Radiation quality correction factors for improved dosimetry in preclinical minibeam radiotherapy.

BACKGROUND: In reference dosimetry, radiation quality correction factors are used in order to account for changes in the detector's response among different radiation qualities, improving dosimetric accuracy. PURPOSE: Reference dosimetry radiation quality corrections factors for the PTW microDiamond were calculated for preclinical X-ray and proton minibeams, and their impact in dosimetric accuracy was evaluated. METHODS: A formalism for the calculation of radiation quality correction factors for absolute dosimetry in minibeam fields was developed. Following our formalism, radiation quality correction factors were calculated for the PTW microDiamond detector, using the Monte Carlo method. Models of the detector, and X-ray and proton irradiation platform, were imported into the TOPAS Monte Carlo simulation toolkit. The radiation quality correction factors were calculated in the following scenarios: (i) reference dosimetry open field to minibeam center of the central peak, (ii) different positions at the minibeam profile (along the peaks and valleys direction) to the center of the central minibeam, and (iii) some representative depth positions. In addition, the radiation quality correction factors needed for the calculation of the peak-to-valley dose ratio at different depths were calculated. RESULTS: An important overestimation of the dose (about 10%) was found in the case of the open to minibeam field for both X-rays and proton beams, when the correction factors were used. Smaller differences were observed in the other cases. CONCLUSIONS: The usage of the PTW microDiamond detector requires radiation quality correction factors in order to be used in minibeam reference dosimetry.

A scanning dynamic collimator for spot-scanning proton minibeam production.

In proton minibeam radiation therapy, proton minibeams are typically produced by modulating a uniform field using a multislit collimator. Multislit collimators produce minibeams of fixed length and width, and a new collimator has to be manufactured each time a new minibeam array is required, limiting its flexibility. In this work, we propose a scanning dynamic collimator for the generation of proton minibeams arrays. The new collimator system proposed is able to produce any minibeam required on an on-line basis by modulating the pencil beam spots of modern proton therapy machines, rather than a uniform field. The new collimator is evaluated through Monte Carlo simulations and the produced proton minibeams are compared with that of a multislit collimator. Furthermore, a proof of concept experiment is conducted to demonstrate the feasibility of producing a minibeam array by repositioning (i.e. scanning) a collimator. It is concluded that besides the technical challenges, the new collimator design is producing equivalent minibeam arrays to the multislit collimator, whilst is flexible to produce any minibeam array desired.

X-rays minibeam radiation therapy at a conventional irradiator: Pilot evaluation in F98-glioma bearing rats and dose calculations in a human phantom.

Minibeam radiation therapy (MBRT) is a type of spatial fractionated radiotherapy that uses submillimetric beams. This work reports on a pilot study on normal tissue response and the increase of the lifespan of glioma-bearing rats when irradiated with a tabletop x-ray system. Our results show a significant widening of the therapeutic window for brain tumours treated with MBRT: an important proportion of long-term survivals (60%) coupled with a significant reduction of toxicity when compared with conventional (broad beam) irradiations. In addition, the clinical translation of the minibeam treatment at a conventional irradiator is evaluated through a possible human head treatment plan.

Full 3D position reconstruction of a radioactive source based on a novel hyperbolic geometrical algorithm.

A new method to locate, with millimetre uncertainty, in 3D, a γ -ray source emitting multiple γ -rays in a cascade, employing conventional LaBr3(Ce) scintillation detectors, has been developed. Using 16 detectors in a symmetrical configuration the detector energy and time signals, resulting from the γ -ray interactions, are fed into a new source position reconstruction algorithm. The Monte-Carlo based Geant4 framework has been used to simulate the detector array and a 60Co source located at two positions within the spectrometer central volume. For a source located at (0,0,0) the algorithm reports X, Y, Z values of -0.3 ± 2.5, -0.4 ± 2.4, and -0.6 ± 2.5 mm, respectively. For a source located at (20,20,20) mm, with respect to the array centre, the algorithm reports X, Y, Z values of 20.2 ± 1.0, 20.2 ± 0.9, and 20.1 ± 1.2 mm. The resulting precision of the reconstruction means that this technique could find application in a number of areas including nuclear medicine, national security, radioactive waste assay and proton beam therapy.

Versatile magnetic microdiscs for the radio enhancement and mechanical disruption of glioblastoma cancer cells.

This study describes the use of highly versatile, lithographically defined magnetic microdiscs. Gold covered magnetic microdiscs are used in both radiosensitizing cancer cells, acting as intracellular emitters of secondary electrons during radiotherapy, and as well as inducing mechanical damage by exerting a mechanical torque when exposed to a rotating magnetic field. This study reveals that lithographically defined microdiscs with a uniform size of 2 microns in diameter highly increase the DNA damage and reduce the glioblastoma colony formation potential compared to conventional radiation therapy. Furthermore, the addition of mechanical disruption mediated by the magnetic component of the discs increased the efficiency of brain cancer cell killing.

Insights into the non-homologous end joining pathway and double strand break end mobility provided by mechanistic in silico modelling.

After radiation exposure, one of the critical processes for cellular survival is the repair of DNA double strand breaks. The pathways involved in this response are complex in nature and involve many individual steps that act across different time scales, all of which combine to produce an overall behaviour. It is therefore experimentally challenging to unambiguously determine the mechanisms involved and how they interact whilst maintaining strict control of all confounding variables. In silico methods can provide further insight into results produced by focused experimental investigations through testing of the hypotheses generated. Such computational testing can asses competing hypotheses by investigating their effects across all time scales concurrently, highlighting areas where further experimental work can have the most significance. We describe the construction of a mechanistic model by combination of several hypothesised mechanisms reported in the literature and supported by experiment. Compatibility of these mechanisms was tested by fitting simulation to results reported in the literature. To avoid over-fitting, we used an approach of sequentially testing individual mechanisms within this pathway. We demonstrate that using this approach the model is capable of reproducing published protein kinetics and overall repair trends. This provides evidence supporting the feasibility of the proposed mechanisms and revealed how they interact to produce an overall behaviour. Furthermore, we show that the assumed motion of individual double strand break ends plays a crucial role in determining overall system behaviour.

Modelling direct DNA damage for gold nanoparticle enhanced proton therapy.

Gold nanoparticles have been proven as potential radiosensitizer when combined with protons. Initially the radiosensitization effect was attributed to the physical interactions of radiation with the gold and the production of secondary electrons that induce DNA damage. However, emerging data challenge this hypothesis, supporting the existence of alternative or supplementary radiosensitization mechanisms. In this work we incorporate a realistic cell model with detailed DNA geometry and a realistic gold nanoparticle biodistribution based on experimental data. The DNA single and double strand breaks, and damage complexity are counted under various scenarios of different gold nanoparticle size, biodistribution and concentration, and proton energy. The locality of the effect, i.e. the existence of higher damage at a location close to the gold distribution, is also addressed by investigating the DNA damage at a chromosomal territory. In all the cases we do not observe any significant increase in the single/double strand break yield or damage complexity in the presence of gold nanoparticles under proton irradiation; nor there is a locality to the effect. Our results show for the first time that the physical interactions of protons with the gold nanoparticles should not be considered directly responsible for the observed radiosensitization effect. The model used only accounts for DNA damage from direct interactions, whilst considering the indirect effect, and it is possible the radiosensitization effect to be due to other physical effects, although we consider that possibility unlikely. Our conclusion suggests that other mechanisms might have greater contribution to the radiosensitization effect and further investigation should be conducted.