Microbeam Radiation Therapy (MRT) is a drastically novel approach of radiosurgery, challenging the understanding of how normal tissues respond to radiation therapy, where X-rays generated by a synchrotron light source are collimated into wafers of high-dose (hundreds of Gray), thin (50 µm) parallel microbeams. Recent work showed that MRT dose prescription must consider a dual approach: separating normal tissue dose constraints tied to the valley dose prescription and anti-tumor effects, depending on the prescribed number of ports. Here, we consolidate this assumption by increasing the number of MRT incidences to irradiate 9L-bearing rats with a cumulated valley dose of 10 Gy. 9L-bearing rats were irradiated by eight ports of conventional Broad Beam (BB) or MRT. Animals were followed up clinically by MR imaging, histopathology and survival analysis. MRI follow-up revealed that MRT significantly amplified antitumor effect and tumor tissue damage while improving the clinical score of animals. Ten Gy, delivered by either BB or MRT, increased median survival time to 15 and 39.5 days after irradiation, respectively. Neither complete ablation of brain tumors nor long-term survival was achieved, but multiport MRT (eight ports) showed an outstanding dose equivalence factor (×2.9), which needs to be tested in a clinical environment.

Microbeam Radiation Therapy (MRT) is currently on the verge of entering the clinical phase, necessitating robust quality assurance (QA) with appropriate dosimeters to ensure patient safety. However, MRT dosimetry presents significant challenges due to its intrinsic characteristics, including steep dose gradients with alternating high and low dose regions-referred to as peaks and valleys (valley doses comprising only 5-7% of peak doses)-micrometric resolution requirements, the use of low-to-medium energy X-rays and extremely high dose rates of up to 16 kGy/s. Currently, Gafchromic films are considered the gold standard for patient QA. Previous studies have reported discrepancies of 10-30% between measured and calculated peak and valley doses. This study aimed to evaluate four types of films (EBT-3, EBT-XD, MD-V3, and HD-V2) to determine the most suitable option for MRT QA. To support dosimetric benchmarking, the microDiamond detector was used as the reference for MRT measurements, and the ionization chamber for broad beam reference dosimetry. Discrepancies were observed between calculated and film-measured peak and valley doses, and several hypotheses were proposed to explain these differences. Possible causes include simplifications in dose calculation engines, intrinsic limitations of the films, uncertainties in experimental setups, and variations in readout methods. The study suggests that MD-V3 may be the most suitable film for MRT dosimetry, offering a dynamic range that effectively covers both peak and valley doses.

OBJECTIVE:One-third of patients with epilepsy, particularly those with mesial temporal lobe epilepsy (MTLE), remain resistant to medication. Resective surgery, the gold standard, is highly invasive and carries significant risks. Here, using a mouse model, we explored the potential of microbeam radiation therapy (MRT), a new technique based on the spatial microfractionation of high-flux X-rays, as a non-invasive alternative for treating MTLE. METHODS:MTLE was modeled in male C57BL6/J mice via unilateral kainate injection in the dorsal hippocampus. Mice with magnetic resonance imaging (MRI)-validated hippocampal sclerosis (HS) were irradiated at the European Synchrotron Radiation Facility (ESRF) using MRT with either a single trajectory (peak doses = 125-500 Gy) or multiple trajectories (2 or 5 ports at a cumulated peak dose of 125 Gy at the target). Their focal seizures were then monitored with use of electroencephalography (EEG) during 8 weeks, upon which immunochemistry was performed to assess potential tissular toxicity. RESULTS:Anteroposterior 1-port MRT significantly reduced EEG-recorded focal seizures at 125 and 250 Gy, in a dose-dependent manner. However, increased mortality was observed at 500 Gy. Immunohistolabeling revealed neuronal loss (revealed by NeuN staining), microgliosis (revealed by Iba1 straining), and astrogliosis (revealed by GFAP staining) limited to the microbeam tracks at all doses in the injected hippocampus and adjacent brain structures (e.g., cortex). Five-port MRT with a peak dose of 125 Gy at the target improved the antiepileptic effect, whereas no significant tissue alterations outside the microbeam tracks were detected by histological assessment. SIGNIFICANCE:This proof-of-concept study highlights MRT as a promising non-invasive therapy for drug-resistant focal epilepsies with optimal peak doses of 125-250 Gy, and it suggests that distributing the dose through multiple angles optimizes the therapeutic effect. MRT could provide a safer alternative to surgery, warranting further investigations.

Despite the regular discovery of new molecules, one-third of epileptic patients are resistant to antiepileptic drugs. Only a few can benefit from resective surgery, the current gold standard. Although effective in 50–70% of cases, this therapy remains risky, costly, and can be associated with long-term cognitive or neurological side effects. In addition, patients are increasingly reluctant to have a craniotomy, emphasizing the need for new less invasive therapies for focal drug-resistant epilepsies. Here, we review different minimally invasive approaches already in use in the clinic or under preclinical development to treat drug-resistant epilepsies. Localized thermolesion of the epileptogenic zone has been developed in the clinic using high-frequency thermo-coagulations or magnetic resonance imaging-guided laser or ultrasounds. Although less invasive, they have not yet significantly improved the outcomes when compared with resective surgery. Radiosurgery techniques have been used in the clinic for the last 20 years and have proven efficiency. However, their efficacy is not better than resective surgery, and various side effects have been reported as well as the potential risk of sudden unexpected death associated with epilepsy. Recently, a new strategy of radiosurgery has emerged using synchrotron-generated X-ray microbeams: microbeam radiation therapy (MRT). The low divergence and high-flux of the synchrotron beams and the unique tolerance to MRT by healthy brain tissues, allows a precise targeting of specific brain regions with minimal invasiveness and limited behavioral or functional consequences in animals. Antiepileptic effects over several months have been recorded in animal models, and histological and synaptic tracing analysis suggest a reduction of neuronal connectivity as a mechanism of action. The possibility of transferring this approach to epileptic patients is discussed in this review.

PURPOSE:Novel radiation therapy approaches have increased the therapeutic efficacy for malignant brain tumors over the past decades, but the balance between therapeutic gain and radiotoxicity remains a medical hardship. Synchrotron microbeam radiation therapy, an innovative technique, deposes extremely high (peak) doses in micron-wide, parallel microbeam paths, whereas the diffusing interbeam (valley) doses lie in the range of conventional radiation therapy doses. In this study, we evaluated normal tissue toxicity of whole-brain microbeam irradiation (MBI) versus that of a conventional hospital broad beam (hBB). METHODS AND MATERIALS:Normal Fischer rats (n = 6-7/group) were irradiated with one of the two modalities, exposing the entire brain to MBI valley/peak doses of 0/0, 5/200, 10/400, 13/520, 17/680, or 25/1000 Gy or to hBB doses of 7, 10, 13, 17, or 25 Gy. Two additional groups of rats received an MBI valley dose of 10 Gy coupled with an hBB dose of 7 or 15 Gy (groups MBI17* and MBI25*). Behavioral parameters were evaluated for 10 months after irradiation combined with veterinary observations. RESULTS:MBI peak doses of ≥680 Gy caused acute toxicity and death. Animals exposed to hBB or MBI dose-dependently gained less weight than controls; rats in the hBB25 and MBI25* groups died within 6 months after irradiation. Increasing doses of MBI caused hyperactivity but no other detectable behavioral alterations in our tests. Importantly, no health concerns were seen up to an MBI valley dose of 17 Gy. CONCLUSIONS:While acute toxicity of microbeam exposures depends on very high peak doses, late toxicity mainly relates to delivery of high MBI valley doses. MBI seems to have a low impact on normal rat behavior, but further tests are warranted to fully explore this hypothesis. However, high peak and valley doses are well tolerated from a veterinary point of view. This normal tissue tolerance to whole-brain, high-dose MBI reveals a promising avenue for microbeam radiation therapy, that is, therapeutic applications of microbeams that are poised for translation to a clinical environment.

Background and Purpose: Microbeam Radiation Therapy (MRT) aims to deliver higher doses to the target while minimizing radiation damage to healthy tissues using synchrotron x-ray microbeams. Translational MRT research has now started, driven by promising results from preclinical studies. This study aimed to propose a first dose-outcome model by analyzing micrometric dose distributions obtained with high-resolution 3D dose calculations, accounting for the inherent physical dose distribution complexity in MRT. The feasibility of integrating penMRT, our full Monte Carlo multiscale dose calculation algorithm based on PENELOPE into translational research on veterinary patients was also investigated. Material and Methods: Micrometric dose distributions were calculated in tumor-bearing rats and for a veterinary patient with penMRT, for conformal multi-directional MRT treatment plans. Absorbed dose maps were obtained with 0.005 × 0.005 × 1 mm3 voxel sizes. High-resolution dose-volume histograms were extracted and analyzed against radiobiology studies. Results: The complexity of the MRT dose distribution was properly rendered at a micrometer scale on 3D dose maps, with well separated dose regions observed on the differential dose-volume histograms. The median survival time of glioma-bearing rats varied linearly with the volume fraction of the planning target volume that received doses higher than 50 Gy (R2 = 0.98). The feasibility of using penMRT for treatment planning in large volumes has been shown on a veterinary patient. Conclusions: This study demonstrated the significant added value of penMRT for planning and prescribing MRT treatments. It also shed light on the correlation between the high-resolution 3D dose distributions and the treatment outcome.

Synchrotron Microbeam Radiation Therapy (MRT) has repeatedly proven its superiority compared with conventional radiotherapy for glioma control in preclinical research. The clinical transfer phase of MRT has recently gained momentum; seven dogs with suspected glioma were treated under clinical conditions to determine the feasibility and safety of MRT. We administered a single fraction of 3D-conformal, image-guided MRT. Ultra-high-dose rate synchrotron X-ray microbeams (50 µm-wide, 400 µm-spaced) were delivered through five conformal irradiation ports. The PTV received ~25 Gy peak dose (within microbeams) per port, corresponding to a minimal cumulated valley dose (diffusing between microbeams) of 2.8 Gy. The dogs underwent clinical and MRI follow-up, and owner evaluations. One dog was lost to follow-up. Clinical exams of the remaining six dogs during the first 3 months did not indicate radiotoxicity induced by MRT. Quality of life improved from 7.3/10 [±0.7] to 8.9/10 [±0.3]. Tumor-induced seizure activity decreased significantly. A significant tumor volume reduction of 69% [±6%] was reached 3 months after MRT. Our study is the first neuro-oncologic veterinary trial of 3D-conformal Synchrotron MRT and reveals that MRT does not induce acute to subacute radiotoxicity in normal brain tissues. MRT improves quality of life and leads to remarkable tumor volume reduction despite low valley dose delivery. This trial is an essential step towards the forthcoming clinical application of MRT against deep-seated human brain tumors.

Microbeam radiation therapy (MRT) is a radiotherapy technique combining spatial fractionation of the dose distribution on a micrometric scale, X-rays in the 50–500 keV range and dose rates up to 16 × 103 Gy s−1. Nowadays, in vivo dosimetry remains a challenge due to the ultra-high radiation fluxes involved and the need for high-spatial-resolution detectors. The aim here was to develop a striped diamond portal detector enabling online microbeam monitoring during synchrotron MRT treatments. The detector, a 550 µm bulk monocrystalline diamond, is an eight-strip device, of height 3 mm, width 178 µm and with 60 µm spaced strips, surrounded by a guard ring. An eight-channel ASIC circuit for charge integration and digitization has been designed and tested. Characterization tests were performed at the ID17 biomedical beamline of the European Synchrotron Radiation Facility (ESRF). The detector measured direct and attenuated microbeams as well as interbeam fluxes with a precision level of 1%. Tests on phantoms (RW3 and anthropomorphic head phantoms) were performed and compared with simulations. Synchrotron radiation measurements were performed on an RW3 phantom for strips facing a microbeam and for strips facing an interbeam area. A 2% difference between experiments and simulations was found. In more complex geometries, a preliminary study showed that the absolute differences between simulated and recorded transmitted beams were within 2%. Obtained results showed the feasibility of performing MRT portal monitoring using a microstriped diamond detector. Online dosimetric measurements are currently ongoing during clinical veterinary trials at ESRF, and the next 153-strip detector prototype, covering the entire irradiation field, is being finalized at our institution.

Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident synchrotron beam into arrays of parallel microbeams, typically a few tens of micrometres wide and depositing several hundred Gray. This high dose, high dose rate, spatially fractionated radiotherapy has a high therapeutic impact on tumors, especially in intracranial locations. MRT leads to better control of incurable high-grade glioma than from homogeneous radiotherapy. The schedule of MRT within a conventional irradiation protocol (three fractions of 11 Gy) of brain tumors was evaluated on the 9L glioma model in rats. MRT delivered as a first fraction increased the median survival time of the animals by four days compared with conventional radiotherapy, while the last MRT fraction improved the lifespan by 148% (+15.5 days compared with conventional radiotherapy, p < 0.0001). The most efficient radiation regimen was obtained when the MRT-boost was applied as the last fraction, following two conventional clinical exposures.

Background Microbeam radiation therapy (MRT) is a treatment modality based on spatial fractionation of synchrotron generated X-rays into parallel, high dose, microbeams of a few microns width. MRT is still an underdevelopment radiosurgery technique for which, promising preclinical results on brain tumors and epilepsy encourages its clinical transfer. Purpose A safe clinical transfer of MRT needs a specific treatment planning system (TPS) that provides accurate dose calculations in human patients, taking into account the MRT beam's properties (high-dose gradients, spatial fractionation, polarization effects). So far, the most advanced MRT TPS, based on a hybrid dose calculation algorithm, is limited to a macroscopic rendering of the dose and does not account for the complex dose distribution inherent to MRT if delivered as conformal irradiations with multiple incidences. For overcoming these limitations, a multi-scale full Monte-Carlo calculation engine called penMRT has been developed and benchmarked against two general-purpose Monte Carlo (MC) codes: penmain based on PENELOPE and Gate based on Geant4. Methods PenMRT, is based on the PENELOPE (2018) MC code, modified to take into account the voxelized geometry of the patients (computed tomography [CT]-scans) and is offering an adaptive micrometric dose calculation grid independent of the CT size, location, and orientation. The implementation of the dynamic memory allocation in penMRT, makes the simulations feasible within a huge number of dose scoring bins. The possibility of using a source replication approach to simulate arrays of microbeams, and the parallelization using OpenMPI have been added to penMRT in order to increase the calculation speed for clinical usages. This engine can be implemented in a TPS as a dose calculation core. Results The performance tests highlight the reliability of penMRT to be used for complex irradiation conditions in MRT. The benchmarking against a standard PENELOPE code did not show any significant difference for calculations in centimetric beams, for a single microbeam and for a microbeam array. The comparisons between penMRT and Gate as an independent MC code did not show any difference in the beam paths, whereas, in valley regions, relative differences between the two codes rank from 1% to 7.5% which are probably due to the differences in physics lists that are used in these two codes. The reliability of the source replication approach has also been tested and validated with an underestimation of no more than 0.6% in low-dose areas. Conclusions Good agreements (a relative difference between 0% and 8%) were found when comparing calculated peak to valley dose ratio values using penMRT, for irradiations with a full microbeam array, with calculated values in the literature. The high-resolution calculated dose maps obtained with penMRT are used to extract differential and cumulative dose-volume histograms (DVHs) and analyze treatment plans with much finer metrics regarding the irradiation complexity. To our knowledge, these are the first high-resolution dose maps and associated DVHs ever obtained for cross-fired microbeams irradiation, which is bringing a significant added value to the field of treatment planning in spatially fractionated radiation therapy.

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 radio-surgical 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-mu m-wide microbeams, replicated with a pitch of 400 mu m) of synchrotron-generated x-rays. The dose prescription adjusted a minimal cumulated valley dose of 2.8 Gy to the pinning target volume (PTV) (cinical target volume (CTV)+ 1 mm). Thus, each beam delivered 20 to 25 Gy to the target as peak doses, and similar to 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. (C) 2022 Elsevier Inc. All rights reserved.

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 radiation therapy, an alternative radiosurgical treatment under preclinical investigation, aims to safely treat muzzle tumors in pet animals. This will require data on the largely unknown radiation toxicity of microbeam arrays for bones and teeth. To this end, the muzzle of six young adult New Zealand rabbits was irradiated by a lateral array of microplanar beamlets with peak entrance doses of 200, 330 or 500 Gy. The muzzles were examined 431 days postirradiation by computed microtomographic imaging (micro-CT) ex vivo, and extensive histopathology. The boundaries of the radiation field were identified histologically by microbeam tracks in cartilage and other tissues. There was no radionecrosis of facial bones in any rabbit. Conversely, normal incisor teeth exposed to peak entrance doses of 330 Gy or 500 Gy developed marked caries-like damage, whereas the incisors of the two rabbits exposed to 200 Gy remained unscathed. A single, unidirectional array of microbeams with a peak entrance dose ≤200 Gy (valley dose14 Gy) did not damage normal bone, teeth and soft tissues of the muzzle of normal rabbits longer than one year after irradiation. Because of that, Microbeam radiation therapy of muzzle tumors in pet animals is unlikely to cause sizeable damage to normal teeth, bone and soft tissues, if a single array as used here delivers a limited entrance dose of 200 Gy and a valley dose of ≤14 Gy.

Delivery of high-radiation doses to brain tumors via multiple arrays of synchrotron X-ray microbeams permits huge therapeutic advantages. Brain tumor (9LGS)-bearing and normal rats were irradiated using a conventional, homogeneous Broad Beam (BB), or Microbeam Radiation Therapy (MRT), then studied by behavioral tests, MRI, and histopathology. A valley dose of 10 Gy deposited between microbeams, delivered by a single port, improved tumor control and median survival time of tumor-bearing rats better than a BB isodose. An increased number of ports and an accumulated valley dose maintained at 10 Gy delayed tumor growth and improved survival. Histopathologically, cell death, vascular damage, and inflammatory response increased in tumors. At identical valley isodose, each additional MRT port extended survival, resulting in an exponential correlation between port numbers and animal lifespan (r2 = 0.9928). A 10 Gy valley dose, in MRT mode, delivered through 5 ports, achieved the same survival as a 25 Gy BB irradiation because of tumor dose hot spots created by intersecting microbeams. Conversely, normal tissue damage remained minimal in all the single converging extratumoral arrays. Multiport MRT reached exceptional ~2.5-fold biological equivalent tumor doses. The unique normal tissue sparing and therapeutic index are eminent prerequisites for clinical translation.

Purpose: Synchrotron microbeam radiation therapy (MRT) is based on the spatial fractionation of the incident, highly collimated synchrotron beam into arrays of parallel microbeams depositing several hundred grays. It appears relevant to combine MRT with a conventional treatment course, preparing a treatment scheme for future patients in clinical trials. The efficiency of MRT delivered after several broad-beam (BB) fractions to palliate F98 brain tumors in rats in comparison with BB fractions alone was evaluated in this study. Methods and Materials: Rats bearing 106 F98 cells implanted in the caudate nucleus were irradiated by 5 fractions in BB mode (3 x 6 Gy + 2 x 8 Gy BB) or by 2 boost fractions in MRT mode to a total of 5 fractions (3 x 6 Gy BB + MRT 2 x 8 Gy valley dose; peak dose 181 Gy [50/200 mu m]). Tumor growth was evaluated in vivo by magnetic resonance imaging follow-up at T-1, T-7, T-12, T-15, T-20, and T-25 days after radiation therapy and by histology and flow cytometry. Results: MRT-boosted tumors displayed lower cell density and cell proliferation compared with BB-irradiated tumors. The MRT boost completely stopped tumor growth during similar to 4 weeks and led to a significant increase in median survival time, whereas tumors treated with BB alone recurred within a few days after the last radiation fraction. Conclusions: The first evidence is presented that MRT, delivered as a boost of conventionally fractionated irradiation by orthovoltage broad x-ray beams, is feasible and more efficient than conventional radiation therapy alone. (C) 2020 Elsevier Inc. All rights reserved.

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.