Serum Levels of 8-Hydroxy-2'-Deoxyguanosine DNA in Patients with Breast Cancer and Endometrial Cancer with and without Diabetes Mellitus.

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.

[Hormone-associated properties and plasticity of omental fat: the relation with clinical-morphological features of endometrial cancer in patients with different obesity phenotypes].

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.

[Pre-surgical hormonal-metabolic state in endometrial cancer patients who underwent laparoscopy or laparotomy].

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.

[Obesity and characteristics of endometrial cancer: are there any changes over several decades?].

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.

[Microviscosity of erythrocyte membranes in breast cancer patients: connection with the receptor phenotype of the tumor].

The state of the viscosity of erythrocyte membranes in breast cancer patients (68--in menopause and 32--with menstrual cycle) was studied in comparison with the content of steroid hormone receptors in the tumor tissue and the age of patients. It is showed that the less hormone dependence of the tumor the higher viscosity of erythrocyte membranes that manifested by a decrease in the coefficient of eximerization (CE) of pyrene in the protein/lipid and in particular, lipid/lipid membrane layers. Increasing CE of pyrene in lipid/lipid layer of erythrocyte membranes above 1.7 units, reflecting a decline in their microviscosity, could be considered as an additional extra-tumor criterion for identification of the tumor as of hormone dependent type.

[Family diabetes and its consequences in cancer patients].

Preliminary data are confirmed on the more rare prevalence of family history of diabetes mellitus (DM) in cancer patients, mainly females, with diabetes in comparison with diabetics without cancer pathology. Familial diabetes does not worsen additionally tumor characteristics against the same in patients with non-familial diabetes. More than that, familial diabetes in diabetics with breast cancer goes together with lesser size of tumor and demonstrates an inclination to the rarer distant metastases in breast and endometrial cancer patients. The signs of systemic DNA damage (evaluated, in particular, on the basis of 8-OH-dG serum levels) are pronounced in postmenopausal diabetic cancer patients with familial diabetes in lesser degree than in non-familial variant of DM. In toto, this allows to consider family history of DM in patients with type-2 diabetes as a particular factor of tumor growth containment, which mechanisms and causes, warrant further studies.

[Hormonal-metabolic pattern of postmenopausal females with new onset of diabetes mellitus type 2: the role of cancer and hereditary predisposition to diabetes].

85 females were studied, 35 females had new onset of diabetes (DM2) and in 50 women DM2 was associated with recently diagnosed cancer (C+DM2). Group C+DM2 was characterized by higher levels ofbody mass index, insulinemia, estradiolemia, interleukin 6 in serum, and glyoxalase I activity in mononuclears. At the same time patients in C+DM2 group who had familial predisposition to DM2 were characterized by lower body mass index, body fat content, waist circumference, insulinemia, serum interleukin 6, viscosity of erythrocyte membranes and percent of comets in mononuclears in comparison with patients without familial predisposition to DM2. These trends were mostly opposite to the data of subgroups comparison (with or without relatives with DM2) in females with DM2 without cancer. The conclusion is made that the hereditary load with DM2 is differently realized in diabetics with higher or lower predisprosition to cancer that deserves further study.

Endocrine metabolic disorders in patients with breast cancer, carriers of BRCA1 gene mutations.

Two groups of breast cancer patients (53±2 years) in clinical remission receiving no specific therapy were examined: group 1, with BRCA1 gene mutations (N=11) and group 2, without mutations of this kind (N=11). The two groups did not differ by insulinemia and glycemia, insulin resistance index, blood levels of thyrotropic hormone, sex hormone-binding globulin, insulin-like growth factor-1, triglycerides, or lipoproteins. In group 1, blood estradiol level was higher. Intensive glucose-induced generation of reactive oxygen species in these patients was associated with a decrease of cholesterolemia, of the C-peptide/insulin proportion, and a trend to higher urinary excretion of 4-hydroxyestrone, one of the most genotoxic catecholestrogens. BRCA1 gene mutations in breast cancer patients were associated with signs of estrogenization and a pro-genotoxic shift in the estrogen and glucose system, which could modulate the disease course and requires correction.

[The influence of metformin and N-acetylcysteine on mammographic density in postmenopausal women].

Mammographic breast density (MBD) value is currently one of the strong predictors for mammary carcinoma development. There are also other conditions predisposing to MBD increase with hormone-related markers different from those used in breast cancer, while pharmacological methods for MBD reduction are few and still considered experimental. In the current study 25 postmenopausal women received daily for a median 10.5 months 1-1.5 g of antidiabetic biguanide metformin (siofor) (n = 14) or 400-600 mg of antigenotoxic drug N-acetylcysteine (n = 11). In both groups MBD was measured before and after treatment. The effects of both drugs were quite similar. Metformin use lead to lower MBD in 4 of 14 (28.5%) women with mean MBD decrease of -1,24% (absolute dynamics) and -5.03% (relative value). In N-acetylcysteine group this effect was observed in 27.3% of cases, with -2.0% absolute dynamics and -6.1% relative dynamics. In metformin group the most evident absolute and relative dynamics was observed in patients with no signs of metabolic syndrome, -10.86% compared to -2.45%. In 7 women the metformin use also lead to decrease of dense and increase of non-dense areas on digital scans, leading to decrease in dense to non-dense area volume ratio. Therefore, the similar effects of metformin and N-acetylcysteine are probably explained mostly not by insulin resistance elimination by metformin, but by altered cell proliferation, apoptosis and DNA repair.

[Decrease of testosterone level in blood of breast cancer patients of reproductive age after neoadjuvant chemotherapy].

Of examined 37 breast cancer patients (average age 42,3 +/- 1,2 years) 25 had not had any specific therapy by the date of investigation and the rest 12 had received in average 5,3 +/- 0,6 cycles of neoadjuvant chemotherapy mainly TAC and FAC. It was revealed that such kind of treatment conformed to valid decrease of both testosterone level and ratio value [(testosterone concentration/follicle stimulating hormone concentration, FSH) x 100] in blood serum. Testosterone level in blood of patients in fact decreased to similar values both in amenorrhea induced by adjuvant chemotherapy and saving menorrhea. This is a confirmation that maintenance of menorrhea does not mean intactness of ovarian function (ovarian reserve) and indicates that evaluation of testosteronemia in these circumstance at least does not give in estimation of estradiol and FSH's content in blood. Further attention could be paid to study testosteronemia before and after neoadjuvant chemotherapy as a potential additional prognostic factor of efficacy of this treatment for breast cancer patients.

[Clinical significance of three-week thyroglobulin test in patients with thyroid cancer undergoing thyroidectomy].

High level of thyroglobulin (Tg) after thyroidectomy has been shown to be an early marker of either metastases or local recurrence of differentiated thyroid cancer (DTC). The aim of this study was to evaluate the relation between Tg level estimated on the third week after thyroidectomy and clinic-pathologic characteristics of DTC as a possible prognostic criterion used to mark the patients with radioiodine therapy indications. Research data on 45 patients (39 women, 6 men, age 22-75 years) with DTC and without high level of Tg autoantibodies have been included in the study. Eleven patients underwent surgical treatment due to disease recurrence. In all patients Tg and thyroid hormones levels were measured before the thyroidectomy and on the third week after it. The postoperative level of Tg as TTM coefficient (ratio of postoperative Tg to daily L-thyroxin dose in mcg to body weight in kg) was higher in patients with unfavorable prognosis: (a) capsular invasion, (b) cervical lymph nodes metastases, (c) advanced disease stage, (d) high risk of recurrence. The postoperative serum Tg levels were similar in primary disease patients and patients with DTC recurrence. There was no relation between preoperative Tg level and any prognostic factors although there was a tendency to higher (more than 2 ng/ml) Tg levels in patents with high preoperative Tg levels. Finally, the serum Tg level on the third week after thyroidectomy is a valuable prognostic criterion and can be used in DTC to determine the radioiodine therapy indications.

[Features of carcinogenesis and aging in knockout male mice PARP-1].

Poly(ADP-ribosyl)ation polymerase-1 (PARP-1) is a major factor of DNA repair. Age-related parameters such as body weight and blood cholesterol in knockout male mice PARP-1 were more pronounced as compared with controls. Mean life span was shorter (486 +/- 31.7 and 723 +/- 22.6 days, respectively, (p = 0.000005) while initial risk of death (beta) was 8 times as high as in mice PARP-1(+/+). Mean latency of all tumors in knockout and control mice was 656 +/- 43.5 and 782 +/- 33.8 days, respectively, (p < 0.05). Among the most frequent neoplasms were tumors of the liver (experimental--22% and control--8%, respectively) (p = 0.03) and lungs (8% and 12%, respectively). Hence, mice PARP-1(-/-) revealed certain typical charhacteristics of accelerated aging, shorter life span, earlier carcinogenesis and higher rates of liver tumor incidence as compared with mice PARP-1(+/+). Our evidence highlights the role of DNA repair in carcinogenesis and aging.

[Study of dual ("joker") function of glucose in cancer patients].

A relationship was studied between generation of glucose-induced reactive oxygen species capable of causing damage to DNA (genotoxic or G-effect) and insulin secretion (endocrine or hormonal effect - H-effect) in primary menopausal patients with endomrnetrial carcinoma (EC) (32) or colonic cancer (CC) (16). The study group was compared with healthy menopausal women (25) and patients with an impaired glucose tolerance (IGT) (21). Besides, we examined 32 menopausal patients (CC--6 and EC--26) more than 12 months after surgery. The following basic patterns were established: (1) H-effect was reported in EC-1 and 1GT groups nmore often than in healthy peers and those with EC-2: (2) G-effect tended to prevail in CC patients and those with EC-2 and in patients with EC-1 twelve months after operation; (3) G-effect occurred more often in primary EC patients, particularly, those with EC-2 (71%) and IGT (58%) (as compared with CC patients (33%) and healthy females (p < or = 0.001). It is suggested that a comparison of the two effects might provide a criterion for use of relevant means of prevention of certain malignancies or correction of disorders in cancer patients following radical treatment.

Evaluation of the proportion of hormonal and progenotoxic effects of estrogens and glucose in cancer patients.

he progenotoxic (G, generation of reactive oxygen forms in mononuclears) and hormonal (H, reactive insulinemia) effects of oral glucose, on the one hand, and the same effects of estradiol (10(-8)and 10(-5)M) in vitro on blood mononuclears (G: by comet tail length; H: by expression of AMP kinase and TNF and IL-6 secretion), on the other, were compared with consideration for the concepts on endocrine genotoxic switch-over in patients with breast cancer and endometrial cancer in remission. Coculturing of mononuclears with estradiol in general led to an increase in comet tail and was associated with a trend to more intense expression of AMP kinase and IL-6 secretion. The reaction to estradiol (primarily in a concentration of 10(-8)M) evaluated by the expression of AMP kinase and TNF secretion was more intensive than the reaction evaluated by comet tail lengths or by percentage of cells with comets in women with predominating progenotoxic effect of glucose vs. hormonal effect. This fact can be used as a landmark in search for means for optimization of the status and proportion of effects in the estrogen and glucose systems.

[Influence of metformin and N-acetylcysteine on hormonal and genotoxic effects of estrogens and glucose in convalescent cancer patients].

Our study involved 25 postmenopausal patients (endometrial carcinoma--16, breast (6) and colorectal (3) cancer, aged 56.8 +/- 0.9). All patients were in clinical remission. None had received any specific therapy for at least 12 months. After a laboratory endocrine-genotoxic switch evaluation, 17 patients were given an antidiabetic drug--biguanide metformin--or N-acetylcysteine as antioxidant (8) for 3 months. A checkup was carried out on completion of the course. As a result, hormonal and progenotoxic effects of glucose were found to be inhibited significantly. Much less pronounced was the impact on relevant effects of estradiol which were investigated vis-a-vis nature of blood mononuclear response in vitro. Both isolated and combined administration of said drugs used for endocrine-metabolic rehabilitation is justified.

[Criteria for evaluating the effectiveness of aromatase inhibitors in the neoadjuvant treatment of patients with endometrial carcinoma].

Clinical and experimental effects of neoadjuvant treatment of endometrial cancer patients with non-steroidal aromatase inhibitors: letrozole (femara, n=10, 2.5 mg/day, 14 days), anastrozole (arimidex, n=15,1 mg/day, 28 days) and exemestane (aromazine, n=13, 25 mg/day, 14 days) were compared. Administration of anastrozole was mostly frequently followed by pain relief in the lower abdomen and/or decreased rates of uterine discharge. Endometrial wall thickness (M-echo signal) decreased significantly in 60% of patients receiving anastrozole, exemestane - 58.3% and letrozole - 40%. Substantial drop in intratumoral aromatase and blood estradiol levels occurred more frequently after anastrozole and letrozole while progesterone receptor levels in tumor were markedly lower after exemestane administration. Assay of blood LH (except letrozole), FSH and cholesterol appeared to be of less relevance. On the contrary, significance of assessment of marker Ki-67 expression, which, in the case of anastrozole, dropped in 6 out of 12 patients after a 28-day course, could hardly be underestimated.

[Autoantibodies to steroid-producing ovarian cells in cancer patients].

Our investigation included 158 women, aged 23-73: patients with tumors of the ovary, breast and endometrium--117 and subjects without oncological pathology--41. Autoantibodies to microsomal fraction of follicular ovarian cells (> 500 Unit/ml) in healthy subjects were revealed 8.3% while in patients with ovarian, breast and endometrial malignancies (without significant differences between benign and malignant tumors) in 33.30%, 45.60% and 25.0%, respectively. Higher level of anti-ovarian autoantibodies involved an inverse correlation between blood levels of FSH and estradiol in ovarian and endometrial carcinoma patients. It also co-occurred with a tendency of increasing levels of autoantibodies to thyroglobulin. Whatever apparent predictive accuracy in oncological clinic, high concentrations of anti-ovarian autoantibodies point to certain shifts taking place in the formation of reproductive system pathology. Besides, they may have considerable prognostic significance.

[The dual (joker) function of glucose: study of its association with aging and glucose metabolism disorders].

Relation was studied between generation of glucose-induced reactive oxygen species (ROS), which appear to be related to DNA damage (genotoxic effect, G), and insulin secretion (endocrine or hormonal effect, H) in women of different ages (one group under 45 and the other one over 45; n=25 and n=14, respectively). The healthy women in those two groups were compared with patients in whom we had found an impaired glucose tolerance (IGT) or type 2 diabetes mellitus (DM) (n=17, mean age 57.3 +/- 2.7). The hormonal effect of glucose was more pronounced in the senior group, and especially in group with IGT, if compared with the younger group. Genotoxic effect of glucose was discovered more frequently in the younger group, mainly in smoking women. Comparison of G/H effects showed that the evaluation of glucose-induced genotoxity (GIGT) was more frequent in the IGT group than in the senior group (p < 0.05). No difference was detected in the GIGT frequency values in the two healthy groups. It may therefore be concluded that GIGT did not increase within the ambit of ageing studied in this work, while it increased in the IGT group. It is possible that the high frequency of the G effect in the IGT group could be a marker of oxidative stress and/or predisposition to complications in DM. The dual (joker) function of glucose and the prevalence of G effects over H effects may be of use in choosing the method of correction for each particular case.

[Progenotoxic shift in mammary adipose tissue (adipogenotoxicosis): association with clinical and biological characteristics of breast cancer].

The study is concerned with identification of a relationship between levels of production and accumulation of compounds capable of hormonal and progenotoxic effects in mammary fat, on the one hand, and characteristics of tumor tissue in breast cancer, on the other. Mammary fat was sampled at a distance of 1.5-2 cm from tumor edge (79 pts.). Case histories were used to provide data on clinical stage, size, grade and regional lymph node involvement. Levels were assayed of leptin, adiponectin, tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6), nitric oxide (NO), thiobarbiturate-reactive products (TBRP) and DNA oxidative damage marker (8-OH-dG) from 4hr-incubates of fat tissue culture. Mammary fat aromatase was assayed by radiometrical means while macrophage-assisted fat infiltration (CD68) and estrogen-4-hydroxylase (CYP1B1) expression were evaluated immunohistochemically. Radio-competitive and immunohistochemical methods were used to assay estrogen (ER) and progesterone (PR) receptor levels in tumor and tumor-related expression of cytokeratins 5/6 ("basal") and 7/8 ("luminal" epithelium), respectively. As far as hormonal properties of mammary fat were concerned, there were direct correlations between aromatase concentration, on the one hand, and tumor stage and size, on the other, and adiponectin secretion and CK7 expression in tumor. Besides, an inverse correlation was found between mammary fat-mediated release of leptin and adiponectin, on the one hand, and stage and regional lymph node involvement, on the other. The following main relationships were identified by comparison of the clinico-biological characteristics of tumor and markers of proinflammatory/progenotoxic properties of mammary adipose tissue: tendency toward direct correlation with IL-6 and 8-OH-dG in fat (tumor progress stage); direct correlation with TNF-alpha secretion rate (malignancy grade); lymph node involvement--tendency toward direct correlation with NO generation; CK5 expression in tumor--tendency toward direct correlation with 8-OH-dG, TBRP and CD68 fat infiltration; CK7 expression in tumor--tendency toward inverse correlation with NO generation in adipose tissue; ER-negative phenotype of tumor--tendency toward higher generation of TBRP, NO and TNF/leptin in fat. Hence, shift toward predominance of proinflammatory/progenotoxic properties of mammary adipose tissue (adipogenotoxicosis) is associated with signs of less favorable course of tumor process in the mammary gland which calls for working out adequate measures.

[Gail coefficient as a risk factor and prognosticator for the course of breast cancer: correlation with hormonal and metabolic parameters and clinical and morphologic features].

Gail coefficient (GC) generally used in breast cancer predictions for the next 5 year--or entire survival was determined in both patients and healthy controls of the same age, residents of St. Petersburg. Simultaneously, a correlation was established with hormono-metabolic indices, receptor pattern, tumor stage and size and some other characteristics. GC in cancer patients with age <50 was significantly higher than in control. In menopausal cancer patients, greater GC correlated with such parameters as body mass, weight index, glucose, total cholesterol and low density lipoproteids after fasting. The latter group showed a tendency towards enhanced estradiol and testosterone in blood serum. In reproductive patients with elevated GC, estradiol level rise was significantly lower and most tumors were receptor-negative. However, involvement of regional nodes was relatively rare. To summarize, GC determination characterizes risk and certain clinico-morphological features of distinction between reproductive and menopausal patients.