchings forming so called basic triad, which is born under the influence of age-associated endocrine shifts and environmental factors. Aside from steroids-related system of increased cancer risk, attention should be paid to non-steroid ones (in particular insulin resistance- and inflammatory cytokines-associated), with their close connection to immune system functional state, low-grade chronic inflammation, obesity phenotype, and pro-/anti-inflammatory lipid factors ratio. In total, it confirms and importance of timely preventive interventions on both ontogenesis stages, early and late ones, which are often separated by several decades.

Introduction. In clinical practice, differential diagnosis of nodular thyroid diseases poses a serious problem which can be solved by development of new, safe, and specific thyroid tumor markers. Small regulatory RNAs (microRNA, miRNA) are a class of molecules that control gene expression at the post-transcriptional level. miRNAs, both intracellular and secreted into the extracellular space, can be used as markers of various diseases, including cancer. Stability of extracellular miRNAs is determined by binding to proteins and lipoproteins, or by “packing” into membrane microvesicles – exosomes. It is considered that exosomes with specific miRNA content are a result of active and biologically significant secretion, while release of other forms of miRNA is associated with apoptotic or necrotic cell death. This determines diagnostic value of exosomal fraction of circulating miRNAs, which may reflect presence or clinically significant properties of a tumor.The study objective was to explore a method of exosomal miRNA isolation, identify marker miRNAs, and estimate diagnostic value of their analysis.Methods. We used serum samples from 57 patients with nodular thyroid diseases and 13 healthy donors. Exosomes were isolated from serum by ultracentrifugation and analyzed by atomic force microscopy, laser correlation spectroscopy, and western blotting. Analysis of exosomal miRNAs was carried out by RT-PCR.Results. We have identified a specific correlation between certain miRNAs and status of thyroid nodular disease. Expression profiles of three miRNAs (miRNA-21, miRNA-146a, and miRNA-181a) exhibited specific characteristics for different forms of nodular thyroid disease and their analysis may have diagnostic value.Conclusions. Exosomes isolated by ultracentrifugation from serum are a source of RNA suitable for subsequent analysis of miRNA. The levels of different miRNAs in serum exosomes may differ by 1–2 times. «Marker» exosomal miRNAs have specific profiles in circulating exosomes of patients with different thyroid nodules. Clinical significance of testing exosomal miRNAs in patients with benign and malignant nodules of the thyroid gland can be increased by a parallel assessment of several molecules and analysis of the profile of their representation in exosomes. MiRNA-181a, -146a, and -21 form a diagnostic combination of «marker» molecules present in the circulating exosomes, which can be extended and used for diagnosis (differential diagnosis) of thyroid nodules.

Processes essential for hormone-dependent carcinogenesis occur at different developmental stages, even the earliest. Early deviations in the hormone–metabolic status often inversely correlate with the risk of common age-associated noncommunicable diseases, in particular, tumors in hormone-dependent tissues and cardiovascular disorders. Another paradox is the increase in reproductive system tumor incidence at the age associated with lower production of mitogenic hormones. Therefore, one should take into account the production of steroids directly in target tissues and recognize the importance of the progenotoxic effect of estrogens and their derivatives. Another noteworthy aspect is the role of endocrine–genotoxic switchings, which form the so-called basic triad, generated by age-associated endocrine shifts and environmental factors. In addition to the steroid-dependent set of cancer risk factors, attention should be paid to nonsteroid ones (such as those associated with insulin resistance or inflammatory cytokines), since they are tightly connected with the immune system functional state, mild chronic inflammation, obesity phenotype, and pro-/antiinflammatory lipid factor ratio. All these considerations confirm the importance of timely preventive interventions at early and late developmental stages, which are often several decades apart.

73 randomly selected from the entire array menopausal endometrial cancer patients (34 of whom were subjected to further surgery by laparotomy and 39 - by laparoscopic ap- proach) were examined 48-72 hours before surgery. Patients passed anthropometry, their medical history was collected, and in the blood serum, taken on an empty stomach, glucose, gly- cated hemoglobin, lipid fractions, insulin, thyrotropin, estradiol and testosterone levels were measured while insulin resistance index was calculated. Although patients who later went through laparoscopic surgery were characterized by somewhat higher body mass and waist circumference, other investigated pa- rameters did not differ between laparoscopy and laparotomy groups. Moreover a frequency of so called "metabolically healthy" obesity appeared to be even higher in laparoscopic group. Taken together this confirms the fact that the overweight should not be considered as contraindication for videosurgery in patients with endometrial cancer. At the same time it is desirable to compare distant oncological results with individual characteristics of pre-surgical hormonal-metabolic status of pa- tients depending on the surgery type and obesity phenotype.

The authors aimed to compare expression of UCP1, aromatase (CYP19), markers of macrophage infiltration (CD68, CD163), omentin and PTEN in omental fat of endometrioid or non-endometrioid endometrial cancer (EC) patients with signs of standard (SO) or metabolically healthy obesity (MHO) by immunohistochemical (IHC) or real-time PCR methods. Totally 57 omental fat samples collected during surgery in EC pts (average age 60.1) were studied. According to IHC data, statistically significant decrease in expression of aromatase and CD68 was revealed in omental fat of MHO patients. Expression of UCP1 demonstrated an inclination to decrease in the same group, simultaneously showing correlation with clinical stage of EC. According to real time PCR data, omentin expression displayed tendency to an increase with increase in body mass index (whole group), clinical stage of EC (in SO subgroup) and serum omentin level (MHO subgroup). No any difference in studied omental fat parameters was discovered between patients with endometrioid and non-endometrioid EC. Thus, omental fat properties in EC patients are associated with obesity phenotype and not with histologic subtype of this cancer. Apparently, the features of omental fat depot characteristic for visceral adipose tissue at least are equal to its attributes as a brown fat compartment. Decrease, according to IHC info, of the estrogen biosynthesis and macrophagal infiltration in omental fat of EC patients with MHO phenotype may indicate additional mechanisms for more favorable in this case clinical course of uterine body cancer. Supported by RFBR grant 15-04-00384.

Background. Malignant phenotype of cancer cells and metastatic potency of the tumor are determined by genetic factors. In addition, normal biological environment, including the nano-vesicles or exosomes, plays an important role in regulation of the structural and functional characteristics of malignant cells. Objective: presented study was aimed to evaluate mechanisms and to estimate effect of interaction of plasma exosomes and breast cancer cells in experimental conditions. Materials and methods. We used breast cancer cell culture MDA-MB-231 and exosomes isolated from plasma and cultural medium. Exosomes were analyzed by dynamic light scattering method and western blotting. Functional effects of exosomes were evaluated in in vitro and in vivo models. Results. In the present study we demonstrated that plasma exosomes stimulate the adhesion and the motility of breast cancer cells and induce the process of metastatic dissemination. Contact interaction of exosomes with cell surface is sufficient for stimulatory effect that is mediated by exosomal fibronectin and FAK-dependent signaling cascade. Conclusions. Further investigation of plasma exosomes structure and functions is required to better understand their input in regulation of malignant cell phenotype. This research has a potential to provide novel approaches for cancer therapy.

Blood levels of 8-hydroxy-2’-deoxyguanosine (8-OHdG) were measured by enzyme immunoassay after overnight fasting in untreated breast cancer and endometrial cancer patients ( N =170) of mainly postmenopausal age with and without type 2 diabetes mellitus. The concentrations of 8-OHdG in patients with breast cancer were higher than in patients with endometrial cancer and in patients with breast cancer and diabetes in comparison with patients with breast cancer without diabetes. No correlations of blood 8-OHdG levels with glycemia, age, and clinical stage of disease were detected. In cancer patients with diabetes, the concentration of 8-OHdG increases proportionally to the increase in body mass index, though this does not lead to disappearance of the above differences between patients with breast cancer and endometrial cancer by the level of 8-OHdG. The causes of the trend to a less favorable course of tumor process in patients with breast cancer and diabetes in comparison with endometrial cancer and diabetes deserve further studies.

The aim of the study was to assess efficacy and safety of combined therapy with dacarbazine and melatonin or metformin in comparison with dacarbazine alone in the 1st line of therapy of cutaneous melanoma. Thirty-six patients with disseminated melanoma, therapy naïve, were included between March 2014 and December 2015. Patients received DTIC 1000 mg/m2 in day 1 of 28-day cycle either as monotherapy (group 1) or in combination with melatonin 3 mg PO daily (group 2) or metformin 850 mg 2 times a day PO daily (group 3). Thirty-four patients were randomized (15-in group 1, 8 - in group 2, 13 - in group 3) and received 119 cycles of therapy. Response rate was 11% in groups 1 and 2, and 8,3% - in group 3 (p=0,57). Median time to progression was 52, 79 and 63 days, respectively in the 1st, 2nd and 3rd group (р=0,468). Two patients from the 2nd and 3rd group showed delayed response to therapy. No adverse events of grade 3-4 were seen. Thus, DTIC with melatonin or metformin was well tolerated. No meaningful increase of adverse event incidence was seen. No benefit of either combination was shown in this interim analysis. Delayed responses in melatonin and metformin combination groups were registered. This suggests immunologic effect of both drugs and warrants further study.

The role of real-time elastography or sonoelastography has been widely discussed recently. However, there are practically no publications which showed the influence of endocrine status in the process for improving of diagnostic value of this method; this issue was the aim of our study. 128 patients (31 – benign adenomas and 97 – thyroid cancer: 13 – follicular and 84 – papillary) were evaluated prospectively. Mean age was 48.3 ± 15.9 years. It was confirmed that the blue colour or 4–5 elastotype of sonoelastography was mainly discovered in thyroid cancer vs adenoma (73.2 % vs 25.8 %, χ2 = 18.96, р = 0.0001). Parameters of the sensitivity, specificity and accuracy were equal 90.7 %, 54.8 % and 82.0 % for sonoelastography, and 95.9 %, 45.2 % and 83.6 % for fine-needle aspiration biopsy, respectively. The combination of sonoelastography with fine-needle aspiration biopsy or with body mass index, presurgical glucose or thyroid-stimulating hormone level increased specificity of sonoelastography by 65.0 %, 70.0 %, 64.7 % and 63.2 %, respectively. Thus, sonoelastography had the same diagnostic accuracy as fine-needle aspiration biopsy in predicting of thyroid cancer. The specificity of sonoelastography could be increased by combination with fine-needle aspiration biopsy as well as thyroid-stimulating hormone or glucose level and body mass index value.

It is shown that endometrial cancer features (including expression of the PTEN and HER-2/neu proteins) are connected dissimilarly with body mass index and with the belonging of the patients to the groups with standard, SO and metabolically healthy obesity, MHO. In the course of the last half-century an increases are discovered in the height and weight of the females with endometrial cancer that moves in the opposite direction with a reduction of the share of MHO cases among obese patients. This conclusion should be taken into account when one considers the means for contemporary prevention of both obesity and cancer of uterine body.

There is now extensive proof that high percentage of mammographic density (MD) is an independent risk factor for breast cance.r Taking this into account, the research data are summarized with regard to relation of MD to anthropometric, as well as hormonal, genetic and genotoxic factors. There is a negative correlation between MD and such risk factors as age, number of deliveries, BMI and waist-hip ratio. Most inves- tigations show a direct connection between MD and prolactin level or insulin-like growth factor in blood, mostly in premenopaus al women. Relations of MD with blood estrogens, testosterone, sex hormone binding globulin prove to be too diverse to be taken in account of. It is pos- sible that the action of hormones, especially estrogens, is mediated through their metabolites catecholestrogens and / or reactive oxygen spe- cies. There is certain evidence that a genetic component plays a role in MD. It refers to COMT Val158Met, IGF-I rs6220 A> G and UGT1A1 in premenopausal women, and to ESR1 (XbaI и PvuII) in menopausal cases.Although it is obvious that the risk of breast cancer related to MD is brought about by many factors, there is a necessity for studying addi- tional criteria modifying the process, as well as for searching means for preventing it.

Over last ten years, the clinical significance of real-time elastography or sonoelastography (SEG) has been widely discussed for the discovery of thyroid cancer. However, there is no works which revealed the relation between parameters of SEG and endocrine status of the patients for improving of diagnostic value of this method; this issue was the aim of our study. 81 patients (20 - benign adenomas and 61 - thyroid cancer (TC): 13 - follicular and 48 - papillary) were evaluated prospectively. Mean age was 48.0 ± 16.4 years. It was shown that the blue colour or 4-5 elastotype of SEG was mainly discovered in TC vs adenoma (65.6% vs 20.0% χ2 = 12.61, р = 0.0004). At the same time, the Strain Ratio more than 3.0 was frequently revealed in TC patients vs adenoma (57.4% vs 40.0%) but it did not reach level of significance (χ2 = 1,83, р = 0,18). Parameters of the sensitivity, specificity and accuracy were equal 90.2%, 60.0% and 82.7% for SEG, and 96.7%, 40.0% and 82.7% for fine-needle aspiration biopsy (FNAB), respectively. The combination of 38 SEG with FNAB or with body mass index increased specificity of SEG by 65% and 70%, respectively. The combination of SEG with another measures of hormone-metabolic status (glucose level, TSH, thyroglobulin, etc) did not improve diagnostic accuracy of SEG. In result, SEG was slightly more specific than FNAB in predicting malignancy of the thyroid nodules. The specificity of SEG could be increased by combination with both FNAB and anthropometry. Further improvement of presurgical diagnosis of TC, especially follicular TC, could be possibly reached via the combination of cytological, hormonal, genetic and instrumental methods, including shear wave elastography.