The effect of high-energy (660 MeV) proton irradiation at the phasotron accelerator in FLASH mode (80 Gy/s) compared with the standard proton exposure power of 3.0 Gy/min was studied. When irradiated in two modes at doses of 1.0 and 1.5 Gy, the induction of cytogenetic damage in bone marrow cells and the state of lymphoid organs (thymus and spleen) were evaluated; survival under total in vivo irradiation of mice was analyzed at doses of 7.0 and 8.0 Gy. The growth rate of a model tumor under ex vivo irradiation was determined at doses of 40 and 60 Gy. It has been shown that irradiation of animals in the FLASH mode at a dose of 1.5 Gy protected the proliferative activity of the spleen and also led to a decrease in cytogenetic damage in bone marrow erythrocytes according to the micronucleus test compared with the standard irradiation mode at a dose of 1.5 Gy, that is, a milder effect of the FLASH mode dose was observed. However, irradiation of mice in FLASH mode at high doses (7.0 and 8.0 Gy) led to earlier death of animals compared to the standard irradiation regime. A tumor node formed with further growth only after FLASH irradiation of a suspension of Ehrlich ascites carcinoma at a dose of 40 Gy; in all other groups a tumor was not formed.

JINR in collaboration with the St. Petersburg-based Efremov Institute of Electrophysical Apparatus (NIIEFA) is developing a superconducting isochronous cyclotron MSC230, which is intended to conduct research in radiobiology and to develop proton flash radiotherapy techniques. In relation to this, formation of a high-intensity proton beam with the energy selectable in a range of 120–230 MeV, a dose rate of 50–100 Gy/s, and homogeneous in cross section with a diameter of 13–15 cm at the new accelerator is explored. Results of modeling by the Monte Carlo method and measurements of the depth-dose distributions of a proton beam, the energy spectrum of which is modified to obtain an extended homogeneous plateau at the end of the range (spread-out Bragg peak), are presented. This is achieved by using so-called ridge filters. A method for design and manufacturing ridge filters using a 3D printer that can change the length of the plateau in a fairly wide range of values by rotating it relative to the beam axis is presented. The results of the study lend a hope that two sets, each consisting of 5–6 such filters, will be able to span the entire required range of the Bragg peak plateau, and for all values of the selected energy.

Flash irradiation is an innovative method of therapy, which ensures that the therapeutic dose is brought to the pathological focus in times of the order of several tens of milliseconds. In this mode of irradiation, the degree of damage to normal tissues surrounding the tumor that fall under the influence of radiation decreases; at the same time, the effect on cancer cells remains at almost the same level, which improves the prospect of local control of the tumor with a lower frequency of side effects. The exact radiobiological mechanisms underlying the flash effect are not completely clear. This paper presents the results of work on the formation of a high-intensity proton beam with an energy of 660 MeV from the phasotron accelerator of the Joint Institute for Nuclear Research (Dubna), designed to conduct radiobiological studies of flash irradiation therapy on cell cultures and small laboratory animals (mice and rats). The survival rate of A549 cells under proton beam irradiation in flash and standard modes was compared. A difference was found in the change in the survival rate of A549 cells irradiated in flash and standard modes. The magnitude of the flash effect was represented by the dose change factor.

FLASH radiotherapy is the innovative radiotherapy technique in which the short treatment times, few tens of milliseconds, are used to deliver a therapeutic dose of radiation to the tumor. This novel approach reduces damage and minimizes the dose to normal tissues surrounding the tumor and to tissues that are affected by radiation, whilst maintaining the treatment effect on cancer cells. This regimen may improve the level of local control of the tumor and lower the occurrence of side effects. To date, the exact radiobiological mechanisms underpinning the FLASH effect are not completely understood. The paper presents the results on the delivery of a high-intensity proton beam at an energy of 660 MeV produced by Phasotron, a proton accelerator at the Joint Institute for Nuclear Research, Dubna. This proton beam has been created to perform radiobiological studies involving cell cultures and small laboratory animals (mice, rats) using FLASH radiation. Also, the survival rates were compared between A549 cells irradiated at extremely high dose rates (FLASH technique) and those exposed to conventional irradiation with the lower dose rate. It was found that there is a difference between these groups of A549 cells in the survival rates. The magnitude of the FLASH effect is represented by a factor of different dose rates.

The FLASH effect of high-energy (660 MeV) proton irradiation using the Phasotron accelerator with the capacity of delivering dose rates of 80 Gy/s has been studied and compared to the effect after exposure to proton radiation at a conventional dose rate of 3 Gy/min. After FLASH and conventional dose-rate irradiation with doses of 1.0 and 1.5 Gy, the induction of cytogenetic damage to bone marrow cells and the state of lymphoid organs (thymus and spleen) were estimated; at doses of 7.0 and 8.0 Gy, the survival rate after total irradiation of mice in vivo was analyzed; and at doses of 40 and 60 Gy, the tumor growth rate was determined after irradiation ex vivo. It has been shown that irradiation of animals using the FLASH mode at a dose of 1.5 Gy protects the proliferative activity of the spleen and also leads to a decrease in cytogenetic injuries in bone marrow erythrocytes, based on the micronucleus test, as compared to the conventional irradiation at a dose of 1.5 Gy; thus, the FLASH effect has lower toxicity compared to conventional radiation. However, irradiation of mice, the FLASH effect which delivers high doses (7.0 and 8.0 Gy) of radiation, leads to earlier death of animals compared to those exposed to conventional radiation. Only after FLASH irradiation of a suspension of Ehrlich ascites carcinoma at a dose of 40 Gy, a tumor node with further growth was formed; no tumors were formed in all other groups.

The NICA accelerator complex includes beam transfer lines and stations for applied research. The first commissioning of the Station of Chip Irradiation (SOCHI) was performed at the end of 2021with С4+ heavy ions extracted from the linear accelerator (HILAC) at an energy of 3.2 MeV/n. The new SOCHI beam transfer line is integrated in the existing HILAC-Booster beamline. The Irradiation Setup for Components of Radioelectronic Apparatus (ISCRA) with ion energy ranging from 150 to 500 MeV/n and the Setup for Investigation of Medical Biological Objects (SIMBO) with the ion energy ranging from 400 to1100 MeV/n are based on the beams extracted from Nuclotron. The equipment of ISCRA and SIMBO stations has been manufactured and is planned to mount in the end of 2022. The beamlines are being designed now. The technical parameters of the beamlines and stations and the results of the first run of the SOCHI station are presented in this study.

Flash-therapy is a rapidly developing field of radiology that has the potential to revolutionize future cancer treatment techniques. The method involves delivery the therapeutic radiation dose to the tumor volume at an ultra-high dose rate in the beam, several orders of magnitude higher than that usually used in conventional radiotherapy. In this mode of irradiation, the degree of damage to normal tissues surrounding the tumor and falling under the influence of radiation decreases, at the same time, the effect on cancer cells remains at the same level, which preserves the prospect of local control of the tumor with a lower frequency of side effects. The paper presents the results on the delivery of a high-intensity proton beam with an energy of 660 MeV from the Phasotron of the Joint Institute for Nuclear Research, Dubna, designed for radiobiological studies under flash therapy irradiation of cell cultures and small laboratory animals (mice, rats). In addition, the main design features and parameters of the created detectors for measuring the characteristics of this beam are presented.

Purpose: To study was to study the effect of GNP nanoparticles on tumor cells of human lung carcinoma A 549 when irradiated with protons. Materials and methods: Cell culture: Human lung carcinoma cells A 549. Gold nanoparticles Au/PEG 6000/W 200/30 nm: A colloidal solution of gold nanoparticles purchased from the firm M 9 Nanomaterials & Technologies was used in the work. Proton irradiation: The irradiation of cells was carried out on a therapeutic proton beam in the Medical and Technical Complex of the Laboratory of Nuclear Problems Joint Institute for Nuclear Research. Determination of radiosensitivity of cells: By determining the clonogenic survival of cells. Determination of the genotoxic activity of nanoparticles under the action of proton irradiation: investigated using a micronucleus test with blocking cytokinesis. The genotoxicity of gold nanoparticles was estimated by the number of micronuclei per 1000 binuclear cells. Micronucleus were counted only in binuclear cells. At least 1000 binuclear cells were calculated for each dose, experiments were carried out in three repeats. Results: The frequency of micronucleus formation indicates an increase in the genotoxic effect of nanoparticles when irradiated with protons at a dose of 2 Gy. Proton irradiation caused an increase in the frequency of micronucleus formation depending on the concentration of nanoparticles. When irradiated with protons at a dose of 2 Gy in the presence and absence of nanoparticles, the difference in the frequency of micronucleus formation for the concentration of nanoparticles was 2.5 mg/ml – 1.1; for 5 mg/ml and 10 mg/ml – 1.2; for 15 mg/ml – 1.3 and for 30 mg/ml –1.5. Cell survival curves reflect a decrease in their survival rate when metal nanoparticles with high Z are added, which reflects the occurrence of radiosensitization effects. The gain for 10 % and 50 % survival rates is 1.4 and 2.5, respectively. Conclusions: Under the influence of proton irradiation, the genotoxic activity of gold nanoparticles in human lung carcinoma cells A 549 increases, depending on their concentration. The survival rate of human lung carcinoma A 549 cells irradiated with protons in the presence of gold nanoparticles decreases.

Nowadays space exploration has faced the issue of radiation risk to microelectronics and biological objects. The new beamlines and irradiation stations of the Nuclotron-based Ion Collider fAcility (NICA) at JINR are currently under construction to study this issue. The beamline parameters, different methods for homogeneous irradiation of targets such as scanning, and beam profile shaping by octupole magnets are discussed. A short description of the building infrastructure, magnet elements, and detectors for these beamlines is also given.

Within the framework of the NICA project an Innovation Block is being constructed. It includes an applied research station for microchips with a package for Single Event Effects (SEE) testing (energy range of 150-500 MeV/n, the SODIT station), an applied research station for testing of decapsulated microchips (ion energy up to 3,2 MeV/n, the SOCIT station), and an applied research station for space radiobiological research and modelling of influence of heavy charged particles on cognitive functions of the brain of small laboratory animals and primates (energy range 500-1000 MeV/n, the SODIB station). The systems for diagnostics and control of the beam characteristics during the certification and adjustment as well as the systems for online diagnostics and control of the beam characteristics of the SOCIT, SODIT and SODIB applied research stations are described.

Applied research at the NICA accelerator complex include the following areas that are under construction: single event effects testing on capsulated microchips (energy range of 150-500 MeV/n) at the Irradiation Setup for Components of Radioelectronic Apparature (ISCRA) and on decapsulated microchips (ion energy up to 3,2 MeV/n) at the Station of CHip Irradiation (SOCHI), space radiobiological research and modelling of influence of heavy charged particles on cognitive functions of the brain of small laboratory animals and primates (ener-gy range 500-1000 MeV/n) at the Setup for Investigation of Medical Biological Objects (SIMBO). Description of main systems and beam parameters at the ISCRA, SOCHI and SIMBO applied research stations is presented. The new beam transfer lines from the Nuclotron to ISCRA and SIMBO stations, and from HILAC to SOCHI station are being constructed. Description of the transfer lines layout, the magnets and diagnostic detectors, results of the beam dynamics simulations are described given.

Для облучения новообразований, расположенных вблизи жизненно важных радиочувствительных структур и органов необходимо обеспечить точное пространственное совмещение пучка с мишенью в сеансах протонной терапии. Целью работы является сравнение и анализ распределений доз, полученных в программе планирования протонного пучка и измеренных в результате эксперимента с применением радиохромных пленок в Медико-техническом комплексе (МТК) Лаборатории ядерных проблем (ЛЯП) Объединенного института ядерных исследований (ОИЯИ). На первом этапе измерений было определено соответствие степени потемнения пленки от дозы облучения. Для этого из одного листа пленки были вырезаны тринадцать кусочков размером 20×20 мм, которые затем облучали дозами (0; 0.25; 0.5; до 3 Гр). На их основе построена калибровочная кривая и рассчитано уравнение аппроксимации, которое использовано для перевода значений матрицы потемнения облученных пленок в значения поглощенной дозы. Продольный и поперечный спад дозы от уровня 80% до уровня 20% происходит соответственно на глубине 9.2±0.3 мм и на ширине 9.0±0.3 мм.

Для облучения новообразований, расположенных вблизи жизненно важных радиочувствительных структур и органов, разработана методика трехмерной конформной протонной лучевой терапии в Медико-техническом комплексе Лаборатории ядерных проблем Объединенного института ядерных исследований (Дубна), при которой максимум сформированного дозного распределения наиболее точно совпадает с формой мишени. При этом доза резко спадает за границами мишени, что позволяет проводить облучение ранее не доступных для лучевой терапии локализаций. В настоящей работе приводятся основные технологические этапы предлучевой подготовки и проведения облучения по разработанной методике.

This article considers an automated range shifter of variable thickness intended to adjust the proton beam energy in the 3D conformal proton radiotherapy of oncological diseases of the head and the neck. The range shifter was developed at the medico-technical complex of the Joint Institute for Nuclear Research (Dubna, Russia). The results of the experimental tests of the device show that it successfully fulfills its intended purpose. The developed range shifter is intended to be used as one of the main components of a new system for dynamic irradiation of deep-seated targets of complex shape.

To ensure the conformal depth-dose distribution of a proton beam within a target volume, complex shaped range shifters (so-called boluses), which account for the heterogeneous structure of patient tissue and organs in the beam path, were calculated and manufactured. The precise manufacturing of proton compensators used for patient treatment is a vital step in quality assurance in proton therapy. In this work a software-hardware complex that verifies the quality and precision of bolus manufacturing at the Medico-Technical Complex (MTC) was developed. The boluses consisted of a positioning system with two photoelectric biosensors. We evaluated 20 boluses used in proton therapy of five patients. A total number of 2562 experimental points were measured, of which only two points had values that differed from the calculated value by more than 0.5 mm. The other data points displayed a deviation within ±0.5 mm from the calculated value. The technology for bolus verification developed in this work can be used for the high precision testing of geometrical parameters of proton compensators in radiotherapy.

The use of fundamental Nuclear Physics in Nuclear Medicine has a significant impact in the fight against cancer. Hadrontherapy is an innovative cancer radiotherapy method using nuclear particles (protons, neutrons and ions) for the treatment of early and advanced tumors. The main goal of proton therapy is to deliver high radiation doses to the tumor volume with minimal damage to healthy tissues and organs. The purpose of this work was to investigate the dosimetric errors in clinical proton therapy dose calculation due to the presence of metallic implants in the treatment plan, and to determine the impact of the errors. The results indicate that the errors introduced by the treatment planning systems are higher than 10% in the prediction of the dose at isocenter when the proton beam is passing directly through a metallic titanium alloy implant. In conclusion, we recommend that pencil-beam algorithms not be used when planning treatment for patients with titanium alloy implants, and to consider implementing methods to mitigate the effects of the implants.

A medico-technical system for hadron radiotherapy of cancer patients based on a 660-MeV proton phasotron was constructed. It is now used at the Joint Institute for Nuclear Research (Dubna, Russia). Upgrade of methods, hardware, and software for radiotherapy is one of the main tasks for further improvement of the system. This work considers the construction of a device for measurement of proton beam depth–dose curve in a treatment room, which is very important for conformal proton beam therapy and dynamic irradiation of a deeply lying target.

The proton beam radiosurgery was performed to 65 patients with brain AVM since December, 2001 till February, 2012, in Joint Institute for Nuclear Research, Dubna, Russia. We have analyzed data for 56 patients. The follow up time varied from 24 to 109 months. The volumes of brain AVMs varied from 0.92 to 82 cc. The mean isocenter dose was 24.61 +/- 0.12 Gy E. The edge of the target was included in 70-90% isodose. The proton beam surgery was splitted in two similar doses and delivered in two consecutive days in vast majority of patients. Ten patients were missed for follow up due to some reasons. The radiosurgery was resulted in full obliteration of AVM in 23 from remaining 46 (50%) patients. There was full obliteration in 46.6% of patients with volume of AVM 10-24.9 cc; and this rate is significantly more than for photon radiosurgery of same size brain AVM. The partial obliteration was obtained in 21 patients. Only one patients suffered hemorrhage from partially obliterated AVM. We could not see any effect in 2 patients. There were delayed radiation toxicity in 5 patients in 12 months after treatment: in 4 patients, these reactions were assessed as 2 according to RTOG scale and were dissipated in 1 month after commencement of corticosteroid treatment. There was radiation necrosis in one patient, and it was relieved in 12 months after several courses of dehydration and corticosteroid therapy. So, proton beam therapy is effective and safe modality for treatment of inoperable brain AVM, especially of middle- and large size.