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International audience; 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. (C) 2021 The Authors. Published by Elsevier Inc.

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.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.

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.

This study is the first proof of concept that the FLASH effect can be triggered by X-rays. Our results show that a 10 Gy whole-brain irradiation delivered at ultra-high dose-rate with synchrotron generated X-rays does not induce memory deficit; it reduces hippocampal cell-division impairment and induces less reactive astrogliosis.

Microbeam radiation therapy (MRT) is a developing radiotherapy, based on the use of beams only a few tens of micrometres wide, generated by synchrotron X-ray sources. The spatial fractionation of the homogeneous beam into an array of microbeams is possible using a multislit collimator (MSC), i.e. a machined metal block with regular apertures. Dosimetry in MRT is challenging and previous works still show differences between calculated and experimental dose profiles of 10–30%, which are not acceptable for a clinical implementation of treatment. The interaction of the X-rays with the MSC may contribute to the observed discrepancies; the present study therefore investigates the dose contribution due to radiation interaction with the MSC inner walls and radiation leakage of the MSC. Dose distributions inside a water-equivalent phantom were evaluated for different field sizes and three typical spectra used for MRT studies at the European Synchrotron Biomedical beamline ID17. Film dosimetry was utilized to determine the contribution of radiation interaction with the MSC inner walls; Monte Carlo simulations were implemented to calculate the radiation leakage contribution. Both factors turned out to be relevant for the dose deposition, especially for small fields. Photons interacting with the MSC walls may bring up to 16% more dose in the valley regions, between the microbeams. Depending on the chosen spectrum, the radiation leakage close to the phantom surface can contribute up to 50% of the valley dose for a 5 mm × 5 mm field. The current study underlines that a detailed characterization of the MSC must be performed systematically and accurate MRT dosimetry protocols must include the contribution of radiation leakage and radiation interaction with the MSC in order to avoid significant errors in the dose evaluation at the micrometric scale.

The X-Tream dosimetry system developed at the Centre for Medical Radiation Physics (University of Wollongong, Australia) utilises a high resolution silicon Single Strip Detector to characterise synchrotron radiation microbeams for the purpose of Quality Assurance of Microbeam Radiation Therapy. Firstly, a comparison of the Silicon Strip Detector performance with respect to a conventional PinPoint Ionisation Chamber for broad beams and microbeams is given. These results are then extended to characterise the horizontal microbeam radiation field available in the high flux experimental hutch of the Imaging and Medical BeamLine at the Australian Synchrotron. The Silicon Strip Detector measured depth dose curve of the broad beam agrees very well with the PinPoint Ionisation Chamber measurements between 10 and 50 mm depth in water. Significant deviations from the PinPoint Ionisation Chamber response are observed with increasing depth. Microbeam profiles measured by the Silicon Strip Detector are well resolved but clearly affected by misalignment of the Silicon Strip Detector with respect to the microbeams. Future beamline technical improvements will alleviate this issue.

Purpose Radiotherapy is known to enhance permeability of brain tumor vessels. Our study compared the blood barrier permeability changes induced by synchrotron microbeam radiation therapy (MRT, which relies on spatial fractionation of the incident X-ray beam into parallel micron-wide beams) with changes induces by a spatially uniform synchrotron X-ray radiotherapy. Methods and Materials Male rats bearing malignant intracranial F98 gliomas were randomized into 3 groups: untreated, exposed to MRT (peak and valley dose: 241 and 10.5 Gy respectively) or exposed to broad beam irradiation (BB) delivered at comparable doses (i.e., equivalent to MRT valley dose); both applied by two arrays, intersecting orthogonally the tumor region. Vessel permeability was monitored in vivo by magnetic resonance imaging (MRI) 1 day before (T-1) and 1, 2, 7 and 14 days after treatment start. To find out whether physiological parameters influence vascular permeability, we have evaluated vessel integrity in tumor area with different values for cerebral blood flow, blood volume, oedema and tissue oxygenation. Results MRT does not modify the vascular permeability of normal brain tissue. MRT-induced increase of tumor vascular permeability was detectable from T 2 with a maximum at T 7 after exposure while BB enhanced vessel permeability only at T 7 . At this stage, MRT was more efficient at increasing tumor vessel permeability (BB vs untreated: +19.1%; p=0.0467; MRT vs untreated: +44.8%; p 14 (MRT vs BB, +22.6%; p=0.0199). We also showed that MRT was more efficient at targeting highly oxygenated (high blood volume and flow) and more proliferative parts of the tumor than BB. Conclusions MRT-induced increased tumor vascular permeability is (i) significantly greater, (ii) earlier and more prolonged than that induced by BB irradiation, especially in highly proliferative tumor areas and (iii) targets all tumor areas discriminated by physiological characteristics, including those not damaged by homogeneous irradiation.

International audience; Highlights •MRT is a form of synchrotron generated X-ray radiosurgery dedicated to brain tumours. •Normal tissue tolerates high X-ray dose thanks through lattice of microbeams. •MRT operates at very high dose rate (kGy·s−1) and triggers FLASH effect in vivo.AbstractThis 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.

International audience; Highlights •A methodology has been developed for patient specific quality assurance in MRT. •The segmentation of peaks and valleys doses can be done on Gafchromic films for direct comparisons with MRT treatment plan. •Gamma-index tests performed on normalised dose distributions exhibit over 90% passing rate. •Some discrepancies remain on the absolute isocenter doses and require further investigation. •Despite these discrepancies, large animal MRT studies are starting at the ESRF based on valley doses prescription.AbstractMicrobeam radiation therapy (MRT) uses synchrotron arrays of X-ray microbeams to take advantage of the spatial fractionation effect for normal tissue sparing. In this study, radiochromic film dosimetry was performed for a treatment where MRT is introduced as a dose boost in a hypofractionated stereotactic radiotherapy (SRT) scheme. The isocenter dose was measured using an ionization chamber and two dimensional dose distributions were determined using radiochromic films. To compare the measured dose distribution to the MRT treatment plan, peak and valley were displayed in separate dosemaps. The measured and computed isocenter doses were compared and a two-dimensional 2%/2 mm normalized Math Eq-index analysis with a 90% passing rate criterion was computed. For SRT, a difference of 2.6% was observed in the dose at the isocenter from the treatment plan and film measurement, with a passing rate of 96% for the Math Eq-index analysis. For MRT, peak and valley doses differences of 25.6% and 8.2% were observed, respectively but passing rates of 96% and 90% respectively were obtained from the normalized Math Eq-index maps. The differences in isocenter doses measured in MRT should be further investigated. We present the methodology of patient specific quality assurance (QA) for studying MRT dose distributions and discuss ideas to improve absolute dosimetry. This patient specific QA will be used for large animal trials quality assurance where MRT will be administered as a dose boost in conventional SRT. The observed remaining discrepancies should be studied against approximations in the TPS phantom materials, beams characteristics or film read-out procedures.

International audience; We formulated an ultra-small, gadolinium-based nanoparticle (AGuIX) with theranostic properties to simultaneously enhance MRI tumor delineation and radiosensitization in a glioma model. The 9L glioma cells were orthotopically implanted in 10-week-old Fischer rats. The intra-tumoral accumulation of AGuIX was quantified using MRI T1-maps. Rats randomized to intervention cohorts were subsequently treated with daily temozolomide for five consecutive days before radiotherapy treatment. Collectively, a series of 32 rats were divided into untreated (n = 7), temozolomide-only (n = 7), temozolomide and MRT (n = 9), AGuIX and MRT (n = 7), and triple therapy (temozolomide, AGuIX NPs, and MRT; n = 9) cohorts. AGuIX nanoparticles achieved a maximum intra-tumoral concentration (expressed as concentration of Gd3+) at 1 h after intravenous injection, reaching a mean of 227.9 ± 60 lM. This was compared to concentrations of 10.5 ± 9.2 lM and 62.9 ± 24.7 lM in the contralateral hemisphere and cheek, respectively. There was a slower washout in the intra-tumor region, with sustained tumor-to-contralateral ratio of AGuIX, up to 14-fold, for each time point. The combination of AGuIX or temozolomide with MRT improved the median survival time (40 days) compared to the MeST of control rats (25 days) (p < 0.002). There was a trend towards further increased survival when the three treatments were combined (MeST of 46 days). This study demonstrated the selective accumulation of AGuIX in high grade glioma, as well as the potential survival benefits when combined with chemoradiation.

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.

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.

Chronic pain (CP) is a condition characterized by a wide spectrum of clinical signs and symptoms, missing a sound modelling at the neuronal network scale. Recently, we presented a general theory showing common electrophysiological traits in different CP rat models, i.e. a collapse of relevant functional connectivity network properties, such as modularity, in the somatosensory thalamo-cortical (TC) network. In this work, we preliminary investigated by anin silicoaccurate simulator of the six-layer mammalian cortical networks that evidenced the crucial collapse of network modularity in CP simulated conditions and the consequent reduction of network adaptive processes. On this track, in studies on CP experimental animals affected by sciatic nerve multiple ligature (Bennett-Xie model), by synchrotron-generated X-ray microbeam (MB) irradiations (7 parallel beams, 100um width), we targetedin vivothe CP involved hindlimb somatosensory projection cortex that, because of the doses radiation (360 Gy, peak at each beam), non-invasively produced fast and precise tissue destruction along the 7 beam projections. These parcellated the cortical tissue and restored the cortical network statistics related to modularity and information processing efficiency as evidenced from post irradiationin vivoelectrophysiological recordings. In addition, by MB treatment there was an ensuing removal of behavioral signs of allodynia and hyperalgesia accompanied by recovered normal gait schemes yet preserving the normal sensory thresholds of the experimental rats up to three months after the MB irradiation. Finally, novel and unprecedented therapeutic appraisals for CP are devised.Significance StatementChronic pain (CP) is an excruciating condition with severe effects on patients’ life. Apart from many clinical and experimental studies no current theory on CP is generally accepted. Recently, we proposed a general theory of CP in experimental animals as characterized by strong alteration of the connections among neurons in different brain regions. We show here onin silicosimulations that specific connectivity changes in the somatosensory cortex recover the lost functional integrity. Concurrently, in experimental animals, we re-modulated,in vivo, some anatomical connections of the somatosensory cortex by extremely thin synchrotron generated X-ray microbeam irradiations. The resulting behavioral and electrophysiological signs of CP disappeared yet maintaining normal sensory responses. No adverse or pathological effects on blank animals were observable.

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.

Purpose Microbeam radiation therapy is a developing technique that promises superior tumour control and better normal tissue tolerance using spatially fractionated X-ray beams only tens of micrometres wide. Radiochromic film dosimetry at micrometric scale was performed using a microdensitometer, but this instrument presents limitations in accuracy and precision, therefore the use of a microscope is suggested as alternative. The detailed procedures developed to use the two devices are reported allowing a comparison. Methods Films were irradiated with single microbeams and with arrays of 50 µm wide microbeams spaced by a 400 µm pitch, using a polychromatic beam with mean energy of 100 keV. The film dose measurements were performed using two independent instruments: a microdensitometer (MDM) and an optical microscope (OM). Results The mean values of the absolute dose measured with the two instruments differ by less than 5% but the OM provides reproducibility with a standard deviation of 1.2% compared to up to 7% for the MDM. The resolution of the OM was determined to be ~ 1 to 2 µm in both planar directions able to resolve pencil beams irradiation, while the MDM reaches at the best 20 µm resolution along scanning direction. The uncertainties related to the data acquisition are 2.5–3% for the OM and 9–15% for the MDM. Conclusion The comparison between the two devices validates that the OM provides equivalent results to the MDM with better precision, reproducibility and resolution. In addition, the possibility to study dose distributions in two-dimensions over wider areas definitely sanctions the OM as substitute of the MDM.

The functional roles of the Caudate nucleus (Cd) are well known. Selective Cd lesions can be found in neurological disorders. However, little is known about the dynamics of the behavioral changes during progressive Cd ablation. Current stereotactic radiosurgery technologies allow the progressive ablation of a brain region with limited adverse effects in surrounding normal tissues. This could be of high interest for the study of the modified behavioral functions in relation with the degree of impairment of the brain structures. Using hypofractionated stereotactic radiotherapy combined with synchrotron microbeam radiation, we investigated, during one year after irradiation, the effects of unilateral radio-ablation of the right Cd on the behavior of Yucatan minipigs. The right Cd was irradiated to a minimal dose of 35.5 Gy delivered in three fractions. MRI-based morphological brain integrity and behavioral functions, i.e. locomotion, motivation/hedonism were assessed. We detected a progressive radio-necrosis leading to a quasi-total ablation one year after irradiation, with an additional alteration of surrounding areas. Transitory changes in the motivation/hedonism were firstly detected, then on locomotion, suggesting the influence of different compensatory mechanisms depending on the functions related to Cd and possibly some surrounding areas. We concluded that early behavioral changes related to eating functions are relevant markers for the early detection of ongoing lesions occurring in Cd-related neurological disorders.

Out-of-field effects are of considerable interest in radiotherapy. The mechanisms are poorly understood but are thought to involve signaling processes, which induce responses in non-targeted cells and tissues. The immune response is thought to play a role. The goal of this research was to study the induction of abscopal effects in the bladders of NU-Foxn1 mice after irradiating their brains using Pencil Beam (PB) or microbeam (MRT) irradiation at the European Synchrotron Radiation Facility (ESRF) in Grenoble, France. Athymic nude mice injected with F98 glioma cells into their right cerebral hemisphere 7 d earlier were treated with either MRT or PB. After recovery times of 2, 12, and 48 h, the urinary bladders were extracted and cultured as tissue explants for 24 h. The growth medium containing the potential signaling factors was harvested, filtered, and transferred to HaCaT reporter cells to assess their clonogenic survival and calcium signaling potential. The results show that in the tumor-free mice, both treatment modalities produce strong bystander/abscopal signals using the clonogenic reporter assay; however, the calcium data do not support a calcium channel mediated mechanism. The presence of a tumor reduces or reverses the effect. PB produced significantly stronger effects in the bladders of tumor-bearing animals. The authors conclude that immunocompromised mice produce signals, which can alter the response of unirradiated reporter cells; however, a novel mechanism appears to be involved.

Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident, highly focused synchrotron beam into arrays of parallel microbeams, typically a few tens of microns wide and depositing several hundred grays. This irradiation modality was shown to have a high therapeutic impact on tumors, especially in intracranial locations. However, mechanisms responsible for such a property are not fully understood.Thanks to recent progress in dosimetry, we compared the effect of MRT and synchrotron broad beam (BB) radiation therapy delivered at comparable doses (equivalent to MRT valley dose) on tumor growth control and on classical radiobiological functions by histologic evaluation and/or transcriptomic analysis.MRT significantly improved survival of rats bearing 9L intracranial glioma compared with BB radiation therapy delivered at a comparable dose (P.001); the efficacy of MRT and BB radiation therapy was similar when the MRT dose was half that of BB. The greater efficacy of MRT was not correlated with a difference in cell proliferation (Mki67 and proliferating cell nuclear antigen) or in transcriptomic stimulation of angiogenesis (vascular endothelial growth factor A or tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 2) but was correlated with a higher cell death rate (factor for apoptosis signals) and higher recruitment of macrophages (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and CD68 transcripts) a few days after MRT.These results show the superiority of MRT over BB radiation therapy when applied at comparable doses, suggesting that spatial fractionation is responsible for a specific and particularly efficient tissue response. The higher induction of cell death and immune cell activation in brain tumors treated by MRT may be involved in such responses.

Purpose: Upcoming veterinary trials in microbeam radiation therapy (MRT) demand for more advanced irradiation techniques than in preclinical research with small animals. The treatment of deep-seated tumors in cats and dogs with MRT requires sophisticated irradiation geometries from multiple ports, which impose further efforts to spare the normal tissue surrounding the target. Methods: This work presents the development and benchmarking of a precise patient alignment protocol for MRT at the biomedical beamline ID17 of the European Synchrotron Radiation Facility (ESRF). The positioning of the patient prior to irradiation is verified by taking x-ray projection images from different angles. Results: Using four external fiducial markers of 1.7 mm diameter and computed tomography-based treatment planning, a target alignment error of less than 2 mm can be achieved with an angular deviation of less than 2∘. Minor improvements on the protocol and the use of smaller markers indicate that even a precision better than 1 mm is technically feasible. Detailed investigations concerning the imaging dose lead to the conclusion that doses for skull radiographs lie in the same range as dose reference levels for human head radiographs. A currently used online dose monitor for MRT has been proven to give reliable results for the imaging beam. Conclusions: The ESRF biomedical beamline ID17 is technically ready to apply conformal image-guided MRT from multiple ports to large animals during future veterinary trials.

A radiation colour former amino fluoran dye, Pergascript Orange (PGO), in a polyvinyl butyral solution containing a colour developer, hexachloroethane (HCE), was prepared and investigated for radiotherapy dosimetry of 60Co, 6 MV and 15 MV photons. PGO, a colourless dye, reacts with the acid produced upon radiation exposure of HCE, enabling the lactone ring to open and the orange colour of PGO to develop. The ring opening of PGO was confirmed by the appearance of a broad peak of OH− at 3360 cm−1, C O carboxylic peak at 1763 cm−1, and an iminium group peak at 1640 cm−1. The dose response of all prepared compositions was linear in the dose range of 1–20 Gy. Increasing HCE in the dosimeter matrix from 63 mM to 106 mM enhanced the radiation sensitivity by ≈58%. The radiation sensitivity of PGO-PVB (PGO-P) dosimeter is comparable with Fricke gel and higher than N-(Isobutoxymethyl) acrylamide polymer gel dosimeters. The experimental results reveal an energy-independent response (≈1.2% variation at 1σ) in the studied range of radiotherapy beam quality from 60Co beams to the beams from Linacs with a maximum energy of 15 MeV. Based on the theoretical study, this dosimeter is water equivalent from 80 keV to 10 MeV. The overall uncertainty was found to be 4.5% at the 95% confidence level, indicating the possibility of using PGO-P dosimeter in conventional radiotherapy dose verification.

Purpose: This review follows the development of microbeam technology from the early days of single cell irradiations, to investigations of specific cellular mechanisms and to the development of new treatment modalities in vivo. A number of microbeam applications are discussed with a focus on preclinical modalities and translation towards clinical application.Conclusions: The development of radiation microbeams has been a valuable tool for the exploration of fundamental radiobiological response mechanisms. The strength of micro-irradiation techniques lies in their ability to deliver precise doses of radiation to selected individual cells in vitro or even to target subcellular organelles. These abilities have led to the development of a range of microbeam facilities around the world allowing the delivery of precisely defined beams of charged particles, X-rays, or electrons.In addition, microbeams have acted as mechanistic probes to dissect the underlying molecular events of the DNA damage response following highly localised dose deposition. Further advances in very precise beam delivery have also enabled the transition towards new and exciting therapeutic modalities developed at synchrotrons to deliver radiotherapy using plane parallel microbeams, in Microbeam Radiotherapy (MRT).

International audience; Purpose: To analyze the effects of micro-beam irradiation (MBI) on the normal tissues of the mouse ear.Methods and Materials: Normal mouse ears are a unique model, which in addition to skin contain striated muscles, cartilage, blood and lymphatic vessels, and few hair follicles. This renders the mouse ear an excellent model for complex tissue studies. The ears of C57BL6 mice were exposed to MBI (50-mu m-wide micro-beams, spaced 200 mu m between centers) with peak entrance doses of 200, 400, or 800 Gy (at ultra-high dose rates). Tissue samples were examined histopathologically, with conventional light and electron microscopy, at 2, 7, 15, 30, and 240 days after irradiation (dpi). Sham-irradiated animals acted as controls.Results: Only an entrance dose of 800 Gy caused a significant increase in the thickness of both epidermal and dermal ear compartments seen from 15 to 30 dpi; the number of sebaceous glands was significantly reduced by 30 dpi. The numbers of apoptotic bodies and infiltrating leukocytes peaked between 15 and 30 dpi. Lymphatic vessels were prominently enlarged at 15 up to 240 dpi. Sarcomere lesions in striated muscle were observed after all doses, starting from 2 dpi; scar tissue within individual beam paths remained visible up to 240 dpi. Cartilage and blood vessel changes remained histologically inconspicuous.Conclusions: Normal tissues such as skin, cartilage, and blood and lymphatic vessels are highly tolerant to MBI after entrance doses up to 400 Gy. The striated muscles appeared to be the most sensitive to MBI. Those findings should be taken into consideration in future micro-beam radiation therapy treatment schedules. (C) 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Recent results from the Franco-Swiss team of Institute Curie and Centre Hospitalier Universitaire Vaudois demonstrate a remarkable sparing of normal tissue after irradiation at ultra-high dose rate (>40 Gy s−1). The “FLASH” radiotherapy maintains tumour control level, suggesting that ultra-high dose rate can substantially enhance the therapeutic window in radiotherapy. The results have been obtained so far only with 4–6 MeV electrons in lung and brain mouse model. Nevertheless, they have attracted a great attention for the potential clinical applications. Oxygen depletion had been discussed many years ago as a possible mechanism for reduction of the damage after exposure to ultra-high dose rate. However, the mechanism underlying the effect observed in the FLASH radiotherapy remains to be elucidated.

Microbeam radiation therapy (MRT), a novel form of spatially fractionated radiotherapy (RT), uses arrays of synchrotron-generated X-ray microbeams (MB). MRT has been identified as a promising treatment concept that might be applied to patients with malignant central nervous system (CNS) tumours for whom, at the current stage of development, no satisfactory therapy is available yet. Preclinical experimental studies have shown that the CNS of healthy rodents and piglets can tolerate much higher radiation doses delivered by spatially separated MBs than those delivered by a single, uninterrupted, macroscopically wide beam. High-dose, high-precision radiotherapies such as MRT with reduced probabilities of normal tissue complications offer prospects of improved therapeutic ratios, as extensively demonstrated by results of experiments published by many international groups in the last two decades. The significance of developing MRT as a new RT approach cannot be understated. Up to 50% of cancer patients receive conventional RT, and any new treatment that provides better tumour control whilst preserving healthy tissue is likely to significantly improve patient outcomes.

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.

Purpose: Microbeam radiation therapy (MRT) is a still preclinical tumor therapy approach that uses arrays of a few tens of micrometer wide parallel beams separated by a few 100 μm. The production, measurement, and planning of such radiation fields are a challenge up to now. Here, the authors investigate the feasibility of radiochromic film dosimetry in combination with a microscopic readout as a tool to validate peak and valley doses in MRT, which is an important requirement for a future clinical application of the therapy. Methods: Gafchromic® HD-810 and HD-V2 films are exposed to MRT fields at the biomedical beamline ID17 of the European Synchrotron Radiation Facility (ESRF) and are afterward scanned with a microscope. The measured dose is compared with Monte Carlo calculations. Image analysis tools and film handling protocols are developed that allow accurate and reproducible dosimetry. The performance of HD-810 and HD-V2 films is compared and a detailed analysis of the resolution, noise, and energy dependence is carried out. Measurement uncertainties are identified and analyzed. Results: The dose was measured with a resolution of 5 × 1000 μm2 and an accuracy of 5% in the peak and between 10% and 15% in the valley region. As main causes for dosimetry uncertainties, statistical noise, film inhomogeneities, and calibration errors were identified. Calibration errors strongly increase at low doses and exceeded 3% for doses below 50 and 70 Gy for HD-V2 and HD-810 films, respectively. While the grain size of both film types is approximately 2 μm, the statistical noise in HD-V2 is much higher than in HD-810 films. However, HD-810 films show a higher energy dependence at low photon energies. Conclusions: Both film types are appropriate for dosimetry in MRT and the microscope is superior to the microdensitometer used before at the ESRF with respect to resolution and reproducibility. However, a very careful analysis of the image data is required. Dosimetry at low photon energies should be performed with great caution due to the energy sensitivity of the films. In this respect, HD-V2 films showed to have an advantage over HD-810 films. However, HD-810 films have a lower statistical noise level. When a higher resolution is required, e.g., for the dosimetry of pencil beam irradiations, noise may render HD-V2 films inapplicable.

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.

International audience; La principale problématique en radiothérapie anticancéreuse est de délivrer une dose maximale (énergie absorbée par unité de masse) de rayonnements ionisants à la cible, tout en épargnant les tissus sains avoisinants. Une option prometteuse, permettant d’atteindre cet effet différentiel significativement plus élevé dans le cadre du traitement de petites lésions cérébrales isolées, est l’utilisation de matrices de microfaisceaux de rayons x à très forts débits de dose [1]. La radiothérapie par micro-faisceaux (MRT) est une technique de radiothérapie innovante, basée sur le fractionnement spatial de la dose en utilisant des matrices de micro-faisceaux de rayons-x parallèles, d’une largeur comparable à celle d’un cheveu (~ 50 micromètres) et séparés par des zones qui ne voient que le rayonnement diffusé. De nombreuses études précliniques ont démontré que la MRT augmente significativement la dose administrée à la tumeur par rapport à la radiothérapie conventionnelle tout en permettant de mieux préserver les tissus sains sur le trajet des faisceaux d’irradiation [2]. Bien que la MRT soit actuellement limitée à la recherche dans les établissements de rayonnement synchrotron en raison du débit de dose très élevé requis pour sa mise en contrôle (5 000 fois plus élevé que la radiothérapie clinique), les cliniciens et les chercheurs collaborent étroitement avec les scientifiques du synchrotron pour transférer cette technique vers les essais cliniques.Le principal verrou d’un point de vue des problématiques de physique médicale associées à cette technique concerne la dosimétrie expérimentale (méthodes physiques permettant de mesurer quantitativement l’énergie absorbée par unité de masse dans les tissus irradiés, ou dans un mileu équivalent). En effet au regard de la taille des faisceaux et des débits de dose associés, Nous sommes très proches limites théoriques des méthodes existantes. Par exemple, le transfert clinique de la MRT nécessite la mise en oeuvre de codes de pratique cliniques pour la mesure de la dose qui, bien qu’ils soient établis dans la radiothérapie clinique conventionnelle, ils ne sont pas applicables à la MRT en raison du spectre des rayons X, des débit de dose élevés et des limitations des détecteurs [3].L’objectif de cette présentation est de faire un état des lieux des solutions dosimétriques existantes pour la MRT et de proposer quelques pistes permettant un contrôle encore plus précis de la dose.

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 theGeant4Monte Carlo toolkit interfaced with theSHADOWX-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 thePENELOPEcode. 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.

Microbeam radiation therapy (MRT) is a new radiation treatment modality in the pre-clinical stage of development at the ID17 Biomedical Beamline of the European synchrotron radiation facility (ESRF) in Grenoble, France. MRT exploits the dose volume effect that is made possible through the spatial fractionation of the high dose rate synchrotron-generated x-ray beam into an array of microbeams. As an important step towards the development of a dosimetry protocol for MRT, we have applied the International Atomic Energy Agency's TRS 398 absorbed dose-to-water protocol to the synchrotron x-ray beam in the case of the broad beam irradiation geometry (i.e. prior to spatial fractionation into microbeams). The very high dose rates observed here mean the ion recombination correction factor, k s , is the most challenging to quantify of all the necessary corrections to apply for ionization chamber based absolute dosimetry. In the course of this study, we have developed a new method, the so called 'current ramping' method, to determine k s for the specific irradiation and filtering conditions typically utilized throughout the development of MRT. Using the new approach we deduced an ion recombination correction factor of 1.047 for the maximum ESRF storage ring current (200 mA) under typical beam spectral filtering conditions in MRT. MRT trials are currently underway with veterinary patients at the ESRF that require additional filtering, and we have estimated a correction factor of 1.025 for these filtration conditions for the same ESRF storage ring current. The protocol described herein provides reference dosimetry data for the associated Treatment Planning System utilized in the current veterinary trials and anticipated future human clinical trials.

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.

We present here the latest results from tests performed at the ESRF ID17 and ID21 beamlines for the characterization of novel beam monitors for Microbeam Radiation Therapy (MRT), which is currently being implemented at ID17. MRT aims at treating solid tumors by exploiting an array of evenly spaced microbeams, having an energy spectrum distributed between 27 and 600 keV and peaking at 100 keV. Given the high instantaneous dose delivered (up to 20 kGy/s), the position and the intensity of the microbeams has to be precisely and instantly monitored. For this purpose, we developed dedicated silicon microstrip beam monitors. We have successfully characterized them, both with a microbeam array at ID17, and a submicron scanning beam at ID21. We present here the latest results obtained in recent tests along with an outlook on future developments.

Our goal was the visualizing the vascular damage and acute inflammatory response to micro- and minibeam irradiation in vivo. Microbeam (MRT) and minibeam radiation therapies (MBRT) are tumor treatment approaches of potential clinical relevance, both consisting of parallel X-ray beams and allowing the delivery of thousands of Grays within tumors. We compared the effects of microbeams (25–100 μm wide) and minibeams (200–800 μm wide) on vasculature, inflammation and surrounding tissue changes during zebrafish caudal fin regeneration in vivo. Microbeam irradiation triggered an acute inflammatory response restricted to the regenerating tissue. Six hours post irradiation (6 hpi), it was infiltrated by neutrophils and fli1a+ thrombocytes adhered to the cell wall locally in the beam path. The mature tissue was not affected by microbeam irradiation. In contrast, minibeam irradiation efficiently damaged the immature tissue at 6 hpi and damaged both the mature and immature tissue at 48 hpi. We demonstrate that vascular damage, inflammatory processes and cellular toxicity depend on the beam width and the stage of tissue maturation. Minibeam irradiation did not differentiate between mature and immature tissue. In contrast, all irradiation-induced effects of the microbeams were restricted to the rapidly growing immature tissue, indicating that microbeam irradiation could be a promising tumor treatment tool.

Among the new emerging cancer therapies, Microbeam Radiation Therapy (MRT) is currently showing very promising results in terms of limiting or decreasing tumor growth while keeping the damage to healthy tissue to a minimum. The MRT is able to deliver unprecedented dose rates of up to 20 kGy/s, posing important questions in terms of treatment planning and patient safety during treatment. For this reason, a beam monitoring system must be built, in which a detector acquires the microbeam array profile in real-time. In case of anomalies detection, the detector signals the beam-line to close the shutter as an emergency safety measure. Many sensors technologies for beam monitoring are currently being considered and silicon strip detectors seem to be very promising candidates. In this study the characterisation in full MRT conditions of a novel silicon strip detector is reported explaining strengths and weaknesses of the devices. Modifications to the sensor layout are also suggested in this study.

We recently developed the synthesis of ultrasmall gadolinium-based nanoparticles (GBN), (hydrodynamic diameter i.e. 15 ppb of gadolinium) for an important increase of the therapeutic effect of irradiation. Such a promising and unexpected result is assigned to a suited distribution of GBN within the tumor, as revealed by the X-ray fluorescence (XRF) maps.

International audience; 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.

To further evaluate the use of microbeam irradiation (MBI) as a potential means of non-invasive brain tumor treatment by investigating the induction of a bystander effect in non-irradiated tissue.Adult rats were irradiated with 35 or 350 Gy at the European Synchotron Research Facility (ESRF), using homogenous (broad beam) irradiation (HI) or a high energy microbeam delivered to the right brain hemisphere only. The proteome of the frontal lobes were then analyzed using two-dimensional electrophoresis (2-DE) and mass spectrometry.HI resulted in proteomic responses indicative of tumourigenesis; increased albumin, aconitase and triosphosphate isomerase (TPI), and decreased dihydrolipoyldehydrogenase (DLD). The MBI bystander effect proteomic changes were indicative of reactive oxygen species mediated apoptosis; reduced TPI, prohibitin and tubulin and increased glial fibrillary acidic protein (GFAP). These potentially anti-tumourigenic apoptotic proteomic changes are also associated with neurodegeneration. However the bystander effect also increased heat shock protein (HSP) 71 turnover. HSP 71 is known to protect against all of the neurological disorders characterized by the bystander effect proteome changes.These results indicate that the collective interaction of these MBI-induced bystander effect proteins and their mediation by HSP 71, may confer a protective effect which now warrants additional experimental attention.

Synchrotron microbeam radiation therapy (MRT) is an advanced form of radiotherapy for which it is extremely difficult to provide adequate quality assurance. This may delay or limit its clinical uptake, particularly in the paediatric patient populations for whom it could be especially suitable. This study investigates the extent to which new developments in 3D dosimetry using optical computed tomography (CT) can visualise MRT dose distributions, and assesses what further developments are necessary before fully quantitative 3D measurements can be achieved. Two experiments are reported. In the first cylindrical samples of the radiochromic polymer PRESAGE(®) were irradiated with different complex MRT geometries including multiport treatments of collimated 'pencil' beams, interlaced microplanar arrays and a multiport treatment using an anthropomorphic head phantom. Samples were scanned using transmission optical CT. In the second experiment, optical CT measurements of the biologically important peak-to-valley dose ratio (PVDR) were compared with expected values from Monte Carlo simulations. The depth-of-field (DOF) of the optical CT system was characterised using a knife-edge method and the possibility of spatial resolution improvement through deconvolution of a measured point spread function (PSF) was investigated. 3D datasets from the first experiment revealed excellent visualisation of the 50 μm beams and various discrepancies from the planned delivery dose were found. The optical CT PVDR measurements were found to be consistently 30% of the expected Monte Carlo values and deconvolution of the microbeam profiles was found to lead to increased noise. The reason for the underestimation of the PVDR by optical CT was attributed to lack of spatial resolution, supported by the results of the DOF characterisation. Solutions are suggested for the outstanding challenges and the data are shown already to be useful in identifying potential treatment anomalies.

Intensive synchrotron X-ray microbeams form an integral part of microbeam radiation therapy (MRT). MRT is a novel radiation medicine modality being developed for inoperable and otherwise untreatable brain tumours. The extremely high dose rate (∼20 kGy/s), laterally fractionated radiation field and steep dose gradients utilized in this therapy make real-time dosimetry a significant challenge. In order for this treatment to advance to the clinical trial stage of development real-time dosimetry systems must be developed. This paper demonstrates the capabilities of a new dosimetry system based on an epitaxial silicon detector. The system combines high spatial resolution and real-time readout and we have measured the lateral dose profile of the MRT radiation field which incorporates 59 X-ray microbeams. All microbeam peaks and valley regions between two microbeams are clearly resolved. The measured detector response at any point is reproducible to within 0.5% after scaling for the known synchrotron storage ring beam current lifetime. The variation of the lateral dose profile at different depths in a PMMA phantom has been measured with the results compared to those from Penelope Monte Carlo simulations. The trend in the measured response with depth agrees with the simulation data (within the experimental variation of the central five microbeams peaks and valleys measured). However the measured peak-to-valley ratio response is a factor of 4.5 ± 0.1 times lower than that expected. The disagreement was further investigated and shown to be contributed to by charge recombination effects at the low bias voltages used.