Aberrant neuronal connectivity in the cortex drives generation of seizures in rat absence epilepsy.

Absence epilepsy belongs to genetic epilepsies and is characterized by recurrent generalized seizures that are concomitant with alterations of consciousness and associated with cognitive comorbidities. Little is known about the mechanisms leading to occurrence of epileptic seizures (i.e. epileptogenesis) and, in particular, it remains an open question as to whether neuronal hypersynchronization, a key feature in seizure initiation, could result from aberrant structural connectivity within neuronal networks endowing them with epileptic properties. In the present study, we addressed this question using a genetic model of absence epilepsy in the rat where seizures initiate in the whisker primary somatosensory cortex (wS1). We hypothesized that alterations in structural connectivity of neuronal networks within wS1 contribute to pathological neuronal synchronization responsible for seizures. First, we used rabies virus-mediated retrograde synaptic tracing and showed that cortical neurons located in both upper- and deep-layers of wS1 displayed aberrant and significantly increased connectivity in the genetic model of absence epilepsy, as highlighted by a higher number of presynaptic partners. Next, we showed at the functional level that disrupting these aberrant wS1 neuronal networks with synchrotron X-ray-mediated cortical microtransections drastically decreased both the synchronization and seizure power of wS1 neurons, as revealed by in vivo local field potential recordings with multichannel probes. Taken together, our data provide for the first time strong evidence that increased structural connectivity patterns of cortical neurons represent critical pathological substrates for increased neuronal synchronization and generation of absence seizures.

Microbeam Irradiation as a Simultaneously Integrated Boost in a Conventional Whole-Brain Radiotherapy Protocol.

Microbeam radiotherapy (MRT), an experimental high-dose rate concept with spatial fractionation at the micrometre range, has shown a high therapeutic potential as well as good preservation of normal tissue function in pre-clinical studies. We investigated the suitability of MRT as a simultaneously integrated boost (SIB) in conventional whole-brain irradiation (WBRT). A 174 Gy MRT SIB was administered with an array of quasi-parallel, 50 µm wide microbeams spaced at a centre-to-centre distance of 400 µm either on the first or last day of a 5 × 4 Gy radiotherapy schedule in healthy adult C57 BL/6J mice and in F98 glioma cell cultures. The animals were observed for signs of intracranial pressure and focal neurologic signs. Colony counts were conducted in F98 glioma cell cultures. No signs of acute adverse effects were observed in any of the irradiated animals within 3 days after the last irradiation fraction. The tumoricidal effect on F98 cell in vitro was higher when the MRT boost was delivered on the first day of the irradiation course, as opposed to the last day. Therefore, the MRT SIB should be integrated into a clinical radiotherapy schedule as early as possible.

X-Tream quality assurance in synchrotron X-ray microbeam radiation therapy.

Microbeam radiation therapy (MRT) is a novel irradiation technique for brain tumours treatment currently under development at the European Synchrotron Radiation Facility in Grenoble, France. The technique is based on the spatial fractionation of a highly brilliant synchrotron X-ray beam into an array of microbeams using a multi-slit collimator (MSC). After promising pre-clinical results, veterinary trials have recently commenced requiring the need for dedicated quality assurance (QA) procedures. The quality of MRT treatment demands reproducible and precise spatial fractionation of the incoming synchrotron beam. The intensity profile of the microbeams must also be quickly and quantitatively characterized prior to each treatment for comparison with that used for input to the dose-planning calculations. The Centre for Medical Radiation Physics (University of Wollongong, Australia) has developed an X-ray treatment monitoring system (X-Tream) which incorporates a high-spatial-resolution silicon strip detector (SSD) specifically designed for MRT. In-air measurements of the horizontal profile of the intrinsic microbeam X-ray field in order to determine the relative intensity of each microbeam are presented, and the alignment of the MSC is also assessed. The results show that the SSD is able to resolve individual microbeams which therefore provides invaluable QA of the horizontal field size and microbeam number and shape. They also demonstrate that the SSD used in the X-Tream system is very sensitive to any small misalignment of the MSC. In order to allow as rapid QA as possible, a fast alignment procedure of the SSD based on X-ray imaging with a low-intensity low-energy beam has been developed and is presented in this publication.

In vivo pink-beam imaging and fast alignment procedure for rat brain tumor radiation therapy.

A fast positioning method for brain tumor microbeam irradiations for preclinical studies at third-generation X-ray sources is described. The three-dimensional alignment of the animals relative to the X-ray beam was based on the X-ray tomography multi-slices after iodine infusion. This method used pink-beam imaging produced by the ID17 wiggler. A graphical user interface has been developed in order to define the irradiation parameters: field width, height, number of angles and X-ray dose. This study is the first reporting an image guided method for soft tissue synchrotron radiotherapy. It allowed microbeam radiation therapy irradiation fields to be reduced by a factor of ∼20 compared with previous studies. It permitted more targeted, more efficient brain tumor microbeam treatments and reduces normal brain toxicity of the radiation treatment.

Identification of AREG and PLK1 pathway modulation as a potential key of the response of intracranial 9L tumor to microbeam radiation therapy.

Synchrotron microbeam radiation therapy (MRT) relies on the spatial fractionation of a synchrotron beam into parallel micron-wide beams allowing deposition of hectogray doses. MRT controls the intracranial tumor growth in rodent models while sparing normal brain tissues. Our aim was to identify the early biological processes underlying the differential effect of MRT on tumor and normal brain tissues. The expression of 28,000 transcripts was tested by microarray 6 hr after unidirectional MRT (400 Gy, 50 µm-wide microbeams, 200 µm spacing). The specific response of tumor tissues to MRT consisted in the significant transcriptomic modulation of 431 probesets (316 genes). Among them, 30 were not detected in normal brain tissues, neither before nor after MRT. Areg, Trib3 and Nppb were down-regulated, whereas all others were up-regulated. Twenty-two had similar expression profiles during the 2 weeks observed after MRT, including Ccnb1, Cdc20, Pttg1 and Plk1 related to the mitotic role of the Polo-like kinase (Plk) pathway. The up-regulation of Areg expression may indicate the emergence of survival processes in tumor cells triggered by the irradiation; while the modulation of the "mitotic role of Plk1" pathway, which relates to cytokinetic features of the tumor observed histologically after MRT, may partially explain the control of tumor growth by MRT. The identification of these tumor-specific responses permit to consider new strategies that might potentiate the antitumoral effect of MRT.

Energy spectra considerations for synchrotron radiotherapy trials on the ID17 bio-medical beamline at the European Synchrotron Radiation Facility.

The aim of this study was to validate the kilovoltage X-ray energy spectrum on the ID17 beamline at the European Synchrotron Radiation Facility (ESRF). The purpose of such validation was to provide an accurate energy spectrum as the input to a computerized treatment planning system, which will be used in synchrotron microbeam radiotherapy trials at the ESRF. Calculated and measured energy spectra on ID17 have been reported previously but recent additions and safety modifications to the beamline for veterinary trials warranted a fresh investigation. The authors used an established methodology to compare X-ray attenuation measurements in copper sheets (referred to as half value layer measurements in the radiotherapy field) with the predictions of a theoretical model. A cylindrical ionization chamber in air was used to record the relative attenuation of the X-ray beam intensity by increasing thicknesses of high-purity copper sheets. The authors measured the half value layers in copper for two beamline configurations, which corresponded to differing spectral conditions. The authors obtained good agreement between the measured and predicted half value layers for the two beamline configurations. The measured first half value layer was 1.754 ± 0.035 mm Cu and 1.962 ± 0.039 mm Cu for the two spectral conditions, compared with theoretical predictions of 1.763 ± 0.039 mm Cu and 1.984 ± 0.044 mm Cu, respectively. The calculated mean energies for the two conditions were 105 keV and 110 keV and there was not a substantial difference in the calculated percentage depth dose curves in water between the different spectral conditions. The authors observed a difference between their calculated energy spectra and the spectra previously reported by other authors, particularly at energies greater than 100 keV. The validation of the beam spectrum by the copper half value layer measurements means the authors can provide an accurate spectrum as an input to a treatment planning system for the forthcoming veterinary trials of microbeam radiotherapy to spontaneous tumours in cats and dogs.

The in vivo radiosensitizing effect of gold nanoparticles based MRI contrast agents.

Owing to the high atomic number (Z) of gold element, the gold nanoparticles appear as very promising radiosensitizing agents. This character can be exploited for improving the selectivity of radiotherapy. However, such an improvement is possible only if irradiation is performed when the gold content is high in the tumor and low in the surrounding healthy tissue. As a result, the beneficial action of irradiation (the eradication of the tumor) should occur while the deleterious side effects of radiotherapy should be limited by sparing the healthy tissue. The location of the radiosensitizers is therefore required to initiate the radiotherapy. Designing gold nanoparticles for monitoring their distribution by magnetic resonance imaging (MRI) is an asset due to the high resolution of MRI which permits the accurate location of particles and therefore the determination of the optimal time for the irradiation. We recently demonstrated that ultrasmall gold nanoparticles coated by gadolinium chelates (Au@DTDTPA-Gd) can be followed up by MRI after intravenous injection. Herein, Au@DTDTPA and Au@DTDTPA-Gd were prepared in order to evaluate their potential for radiosensitization. Comet assays and in vivo experiments suggest that these particles appear well suited for improving the selectivity of the radiotherapy. The dose which is used for inducing similar levels of DNA alteration is divided by two when cells are incubated with the gold nanoparticles prior to the irradiation. Moreover, the increase in the lifespan of tumor bearing rats is more important when the irradiation is performed after the injection of the gold nanoparticles. In the case of treatment of rats with a brain tumor (9L gliosarcoma, a radio-resistant tumor in a radiosensitive organ), the delay between the intravenous injection and the irradiation was determined by MRI.

The In Vivo Radiosensitizing Effect of Gold Nanoparticles Based MRI Contrast Agents.

Owing to the high atomic number (Z) of gold element, the gold nanoparticles appear as very promising radiosensitizing agents. This character can be exploited for improving the selectivity of radiotherapy. However, such an improvement is possible only if irradiation is performed when the gold content is high in the tumor and low in the surrounding healthy tissue. As a result, the beneficial action of irradiation (the eradication of the tumor) should occur while the deleterious side effects of radiotherapy should be limited by sparing the healthy tissue. The location of the radiosensitizers is therefore required to initiate the radiotherapy. Designing gold nanoparticles for monitoring their distribution by magnetic resonance imaging (MRI) is an asset due to the high resolution of MRI which permits the accurate location of particles and therefore the determination of the optimal time for the irradiation. We recently demonstrated that ultrasmall gold nanoparticles coated by gadolinium chelates (Au@DTDTPA-Gd) can be followed up by MRI after intravenous injection. Herein, Au@DTDTPA and Au@DTDTPA-Gd were prepared in order to evaluate their potential for radiosensitization. Comet assays and in vivo experiments suggest that these particles appear well suited for improving the selectivity of the radiotherapy. The dose which is used for inducing similar levels of DNA alteration is divided by two when cells are incubated with the gold nanoparticles prior to the irradiation. Moreover, the increase in the lifespan of tumor bearing rats is more important when the irradiation is performed after the injection of the gold nanoparticles. In the case of treatment of rats with a brain tumor (9L gliosarcoma, a radio-resistant tumor in a radiosensitive organ), the delay between the intravenous injection and the irradiation was determined by MRI.

Benchmarking and validation of a Geant4-SHADOW Monte Carlo simulation for dose calculations in microbeam radiation therapy.

Microbeam radiation therapy (MRT) is a synchrotron-based radiotherapy modality that uses high-intensity beams of spatially fractionated radiation to treat tumours. The rapid evolution of MRT towards clinical trials demands accurate treatment planning systems (TPS), as well as independent tools for the verification of TPS calculated dose distributions in order to ensure patient safety and treatment efficacy. Monte Carlo computer simulation represents the most accurate method of dose calculation in patient geometries and is best suited for the purpose of TPS verification. A Monte Carlo model of the ID17 biomedical beamline at the European Synchrotron Radiation Facility has been developed, including recent modifications, using the Geant4 Monte Carlo toolkit interfaced with the SHADOW X-ray optics and ray-tracing libraries. The code was benchmarked by simulating dose profiles in water-equivalent phantoms subject to irradiation by broad-beam (without spatial fractionation) and microbeam (with spatial fractionation) fields, and comparing against those calculated with a previous model of the beamline developed using the PENELOPE code. Validation against additional experimental dose profiles in water-equivalent phantoms subject to broad-beam irradiation was also performed. Good agreement between codes was observed, with the exception of out-of-field doses and toward the field edge for larger field sizes. Microbeam results showed good agreement between both codes and experimental results within uncertainties. Results of the experimental validation showed agreement for different beamline configurations. The asymmetry in the out-of-field dose profiles due to polarization effects was also investigated, yielding important information for the treatment planning process in MRT. This work represents an important step in the development of a Monte Carlo-based independent verification tool for treatment planning in MRT.

Investigation of UV optical fibers under synchrotron irradiation.

The focus of the present paper deals, for the first time, with commercial UV optical fibers, characterizing their behaviour as they are subjected to very high flux wiggler generated synchrotron radiation. Five distinct types of UV optical fibers, produced by three manufactures, were exposed to total doses between 5 Gy and 2000 Gy. The exposure to synchrotron radiation was performed in two campaigns. The tests were run off-line and considered the dependence of the radiation induced attenuation (RIA) as function of the total dose. The recovery of the radiation induced colour centres was studied at room temperature and after heating the samples up to 560 K. As a première, we also investigated through THz imaging and spectroscopy the irradiated optical fiber samples. Under these conditions, three of the optical fibers proved to be radiation resistant. The two optical fibers sensitive to synchrotron radiation exhibited a linear variation of the optical absorption at the wavelengths of λ = 229 nm, λ = 248 nm, and λ = 265 nm, for total doses between 60 Gy and 2000 Gy. These two samples showed also an increase of the optical absorption in the UV spectral range when heated to 560 K. The optical fibers sensitive to synchrotron radiation can potentially be used for on-line radiation dosimetry.

Synchrotron X-ray interlaced microbeams suppress paroxysmal oscillations in neuronal networks initiating generalized epilepsy.

Radiotherapy has shown some efficacy for epilepsies but the insufficient confinement of the radiation dose to the pathological target reduces its indications. Synchrotron-generated X-rays overcome this limitation and allow the delivery of focalized radiation doses to discrete brain volumes via interlaced arrays of microbeams (IntMRT). Here, we used IntMRT to target brain structures involved in seizure generation in a rat model of absence epilepsy (GAERS). We addressed the issue of whether and how synchrotron radiotherapeutic treatment suppresses epileptic activities in neuronal networks. IntMRT was used to target the somatosensory cortex (S1Cx), a region involved in seizure generation in the GAERS. The antiepileptic mechanisms were investigated by recording multisite local-field potentials and the intracellular activity of irradiated S1Cx pyramidal neurons in vivo. MRI and histopathological images displayed precise and sharp dose deposition and revealed no impairment of surrounding tissues. Local-field potentials from behaving animals demonstrated a quasi-total abolition of epileptiform activities within the target. The irradiated S1Cx was unable to initiate seizures, whereas neighboring non-irradiated cortical and thalamic regions could still produce pathological oscillations. In vivo intracellular recordings showed that irradiated pyramidal neurons were strongly hyperpolarized and displayed a decreased excitability and a reduction of spontaneous synaptic activities. These functional alterations explain the suppression of large-scale synchronization within irradiated cortical networks. Our work provides the first post-irradiation electrophysiological recordings of individual neurons. Altogether, our data are a critical step towards understanding how X-ray radiation impacts neuronal physiology and epileptogenic processes.

Good Timing Matters: The Spatially Fractionated High Dose Rate Boost Should Come First.

Monoplanar microbeam irradiation (MBI) and pencilbeam irradiation (PBI) are two new concepts of high dose rate radiotherapy, combined with spatial dose fractionation at the micrometre range. In a small animal model, we have explored the concept of integrating MBI or PBI as a simultaneously integrated boost (SIB), either at the beginning or at the end of a conventional, low-dose rate schedule of 5x4 Gy broad beam (BB) whole brain radiotherapy (WBRT). MBI was administered as array of 50 µm wide, quasi-parallel microbeams. For PBI, the target was covered with an array of 50 µm × 50 µm pencilbeams. In both techniques, the centre-to-centre distance was 400 µm. To assure that the entire brain received a dose of at least 4 Gy in all irradiated animals, the peak doses were calculated based on the daily BB fraction to approximate the valley dose. The results of our study have shown that the sequence of the BB irradiation fractions and the microbeam SIB is important to limit the risk of acute adverse effects, including epileptic seizures and death. The microbeam SIB should be integrated early rather than late in the irradiation schedule.

Toward Neuro-Oncologic Clinical Trials of High-Dose-Rate Synchrotron Microbeam Radiation Therapy: First Treatment of a Spontaneous Canine Brain Tumor.

PURPOSE: The high potential of microbeam radiation therapy (MRT) in improving tumor control while reducing side effects has been shown by numerous preclinical studies. MRT offers a widened therapeutic window by using the periodical spatial fractionation of synchrotron generated x-rays into an array of intense parallel microbeams. MRT now enters a clinical transfer phase. As proof of principle and cornerstone for the safe clinical transfer of MRT, we conducted a "first in dog" trial under clinical conditions. In this report, we evaluated whether a 3-dimensional conformal MRT can be safely delivered as exclusive radiosurgical treatment in animal patients METHODS AND MATERIALS: We irradiated a 17.5-kg French bulldog for a spontaneous brain tumor (glioma suspected on magnetic resonance imaging) with conformal high-dose-rate microbeam arrays (50-µm-wide microbeams, replicated with a pitch of 400 µm) of synchrotron-generated x-rays. The dose prescription adjusted a minimal cumulated valley dose of 2.8 Gy to the plnning target volume (PTV) (cinical target volume (CTV)+ 1 mm). Thus, each beam delivered 20 to 25 Gy to the target as peak doses, and ∼1 Gy as valley doses RESULTS: The treatment was successfully delivered. Clinical follow-up over 3 months showed a significant improvement of the dog's quality of life: the symptoms disappeared. Magnetic resonance imaging, performed 3 months after irradiation, revealed reduction in tumor size (-87.4%) and mass effect with normalization of the left lateral ventricle. CONCLUSIONS: To our knowledge, this neuro-oncologic veterinary trial is the first 3-dimensional conformal synchrotron x-ray MRT treatment of a spontaneous intracranial tumor in a large animal. It is an essential last step toward the clinical transfer of MRT in the near future to demonstrate the feasibility and safety of treating deep-seated tumors using synchrotron-generated microbeams.

A Mouse Model for Microbeam Radiation Therapy of the Lung.

PURPOSE: Radiation therapy is an important treatment component for patients with lung cancer. However, the survival time gained with clinical radiation therapy techniques is relatively short. Data from preclinical experiments suggest that synchrotron microbeam radiation therapy could be much better suited to control malignant brain tumors than current clinical concepts of radiation therapy. Even at peak doses of several hundred gray, the extent of functional deficits is low. METHODS AND MATERIALS: We have developed the first mouse model to study the effects of microbeam irradiation in lung tissue. RESULTS: Up to peak doses of 400 Gy, no acute adverse effects were seen. CONCLUSION: This model is well suited to explore the potential of microbeam radiation therapy in the treatment of lung cancer and the response of normal lung tissue and organs at risk.

Non-conventional Ultra-High Dose Rate (FLASH) Microbeam Radiotherapy Provides Superior Normal Tissue Sparing in Rat Lung Compared to Non-conventional Ultra-High Dose Rate (FLASH) Radiotherapy.

Conventional radiotherapy is a widely used non-invasive form of treatment for many types of cancer. However, due to a low threshold in the lung for radiation-induced normal tissue damage, it is of less utility in treating lung cancer. For this reason, surgery is the preferred treatment for lung cancer, which has the detriment of being highly invasive. Non-conventional ultra-high dose rate (FLASH) radiotherapy is currently of great interest in the radiotherapy community due to demonstrations of reduced normal tissue toxicity in lung and other anatomy. This study investigates the effects of FLASH microbeam radiotherapy, which in addition to ultra-high dose rate incorporates a spatial segmentation of the radiation field, on the normal lung tissue of rats. With a focus on fibrotic damage, this work demonstrates that FLASH microbeam radiotherapy provides an order of magnitude increase in normal tissue radio-resistance compared to FLASH radiotherapy. This result suggests FLASH microbeam radiotherapy holds promise for much improved non-invasive control of lung cancer.

A comparative dosimetry study of an alanine dosimeter with a PTW PinPoint chamber at ultra-high dose rates of synchrotron radiation.

The use of synchrotron X-ray sources provides innovative approaches in radiation therapy. The unique possibility to generate quasi-parallel beams promoted the development of microbeam radiation therapy (MRT), an innovative approach able to reduce damages to normal tissues while delivering considerable doses in the lesion. Accurate dosimetry in broad-beam configuration (prior to the spatial fractionation of the incident X-ray fan) is very challenging at ultra-high dose rate synchrotron sources. The available reference dosimetry protocol based on the use of a PTW PinPoint ionization chamber was compared with alanine dosimetry at the European Synchrotron Radiation Facility (ESRF) ID17 Biomedical beamline, an orthovoltage X-ray source with an average dose rate of 11.6 kGy/s. Reference dose measurements of the alanine pellets were performed at the National Centre for Radiation Research and Technology (NCRRT) 60Co facility in Egypt. All alanine dosimeters were analysed by an electron paramagnetic resonance spectrometer. We determined a relative response rESRF = 0.932 ± 0.027 (1σ) of the alanine pellets irradiated at the ESRF compared to the 60Co facility. Considering the appropriate corrections for the ESRF polychromatic spectrum and the different field size used, our result is in agreement with the previous work of Waldeland et al. for which the utilised alanine contained the same amount of binder, and it is consistent with the works of Anton et al. and Butler et al. for which the utilised alanine contained a higher amount of binder. We confirm that alanine is an appropriate dosimeter for ultra-high dose rate calibration of orthovoltage X-ray sources.

First experimental measurement of the effect of cardio-synchronous brain motion on the dose distribution during microbeam radiation therapy.

PURPOSE: Microbeam radiation therapy (MRT) is an emerging radiation oncology modality ideal for treating inoperable brain tumors. MRT employs quasi-parallel beams of low-energy x rays produced from modern synchrotrons. A tungsten carbide multislit collimator (MSC) spatially fractionates the broad beam into rectangular beams. In this study, the MSC creates beams 50 µm wide ("peaks") separated by a center-to-center distance of 400 µm ("valleys"). The peak to valley dose ratio (PVDR) is of critical importance to the efficacy of MRT. The underlying radiobiological advantage of MRT relies on high peak dose for tumor control and low valley dose for healthy tissue sparing. Cardio synchronous brain motion of the order 100-200 µm is comparable to microbeam width and spacing. The motion can have a detrimental effect on the PVDR, full width at half maximum (FWHM) of the microbeams, and ultimately the dose distribution. We present the first experimental measurement of the effect of brain motion on MRT dose distribution. Dosimetry in MRT is difficult due to the high dose rate (up to 15-20 kGy/s) and small field sizes. METHODS: A real-time dosimetry system based on a single silicon strip detector (SSSD) has been developed with spatial resolution ~10 µm. The SSSD was placed in a water-equivalent phantom and scanned through the microbeam distribution. A monodirectional positioning stage reproduced brain motion during the acquisition. Microbeam profiles were reconstructed from the SSSD and compared with Geant4 simulation and radiochromic HD-V2 film. RESULTS: The SSSD is able to reconstruct dose profiles within 2 µm compared to film. When brain motion is applied the SSSD shows a two time increase in FWHM of profiles and 50% reduction in PVDR. This is confirmed by Geant4 and film data. CONCLUSIONS: Motion-induced misalignment and distortion of microbeams at treatment delivery will result in a reduced PVDR and increased irradiation of additional healthy tissue compromising the radiobiological effectiveness of MRT. The SSSD was able to reconstruct dose profiles under motion conditions and predict similar effects on FWHM and PVDR as by the simulation. The SSSD is a simple to setup, real-time detector which can provide time-resolved high spatial resolution dosimetry of microbeams in MRT.

First trial of spatial and temporal fractionations of the delivered dose using synchrotron microbeam radiation therapy.

The technical feasibility of temporal and spatial fractionations of the radiation dose has been evaluated using synchrotron microbeam radiation therapy for brain tumors in rats. A significant increase in lifespan (216%, p < 0.0001) resulted when three fractions of microbeam irradiation were applied to the tumor through three different ports, orthogonal to each other, at 24 h intervals. However, there were no long-term survivors, and immunohistological studies revealed that 9 L tumors were not entirely ablated.

Introducing the concept of spiral microbeam radiation therapy (spiralMRT).

MOTIVATION: With interlaced microbeam radiation therapy (MRT) a first kilovoltage radiotherapy (RT) concept combining spatially fractionated entrance beams and homogeneous dose distribution at the target exists. However, this technique suffers from its high sensitivity to positioning errors of the target relative to the radiation source. With spiral microbeam radiation therapy (spiralMRT), this publication introduces a new irradiation geometry, offering similar spatial fractionation properties as interlaced MRT, while being less vulnerable to target positioning uncertainties. METHODS: The dose distributions achievable with spiralMRT in a simplified human head geometry were calculated with Monte Carlo simulations based on Geant4 and the dependence of the result on the microbeam pitch, total field size, and photon energy were analysed. A comparison with interlaced MRT and conventional megavoltage tomotherapy was carried out. RESULTS: SpiralMRT can deliver homogeneous dose distributions, while using spatially fractionated entrance beams. The valley dose of spiralMRT entrance beams is by up to 40% lower than the corresponding tomotherapy dose, thus indicating a better normal tissue sparing. The optimum photon energy is found to be around [Formula: see text]. CONCLUSIONS: SpiralMRT is a promising approach to delivering homogeneous dose distributions with spatially fractionated entrance beams, possibly decreasing normal tissue side effects in hypofractionated RT.

Ultra high dose rate Synchrotron Microbeam Radiation Therapy. Preclinical evidence in view of a clinical transfer.

This paper reviews the current state of the art of an emerging form of radiosurgery dedicated to brain tumour treatment and which operates at very high dose rate (kGy·s-1). Microbeam Radiation Therapy uses synchrotron-generated X-rays which triggered normal tissue sparing partially mediated by FLASH effect.