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Navruzov Sarimbek Navruzovich, Kahhorov Jamal Nematovich, Khodjaeva Nazima Khayrullaevna, National Cancer Center of Uzbekistan, Ministry of Health of Uzbekistan, Tashkent E-mail: [email protected] Kulabdullaev Gayrat Asatovich, Kim Andrey Alekseevich, Institute of Nuclear Physics, Uzbekistan Academy of Science, Tashkent
Influence of neutron capture therapy to biological subjects
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 0.025 eV. 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. Neutron kerma for biological tissues Kbtn = 1.35-10-4 Gr/s and for 1 ^g. natural gadolinium in 1 g. of biological tissues KGdn = 3.M0-7 Gr/s for this beam was calculated. 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 are presented. Planned scientific researches with application of this beam in Uzbekistan are summarized.
Keywords: neutron capture therapy, sarcoma, gadolinium.
1. Introduction 152Gd (0.205 %), 154Gd (2.23 %), 155Gd (15.10 %), 156Gd (20.60 %),
There are a number of radio resistant malignant tumors, incur- 157Gd (15.70 %), 158Gd (24.50 %), 160Gd (21.60 %). Among them, able traditional methods of radiation therapy. One of a perspective 155Gd and 157Gd have the most excellent neutron capture proper-method of treatment of such tumors is GdNCT. Gadolinium neu- ties with thermal neutron capture cross-section of 60,800 and tron capture therapy (GdNCT) is based on the nuclear capture and 255,000 barns, consequently, which is approximately 16 and 66 times reactions that occur when 155Gd and 157Gd, which is a non-radioac- that of 10B. Nuclear reaction cross sections for other isotopes are tive constituent of natural elemental gadolinium, is irradiated with small, which can be neglected at dose calculations. Therefore, we low energy (0.025 eV) thermal neutrons. This results in the produc- are considered these isotopes doing the basic contribution to the tion ofhigh energy y-rays, internal conversion electrons, X-rays and summary dose (20 % - 155Gd and 80 % - 157Gd) [2]. Initially, Lo-Auger electrons, as shown below. cher have mentioned about suitability of gadolinium as element for
The employment GdNCT for cancer treatment is receiving NCT in 1936 [3]. Then it has not been used long time for NCT. All more and more interest owing to the efficient killing effect of the researches on NCT was realized by using of the best element for Auger electrons, which have demonstrated higher cell lethality than NCT 10B [4-17]. But for treatment of some radio resistant forms of alpha particles [1]. Natural Gd consists of 7 stable isotopes including cancer are require element having properties with the big gradient
Influence of neutron capture therapy to biological subjects
to collect in a tumor. By similar property preparation Gd-DTPA was proposed as contrast substance for a nuclear magnetic resonance diagnostics in 1984 [18]. Since this moment has renewed interest to gadolinium as to usable isotope for NCT. In the first works on application of Gd was considered only dose distribution from the gamma radiation resulting of Gd (n, y) reactions [19-23]. However Martin et al. [24; 25] and Laster et al. [26] have shown, that in experiments with cells effect from Gd (n, y) reactions higher, than received only from gamma radiation. In works [24; 25] it has been explained by Auger electrons. In work [26] this effect was explained by interaction internal conversion and Auger electrons of gadolinium. Precisely explaining this phenomenon is not possible today. For this purpose is required estimation and definition of doses from all radiations appearing from nuclear reactions in gadolinium. Available works are essentially differs from each other [27-34].
In spite of it this effect is already applied for treatment of some radio resistant forms of cancer. In this paper we will briefly summarize current developments in the design neutron sources, gadolinium delivery agent, experiments on biological objects and with chemical dosimeters in Uzbekistan.
2. Studies on biological objects
For last some years the medical-biological studies on NCT were carried out in Institute of Nuclear Physics of Academy of Sciences Republic of Uzbekistan on the channel of medical destination of reactor ofWWR-SM. Series of following studies on various biological objects were performed.
3. Studies of pharmacokinetics of gadolinium-containing chelate preparation Magnevist at intratumoral and intramuscular introduction in mice and rats
Gd-NCT dosimetry requires exact analysis of the gadolinium amount in the irradiated target. For this purpose fast and convenient method for radiographic visualization of gadolinium-containing preparation (Magnevist) was developed. By using this metod the Magnevist pharmacokinetics was carried out after intratumoral injection in mice and intramuscular injection in rats. For experiment white male mice were used. S180 sarcoma strain was inoculated to mice's hip of right rear leg. To study pharmacokinetics ofMagnevist at intramuscular injection normal healthy white rats with weight of approximately 250 g. were used. X-Ray study of rats and mice was produced on Sirescop "Siemens" x-ray equipment. Roentgenograms of mice were skiagraphed before injection (control) and in 1, 2.5, 5 min. after injection and further every 5 min. until 65 min. inclusive after inection. Roentgenograms were processed by means of Image J2x2.1.4.7ud2 software (Wayne Rasband, National Institute of Health, USA). The x-ray contrasting properties of gadolinium-containing preparations (Information leaflet of Optimark preparation of Malinkrodt Inc. company, USA) were used for definition of Magnevist pharmacokinetics.
Based on received data the dependence ofMagnevist's concentration decrease in a tumour from the injected dose is ploted Magnevist injection the optimal concentration of the preparation (80 %) remains for 15-25 minutes depending on the injected dose. Then Magnevist eliminates out of tumour sufficiently fast. In roentgenograms, one can clearly see that on 25th min. a darkening of the kidneys appears. This can indicate that the significant amount of gadolinium accumulates in kidneys. It is necessary take into account the beginning of intensive Magnevist accumulation in kidneys on 25th min. at planning of irradiation sessions. Dynamics of Magnevist at intramuscular inection on rats, which can be used for preparation delivery to bone tumours. In the roentgenogram in 1 minute after injection the darkening caused by Magnevist is well represented. Fast enough
reduction of darkening is observed, that indicate active Magnevist elimination from an injection region, and thus on 40th min. darkening is not observed any more. Thus, at intramuscular injection of Magnevist, optimal concentration of the preparation (to 80 %) preserved within 10 min. Obtained data allowed the semiquantitative estimation of gadolinium amount in injection site. The values of gadolinium amount in irradiated region depending on time is used for correct definition of absorbed dose.
Fig. 1. View of tumour bed - cross-striped muscular tissue with the moderate intermuscular edema and inflammatory infiltrate. Staining by hematoxilin-eosin
I .
r
Fig. 2. Tumour with necrosis in the center. Tumoral cells form blocks without complex disposition, basal membrane is absent. Contours of glands are visible. Magnification 10 x 4. Staining by hematoxilin-eosin
Fig. 3. The same preparation at greater magnification 10 x 10. Staining by hematoxilin-eosin
4. Study of influence of gadolinium-capture reaction on sarcoma ^180 in experiments in vivo on tumour-bearing mice
For experiment were used white mice, in the age of 4 month, weighing 17-25 g. Cells of sarcoma strain C-180 were inoculated on the right back legs of mice. The irradiation was carried out on mature tumours with size 0.3 x 0.3 cm up to 2.0 x 1.5 cm. Preparation Magnevist was injected directly into the center of a tumor immediately before irradiation. The irradiation was carried out by epithermal neutrons beam with the various absorbed dozes — 3, 4 and 5 Gy. Procedure of Magnevist injection and irradiation did not influence on activity of animals. On 24 hours after irradiation animals were sacrificed and samples of tissues for the further histological analysis have been taken. In whole in tumour beds it has been found out lymphoid-hystocyte infiltration.
At some mice the moderate edema of muscles and fibrosis was observed (fig. 1). In group of mice received absorbed doze 3Gy it were found necrosis sites in tumours — islands of pathomospho-sis. Also it was found lymphocytic infiltration around tumour. In tumours with absorbed dozes 4 and 5 Gy the II and III degrees of pathomosphosis were found (fig. 2, fig. 3). At present time studies on animals in vivo for definition of optimum modes of tumours irradiation are continued.
5. Conclusion
The complex with epithermal neutrons beam was developed and created for last years at Institute of Nuclear Physics AS RUz. The medical and biologic researches realized and carried out now have shown accordance with characteristics of a beam to the international standards and suitability of a epithermal neutrons beam for the medical and biological researches concerned with neutron capture therapy. Thus, now the Institute of Nuclear Physics possesses all possibilities (scientific and technical) for carrying out of different
medical and biologic researches on neutron capture therapies. Created technical facility and realized preclinical tests allow us to carry out in future following researches:
• Medical and biological studies on animals in vivo, in vitro, in situ.
• Preclinical studies of new preparations.
• Use of epithermal neutron beam for various medical and biological experiments.
• Dosimetry researches of neutron irradiation conditions of patients.
• Carrying out of fundamental medical and biological studies of neutron irradiation influence on biological objects.
• Development and investigation of new preparations for NCT on the basis of B and Gd.
Acknowledgment
Authors are grateful to Dr. Kh. Z. Tursunov for histological analysis.
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Surgical treatment of pseudoarthrosis of lateral humeral condyle of humerus with cubitus valgus in children
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Khujanazarov Ilkhom Eshkulovich MD, Scientific Research Institute Traumatology and Orthopedics, Tashkent Medical Academy, Republic of Uzbekistan E-mail: [email protected]
Surgical treatment of pseudoarthrosis of lateral humeral condyle of humerus with cubitus valgus in children
Abstract: Object of the research work was 59 patients with lateral humeral condyle pseudoarthrosis with or without cubitus valgus, whom three types of surgical correction are spent depending on weight of deformation, prescription of the got trauma and age of the patients. Pseudoarthrosis liquidation or necrosis field resection are made in 21 patients, for 8 patients are admitted the extraarticular supracondylar osteotomy of humerus with ulnar nerve transposition and stabilization by Ilizarov's apparatus and other 30 patients was corrected by the developing own clinic technique — «Lateral humeral condyle pseudoarthrosis resection of the humerus, supracondylar osteotomy of humerus and osteosynthesis by Ilizarov's apparatus». These differential techniques help to shape the distal part of humerus, thus, restoring the function of the elbow joint. Keywords: lateral humeral condyle, pseudoarthrosis, children, osteotomy.
Introduction
Damages of bone structures of an elbow joint in children, according to various researchers [1; 2; 3; 4; 5], averaged from 16 to 40 % among several kinds of bone fractures and 50-80 % fromall intraar-ticulate damages ofupper extremity. The lateral condyle of humerus is one of basic elements of the distal end of humerus, which is made role as a lateralsupporting point and participates in correct distribution of attaching loading on elbow joint and participates in rotation of forearm bones [4; 5; 8]. Nonunion of the lateral humeralcondyle in time leads to aseptic necrosis of lateral part of distal end of humerus with loosening of its articulate structures. Frequently the part of the block of humerus is resolved. The absence of lateral supporting point leads to aggravation of cubitus valgus with following of consequences [6; 7; 8; 9; 10]. Today this pathology becomes a social and economic problem so children with pathology become persistent invalids.
Purpose was to develop the differentiated approaches for lateral condyle of humerus pseudoarthrosis surgery with cubitus val-gus in children.
Materials and methods
Forobservation underwent 59 children, which are treated since1998 to 2013 yy in Children's Traumatology Department of Research Institute of Traumatology and Orthopedics of Ministry of Health ofRepublic of Uzbekistan with lateral condyle
pseudoarthrosis of humerus with cubitus valgus. For all patientsclin-ic-laboratory analyses, radiologicalmeasurement, a tomography investigation and electromyography of damaged segment are carried out in dynamics in comparison by healthy extremity.
Due toclinic-radiological changes the electronic software productwas developed, that allowsobserving the severityof elbow joint valgus deformity in patients with lateral condyle pseudoarthrosis of humerus, which data are presented in table 1. This developed software product is registered and patented № DGU 01354 in Patent Office Republic of Uzbekistan.
Results and discussions
Distribution of patients who have admitted on treatment with lateral condyle pseudoarthrosis of humerus (after trauma — more than 4 months) due to on age and genderwas made, that presented in table 2. The age of patients fluctuated from 2 till 18.
As follows from presented data in table 1, all patients have been distributed on 5 age groups: 3-7 years — 13 patients (9 boys and 4 girls); 7-11 y. — 17 (10 — boys and 7 girls); 11-15 y. — 25 (18 boys, 7 girls) and adolescent group from 15 till 18 y. — 4 patients.
As has shown the retrospective analysis data, causes ofnonunion occurrence were untimely diagnostics or wrong interpretation of data, omissions duringchoice of treatment tactics and to decrease ofrespon-sibility, infringement of an orthopedic regimen, especially by boys.
