Научная статья на тему 'Clinical and immunological aspects of patients with ovarian cancer on the background of accompanying immunotherapy'

Clinical and immunological aspects of patients with ovarian cancer on the background of accompanying immunotherapy Текст научной статьи по специальности «Клиническая медицина»

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Ключевые слова
РАК ЯИЧНИКОВ / OVARIAN CANCER / ИММУНОТЕРАПИЯ / IMMUNOTHERAPY / ЭКСТРАКОРПОРАЛЬНАЯ ИММУНОФАРМАКОТЕРАПИЯ / EXTRACORPOREAL IMMUNOPHARMACOTHERAPY / ПЛАЗМАФЕРЕЗ / PLASMAPHERESIS / ЦИТОКИНЫ / CYTOKINES / ПОЛИХИМИОТЕРАПИЯ / POLYCHEMOTHERAPY

Аннотация научной статьи по клинической медицине, автор научной работы — Kamishov Sergey Viktorovich, Akhmedov Odil Mukhammadjanovich, Alimova Sanobar Sabirovna

Цель исследования: Изучить клинические и иммунологические аспекты пациенток с раком яичников II-III стадии при комплексном лечении с сопровождающей иммунотерапией. Материалы и методы исследования: В общей сложности 270 пациенток со стадией O2 T2-3N0-1M0 (II-III клинические стадии), которые были обследованы и прошли лечение в отделениях онкогинекологии и химиотерапии Республиканского специализированного научно-практического медицинского центра онкологии и радиологии в Министерство здравоохранения Республики Узбекистан с 2006 по 2015 год были включены в исследование. На этапе клинического обследования у всех пациенток с РЯ собирали историю болезни, анамнестические данные, проводили общее обследование. Все пациентки прошли клинико-лабораторные анализы крови, которые включали изучение общего анализа крови и мочи, биохимических параметров и свертывания крови. Результаты исследования: мы обнаружили увеличение провоспалительных цитокинов в сыворотке периферической крови пациенток с раком яичников. Включение в комплекс сопутствующего лечения ЭИФТ и ЭИФТ + ПФ является одним из способов снижения эндогенной интоксикации во время противоопухолевой лекарственной терапии. Выводы: проведенные исследования показали, что наиболее эффективны в снижении побочных эффектов химиотерапии при комплексном лечении пациентов с РЯ II-III стадией, а также в улучшении субъективного состояния пациентов и их качества жизни, схем иммунотерапии, включающих использование ЭИФТ и ЭИФТ +ПФ, которые уменьшают основные клинические проявления токсичности химиотерапии, улучшают субъективное состояние пациента.

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The aim of the study is to study the clinical and immunological aspects of patients with stage II-III ovarian cancer in complex treatment with accompanying immunotherapy. Materials and methods of research: a total of 270 patients with stage O2 T2-3N0-1M0 (II-III clinical stages) who were examined and treated in oncogynecology and chemotherapy departments of the Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology at the Ministry of Health of the Republic of Uzbekistan from 2006 to 2015 were included in the survey. All patients underwent clinic-laboratorial blood tests, which included the study of a general analysis of blood and urine, biochemical parameters, and blood coagulation. The results of the research: we found an increase in proinflammatory cytokines in the serum of peripheral blood of patients with ovarian cancer. Inclusion in the complex of accompanying treatment of EIPHT and EIPHT + PPh, is one of the ways to reduce endogenous intoxication during antitumor drug therapy. Conclusion: The conducted studies showed that the most effective in reducing the side effects of chemotherapy in the complex treatment of patients with OC stage II-III, as well as in improving the subjective state of patients and their quality of life, immunotherapy schemes including the use of EIPHT and EIPHT + PPh, which reduce the main clinical manifestations of the toxicity of chemotherapy, improves the subjective state of the patient.

Текст научной работы на тему «Clinical and immunological aspects of patients with ovarian cancer on the background of accompanying immunotherapy»

Her-2/neu correlates with the prognostically unfavorable signs of the clinical course of the OC.

References

1. Antoni P.A. CD4+CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2// J. Immu-nother.- 2005. -Vol.28.-P.120-128.

2. Chen L., Flies D.B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227-242.

3. Curiel T.J., Coukos G., Zou L., Alvarez X., Cheng P., Mottram P., et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature medicine. 2004;10:942-948.

4. Gubser, P. M. et al. Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14, 1064-1072 (2013).

5. Hamanishi J., Mandai M., Iwasaki M., Okazaki T., Tanaka Y., Yamaguchi K., et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:3360-3365.

6. Hassan M., Watari H., AbuAlmaaty A., Ohba Y., Sakuragi N. Apoptosis and molecular targeting therapy in cancer. Biomed Res Int 2014; 2014: 150845, http://dx.doi. org/10.1155/2014/150845.

7. Kandalaft L.E., Powell D.J. Jr., Singh N., Coukos G. Immunotherapy for ovarian cancer: what's next? J ClinOncol 2011;29:925-933.

8. Sato E., Olson S.H., Ahn J. et al. Intraepithe-lial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. ProcNatlAcadSci USA 2005;102:18538-18543.

9. Sato E., Olson SH., Ahn J., Bundy B., Nishi-kawa H., Qian F., et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proceedings of the National Academy of Sciences of the United States of America. 2005;102:18538-18543.

10. Spontaneuse apoptosis in ovarian carcinomas a positive association with p53 gene mutation is dependent on growth traction / J. Kupryjanezyk, A. Dansonka Mieszkowska, T. Szymanska [et al.] // J. Cancer (Scotland).— 2000.— Vol. 82.— P. 579-583.

Information about the main author:

9. Kamishov Sergey Viktorovich

10. MD, PhD, chemotherapeutist of chemotherapy department

11. Senior researcher

12. ID: ORCID 0000-0002-1581-6032

13. Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry of Health of the Republic of Uzbekistan, Tashkent, Uzbekistan

14. 100174, Uzbekistan, Tashkent, 383 Farabiy

st.

15. +998 90 978 65 38

16. E-mail: sergei_kamyshov@mail.ru

UDC:615.028-614.03.46-8_

CLINICAL AND IMMUNOLOGICAL ASPECTS OF PATIENTS WITH OVARIAN CANCER ON THE BACKGROUND OF ACCOMPANYING _IMMUNOTHERAPY_

Kamishov Sergey Viktorovich

MD, PhD, senior researcher, chemotherapeutist of chemotherapy department

Akhmedov Odil Mukhammadjanovich MD,PhD, head of oncogynecology Department Alimova Sanobar Sabirovna

MD, chemotherapeutist of chemotherapy department Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry

of Health of the Republic of Uzbekistan, Tashkent, Uzbekistan

АННОТАЦИЯ

Цель исследования: Изучить клинические и иммунологические аспекты пациенток с раком яичников II-III стадии при комплексном лечении с сопровождающей иммунотерапией. Материалы и методы исследования: В общей сложности 270 пациенток со стадией O2 T2-3N0-1M0 (II-III клинические стадии), которые были обследованы и прошли лечение в отделениях онкогинекологии и химиотерапии Республиканского специализированного научно-практического медицинского центра онкологии и радиологии в Министерство здравоохранения Республики Узбекистан с 2006 по 2015 год были включены в исследование. На этапе клинического обследования у всех пациенток с РЯ собирали историю болезни, анамнестические данные, проводили общее обследование. Все пациентки прошли клинико-лабораторные анализы крови, которые включали изучение общего анализа крови и мочи, биохимических параметров и свертывания крови. Результаты исследования: мы обнаружили увеличение провоспалительных цитокинов в сыворотке периферической крови пациенток с раком яичников. Включение в комплекс сопутствующего лечения ЭИФТ и ЭИФТ + ПФ является одним из способов снижения эндогенной интоксикации во время противоопухолевой лекарственной терапии. Выводы: проведенные исследования показали, что наиболее эффективны в снижении побочных эффектов химиотерапии при комплексном лечении пациентов с РЯ II-III

стадией, а также в улучшении субъективного состояния пациентов и их качества жизни, схем иммунотерапии, включающих использование ЭИФТ и ЭИФТ +ПФ, которые уменьшают основные клинические проявления токсичности химиотерапии, улучшают субъективное состояние пациента.

Ключевые слова: рак яичников, иммунотерапия, экстракорпоральная иммунофармакотерапия, плаз-маферез, цитокины, полихимиотерапия

ABSTRACT

The aim of the study is to study the clinical and immunological aspects of patients with stage II-III ovarian cancer in complex treatment with accompanying immunotherapy. Materials and methods of research: a total of 270 patients with stage O2 T2-3N0-1M0 (II-III clinical stages) who were examined and treated in oncogynecology and chemotherapy departments of the Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology at the Ministry of Health of the Republic of Uzbekistan from 2006 to 2015 were included in the survey. All patients underwent clinic-laboratorial blood tests, which included the study of a general analysis of blood and urine, biochemical parameters, and blood coagulation. The results of the research: we found an increase in proinflammatory cytokines in the serum of peripheral blood of patients with ovarian cancer. Inclusion in the complex of accompanying treatment of EIPHT and EIPHT + PPh, is one of the ways to reduce endogenous intoxication during antitumor drug therapy. Conclusion: The conducted studies showed that the most effective in reducing the side effects of chemotherapy in the complex treatment of patients with OC stage II-III , as well as in improving the subjective state of patients and their quality of life, immunotherapy schemes including the use of EIPHT and EIPHT + PPh, which reduce the main clinical manifestations of the toxicity of chemotherapy, improves the subjective state of the patient.

Key words: ovarian cancer, immunotherapy, extracorporeal immunopharmacotherapy, plasmapheresis, cy-tokines, polychemotherapy

Topicality. Thanks to modern achievements of fundamental immunology, molecular biology, biotechnology and genetics, biologically significant indicators have appeared in the arsenal of researchers that can help in the diagnosis, treatment and prediction of various diseases, as well as in the selection of immunotherapeu-tic approaches to therapy. In this regard, in recent years much attention has been paid to cytokines, which are a kind of intercellular language that allow cells to communicate and interact [1,-P. 169; 5,-P.5896; 9,-P.2410]. Cytokines are proteins that are produced primarily by activated cells of the immune system, which provide the function of intercellular cooperation, positive and negative immunoregulation of the body's protective functions [10, -P. 23]. It is known that cytokines regulate the amplitude and duration of inflammatory and immune responses [4,-P. 88;7, -P.3399; 9,-P. 2410]. To date, more than 200 individual substances belonging to the family of cytokines are already known [4,-P. 88; 6, -P. 3591]. Today, cytokines can be isolated into a new independent system of regulation of the body's basic functions that exists along with the nervous and endocrine systems, and is associated primarily with the maintenance of homeostasis [10, -P. 23-27]. At the tissue level, cytokines are responsible for the development of inflammation, and then tissue regeneration. With the development of a systemic inflammatory reaction (acute response), cytokines affect virtually all organs and systems of the body involved in the regulation of homeostasis [1, -P. 169;5,-P. 5896].

Studies of cytokine levels in various human diseases are based on the fact that cytokines are key factors in the immunopathogenesis of a number of immunode-ficient (immunologically-dependent) diseases. Immunodeficiencies are independent diseases and concomitant syndromes, which are characterized by a deficiency of the immune system. Secondary (acquired) immunodeficiency is a clinical and immunological syn-

drome that develops against the background of a previously normally functioning immune system, is characterized by a stable pronounced decrease in the quantitative and functional indices of specific and / or nonspecific immunoresistance factors and is a risk zone for the development of chronic infectious diseases, autoimmune pathology, allergic diseases and tumor growth [10, -P. 23].

Throughout the world, one of the directions of modern medicine, is the study of the role of cytokines in the pathogenesis of diseases. The literature highlights the multifaceted aspects of the study of cytokines in immunodeficient states. However, despite numerous studies in the field of cytokine levels, many questions of complex analysis of cytokines in infectious, autoimmune, immunoproliferative and allergic processes require further study. The cytokine spectrum is an integral indicator, the determination and analysis of which is a necessary clinical and laboratory criterion in the diagnosis of immunodeficiency states. A number of scientific evidences are developing, according to which in the process of neogenesis there is a disbalance between the production of pro-neoplastic (IL-6, IFN-a / fi), antineoplastic (IL-2, TNF-a), and other regulatory cy-tokines. In addition, despite the improvement of diagnostic methods, the treatment of ovarian cancer remains one of the urgent problems of oncology, which is caused by unsatisfactory results of therapy of this disease. Ovarian cancer (OC) occupies a stable 3rd place in the structure of oncogenital pathology. Mortality from OC exceeds mortality from cervical cancer and uterine body combined, despite the advances in diagnosis and treatment. The asymptomatic course of the disease in the early stages, leading to late treatment to the doctor, and, consequently, to detectability with already widespread stages of the disease (up to 70%) leads to a high mortality of patients. The course of the tumor process, in particular, with OC, is accompanied by the formation of endotoxicosis and secondary immune deficiency. It

should be noted that endotoxicosis is a complex, multi-component process that is caused by the accumulation of endotoxic substances in tissues and biological fluids in conditions of a decrease in the physiological processes of detoxification. Carrying out chemotherapy promotes the further growth of endogenous intoxication, suppression of the body's immunocompetence, which complicates the course of the main oncological disease, and sometimes, in the development of organ and systemic disorders, limits the possibilities for an adequate course of antitumor treatment [6, -P. 3591]. Despite the high sensitivity of the tumor to OC to the effects of modern cytostatic drugs, often the possibilities of antitumor treatment are limited, which is associated with their high toxicity and the severity of metabolic disorders at the level of the whole organism [1, -P. 169; 3, -P. 2246]. To increase the possibility of timely chemotherapy, great importance is attached to methods leading to a decrease in endogenous intoxication and an increase in the body's immunoreficiency. Such methods include plasmapheresis and extracorporeal im-munopharmacotherapy. As is known, the use of plas-mapheresis in the complex treatment of cancer patients with the presence of tumor intoxication should be considered as one of the leading methods of detoxification, based on the mechanisms and effects of its effect on the body. The detoxification effect of plasmapheresis lies not only in the direct removal of toxins, xenobiotics, biologically active substances and other various pathological substances from the bloodstream, but also in the active drainage action on the intercellular space, the deprotection of the cellular receptors of organs and the systems of physiological detoxification that lead to an intensification of toxin elimination mechanisms. In connection with the foregoing, immunotherapy is a relatively new direction in which approaches to its implementation, specific techniques, timing, the possibility of combining with other methods of treatment remain insufficiently studied and developed, and, naturally, insufficiently described in the literature.

The aim of the research is to study the clinical and immunological aspects of patients with stage II-III of ovarian cancer in complex treatment with accompanying immunotherapy.

Materials and methods of research. A total of 270 patients with stage O2 T2-3N0-1M0 (II-III clinical stages) who were examined and treated in onco-gynecology and chemotherapy departments of the Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology at the Ministry of Health of the Republic of Uzbekistan from 2006 to 2015 were included in the survey. In accordance with the objectives of the study, patients with OC were randomized to the following groups to assess the effect of immunotherapy on the spectrum of the main cytokines in the complex treatment: the 1st group - 42 practically healthy individuals; the 2nd group - 42 patients with OC before PCT; the 3rd Group - 62 patients with OC after PCT without immunotherapy; the 4th group - 58 patients with OC after PCT in combination with extracorporeal immunopharmacotherapy (EIPHT); The 5th Group - 54 patients with OC after PCT in combination

with extracorporeal immunopharmacotherapy and plas-mapheresis (EIPHT + PPh). The age of patients with ovarian cancer was 23 to 75 years, the average age was 42.6 ± 6.5 years. At the stage of clinical examination in all patients, the OC performed a history of the disease, anamnestic data, a general examination. All patients underwent clinico-laboratory blood tests, which included the study of a general analysis of blood and urine, biochemical parameters, and blood coagulation.

Combined therapy in adjuvant or neoadjuvant regimen was conducted in all patients with OC, including cisplatin polychemotherapy 75 mg / m 2 + cyclophos-phamide 1000 mg / m 2 for 1 day for 4-6 courses 1 time per 3 weeks and surgical treatment in the volume of a radical surgery (Table 2.2). Chemotherapy was performed in both adjuvant and neoadjuvant regimens. EIPHT and EIPHT + PPh in patients with OC using immunomodulators were carried out during the period of radiotherapy and chemotherapy in the hospital. The method of extracorporeal immunopharmacotherapy (EIPHT) was carried out with the aim of reducing the toxic manifestations after carrying out polychemother-apy and improving the immunorefense of the organism. EIPHT was performed by exfusion of 500-1000 ml of autoblood in sterile containers "Gemakon" or "Terumo" and its centrifugation at 3000 rpm for 30 minutes. 50-80 ml of the supernatant of the blood plasma was removed. Then the obtained leukotrombo-mass and erythrocytic mass were incubated with an im-munotropic drug in a total dose of 30 mg at 37 ° C for 60-100 min, with the subsequent return of the conjugate to the circulatory system of the patients. To stimulate the cell link of immunity, an immunotropic preparation of thymic origin, thymalin, was used. Immunotherapy was performed in the hospital, when patients were admitted to chemotherapy and radiation therapy. In total, patients received 2 EIPHT sessions at the beginning of admission to hospital and before discharge from the hospital. Patients of the 5th group, the accompanying treatment was performed before conducting PCT according to the standard standard schemes of detoxification drug therapy in the hospital. Groups of patients by age, stage of oncological disease, concomitant somatic pathology were comparable. Timalin is an extract of the thymus obtained from the organ of cattle. Timalin belongs to the group of immunomodulators. Produced by Samson-Med l.t.d., Russia.

Immunological studies included a serum evaluation of the main cytokines of the immune system. Serum levels of cytokines (IL-1, IL-6) were determined by ELISA using the Human test systems (Germany) in the dynamics of complex treatment.

During the statistical analysis of the data presented in the work, the results of the research were entered into databases prepared in Microsoft Excel XP. Numerical (continuous) values were presented as mean arithmetic mean values and mean error (M ± m). A comparison of the quantitative traits was carried out with the help of the Student's test, for continuous variables - the paired Student test. As a boundary comparative criterion for the statistical significance of reliability, p <0.05 was assumed.

The obtained results of the study and their dis- average age of 42.6 ± 6.5 years. The analysis is pre-cussion. Analysis of age-specific features showed that sented in Table 1. the patients with OC were 23 to 75 years old, with an

Table 1. The distribution of patients with ovarian cancer by age

Age (years) Immunotherapy group (IT)

1 2 3

EIPHT EIPHT+ PPh Without IT

Abs. % Abs. % Abs. %

21-30 13 16,7 12 16,4 18 16,4

31-40 16 20,5 16 21,9 23 20,9

41-50 20 25,6 19 26,0 26 23,6

51-60 15 19,2 14 19,2 19 17,3

61-70 11 14,1 10 13,7 18 16,4

71-80 3 3,8 2 2,7 6 5,5

A study of the patients' anamnesis showed that for the majority of patients with oncogynecologic diseases, anamnesis was 43.3% of patients with OC for 1 to 3 months (Table 2.).

Table 2. Characteristics of anamnestic data in patients with ovarian cancer

Anamnesis Diseases Patients with OC

Abs. %

from 1 to 3 months 113 43,3

from 3 to 6 months 91 34,9

from 6 months to 1 year 34 13,0

More than 1 year 23 8,8

The disease was staged according to the International Clinical Classification of TNM (7th Edition, 2009) (Table 3).

Table 3. The distribution of patients with ovarian cancer by stages of the disease and the TNM system

TNM FIGO Immunotherapy group (IT)

1 2 3

EIPHT EIPHT+ PPh Without IT

Abs. % Abs. % Abs. %

T2aN0M0 IIA 10 12,8 9 12,3 13 11,8

T2bN0M0 IIB 12 15,4 12 16,4 15 13,6

T2cN0M0 IIC 6 7,7 5 6,8 9 8,2

T2aN:M0 IIIC 6 7,7 5 6,8 7 6,4

T2bN:M0 IIIC 4 5,1 2 2,7 7 6,4

T2cN:M0 IIIC 2 2,6 4 5,5 7 6,4

T3aN0M0 IIIA 11 14,1 10 13,7 14 12,7

TsbN0M0 IIIB 10 12,8 8 11,0 10 9,1

TscN0M0 IIIC 6 7,7 6 8,2 8 7,3

TsaN:M0 IIIC 5 6,4 4 5,5 9 8,2

TsbN:M0 IIIC 3 3,8 5 6,8 6 5,5

TscN:M0 IIIC 3 3,8 3 4,1 5 4,5

At step IIA ovarian disease occurs in 32 (11.9%) patients, IIB - 39 (14,9%), IIC - 20 (7,7%), IIIA - 35 (13,4%), IIIB - in 28 (10.7%) and IIIC stage - in 107 (41.4%) patients.

Among the comorbidities of the surveyed patients were: in the first place inflammation of the uterus,

which occurs most often in patients with a history of ovarian cancer - in 74 (28.4%); the cervical cancer takes the second place, this pathology was found in 41 (15.3%) patients (Table 4).

Table 4. The nature of concomitant diseases in patients with ovarian cancer

Concomitant disease OC, n=261

Abs. %

Inflammatory processes of the uterine appendages 74 28,4

Diseases of the gastrointestinal tract 65 24,9

Diseases of the cardiovascular system 32 12,3

Ovarian cyst 30 11,5

Hypertensive disease Stage IIA 19 7,3

Stage IB 7 2,7

Chronic cholecystitis 12 4,6

Asthma 11 4,2

Nodular goiter 14 5,4

Diabetes 12 4,6

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Fibromyoma of the uterus 14 5,4

The diseases of the gastrointestinal tract were also frequent in 65 (24.9%) patients with OC. A study of the cardiovascular system showed that 32 (12.3%) patients with OC, including hypertension in 19 (7.3%) patients with OC, chronic cholecystitis - in 12 (4.6%) patients with OC. In addition, in patients with ovarian cancer, the second ovarian cyst was frequently found - in 30 (11.5) patients and nodular goiter - in 14 (5.4%) patients.

The study of the immunological aspects of ovarian cancer made it possible to identify certain changes. However, despite the available data in the literature, data on the effectiveness of the use of immunotherapy in a combination of PCT in patients with ovarian cancer have not been or are not adequately described. Sufficient information about dysfunctions of the cellular system of the immune system, in particular, violations of effector function of T-lymphocytes and balance of "pro-tumor", "antitumor" and "regulatory" mediators [4, -P.88; 5, -P.5896;10, -P. 23-27]. In our opinion, in connection with the above-mentioned information, im-munotherapy of OC is a relatively new direction used in medicine, and at the same time, with high hopes. Approaches to its implementation, the described methods, the timing of implementation, the possibility of combining with other methods of conservative and surgical treatment remain insufficiently studied and developed. As a result of the conducted studies, a significant and reliable increase in the level of all the cytokines studied was found in comparison with the values of a healthy group of people. The results are shown in Table 5. It follows from the table that the serum levels of IL-ifi were statistically increased in all groups of patients when compared with a group of healthy individuals (group 1). In addition to the 5 th group of patients after PCT in the complex EIPHT + PPh, where there is no significant difference in the content of IL-ip when compared with the 1 st group of practically healthy individuals. Thus, IL-ip was increased 2.6 times in the 2 nd group of patients before PCT, in the 3rd group after PCT without immunotherapy - by 3.9 times, in the 4th group after PCT in the complex EIPHT - 2.11 times and in the 5th group of patients after PCT in the complex EIPHT + PPh - in 1.46 times, where there is no significant difference with the 1 st group. Consequently, the

highest level of IL-ip in serum of peripheral blood was detected in the group of patients after PCT without any immunotherapy options. When analyzing the concentration of IL-ip between the study groups, it was found that a significant difference was observed between all the study groups of patients. A significant decrease in the level of IL-ip in the serum of peripheral blood is observed against the background of the use of immuno-therapy, such methods as EIPHT and EIPHT + PPh. Moreover, the effectiveness of the effect of EIPHT + PPh on the level of IL-ip was most striking, which was confirmed by suppression of the level of IL-ip when compared with the 4th group of patients with the results of the 5th group of patients, EIPHT + PPh in the PCT complex was used. It should be noted that, according to the literature, IL-ip is a key pro-inflammatory cyto-kine, an important role of which belongs to the development of the inflammatory process and the stimulation of the production of other cytokines, such as IL-6, TNF-a, etc. At the same time, IL- 6 [1,-P. 169]. It is known that proinflammatory cytokines, in particular IL-ip and TNF-a, have systemic action through the endocrine and nervous systems. According to the literature, it has been shown that increased values of IL-ip and TNF-a do not play a positive role in the course of the disease. In turn, the violation of the cytokine balance towards hyperproduction of IL-ip is accompanied by excessive symptoms of inflammation, as mentioned above. The study of the state of the mediators of the immune system in malignant processes undergoes certain difficulties, which are expressed in the instability of the oncological process, in the presence of various forms and morphological variants of the disease. In this regard, the study of cytokines in patients with ovarian cancer has not only scientific but also practical value for assessing the state of the immune system and predicting the disease. To date, the immunological parameters of the cellular and humoral immunity factors have been widely covered. However, the issues concerning the cytokine regulation of immunity in malignant processes, in particular the identification of the features of the course of the disease and its prediction remain open. One of the important areas of modern medicine, working at the junction with molecular biology, is the study

of the role of cytokines in the pathogenesis of cancer development.

Table 5. The spectrum of the main cytokines of the immune system in patients with ovarian cancer in the PCT complex_

Indicators Healthy individuals group (the 1st g) Group before PCT (the 2nd g.) Group after PCT without immunotherapy (the3rd g.) Group after PCT on the background of EIPHT (the 4th g.) Group after PCT on the background of EIPHT + PPh (the 5th g.)

IL-1P 11,8±2,9 32,5±1,7* 47,9±1,86*A 24,7±1,84*A# 19,52±1,52A#@

IL-6 6,5±0,45 47,9±2,98* 66,1±2,8*A 33,6±3,91*A# 16,35±1,28*A#@

Note: * - reliability of differences in groups compared to the 1st group; A - reliability of differences compared to the 2nd group; # - reliability of differences compared to the 3rd gr.; @ - reliability of the differences compared to the 4th group. (p <0.05)

The study of IL-6 revealed a statistically significant increase in all groups of patients with ovarian cancer compared with group 1 of healthy individuals. Analysis of the studies showed that serum IL-6 levels were statistically increased in all groups of patients when compared with each other. Comparative analysis of IL-6 levels between the groups revealed that when compared with group 1, the level of IL-6 was increased 6.8 times in the 2nd group of patients before PCT, in the 3rd group after PCT without immunotherapy - in 9,3 times, in the 4th group after PCT in the complex EIPHT - 4.6 times and in the 5th group of patients after PCT in the complex EIPHT + PPh - 2.2 times. Evidently, the highest level of IL-6 in the serum of peripheral blood was detected in the group of patients after PCT without the use of immunotherapy options. It has been shown that after PCT without the use of immuno-therapy in the complex it is manifested by increased values of IL-6. It is known that IL-6 is an important diagnostic index of malignancy of the oncological process. Moreover, the best effect of complex treatment is observed in the group of patients who were immunotherapy methods. Clinically, in such patients there is an improvement in the state of health, absence of signs of intoxication, in this regard, the dose intensity of chemotherapy has been preserved and the time of hospital stay has not increased. The data obtained by us agree with the literature data. As is known, a high level of IL-6 can interfere with effective immunotherapy. There was an imbalance in the content of the main cytokines, which manifested itself in the significant production of IL-ip and IL-6, which can be attributed to intermediate cytokines between pro- and anti-inflammatory cytokines, which in turn indicates the dominance of the production of cytokines of the TX2 type. IL-6 is a plei-otropic cytokine with a wide range of biological activity, which is produced by both lymphoid and non-lymphoid cells of the body [7, -P.3399;9,-P. 2410]. Thus, the EIPHT and EIPHT + PPh in PCT complex in patients with OC with the presence of tumor intoxication causes a positive dynamics of the main parameters of the immune system, as well as a decrease in the level of serum pro-inflammatory cytokines, some of which have a growth-stimulating effect, for example, IL-6 [3,-P. 2246; 5,-P. 5896]. It should be noted that carrying out PCT aggravated the existing deviations from the average level of cytokines of a group of practically

healthy persons and patients to PCT. The peculiarity of patients with OC on the background of PCT was the progressive suppression of the mechanisms of cytokine regulation during chemotherapy.

Thus, we found an increase in proinflammatory cytokines in the serum of peripheral blood of patients with ovarian cancer. Inclusion in the complex of accompanying treatment of EIPHT and EIPHT + PPh, is one of the ways to reduce endogenous intoxication during antitumor drug therapy. Application of the above-mentioned immunotherapy methods, according to the current literature, can serve as a modifier of chemother-apeutic treatment, since its tolerance directly depends on the functional state of the organs and systems of physiological detoxication of the organism, and, not least, the immune system. Therefore, the conducted studies showed that the most effective in reducing the side effects of chemotherapy in the complex treatment of patients with OC stage II-III , as well as in improving the subjective state of patients and their quality of life, immunotherapy schemes including the use of EIPHT and EIPHT + PPh, which reduce the main clinical manifestations of the toxicity of chemotherapy, improves the subjective state of the patient. When comparing the results of treatment of patients in combination of PCT, it is obvious that the use of EIPHT and EIPHT + PPh with subsequent neoadjuvant polychemotherapy in patients with OC with clinical and laboratory signs of endogenous intoxication is justified and effective, since it leads to normalization of the indices of the main serum cytokines of the immune system, allows to improve immediate results of treatment.

References

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2. Aoki Y., Takakuwa K., Kodama S., Tanaka K., Takahashi M., Tokunaga A., et al. Use of adoptive transfer of tumor-infiltrating lymphocytes alone or in combination with cisplatin-containing chemotherapy in patients with epithelial ovarian cancer. Cancer research. 1991;51:1934-1939.

3. Asschert J.G., Vellenga E., Hollema H. et al. Expression of macrophage colony-stimulating factor (M-CSF), interleukin-6, (IL-6), interleukin-1 beta (IL-1 beta), interleukin-11 (IL-11) and tumour necrosis factor-alpha (TNF-alpha) in p53-characterised human ovarian carcinomas // Eur. J. Cancer. 1997. Vol. 33(13). P. 2246-2251.

4. Chang E., Rosenberg S.A. Patients with melanoma metastases at cutaneous and subcutaneous sites are highly susceptible to interleukin-2-based therapy. Journal of immunotherapy (Hagerstown, Md : 1997) 2001;24:88-90.

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epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clinical cancer research: an official journal of the American Association for Cancer Research. 1995;1:501-507.

9. Fyfe G.A., Fisher R.I., Rosenberg S.A., Sznol M., Parkinson D.R., Louie A.C. Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleu-kin-2 therapy. Journal of Clinical Oncology. 1996;14:2410-2411.

10. Kamishov S.V., Pulatov D.A. Supportive immunotherapy in complex treatment of patients with oncogynecologycal diseases // The Scientific Heritage (Budapest, Hungary) 18 (18) 2017 P.1,p. 23-27

Information about the main author:

17. Kamishov Sergey Viktorovich

18. MD, PhD, chemotherapeutist of chemotherapy department

19. Senior researcher

20. ID: ORCID 0000-0002-1581-6032

21. Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry of Health of the Republic of Uzbekistan, Tashkent, Uzbekistan

22. 100174, Uzbekistan, Tashkent, 383 Farabiy

st.

23. +998 90 978 65 38

24. E-mail: sergei_kamyshov@mail.ru

EVALUATION OF THE ROLE OF MOLECULAR BIOLOGICAL TUMOR MARKERS IN CHOOSING IMMUNOTHERAPY METHOD AS SUPPLEMENTARY TREATMENT OF

_OVARIAN AND CERVICAL CANCER_

Kamishov Sergey Viktorovich,

MD,PhD, Senior researcher, chemotherapeutist of Department of chemotherapy Nishanov Danier Anorbaevich MD,PhD, senior researcher,head of pathomorfology Department Akhmedov Odil Mukhammadjanovich MD,PhD, head of oncogynecology Department republican specialized scientific and practical medical center of oncology and radiology of the ministry of health

of the republic of uzbekistan, tashkent.

АННОТАЦИЯ

Цель исследования состояла в том, чтобы исследовать молекулярные биологические маркеры опухолей как метод выбора схемы лечения для пациенток с раком яичников и раком шейки матки при комбинированной терапии. Материалы и методы: В исследование было включено 136 пациенток с раком яичников и 163 больных раком шейки матки с II-III клиническими стадиями заболевания. Все пациенты проходили клинико-лабораторные анализы крови, которые включали изучение общего анализа крови и мочи, биохимических параметров и свертывания крови. Результаты исследования: эти исследования установили важность изучения молекулярной биологии опухолевых маркеров для выбора наиболее оптимальной схемы лечения. Вывод: предварительная оценка уровня экспрессии молекулярных биологических маркеров р53, HER-2 / neu и EGFR позволяет выбрать более эффективный метод иммунотерапии при сопутствующем лечении рака яичников. У пациентов с предварительной оценкой рака шейки матки показана важность уровня экспрессии маркеров р53 и Bcl-2 для выбора метода иммунотерапии при сопровождающем лечении.

Ключевые слова: рак яичников (РЯ), рак шейки матки (РШМ), экстракорпоральная иммунофармако-терапия, молекулярно-биологические опухолевые маркеры: p53, HER-2 / neu, Bcl-2, EGFR.

ABSTRACT

The aim of research was to investigate molecular biological tumor markers as selection criteria methods in

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