A Potential Renewed Use of Very Heavy Ions for Therapy: Neon Minibeam Radiation Therapy.
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ABSTRACT:
SUBMITTER: Prezado Y
PROVIDER: S-EPMC8002595 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:(1) Background: Proton Arc Therapy and Proton Minibeam Radiation Therapy are two novel therapeutic approaches with the potential to lower the normal tissue complication probability, widening the therapeutic window for radioresistant tumors. While the benefits of both modalities have been individually evaluated, their combination and its potential advantages are being assessed in this proof-of-concept study for the first time. (2) Methods: Monte Carlo simulations were employed to evaluate the dose and LET distributions in brain tumor irradiations. (3) Results: a net reduction in the dose to normal tissues (up to 90%), and the preservation of the spatial fractionation of the dose were achieved for all configurations evaluated. Additionally, Proton Minibeam Arc Therapy (pMBAT) reduces the volumes exposed to high-dose and high-LET values at expense of increased low-dose and intermediate-LET values. (4) Conclusions: pMBAT enhances the individual benefits of proton minibeams while keeping those of conventional proton arc therapy. These results might facilitate the path towards patients' treatments since lower peak doses in normal tissues would be needed than in the case of a single array of proton minibeams.
| S-EPMC8749801 | biostudies-literature
Project description:Proton minibeam radiation therapy (pMBRT) is a novel therapeutic strategy that has proven to significantly increase dose tolerances and sparing of normal tissue. It uses very narrow proton beams (diameter ≤1 mm), roughly one order of magnitude smaller than state-of-the-art pencil beams. The current implementation of pMBRT with mechanical collimators is suboptimal as it is inflexible, decreases efficiency and produces additional secondary neutrons. As a potential solution, we explore in this article minibeam generation through magnetic focussing and investigate possibilities for the integration of such a technique at existing clinical centres. For this, a model of the pencil beam scanning (PBS) nozzle and beam at the Orsay Proton Therapy Centre was established and Monte Carlo simulations were performed to determine its focussing capabilities. Moreover, various modifications of the nozzle geometry were considered. It was found that the PBS nozzle in its current state is not suitable for magnetic minibeam generation. Instead, a new, optimised nozzle design has been proposed and conditions necessary for minibeam generation were benchmarked. In addition, dose simulations in a water phantom were performed which showed improved dose distributions compared to those obtained with mechanical collimators.
| S-EPMC6987213 | biostudies-literature
Project description:The goal is to compare, in vitro, the efficiency of minibeam radiotherapy (MBRT) and standard RT in inducing clonogenic cell death in glioma cell lines. With this aim, we report on the first in vitro study performed in an X-ray Small Animal Radiation Research Platform (SARRP) modified for minibeam irradiations. F98 rat and U87 human glioma cells were irradiated with either an array of minibeams (MB) or with conventional homogeneous beams (broad beam, BB). A specially designed multislit collimator was used to generate the minibeams with a with of a center-to-center distance of 1465 (±10)??m, and a PVDR value of 12.4 (±2.3) measured at 1?cm depth in a water phantom. Cells were either replated for clonogenic assay directly (immediate plating, IP) or 24?h after irradiation (delayed plating, DP) to assess the effect of potentially lethal damage repair (PLDR) on cell survival. Our hypothesis is that with MBRT, a similar level of clonogenic cell death can be reached compared to standard RT, when using equal mean radiation doses. To prove this, we performed dose escalations to determine the minimum integrated dose needed to reach a similar level of clonogenic cell death for both treatments. We show that this minimum dose can vary per cell line: in F98 cells a dose of 19?Gy was needed to obtain similar levels of clonogenic survival, whereas in U87 cells there was still a slightly increased survival with MB compared to BB 19?Gy treatment. The results suggest also an impairment of DNA damage repair in F98 cells as there is no difference in clonogenic cell survival between immediately and delayed plated cells for each dose and irradiation mode. For U87 cells, a small IP-DP effect was observed in the case of BB irradiation up to a dose of 17?Gy. However, at 19?Gy BB, as well as for the complete dose range of MB irradiation, U87 cells did not show a difference in clonogenic survival between IP and DP. We therefore speculate that MBRT might influence PLDR. The current results show that X-ray MBRT is a promising method for treatment of gliomas: future preclinical and clinical studies should aim at reaching a minimum radiation (valley) dose for effective eradication of gliomas with increased sparing of normal tissues compared to standard RT.
| S-EPMC6134191 | biostudies-other
Project description:(1) Background: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy technique using spatially modulated narrow proton beams. pMBRT results in a significantly reduced local tissue toxicity while maintaining or even increasing the tumor control efficacy as compared to conventional radiotherapy in small animal experiments. In all the experiments performed up to date in tumor bearing animals, the dose was delivered in one single fraction. This is the first assessment on the impact of a temporal fractionation scheme on the response of glioma-bearing animals to pMBRT. (2) Methods: glioma-bearing rats were irradiated with pMBRT using a crossfire geometry. The response of the irradiated animals in one and two fractions was compared. An additional group of animals was also treated with conventional broad beam irradiations. (3) Results: pMBRT delivered in two fractions at the biological equivalent dose corresponding to one fraction resulted in the highest median survival time, with 80% long-term survivors free of tumors. No increase in local toxicity was noted in this group with respect to the other pMBRT irradiated groups. Conventional broad beam irradiations resulted in the most severe local toxicity. (4) Conclusion: Temporal fractionation increases the therapeutic index in pMBRT and could ease the path towards clinical trials.
| S-EPMC8507607 | biostudies-literature
Project description:Minibeam radiation therapy (MBRT) is an innovative synchrotron radiotherapy technique able to shift the normal tissue complication probability curves to significantly higher doses. However, its exploration was hindered due to the limited and expensive beamtime at synchrotrons. The aim of this work was to develop a cost-effective equipment to perform systematic radiobiological studies in view of MBRT. Tumor control for various tumor entities will be addressable as well as studies to unravel the distinct biological mechanisms involved in normal and tumor tissues responses when applying MBRT. With that aim, a series of modifications of a small animal irradiator were performed to make it suitable for MBRT experiments. In addition, the brains of two groups of rats were irradiated. Half of the animals received a standard irradiation, the other half, MBRT. The animals were followed-up for 6.5 months. Substantial brain damage was observed in the group receiving standard RT, in contrast to the MBRT group, where no significant lesions were observed. This work proves the feasibility of the transfer of MBRT outside synchrotron sources towards a small animal irradiator.
| S-EPMC5725561 | biostudies-literature
Project description:Radiotherapy should have low toxicity in the entrance channel (normal tissue) and be very effective in cell killing in the target region (tumour). In this regard, ions heavier than protons have both physical and radiobiological advantages over conventional X-rays. Carbon ions represent an excellent combination of physical and biological advantages. There are a dozen carbon-ion clinical centres in Europe and Asia, and more under construction or at the planning stage, including the first in the USA. Clinical results from Japan and Germany are promising, but a heated debate on the cost-effectiveness is ongoing in the clinical community, owing to the larger footprint and greater expense of heavy ion facilities compared with proton therapy centres. We review here the physical basis and the clinical data with carbon ions and the use of different ions, such as helium and oxygen. Research towards smaller and cheaper machines with more effective beam delivery is necessary to make particle therapy affordable. The potential of heavy ions has not been fully exploited in clinics and, rather than there being a single 'silver bullet', different particles and their combination can provide a breakthrough in radiotherapy treatments in specific cases.
| S-EPMC7612063 | biostudies-literature
Project description:Heavy ion radiation therapy has been increasingly used due to several advantages over low linear energy transfer (LET) photon therapy, but further improvement of its therapeutic efficacy would be necessary. In this review, we summarize effective radiosensitizers for heavy ion radiation therapy and mechanisms associated with the radiosensitization. High LET heavy ions induce more complex and clustered DNA damage than low LET radiation. Inhibition of homologous recombimation repair or nonhomologous end rejoining and dysfunctional cell cycle checkpoint have been reported to sensitize cancer cells to heavy ions. Radiosenstizing agents, including DNA damage response inhibitors, Hsp90 inhibitors, histone acetylase inhibitors, and nanomaterials have been found to enhance cell killing by heavy ion irradiation through disrupted DNA damage response, cell cycle arrest, or other cellular processes. The use of these radiosensitizers could be a promising strategy to enhance the efficacy of heavy ion radiation therapy.
| S-EPMC6871583 | biostudies-literature
Project description:Radiotherapy (RT) is one of the most frequently used methods for cancer treatment. Despite remarkable advancements in RT techniquesthe treatment of radioresistant tumours (i.e. high-grade gliomas) is not yet satisfactory. Finding novel approaches less damaging for normal tissues is of utmost importance. This would make it possible to increase the dose applied to tumours, resulting in an improvement in the cure rate. Along this line, proton minibeam radiation therapy (pMBRT) is a novel strategy that allows the spatial modulation of the dose, leading to minimal damage to brain structures compared to a high dose (25 Gy in one fraction) of standard proton therapy (PT). The aim of the present study was to evaluate whether pMBRT also preserves important cerebral functions. Comprehensive longitudinal behavioural studies were performed in irradiated (peak dose of 57 Gy in one fraction) and control rats to evaluate the impact of pMBRT on motor function (motor coordination, muscular tonus, and locomotor activity), emotional function (anxiety, fear, motivation, and impulsivity), and cognitive function (learning, memory, temporal processing, and decision making). The evaluations, which were conducted over a period of 10 months, showed no significant motor or emotional dysfunction in pMBRT-irradiated rats compared with control animals. Concerning cognitive functions, similar performance was observed between the groups, although some slight learning delays might be present in some of the tests in the long term after irradiation. This study shows the minimal impact of pMBRT on the normal brain at the functional level.
| S-EPMC7419511 | biostudies-literature
Project description:PurposeTo evaluate the clinical potential of spot-scanning hadron arc (SHArc) therapy with a heavy-ion gantry.Methods and materialsA series of in silico studies was conducted via treatment plan optimization in FRoG and the RayStation TPS to compare SHArc therapy against reference plans using conventional techniques with single, parallel-opposed, and 3-field configurations for 3 clinical particle beams (protons [p], helium [4He], and carbon [12C] ions). Tests were performed on water-equivalent cylindrical phantoms for simple targets and clinical-like scenarios with an organ-at-risk in proximity of the target. Effective dose and dose-averaged linear energy transfer (LETD) distributions for SHArc were evaluated against conventional planning techniques applying the modified microdosimetric kinetic model for considering bio-effect with (α/β)x = 2 Gy. A model for hypoxia-induced tumor radio-resistance was developed for particle therapy with dependence on oxygen concentration and particle species/energy (Zeff/β)2 to investigate the impact on effective dose.ResultsSHArc plans exhibited similar target coverage with unique treatment attributes and distributions compared with conventional planning, with carbon ions demonstrating the greatest potential for tumor control and normal tissue sparing among the arc techniques. All SHArc plans exhibited a low-dose bath outside the target volume with a reduced maximum dose in normal tissues compared with single, parallel-opposed, and 3-field configuration plans. Moreover, favorable LETD distributions were made possible using the SHArc approach, with maximum LETD in the r = 5 mm tumor core (~8 keVμm-1, ~30 keVμm-1, and ~150 keVμm-1 for p, 4He, and 12C ions, respectively) and reductions of high-LET regions in normal tissues and organs-at-risk compared with static treatment beam delivery.ConclusionSHArc therapy offers potential treatment benefits such as increased normal tissue sparing. Without explicit consideration of oxygen concentration during treatment planning and optimization, SHArc-C may mitigate tumor hypoxia-induced loss of efficacy. Findings justify further development of robust SHArc treatment planning toward potential clinical translation.
| S-EPMC8010580 | biostudies-literature
Project description:Nuclear factor κB (NF-κB) activation might be central to heavy ion-induced detrimental processes such as cancer promotion and progression and sustained inflammatory responses. A sensitive detection system is crucial to better understand its involvement in these processes. Therefore, a DD-tdTomato fluorescent protein-based reporter system was previously constructed with human embryonic kidney (HEK) cells expressing DD-tdTomato as a reporter under the control of a promoter containing NF-κB binding sites (HEK-pNFκB-DD-tdTomato-C8). Using this reporter cell line, NF-κB activation after exposure to different energetic heavy ions (16O, 95 MeV/n, linear energy transfer-LET 51 keV/µm; 12C, 95 MeV/n, LET 73 keV/μm; 36Ar, 95 MeV/n, LET 272 keV/µm) was quantified considering the dose and number of heavy ions hits per cell nucleus that double NF-κB-dependent DD-tdTomato expression. Approximately 44 hits of 16O ions and ≈45 hits of 12C ions per cell nucleus were required to double the NF-κB-dependent DD-tdTomato expression, whereas only ≈3 hits of 36Ar ions were sufficient. In the presence of Shield-1, a synthetic molecule that stabilizes DD-tdTomato, even a single particle hit of 36Ar ions doubled NF-κB-dependent DD-tdTomato expression. In conclusion, stabilization of the reporter protein can increase the sensitivity for NF-κB activation detection by a factor of three, allowing the detection of single particle hits' effects.
| S-EPMC8703744 | biostudies-literature