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Tursunova Nodira Isroilovna, assistant of department Oncology, Tashkent Medical Academy E-mail: dr.nik8888@mail.ru Atakhanova Nigora Ergashevna, Head of department Oncology Tashkent Medical Academy E-mail: nigora_atakhanova@tma.uz
THE SIGNIFICANCE OF PREOPERATIVE RADIATION THERAPY IN THE TREATMENT OF UTERINE BODY CANCER, DEPENDING ON P53 AND BCL-2
Abstract:
Actuality: Endometrial cancer occupies the first place in the structure of oncological pathology, the rate of growth of incidence rates of endometrial cancer is higher than those of other malignant tumors of the reproductive system in women.
Objective: to determine the value of preoperative brachytherapy in patients with endometrial cancer, depending on the state of the mutant gene p53 and the regulator of apoptosis bcl-2.
Methods: We studied 105 patients with stage I-II endometrial cancer for the period from 2006 to 2016. Immu-nohistochemical method was used to study the genes of apoptosis p 53 and bcl-2 in materials taken during scraping of the uterine cavity, as well as the endometrium of operated uterus preliminarily subjected to pre-operative radiotherapy on the apparatus "Moulti Soursce BEBIG".
Results: Analysis of survival data of patients showed a significant advantage of patients receiving preoperative brachytherapy. 5-year disease-free survival in the control group was 60 ± 8.6%, while in the main group there was 89 ± 9.9%, respectively ^ < 0.05).
Conclusion: brachytherapy to split the mutant p 53 gene and regulator (inactivator) of apoptosis ofbcl-2 in intact tissues prior to invasive manipulation of endometrial cancer in patients.
Keywords: endometrial cancer, brachytherapy, immunohistochemistry, p 53, bcl-2.
Endometrial cancer is a tumor with a complex mecha- Analyzing data on the frequency of local tumor recurrenc-
nism of malignant transformation of the uterine epithelium, es (in 10-15% of patients), regional and distant metastases in the occurrence of which play a roleendocrine-metabolic (in 12-27% of patients), which are the main causes of mortal-disturbances caused by the damage to neurohumoral systems ity from cancer of this localization [1; 6; 7], it is necessary to responsible for the correlation between various organs of the state that the possibility of radiotherapy in the treatment of reproductive and endocrine systems [2; 3; 9]. endometrial cancer has not yet been fully realized.
The study of the regularity of the appearance of endo- Last decades made significant changes in radiobiologi-
metrial tumors and the nature of organ / out-of-organ dis- cal, methodological and even strategical approaches to radia-semination, as well as an analysis of the causes of the devel- tion therapy as one of the main special methods of antitumor opment of relapses and metastases of endometrial cancer, treatment of malignant neoplasms of the female reproductive significantly weakened the opinion about the relatively "be- system and, in particular, endometrial cancer. nign" course of malignant tumors of the uterus body. It has The aim of the study is to determine the value of pre-
been shown that even within a single clinical stage of the operative brachytherapy in patients with endometrial can-disease, the results of treatment can vary widely, depending cer, depending on the state of the mutant gene p 53 and the on the risk factors [1; 5; 8]. regulator of apoptosis bcl-2.
Evaluation of the results of treatment of endometrial can- Materials and methods
cer indicates a high efficiency in the initial stages of combina- The study analyzed the data of105 patients with stage I-II
tion therapy, which allows achieving a 5-year survival rate in endometrial cancer treated at the Tashkent City Oncology 85-95% of patients with stage I, 65-70% with stage II and Dispensary for the period from 2006 to 2016. The medical his-only 29% with stage III [2; 4; 5; 9]. tory, polyclinic cards, protocols of operations, the description
of surgical preparations, histological and immunohistochemi-cal conclusions were studied.
Morphological confirmation of the diagnosis was obtained in all 105 patients with endometrial cancer. In the study we used the materials from scraping the uterus cavity, as well as the endometrium of the operated uterus, previously subjected to pre-operative radiotherapy on the apparatus "Moulti Soursce BEBIG".In the study of histological preparations were taken into accountthe following factors: the nature of tumor growth, the depth of invasion in the myometrium, the necrosis focus in the tumor, and the degree of malignancy of the tumor.
A mutant apoptosis gene ofp 53 and an apoptosis regulator ofbcl-lymphocytes were studied using an avidin-biotin peroxidase method (ABC kit, Vector Laboratories, Burlingame, CA) and using mouse antibodies, anti-human monoclonal antibodies, clone D07 (DAKO, Copenhagen, Denmark) 2.
All patients were divided into 2 groups: I - the main group of patients comprised 60 patients, who received preoperative brachytherapy in a total focal dose (TFD) of 20 Gy, followed by surgical intervention in the volume of extirpation of the uterus with appendages within 24-48 hours. After the operation, all patients received intracavitary radiotherapy up to 40 Gy on TFD, as well as remote gamma therapy on the "TERA.-BALT" device in a TFD of 40-50 Gy.
II - a control group was made up of 45 women who, after scraping the uterine cavity and verifying the diagnosis, immediately underwent surgical treatment, after which they received combined radiation therapy (remote gamma therapy TFD = 40-50Gy + intracavitary radiotherapy TFD = 30-40Gy).
For every patient, a special card was inserted, which included 97 signs characterizing the features of the organism, the disease, the treatment performed and the follow-upre-sults. The received data were entered into the memory of a personal computer PC Pentium IV and processed using a set of application programs. The computation and comparison of the reliable differences in the average values, as well as the comparison of the reliability of the differences in the event frequencies (using the Student's t-test), were carried out using a package for computer analysis of SAS.
Statistical analysis of the data was carried out using the standard Statistica software package (version 7.0, Statsoft Inc., USA). Survival analysis (using the Kaplan-Mayer method) and evaluating the reliability of differences were performed using a log-rank test using the "Survival" program. Differences were considered reliable atp < 0.05.
Results and discussion
In the main group endometrioid adenocarcinoma was diagnosed in 41(68.3%) patients, of which a highly differentiated adenocarcinoma was observed in 19(31.6%), moderately differentiated in 16(26.3%), low-grade in 6(10.5%) patients, respectively. Rare forms of uterine cancer have also been observed, such as glandular-squamous cell carcinoma in 9(15%), serous-papillary carcinoma in 10(16.6%) patients, respectively. In the control group, the histological distribution of patients was carried out according to the following: endometrioid adenocarcinoma - 27(60%), of them highly differentiated in 20(44.5%), moderately differentiated in 5(11.1%) patients, low-grade in 2(4.4%) of the patient, glandular-squamous cell carcinoma - 11(24.4%), serous-papillary carcinoma in 7(15.6%) patients, respectively.
Figure 1. Distribution of patients depending on the histological type of bcl-2 and p 53 positive patients
In the main group from 60 patients 43(71.6%) patients were positive with bcl-2, 19(31.6%) of them highly differentiated, 10(16.7%) moderately differentiated, 4(6.7%) low-grade adenocarcinomas, 6 (10%) glandular-squamous carcinomas, and 4(6.7%) serous-papillary carcinomas. At the same time mutant p53 was detected in 48(80%) patients. The distribution of these 48 p53 expressed patients was as follows: 10(16.7%) - highly differentiated, 14(23.3%) - moderately differentiated, 6(10%) - low-grade adenocarcinoma, 9(15%) - glandular squamous cell carcinoma, 9(15%) - serous-papillary carcinoma.
In the control group from 45 patients 21(46.7%) patients with endometrioid adenocarcinoma were bcl-2 positive, (17(37.8%) - highly differentiated, 2(4.4%) - moderately differentiated, 2(4.4%) - low-grade adenocarcinoma) and 4(8.9%) patients with glandular-squamous cell carcinoma and 6(13.3%) patients with serous-papillary carcinoma were positive. Expression of p 53 was detected in 39(86.7%) patients (except for 6 patients with highly differentiated adeno-
carcinoma
Figure 2. Distribution of patients depending on the splitting of bcl-2 and p 53 genes after predoperative brachytherapy.
In the analysis of postoperative materials, it was revealed that after the preoperative brachytherapy in 15 patients with (78.9%) highly differentiated, 8 patients with moderate (80%) and low-grade adenocarcinoma, and in all patients with rare forms of cancer of the uterus, the tumor became bcl- 2 negative. Also splitting of the mutant p 53 gene was detected in 87.5% of patients (except for 2 patients with low-grade adenocarcinomas, 1 patient with glandular-squamous adenocarcinoma, 3 patients with serous-papillary adenocar-cinomas) (p < 0.05).
In the study of postoperative materials in the control group, it was found that the values of bcl-2 and mutant p 53 remained the same as in endometrial scraping, i.e. without changes.
Analysis of survival data of patients showed a significant advantage of patients in the main group. 5 - year recurrence-free survival in the control group was 60 ± 8.6%, while in the main group there was 89 ± 9.9%, respectively (p < 0.05).
In the control group, 14 patients had relapsed disease, 3 lung metastases and 2 bone metastases for 3 years. In the main
group, 3 patients had metastases in the bone, 3 patients with metastases in the lungs and 1 patient with a recurrence of the vaginal stump with accumulation of ascites fluid.
Conclusion: According to the results of immunohisto-chemical staining of sections for the study of Bcl-2 protoon-cogene, Bcl-2 positive tumors were mainly found in high-and moderate differentiated endometrioid adenocarcinomas (62%) and glandular-squamous cell carcinomas (78%).
Mutant p 53 was detected in serous-papillary tumors 1.3 times more often than in endometrioid adenocarcinoma (p < 0.05). When studying the degree of malignancy of the endometrioid adenocarcinoma, p 53 was directly correlated with a low degree of tumor differentiation (G3).
In preoperative brachytherapy, disease-free survival of patients increases to 89 ± 9.9%, compared with patients who did not receive neoadjuvant intracavitary radiation therapy. This is explained by the possibility of brachytherapy to cleave the mutant p 53 gene and regulator (inactivator) of apoptosis of bcl-2 in intact tissues prior to invasive manipulation of endometrial cancer in patients. Also, the transportability of tumor
cells and, consequently, the danger of their intraoperative dis- Conflicts of interest: The authors received no financial
semination decreases, at that time increasing the indices of the support for their research, and they report no conflicts of in-
disease-free period and overall survival. terest. The authors alone are responsible for the content and
writing of the paper.
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