Научная статья на тему 'Preclinical studies of neutron capture therapy effectiveness in the treatment of malignant tumours, at the nuclear reactor hvr-sm InP as of RUz Preclinical studies of neutron capture therapy effectiveness in the treatment of malignant tumours, at the nuclear reactor hvr-sm InP as of RUz'

Preclinical studies of neutron capture therapy effectiveness in the treatment of malignant tumours, at the nuclear reactor hvr-sm InP as of RUz Preclinical studies of neutron capture therapy effectiveness in the treatment of malignant tumours, at the nuclear reactor hvr-sm InP as of RUz Текст научной статьи по специальности «Медицинские технологии»

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European science review
Ключевые слова
NEUTRON CAPTURE THERAPY / ONCOLOGY / RADIOLOGY / REACTOR / NEUTRON

Аннотация научной статьи по медицинским технологиям, автор научной работы — Khodjaeva Nazima Khayrullaevna, Navruzov Sarimbek Navruzovich, Kahhorov Jamal Nematovich, Kulabdullaev Gayrat Asatovich, Кim Andrey Alekseevich

Developed for treatment of radio resistant malignant tumors the Gadolinium neutron capture therapy (GdNCT) is based on the nuclear capture and reactions that occur when 155Gd and 157Gd, which are non-radioactive constituents of natural elemental gadolinium, are irradiated by thermal neutrons with low energy, In this article, results of scientific researches on development GdNCT in Uzbekistan are presented. The beam of epithermal neutrons with characteristics satisfying the all requirements of IAEA was received. As gadolinium delivery agent the well-known pharmacological preparation Magnevist was chosen. For absorbed dose calculation, the Magnevist pharmacokinetics was studied after intratumoral injection in mice and intramuscular injection in rats. Results of researches of influence epithermal neutrons beam on binding ability of transport proteins of human blood, on tumor cells С-180 at mice and on surgical material of human stomach adenocarcinoma are presented. Planned scientific researches with application of this beam in Uzbekistan are summarized.

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Текст научной работы на тему «Preclinical studies of neutron capture therapy effectiveness in the treatment of malignant tumours, at the nuclear reactor hvr-sm InP as of RUz Preclinical studies of neutron capture therapy effectiveness in the treatment of malignant tumours, at the nuclear reactor hvr-sm InP as of RUz»

Infiltration in the spinal canal were detected in 45 (32.1 %) patients. Radiographs abscesses are well identified in the thoracic spine, where they are seen against the backdrop of the air of the lung tissue. Retroperitoneal abscesses were detected by indirect signs of expansion m.iliopsoas major circuits, when they reached a considerable size. It was impossible to see the abscess of the soft tissue of the back and small paravertebral abscesses in the lumbar spine.

The contours of abscesses and their relationship with the surrounding organs at radiographs and tomograms could not always identify. CT and MRI are equally well detected abscesses, their cameras, relations with the vertebrae and surrounding organs and tissues, especially after the internal contrast. At an early stage of formation of an abscess was observed infiltration of fat around the body of a vertebra. MRI advantage — the ability to study that reveals abscesses relations not only with the surrounding tissues,

and their connection with each other. Comprehensive assessment of bone structure changes detected on rentge-notomogramma and CT scan, and pathological changes in the MRI signal, gave an idea of the morphological changes in the spinal column and tuberculous spondylitis phase.

Conclusions

The use of CT and MRI opened up new possibilities in the diagnosis of tuberculosis spondylitis; CT and MRI are highly effective in the detection of spinal cord compression in patients with tuberculosis spondylitis. The diagnostic efficacy of CT — 98.1 %, MRI — 100 %. MRI is more effective in determining the extent of compression (100 %) and is the only method of visualization of changes in the spinal cord. The use of CT and MRI in the postoperative period allows to obtain objective criteria for evaluating the effectiveness of surgical treatment and to determine further treatment policy.

References:

1. Кульчавеня Е. В. Клинико-эпидемиологические особенности современного туберкулёзного спондилита//Туберкулез и болезни легких. - 2013. - № 1. - С. 41-45.

2. Советова Н. А. Туберкулезный спондилит у взрослых (клинико-лучевые проявления)//Туберкулез и болезни легких. - 2014. -№ 2. - С. 10-14.

3. Смердин С. В. Возможности лучевой диагностики туберкулезного спондилита//Туберкулез и болезни легких. - 2014. - № 7. -С. 65-70.

Khodjaeva Nazima Khayrullaevna, Navruzov Sarimbek Navruzovich, Kahhorov Jamal Nematovich, National Cancer Center of Uzbekistan, Ministry of Health of Uzbekistan E-mail: [email protected] Kulabdullaev Gayrat Asatovich, Rim Andrey Alekseevich, Institute of Nuclear Physics, Uzbekistan Academy of Science

Preclinical studies of neutron capture therapy effectiveness in the treatment of malignant tumours, at the nuclear reactor HVR-SM INP AS of RUz

Abstract: Developed for treatment of radio resistant malignant tumors the Gadolinium neutron capture therapy (GdNCT) is based on the nuclear capture and reactions that occur when 155Gd and 157Gd, which are non-radioactive constituents of natural elemental gadolinium, are irradiated by thermal neutrons with low energy, In this article, results of scientific researches on development GdNCT in Uzbekistan are presented. The beam of epithermal neutrons with characteristics satisfying the all requirements of IAEA was received. As gadolinium delivery agent the well-known pharmacological preparation Magnevist was chosen. For absorbed dose calculation, the Magnevist pharmacokinetics was studied after intratumoral injection in mice and intramuscular injection in rats. Results of researches of influence epithermal neutrons beam on binding ability of transport proteins of human blood, on tumor cells C-180 at mice and on surgical material of human stomach adenocarcinoma are presented. Planned scientific researches with application of this beam in Uzbekistan are summarized.

Keywords: Neutron capture therapy, oncology, radiology, reactor, neutron.

Currently, there is a significant increase of human life expec- the situation in the world. WHO predicts anincreasing tends of tancy in average associated with the intensive development of mortality from cancer in 2020, which may be more than 12 million scientific and technological progress and improving of life qual- people and exceeding the total deaths from tuberculosis, malaria ity. This phenomenon has caused increasing incidence of cancer and HIV infection [5; 7; 8].

pathology [3]. One of the most effective treatments of malignant tumors is

The World Health Organization (WHO) had concluded that radiotherapy in different types and about 70 % of cancers patients one offive people on the planet is dying from cancer, after analyzing are need it [2].

Preclinical studies of neutron capture therapy effectiveness in the treatment of malignant tumours.

An actual problem of modern oncology is the problem of the electoral lesion of the tumor, which can be solvedby the method of neutron capture therapy.

Neutron capture therapy is based on the irradiation flux of epithermal neutron fluxes in conjunction with the administration of drugs (containing boron, gadolinium) selectively accumulate in tumors, which occur in the interaction of the nuclear reaction with the release of large amounts of energy [6]. This method provides-conformality — maximal biological effects to the tumor, with minimal impact on normal tissues surrounding the tumor.

After the modernization of one of the horizontal channels of research nuclear reactor HVR-SM INP AS of RUz allowedfrom energy spectrum of reactor neutron pick out he flux of epithermal neutrons highlights with characteristics suitable for the development of NCT method [1; 4].

Due to the absence of unified equipment — each channel — collimator has a specific range of neutron fluxes and there is no any unifiedmethodology for neutron capture therapy. Therefore, there arenumber of problems to solve researchers for development of this technique: from the creation of the therapeutic beam irradiation to develop a methodology in this beam [1; 4].

The aim of our study was to develop a technique of neutron capture therapy in the treatment of experimental tumorstrains using gadolinium-containing drug Magnevist at a nuclear reactor of INP Uzbekistan.

Materials and methods

We have performed three series of experiments on male outbred mice, weighing 17-40 g. at the age of 4 months. Experiments have been conducted under the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (EuropeanCouncil, Strasburg 2004). All mice were kept in a vivarium, bait pellets and had free access to water. The animals were under daily observation, special attention when assessing the overall state of the mice, was directed on: locomotor activity, feeding activity and drinking, grooming (cleaning), body weight.

Sarcoma tumor strain C-180 was grafted to the right thigh, with the principles of antisepsis. Experiments were performed on 20th day after tumor inoculation.

The pharmacokinetics of drug was pre-studied on inoculated with tumor mice. Due to it, mice were subjected to fixation, followed by intratumoral administration of gadolinium-containing drug

Magnevistwhich hasan x-ray contrast property. Pharmacokinetic study was performed on X-ray diagnostic apparatus firm Siemens, by registering Magnevist circulation time through the body. Average tumor volume was 135 mm3. The drug was administered in strict center of the tumor. The maximum drug concentration in the tumor is registered immediately after administration. T / is registered at 6.5 minutes after administration. After 15 minutes the drug is mainly accumulated in the kidney and partly in the liver, in lungs and heart.

Total radiation of mice were occurred on the ninth horizontal channel of research nuclear reactor HVR-SM INP AS ofRUz, neutron beam density 6.5-108 n/cm 2 • s, immediately after the introduction of Magnevist. The study group consisted of 6 mice irradiated with epithermal neutron fluxes and the total absorbed dose was 6 Gy. 6 mice in the control group were irradiated with a neutron flux to the total absorbed dose of 3 Gy.

Magnevist (Bayer Shering A. G., Germany) was intratumoral-ly injected to mice prior to irradiation, in 1 ml ofwhich is 469.01 mg. of gadopentetatdimegyumine (78.77 mg. Gd), diethylenetriamine-pentaacetic acid, 0.99 mg. of meglumine, a dosage of 0.1 mmol/kg. Then mice were placed in a «lock- container for radiation and neutron — capture therapy of experimental rats and mice" (a reasonable proposal #635 10.05.2012).

Tumor size was measured before the experiment on 5th,10th,16th,25thdays after irradiation. Formula V=A x B x C was usedfor tumor volume measurements.

Evaluation of the antitumor effect of neutron capture therapy was conducted by examining of the tumor growth percent inhibition.

Results of histological examination of tumor after experimental therapy were assessed according to the therapeutic pathomorphosis classification of G. A. Lavnikova.

Mice were euthanized, decapitation were performed under ether anesthesia on 25th day after the experiment. After that, an autopsy of animals were done, tumor and all organs and tissues sampling for histological examination were done.

Results

Mice over the observation period were active, with preserved reflexes, feeding behavior unchanged. Appearance of mice was wool smooth and shiny.

At mice from both groups was significant inhibition of tumor growth. Inhibition of tumor growth in the study group was 94-97 % and 82-86 % in the control.

a b

Fig. 1. a — Therapeuticpathomorphosislll; b — Therapeuticpathomorphosis IV

Pathomorphosis III (44. 4 %) and IV (27. 8 %) (fig. 1) were ob- were detected extensive areas of necrosis with accumulation of fibro-

served more frequently in the main group than in the control 38.9 % blasts around it and hyalinosis vessels at pathomorphosis IV. and 22.2 %, respectively. Isolated tumor cells with vacuolated nuclei in Also, in the pathohistologicalstudy of internal organs degenera-

necrotic masses were observed at pathomorphosis III. In tumor tissue tive changes were observed, neither in study nor in control groups.

Conclusions

Study of efficiency neutron capture therapy with gadolinium-containing drug Magnevist in the experiment in vivo, showed its high antitumor efficacy: the prevalence of therapeutic

pathomorphosis III, IV degree, a high percentage of tumor growth inhibition without affecting to the internal organs of mice. It should be noted, the higher the neutron dose rate, the greater the effect of neutron capture therapy.

References:

1. Abdullayev G. A., Koblik Y. N., Kulabdullaev G. A. Use of the HVR - SM for method development neutron capture therapy in Uzbekistan//"News of RAS", ver. Physical. - 2009. - 73, № 4. - P. 540-543.

2. Comprehensive audits of radiotherapy practices: a means to improve quality. Group Audit Quality Assurance in Radiation Oncology (QUATRO). International Atomic Energy Agency. - Vienna, 2008.

3. Davydov M. I., Axel E. M. Mortality from cancer of the population of Russia and CIS countries in 2004//Herald of RAS H. H. Blokh-in. - 2006. - T. 17, № 3. - P. 45-77. - App.1.

4. Koblik Y. N., Abdullayev G. A., Kulabdullaev G. A. etc. Channel epithermal neutrons for biomedical research at a nuclear reactor of INP Uzbekistan//Medical Physics. - 2011. - 51, № 3. - P. 31-40.

5. GLOBOCAN 2008 (IARC) Section of Cancer Information (29/8/2012).

6. Salt C., Lennox A. J., Takagaki M., Maguire J. A., Hosmane N. S. Boron and gadolinium neutron capture therapy//Russian Chemical Bulletin. - 2004. - Volume 53, Issue 9. - P. 1871-1888.

7. WHO Library Cataloguing-in-Publication Data//Atlas of health in Europe/2nd edition. - 2008.

8. World Health Organization and International Union Against Cancer, 2005. Global Action Against Cancer - Updatedversion.

Navruzova Visola Sarimbekovna, National cancer research center of Uzbekistan E-mail: [email protected]

Analysis of clinical outcomes of cervical carcinoma surgery in fertile age patients

Abstract: In the NORC MH Uz we analyzed the outcomes of surgical treatment of 204 young patients with cervical cancer. We observed mainly the patients with exophytic -82 (40.2 %) and 68 endophytic growth (33.3 %) of cervical tumors. Besides standard examination the patients were determined sex hormone level (estradiol, progesterone), CA-125 level, calcium and phosphate level in blood. The treatment effect was evaluated by dynamic monitoring of patients as well as it was studied the quality of life of a young body. Patient's life quality was followed in dynamic by MENQOL American system.

Keywords: cervical cancer, fertile age, squamous cell, systemic chemotherapy, endoarterial regional chemotherapy, sex hormones, fertility-sparing surgery, ovarian transposition, effectiveness of treatment, quality of life, dynamic monitoring.

Today cervical cancer (CC) remains the most common malignant tumor of female genital organs. Every year it is revealed about 500,000 new cases of CC in the world and each year 300,000 wom-

en die from this disease. Herewith, 75 % of cases occur in developing countries in Africa, Latin America and Asia, where CC is firmly takes 1st place in the cancer incidence of the female population, and only 25 % — in economically developed countries in Europe and North America. Annually, the European Union diagnoses more than 25,000 cases of CC and about 12,000 deaths from this disease [1; 5; 7; 8]. In the structure of oncological morbidity of female reproductive system of the Republic of Uzbekistan CC takes second place after breast cancer and the fourth place in the incidence of all cancers in the country [3]. In 2014, intensive incidence rate was 4.6 cases per 100,000 population. The highest cervical cancer incidence has been reported in women of 45-55 yrs. The world reports have estimated that women under 50 years of age comprise 3 % per year, with a particularly significant incidence increase in women up to 29 years, in Russia it is 2.1 % per year. The similar trend to CC increase in women of fertile age has been followed in other countries. Currently, there are following methods of CC treatment: surgery, combined radiotherapy, chemotherapy. However, the principal therapeutic methods for cervical cancer are surgery and radiation which are used both separately and in vari-

ous combinations. In severe cases it is necessary to perform advanced surgery, the volume of which is directly depended on the advance of tumor process. Most CC patients who underwent radical treatment tended to keep the former style of life, social status, and work activities. The quality of life as an integral characteristic of physical, psychological, emotional and social functioning of a woman is based on her subjective perception. When performing radical surgery on young women with CC it is advisable to carry out the transposition of both ovaries in the lateral channels of the abdominal cavity, removing them from subsequent exposure to radiation in order to preserve hormone function considering the serious consequences of post-castration syndrome. A distinctive characteristics of extended hysterectomy with ovarian transposition is the preservation of uterus — ovary and fallopian tube and their neurovascular connections located in the funnel — pelvic ligament [4; 9].

To standard cervical cancer surgery for stage IB1-IIIa is to be an extended hysterectomy with appendages. In fertile age patients ovaries can be preserved and led beyond the pelvis. The advantages of surgical approach to beam are the chance to save ovarian function and vagina elasticity in young patients. Ovarian transposition can be performed at squamous cell carcinoma in high and moderate differentiation and the absence of tumor vascular embolism.

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