Medical Radiology and Radiation Safety. 2019. Vol. 64. No. 2. P. 75–81

DOI: 10.12737/article_5ca60c7bba45e9.77708543

K.N. Lyakhova¹, I.A. Kolesnikova^1,5, D.M. Utina^1,5, Yu.S. Severyukhin^1,5, N.N. Budennaya^1,5, A.N. Abrosimova^2,3, A.G. Molokanov¹, M. Lalkovičova^1,4, A.A. Ivanov^1,2,3

Morphofunctional Indicators of the Effects of Protons on the Central Nervous System

1. Joint Institute for Nuclear Research, Dubna, Russia. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. ;
2. Institute for Biomedical Problems, Moscow, Russia;
3. A.I. Burnazyan Federal Medical Biophysical Center, Moscow, Russia;
4. Institute of Experimental Physics, Košice, Slovakia;
5. University “Nature, Society, Man”, Dubna, Russia

K.N. Lyakhova – Junior Researcher;
I.A. Kolesnikova – Junior Researcher;
D.M. Utina – Junior Researcher;
Yu.S. Severyukhin – Researcher;
N.N. Budennaya – Junior Researcher;
A.N. Abrosimova – Senior Researcher, PhD Biol.;
A.G. Molokanov – Senior Researcher, PhD Tech.;
M. Lalkovičova – Researcher, PhD Biol.; 
A.A. Ivanov – Head of Lab., Dr. Sci. Med., Prof.

Abstract

Purpose: Investigation of the dose–time–effect dependency of the behavior of mice and rats after irradiation with accelerated protons and comparison of these data with the morphological changes in the hippocampus and the cerebellum of rodents.

Material and methods: Experiments were performed on outbred adult female ICR mice (CD-1), SPF categories, body weight 30–35 g, of the age of 10 weeks – total number 61 animals, and on 39 male Sprague Dawley outbred rats weighing 190–230 g, aged 6.5–7.5 weeks. The animals were irradiated with accelerated protons with energy of 70 MeV on the medical beam of the phasotron of the Joint Institute for Nuclear Research (Dubna). Mice were placed in individual containers and irradiated 4 ones at a time. Irradiation was performed in a modified Bragg peak at doses of 0.5; 1; 2.5 and 5 Gy in caudocranial and craniocaudal direction. Rats were divided into 2 groups: intact control and group irradiated with 170 MeV protons at a dose of 1 Gy, dose rate of 1 Gy / min in the craniocaudal direction. The behavioral responses of experimental animals were tested in the Open Field test on days 1, 7, 14, 30, 90 in rats and on days 8, 30, and 90 in mice. Quantitative analysis of the dilution of Purkinje cells in the rat cerebellum was made, as well as morphological changes in the rat hippocampal neurons. It was shown a development of structural changes after irradiation with protons in neurons of different severity at different times after exposure: after 30 and 90 days.

Results: In the period of 1–8 days after proton irradiation of mice and rats in non-lethal doses (0.5–5.0 Gy), there is a dose-independent decrease in the main indicators of the spontaneous locomotor activity of rodents.
By the 90th day after irradiation, there is a clear tendency to normalize the indicators of OIR in all groups of irradiated animals, while the ES remains elevated.
Disruption of motor activity of rodents irradiated with protons in the early period and its relative normalization in the late post-irradiation period occur on the background of an increased number of morphologically altered and dystrophic neurons in the hippocampus and rarefied of Purkinje cells in the cerebellum.

Conclusion: The complex hierarchical structure of the central nervous system, the dependence of its function on the state of the whole organism and its hormonal background, as well as on the state of the blood supply and other factors, along with its high plasticity, require complex physiological, morphological and neurochemical approaches in analyzing the radiobiological effect of corpuscular radiation, taking into consideration the unevenness in dose distribution during irradiation.

Key words: protons, neurons, hippocampus, cerebellum, brain, behavior, open field, orienting-exploratory reaction, emotional status, rats, mice

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For citation: Lyakhova KN, Kolesnikova IA, Utina DM, Severyukhin YuS, Budennaya NN, Abrosimova AN, Molokanov AG, Lalkovičova M, Ivanov AA. Morphofunctional Indicators of the Effects of Protons on the Central Nervous System. Medical Radiology and Radiation Safety. 2019;64(2):75-81. (Russian).

DOI: 10.12737/article_5ca60c7bba45e9.77708543

PDF (RUS) Full-text article (in Russian)

Medical Radiology and Radiation Safety. 2019. Vol. 64. No. 2. P. 61–69

DOI: 10.12737/article_5ca6027479faf5.57356528

A.V. Agapov¹, V.N. Gaevsky¹, E.V. Kizhaev³, Ya.V. Kurgansky^1,2, E.V. Luchin¹, G.V. Mytsin¹, A.G. Molokanov¹, M.A. Tseytlina¹, S.V. Shvidky¹, K.N. Shipulin¹

Experience of Proton Radiotherapy at the Joint Institute for Nuclear Research, Dubna

1. Joint Institute for Nuclear Research, Dubna, Russia. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. ;
2. MSU-9, Dubna, Russia;
3. Russian Medical Academy of Continuous Professional Education, Moscow, Russia

A.V. Agapov – Researcher;
V.N. Gaevsky – Leading Engineer;
E.V. Kizhaev – Head of Dep., Dr. Sci. Med., Prof.;
Ya.V. Kurgansky – Head of Dep.;
E.V. Luchin – Senior Researcher, PhD Med.;
G.V. Mytsin – Head of Dep., PhD Tech.;
A.G. Molokanov – Senior Researcher, PhD Tech.;
M.A. Tseytlina – Research Assistant, PhD Med.;
S.V. Shvidky – Deputy Head of Dep., PhD Tech.;
K.N. Shipulin – Researcher

Abstract

First experiments on using proton beams for radiotherapy of malignant tumours at the 680 MeV proton synchrocyclotron of the V.P. Dzhelepov Laboratory of Nuclear Problems of the Joint Institute for Nuclear Research (DLNP JINR) have been initiated by Prof. V.P. Dzhelepov and were started in 1967. 28 patients with different types of superficially located malignancies, such as skin melanomas, metastases of cancer to peripheral nodes, larynx cancers and so on, were treated during the period of 1967–1971.

Then the method of scanning rotation irradiation of deep-seated tumours was developed and started to use at DLNP JINR. 50 patients with esophagus cancer, larynx cancer and metastases of malignant tumors were treated with that technique.

During the period of 1974–1984 the synchrocyclotron was modified to the Phasotron with the increase of output current. At the same time, a multi-room Medico-technical complex for hadron radiotherapy of cancer patients was constructed. It allows tumour treatment with wide and narrow horizontal beams of protons (70–660 MeV), negative pions (30–80 MeV), high-energy neutrons (mean energy 350 MeV), and with their combinations. The complex includes also the standard gamma-therapy unite Rokus-M with 60Co source for external irradiation. The unique equipment has been developed and constructed, including full-scale PET, X-ray CT for topometry of patients in sitting position, and proton CT.

A new round of the development started in December 1999 when a specialized radiological department of patient capacity of 25 beds was opened in Dubna. Since 2000 regular sessions have been conducted in research of proton therapy efficiency in irradiation of patients with neoplasms located in the head, neck and other parts of the body. 1283 patients have received courses of radiotherapy at the Phasotron beams by the end of 2018.

The technique of 3D conformal proton radiotherapy in which the maximum of the formed dose distribution conforms most accurately to the shape of the irradiated target has been realized and put into operation. In this way, the maximum sparing effect is achieved in normal tissues and organs surrounding the tumor.

The statistical analysis of the proton treatment results of two classes of neoplasms treated with the JINR proton beam (arterio-venous malformation) of the brain and the skull base (chordomas and chondrosarcomas) are presented.

A new project of the development and construction of a modern superconducting cyclotron SC202 dedicated for proton radiotherapy was prepared recently by the staff of the DLNP JINR and Institute of Plasma Physics Chinese Academy of Sciences (Hefei, China). It is supposed that the accelerator will become the base of a new Proton Therapy Centre in Dubna. It will consist of two treatment rooms: the first one will be equipped with static wide horizontal proton beam and a therapeutic chair, and the second one is planned to provide with gantry for a pencil proton beam dynamic scanning and a positioner for supine patient position during irradiation.

Key words: proton therapy, synchrocyclotron, 3-D conformal radiotherapy, boluses, aperture collimators, brain, head and neck tumours, JINR, Dubna

REFERENCES

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16. Gurskiy SV, Karamysheva GA, Karamyshev OV, Kostromin SA, Morozov NA, Samsonov EV, et al. Research and development of a compact superconducting cyclotron SC200 for proton therapy. Proceedings of IPAC2016. 2016:1262-4.

For citation: Agapov AV, Gaevsky VN, Kizhaev EV, Kurgansky YaV, Luchin EV, Mytsin GV, Molokanov AG, Tseytlina MA, Shvidky SV, Shipulin KN. Experience of Proton Radiotherapy at the Joint Institute for Nuclear Research, Dubna. Medical Radiology and Radiation Safety. 2019;64(2):61-9. (Russian).

DOI: 10.12737/article_5ca6027479faf5.57356528

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Medical Radiology and Radiation Safety. 2019. Vol. 64. No. 2. P. 70–74

DOI: 10.12737/article_5ca607bf670c97.49055999

K.E. Medvedeva, I.A. Gulidov, Yu.S. Mardynski, D.V. Gogolin, K.B. Gordon, A.V. Semenov, O.G. Lepilina, A.D. Kaprin, А.А. Kostin, S.A. Ivanov

Proton Therapy for Re-Irradiation of Recurrent Gliomas

A.F. Tsyb Medical Radiological Research Center, Obninsk, Russia. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

K.E. Medvedeva – Junior Researcher;
I.A.Gulidov – Head of Dep., Dr. Sci. Med., Prof.;
Yu.S. Mardynski – Chef Researcher, Corr. Member RAS, Dr. Sci. Med., Prof.;
D.V. Gogolin – Senior Researcher, PhD Med.;
K.B. Gordon – Researcher at the West German Proton Therapy Center, (Essen, Germany), PhD Med.;
A.V. Semenov – Junior Researcher; O.G. Lepilina – Research Assistant;
A.D. Kaprin – Director General, Academic RAS, Dr. Sci. Med., Prof.;
A.A. Kostin – First Deputy of Director General, Dr. Sci. Med., Prof. RAS;
S.A. Ivanov – Director, Dr. Sci. Med., Prof. RAS

Abstract

Purpose: To define efficiency and safety of use of the active scanning proton beam in reirradiation of recurrent malignant gliomas.

Material and methods: Researched group included 26 patients who were treated on a complex of proton therapy Prometeus. 57.7 % of tumors were glioblastoma, 26.9 % – gliomas of GII and 15.4 % GIII gliomas. Proton therapy was carried out with use of the active scanning beam, image-guiding system and use of the individual fixing devices. To all patients PET/CT with 11С-methionine and MRI were carried out, target volume delineation was carried out by results of coregistration of both images.

Results: Terms of observation were from 1 to 32 months. The assessment of direct efficiency is carried out at 19 patients in 3 months after completion of treatment. From the group 52.7 % of patients (n = 10) had disease stabilization. At 11.5 % (n = 3) – partial response. Tumor regression volume varied from 50 to 90 %. Progressing of a disease developed in 31.5 % of the considered cases (n = 6). Other 7 patients expect control inspection. 15.4 % (n =  4) patients developed grade 2 radiodermatitis in the field of radiation fields, the remaining 84.6 % (n =  22) had grade 1 radiodermatitis. Of the entire group of patients, only one case of the development of a late radiation complication in the form of radionecrosis is observed at an observation period of 13 months.

Conclusion: Preliminary results of a research showed that performing proton therapy by the active scanning beam is the effective method of treatment of patients with the diagnosed recurrent gliomas, allowing to increase life expectancy of patients with maintaining satisfactory general condition.

Key words: proton therapy, gliomas, recurrent, reirradiation, radiation complications

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2. Mayer R, Sminia P. Reirradiation tolerance of the human brain. Int J Radiat Oncol Biol Phys. 2008 Apr 1;70(5):1350-60.

3. Langedijk JA. Re-irradiation: new frontiers. Springer, 2011. P. 85-93.

4. NCCN Clinical practice guidelines in oncology. Central nervous system. Version 1.2018. National Comprehensive Cancer Network. 2018.

10. Fogh SE, Andrews DW, Glass J, Curran W, Glass C, Champ C, et al. Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol. 2010 Jun 20;28(18):3048-53. DOI: 10.1200/JCO.2009.25.6941.

11. Kong DS, Lee JI, Park K, Kim JH, Lim DH, Nam DH. Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas. Cancer. 2008 May 1;112(9):2046-51. DOI: 10.1002/ cncr.23402.

5. Klimanov VA, Zabelin MV, Galyautdinova ZhZh. Proton radiation therapy: current state and prospects. Medical Physics. 2017;2:89-96. (Russian).

6. Tsyb AF, Gulidov IA. The current state of radiation therapy of malignant neoplasms. In: Therapeutic Radiologija GEOTAR Publ, 2013. P. 7-12. (Russian).

7. Gulidov IA, Gordon KB, Balakin VE, Galkin VN, Gogolin DV, Kaprin AD, et al. New possibilities for proton therapy in Russia. Problems in Oncology. 2016;62(5):570-2. (Russian).

9. Kohshi K, Yamamoto H, Nakahara A, Katoh T, Takagi M. Fractionated stereotactic radiotherapy using gamma unit after hyperbaric oxygenation on recurrent high-grade gliomas. J Neurooncol. 2007 May;82(3):297-303.

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8. Kobyakov GL, Smolin AV, Bekyashev AKh, Absalyamova OV, Kobyakova EA, Poddubsky AA, Inozemtseva MV. Treatment for recurrent glioblastoma: are there successes? Head and Neck Tumors. 2014.36:12-21. (Russian).

12. Galle J, McDonald M, Simoneaux V, Buchsbaum JC. Reirradiation with proton therapy for recurrent gliomas. Int J Particle Ther. 2015;2(1):11-8.

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15. Kaprin AD, Galkin VN, Zhavoronkov LP, Ivanov VK, et al. Synthesis of fundamental and applied research in the basis for ensuring a high level of scientific results and their introduction into medical practice. Radiation and Risk. 2017;26(2):26-40. (Russian).

For citation: Medvedeva KE, Gulidov IA, Mardynski YuS, Gogolin DV, Gordon KB, Semenov AV, Lepilina OG, Kaprin AD, Kostin АА, Ivanov SA. Proton Therapy for Re-Irradiation of Recurrent Gliomas. Medical Radiology and Radiation Safety. 2019;64(2):70-4. (Russian).

DOI: 10.12737/article_5ca607bf670c97.49055999

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Medical Radiology and Radiation Safety. 2019. Vol. 64. No. 2. P. 52–60

DOI: 10.12737/article_5ca5fc2765c9f5.02525917

V.S. Khoroshkov

History and Prospects of Proton Therapy

Institute for Theoretical and Experimental Physics, Moscow, Russia. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. .

V.S. Khoroshkov – Head of Dep., Dr. Sci. Tech.

Abstract

Purpose: Presentation of the history, status and prospects for the development of proton therapy.

Material and methods: The history of proton therapy (PT) is divided into two periods. The first one – the experimental period lasted since 1954 to 1990, when proton therapy was carried out at the ten facilities in physical institutes. The research accelerators and the horizontal proton beams with a fixed direction are used. The second period is from 1990, when the first clinical proton center was commissioned in a multi-field hospital in the city of Loma Linda, USA. In the first period, the necessary technical tools were developed and the advantages of using accelerated protons in remote radiation therapy formulated by R. Wilson in 1946 were confirmed on a limited (about 9,000) patient population: halving the radiation load on the healthy tissues surrounding the tumor and on the organism as a whole compared to γ- and electron irradiation and high dose gradients at the borders of the dose distributions and the tumors. This allows to increase the dose in the tumor (target), increase the probability of the tumor resorption and at last to irradiate tumors, including small sizes, located near critical organs and structures. By 1990, in three experimental centers in Russia (JINR, ITEP, PNPI) accumulated about 30 % of world clinical experience.

Today, more than 70 multi-cabin and several single-cabin clinical based proton therapy centers operate in the world. Almost all centers are equipped with gantry installations for PT for 95 % of patients. Today proton therapy is indicated and is used for the treatment of 10–15 % of all malignancies of cancer incidence structure.

Results: Healthcare in Russia needs 10–15 multi-cabin proton (and ion) centers. Currently, there are one experimental PT center in the JINR, where up to 100 patients are exposed pea year. The modern proton center was commissioned at the Medical Institute Sergei Berezin in St. Petersburg with two gantry of company Varian. The IBA proton center in Dimitrovgrad is expected. The single-cabin proton complex of domestic production has been operating in Obninsk since 2017. 20th-century technologies and the horizontal beam (without the possibility of its rotation) are used in this complex for treatment of patients with small head and neck tumors.

Conclusion: Equipping the Russian health care facilities with proton therapy facilities is inevitable. Russia will buy them worldwide for decades, like almost all types of high-tech medical equipment, are bought today, or can produce them locally. All the prerequisites needed for production (rich physical – technical experience, scientific and industrial potential) are available.

Key words: proton therapy, cyclotron, synchrotron, gantry, Bragg curve, malignant neoplasm, local tumor control

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For citation: Khoroshkov VS. History and Prospects of Proton Therapy. Medical Radiology and Radiation Safety. 2019;64(2):52-60. (Russian).

DOI: 10.12737/article_5ca5fc2765c9f5.02525917

PDF (RUS) Full-text article (in Russian)