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Stereotactic Synchrotron Radiotherapy (SSRT) and Microbeam Radiation Therapy (MRT) are both novel approaches to treat brain tumor and potentially other tumors using synchrotron radiation. Although the techniques differ by their principles, SSRT and MRT share certain common aspects with the possibility of combining their advantages in the future. For MRT, the technique uses highly collimated, quasi-parallel arrays of X-ray microbeams between 50 and 600 keV. Important features of highly brilliant Synchrotron sources are a very small beam divergence and an extremely high dose rate. The minimal beam divergence allows the insertion of so called Multi Slit Collimators (MSC) to produce spatially fractionated beams of typically ∼25–75 micron-wide microplanar beams separated by wider (100–400 microns center-to-center(ctc)) spaces with a very sharp penumbra. Peak entrance doses of several hundreds of Gy are extremely well tolerated by normal tissues and at the same time provide a higher therapeutic index for various tumor models in rodents. The hypothesis of a selective radio-vulnerability of the tumor vasculature versus normal blood vessels by MRT was recently more solidified. SSRT (Synchrotron Stereotactic Radiotherapy) is based on a local drug uptake of high-Z elements in tumors followed by stereotactic irradiation with 80 keV photons to enhance the dose deposition only within the tumor. With SSRT already in its clinical trial stage at the ESRF, most medical physics problems are already solved and the implemented solutions are briefly described, while the medical physics aspects in MRT will be discussed in more detail in this paper. [ABSTRACT FROM AUTHOR]

Irradiation, delivered by a synchrotron facility, using a set of highly collimated, narrow and parallel photon beams spaced by 1 mm or less, has been termed Microbeam Radiation Therapy (MRT). The tolerance of healthy tissue after MRT was found to be better than after standard broad X-ray beams, together with a more pronounced response of malignant tissue. The microbeam spacing and transverse peak-to-valley dose ratio (PVDR) are considered to be relevant biological MRT parameters. We investigated the MRT concept for proton microbeams, where we expected different depth-dose profiles and PVDR dependences, resulting in skin sparing and homogeneous dose distributions at larger beam depths, due to differences between interactions of proton and photon beams in tissue. Using the FLUKA Monte Carlo code we simulated PVDR distributions for differently spaced 0.1 mm (sigma) pencil-beams of entrance energies 60, 80, 100 and 120 MeV irradiating a cylindrical water phantom with and without a bone layer, representing human head. We calculated PVDR distributions and evaluated uniformity of target irradiation at distal beam ranges of 60–120 MeV microbeams. We also calculated PVDR distributions for a 60 MeV spread-out Bragg peak microbeam configuration. Application of optimised proton MRT in terms of spot size, pencil-beam distribution, entrance beam energy, multiport irradiation, combined with relevant radiobiological investigations, could pave the way for hypofractionation scenarios where tissue sparing at the entrance, better malignant tissue response and better dose conformity of target volume irradiation could be achieved, compared with present proton beam radiotherapy configurations. [ABSTRACT FROM AUTHOR]

Microbeam radiation therapy (MRT) is a new form of preclinical radiotherapy using quasi-parallel arrays of synchrotron X-ray microbeams. While the deposition of several hundred Grays in the microbeam paths, the normal brain tissues presents a high tolerance which is accompanied by the permanence of apparently normal vessels. Conversely, the efficiency of MRT on tumor growth control is thought to be related to a preferential damaging of tumor blood vessels. The high resistance of the healthy vascular network was demonstrated in different animal models by i n vivo biphoton microscopy, magnetic resonance imaging, and histological studies. While a transient increase in permeability was shown, the structure of the vessels remained intact. The use of a chick chorioallantoic membrane at different stages of development showed that the damages induced by microbeams depend on vessel maturation. In vivo and ultrastructural observations showed negligible effects of microbeams on the mature vasculature at late stages of development; nevertheless a complete destruction of the immature capillary plexus was found in the microbeam paths. The use of MRT in rodent models revealed a preferential effect on tumor vessels. Although no major modification was observed in the vasculature of normal brain tissue, tumors showed a denudation of capillaries accompanied by transient increased permeability followed by reduced tumor perfusion and finally, a decrease in number of tumor vessels. Thus, MRT is a very promising treatment strategy with pronounced tumor control effects most likely based on the anti-vascular effects of MRT. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Microbeam radiation therapy (MRT) is a promising preclinical modality for cancer treatment, with remarkable preferential tumoricidal effects, that is, tumor eradication without damaging normal tissue functions. Significant lifespan extension has been demonstrated in brain tumor-bearing small animals treated with MRT. So far, MRT experiments can only be performed in a few synchrotron facilities around the world. Limited access to MRT facilities prevents this enormously promising radiotherapy technology from reaching the broader biomedical research community and hinders its potential clinical translation. We recently demonstrated, for the first time, the feasibility of generating microbeam radiation in a laboratory environment using a carbon nanotube x-ray source array and performed initial small animal studies with various brain tumor models. This new nanotechnology-enabled microbeam delivery method, although still in its infancy, has shown promise for achieving comparable therapeutic effects to synchrotron MRT and has offered a potential pathway for clinical translation. [ABSTRACT FROM AUTHOR]

Purpose: Microbeam radiation therapy (MRT) uses narrow planes of high dose radiation beams to treat cancerous tumors. This experimental therapy method based on synchrotron radiation has been shown to spare normal tissue at up to 1000 Gy of peak entrance dose while still being effective in tumor eradication and extending the lifetime of tumor-bearing small animal models. Motion during treatment can lead to significant movement of microbeam positions resulting in broader beam width and lower peak to valley dose ratio (PVDR), which reduces the effectiveness of MRT. Recently, the authors have demonstrated the feasibility of generating microbeam radiation for small animal treatment using a carbon nanotube (CNT) x-ray source array. The purpose of this study is to incorporate physiological gating to the CNT microbeam irradiator to minimize motion-induced microbeam blurring. Methods: The CNT field emission x-ray source array with a narrow line focal track was operated at 160 kVp. The x-ray radiation was collimated to a single 280 µm wide microbeam at entrance. The microbeam beam pattern was recorded using EBT2 Gafchromic© films. For the feasibility study, a strip of EBT2 film was attached to an oscillating mechanical phantom mimicking mouse chest respiratory motion. The servo arm was put against a pressure sensor to monitor the motion. The film was irradiated with three microbeams under gated and nongated conditions and the full width at half maximums and PVDRs were compared. An in vivo study was also performed with adult male athymic mice. The liver was chosen as the target organ for proof of concept due to its large motion during respiration compared to other organs. The mouse was immobilized in a specialized mouse bed and anesthetized using isoflurane. A pressure sensor was attached to a mouse's chest to monitor its respiration. The output signal triggered the electron extraction voltage of the field emission source such that x-ray was generated only during a portion of the mouse respiratory cycle when there was minimum motion. Parallel planes of microbeams with 12.4 Gy/plane dose and 900 µm pitch were delivered. The microbeam profiles with and without gating were analyzed using γ-H2Ax immunofluorescence staining. Results: The phantom study showed that the respiratory motion caused a 50% drop in PVDR from 11.5 when there is no motion to 5.4, whereas there was only a 5.5% decrease in PVDR for gated irradiation compared to the no motion case. In thein vivo study, the histology result showed gating increased PVDR by a factor of 2.4 compared to the nongated case, similar to the result from the phantom study. The full width at tenth maximum of the microbeam decreased by 40% in gating in vivo and close to 38% with phantom studies. Conclusions: The CNT field emission x-ray source array can be synchronized to physiological signals for gated delivery of x-ray radiation to minimize motion-induced beam blurring. Gated MRT reduces valley dose between lines during long-time radiation of a moving object. The technique allows for more precise MRT treatments and makes the CNT MRT device practical for extended treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A Monte Carlo simulation was applied to study the energy dependence on the transverse dose distribution of microplanar beam radiation therapy (MRT) for deep-seated tumors. The distribution was found to be the peak (in-beam) dose and the decay from the edge of the beam down to the valley. The area below the same valley dose level (valley region) was decreased with the increase in the energy of X-rays at the same beam separation. To optimize the MRT, we made the following two assumptions: the therapeutic gain may be attributed to the efficient recovery of normal tissue caused by the beam separation; and a key factor for the efficient recovery of normal tissue depends on the area size of the valley region. Based on these assumptions and the results of the simulated dose distribution, we concluded that the optimum X-ray energy was in the range of 100-300 keV depending on the effective peak dose to the target tumors and/or tolerable surface dose. In addition, we proposed parameters to be studied for the optimization of MRT to deep-seated tumors. [ABSTRACT FROM AUTHOR]

Purpose: Microbeam Radiation Therapy (MRT), an alternative preclinical treatment strategy using spatially modulated synchrotron radiation on a micrometer scale, has the great potential to cure malignant tumors (e.g., brain tumors) while having low side effects on normal tissue. Dose measurement and calculation in MRT is challenging because of the spatial accuracy required and the arising high dose differences. Dose calculation with Monte Carlo simulations is time consuming and their accuracy is still a matter of debate. In particular, the influence of photon polarization has been discussed in the literature. Moreover, it is controversial whether a complete knowledge of phase space trajectories, i.e., the simulation of the machine from the wiggler to the collimator, is necessary in order to accurately calculate the dose. Methods: With Monte Carlo simulations in the Geant4 toolkit, the authors investigate the influence of polarization on the dose distribution and the therapeutically important peak to valley dose ratios (PVDRs). Furthermore, the authors analyze in detail phase space information provided by Martínez- Rovira et al. ["Development and commissioning of a Monte Carlo photon model for the forthcoming clinical trials in microbeam radiation therapy," Med. Phys. 39(1), 119-131 (2012)] and examine its influence on peak and valley doses. A simple source model is developed using parallel beams and its applicability is shown in a semiadjoint Monte Carlo simulation. Results are compared to measurements and previously published data. Results: Polarization has a significant influence on the scattered dose outside the microbeam field. In the radiation field, however, dose and PVDRs deduced from calculations without polarization and with polarization differ by less than 3%. The authors show that the key consequences from the phase space information for dose calculations are inhomogeneous primary photon flux, partial absorption due to inclined beam incidence outside the field center, increased beam width and center to center distance due to the beam propagation from the collimator to the phantom surface and imperfect absorption in the absorber material of the Multislit Collimator. These corrections have an effect of approximately 10% on the valley dose and suffice to describe doses in MRT within the measurement uncertainties of currently available dosimetry techniques. Conclusions: The source for the first clinical pet trials in MRT is characterized with respect to its phase space and the photon polarization. The results suggest the use of a presented simplified phase space model in dose calculations and hence pave the way for alternative and fast dose calculation algorithms. They also show that the polarization is of minor importance for the clinical important peak and valley doses inside the microbeam field. [ABSTRACT FROM AUTHOR]

MicroBeam Radiosurgery (MBRS, also referred to as Microbeam Radiation Therapy, MRT) is a potential clinical technique for the treatment of solid tumors. MBRS utilizes a series of narrow 30 to 50 μ m beams of ultra-high, lethal dose synchrotron x-ray radiation (peaks) separated by relatively wide spaces of no radiation (valleys) with spacings of 200 to 400 μ m center-to-center. It has been observed that healthy small animal tissue, including neurologic tissue (brain and spinal cord), can recover quickly, but solid tumors take a prolonged time of many months to regrow. This vast difference in recovery period is the basis for the therapeutic effect of MBRS on tumors. The interactions of X rays and tissue cells in alignment with the microbeams cause some deposited dose to be delivered to the tissue between the peak region of the microbeams and spill into the valley regions. It is generally believed that the dose delivered between the microbeam peak regions must be maintained at a low level to maximize the efficacy of MBRS. To date the most widely used criterion for the efficacy of MBRS is known as the Peak-to-Valley Dose Ratio (PVDR). This ratio depends on the geometry of the system along with the X-ray spectra. As most of the experimental work to date has used polychromatic microbeams of X rays, the PVDR will change with the energy range and spectrum. We are reporting novel investigations and present data suggesting considerations additional to the PVDR are needed for the design of a human clinical facility. In this paper we studied X-ray interactions in simulated human biologic material (Water - H 2 O) using the MCNP6 radiation transport computer code. The new slit geometry dependent information includes: (1) rounding of peak shape; (2) decrease of the maximum peak height with decreasing peak slit width; (3) qualitative and quantitative changes to the "skirt" radiation dose delivered in the valley regions adjacent to the peak regions. All these effects were highly dependent on incident X-ray energy because of the transition of the dominant X-ray interaction from the photo-electric effect to atomic Compton scattering with increasing energy in the 50 to 300 keV range. Changes in the radiation dose distributions, as a function of X-ray energy, delivered to both the peak and valley regions after the X-ray interactions were investigated in detail. Insights from understanding how the dose is delivered in the valley regions have implications for the calculations of the clinical radiation dose planning. Accurate dose distribution calculations are necessary in human clinical treatment since it is anticipated that most patients will have received prior radiation therapy treatments that need to be considered in microbeam dose planning so that radiation side-effects and toxicity are accounted for and minimized. This work suggests an X-ray energy range of 130–250 keV is the most appropriate range for a human clinical facility. Using the results of this work, the authors suggest that the PVDR may not be the only criteria one should consider for determining the energy range needed for a human clinical facility; analysis of the data presented demonstrates the benefit of also using the full width at 10% maximum of the distribution. [ABSTRACT FROM AUTHOR]

Purpose: The advent of widespread kV-cone beam computer tomography in image guided radiation therapy and special therapeutic application of keV photons, e.g., in microbeam radiation therapy (MRT) require accurate and fast dose calculations for photon beams with energies between 40 and 200 keV. Multiple photon scattering originating from Compton scattering and the strong dependence of the photoelectric cross section on the atomic number of the interacting tissue render these dose calculations by far more challenging than the ones established for corresponding MeV beams. That is why so far developed analytical models of kV photon dose calculations fail to provide the required accuracy and one has to rely on time consuming Monte Carlo simulation techniques. Methods: In this paper, the authors introduce a novel analytical approach for kV photon dose calculations with an accuracy that is almost comparable to the one of Monte Carlo simulations. First, analytical point dose and pencil beam kernels are derived for homogeneous media and compared to Monte Carlo simulations performed with the Geant4 toolkit. The dose contributions are systematically separated into contributions from the relevant orders of multiple photon scattering. Moreover, approximate scaling laws for the extension of the algorithm to inhomogeneous media are derived. Results: The comparison of the analytically derived dose kernels in water showed an excellent agreement with the Monte Carlo method. Calculated values deviate less than 5% from Monte Carlo derived dose values, for doses above 1% of the maximum dose. The analytical structure of the kernels allows adaption to arbitrary materials and photon spectra in the given energy range of 40-200 keV. Conclusions: The presented analytical methods can be employed in a fast treatment planning system for MRT. In convolution based algorithms dose calculation times can be reduced to a few minutes. [ABSTRACT FROM AUTHOR]

Abstract: One of the key parameters and most difficult challenges related to Microbeam Radiation Therapy (MRT) is the exact measurement of radiation dose delivered. The approach presented here is based on the conversion of the oxidation state of samarium ions (embedded in a suitable glass host) upon exposure to high energy radiation. The conversion from Sm3+ to Sm2+ under the effect of high x-ray irradiation doses has been studied in four oxyfluoride glasses based on Ca, Mg, Sr and Ba. These glasses can easily be prepared in air, contrary to pure fluoride glasses. They provide good transparency in the visible range, essential for analysis by confocal microscopy. Only the Mg-based glasses exhibited a clear conversion of Sm3+ to Sm2+ under x-ray exposure; and hence show potential for use as MRT dosimetry. The conversion did not saturate even up to ~20kGy (dose in air at the sample surface) under a 50keV synchrotron beam. Further, we were able to determine the spatial dose profile of the x-ray beam through confocal fluoroscopic microscopy; and the dose profile matched closely that from the Monte Carlo simulation. [Copyright &y& Elsevier]

Purpose: To investigate biochemical changes in mouse tumour tissue following Microbeam Radiation Therapy (MRT) and Broad Beam (BB) irradiation using synchrotron Fourier-Transform Infrared (FTIR) microspectroscopy. Materials and methods: Synchrotron FTIR microspectroscopy was carried out on mouse tumour sections previously irradiated with BB (11, 22 or 44 Gy), MRT (560 Gy in-beam, 25 μm wide, 200 μm peak separation) or sham-irradiation (0 Gy) from mice culled 4 hours post-irradiation. Results: MRT and BB-irradiated tumour sections showed clear chemical shifts in spectral bands corresponding to functional group vibrations in protein (1654-1630 cm−1), lipid (~1470, 1463 cm−1) and nucleic acid (1130-1050 cm−1). MRT peak and valley regions showed virtually identical absorbance patterns in protein and lipid regions. However, we observed chemical shifts corresponding to the nucleic acid region (1120-1050 cm−1) between the peak and valley dose regions. Chemical maps produced from integrating absorbance bands of interest over the scanned tumour area did not reveal any microbeam paths. Conclusions: The lack of difference between MRT peak and valley irradiated areas suggests a holistic tissue response to MRT that occurs within 4 h, and might be the first evidence for a mechanism by which MRT kills the whole tumour despite only a small percentage receiving peak irradiation. [ABSTRACT FROM AUTHOR]

Microbeam radiation therapy (MRT), a preclinical form of radiosurgery, uses spatially fractionated micrometre-wide synchrotron-generated X-ray beams. As MRT alone is predominantly palliative for animal tumors, the effects of the combination of MRT and a newly synthesized chemotherapeutic agent JAI-51 on 9L gliosarcomas have been evaluated. Fourteen days (D14) after implantation (D0), intracerebral 9LGS-bearing rats received either MRT, JAI-51 or both treatments. JAI-51, alone or immediately after MRT, was administered three times per week. Animals were kept up to ∼20 weeks after irradiation or sacrificed at D16 or D28 after treatment for cell cycle analysis. MRT plus JAI-51 increased significantly the lifespan compared with MRT alone ( p = 0.0367). JAI-51 treatment alone had no effect on rat survival. MRT alone or associated with JAI-51 induced a cell cycle blockade in G2/M ( p < 0.01) while the combined treatment also reduced the proportion of G0/G1 cells. At D28 after irradiation, MRT and MRT/JAI-51 had a smaller cell blockade effect in the G2/M phase owing to a significant increase in tumor cell death rate (<2c) and a proportional increase of endoreplicative cells (>8c). The combination of MRT and JAI-51 increases the survival of 9LGS-bearing rats by inducing endoreduplication of DNA and tumor cell death; further, it slowed the onset of tumor growth resumption two weeks after treatment. [ABSTRACT FROM AUTHOR]

Abstract: Microbeam radiation therapy is an experimental technique utilising synchrotron X-rays collimated into a planar array of microbeams. Due to the complex structure of the radiation field and high dose rate, this introduces dosimetric challenges. Current dosimetric methods are inadequate in that they lack either real-time readout, or high spatial resolution. A detector system, consisting of the Silicon Multi-Strip Detector and associated readout system was developed at the University of Wollongong. This system performs online, real-time dosimetry, and is designed for placement upstream of the patient as a transmission detector. The interaction of synchrotron radiation with this detector, both in terms of perturbative effects on the beam and interactions within the detector are investigated with the Monte Carlo simulation toolkit, Geant4. The interaction percentage of the detector with the traversing beam was determined as being (1.97 ± 0.01) %. Energy deposition was found to be uniform across the depth of the detector, negating the most proximal and distal 5-μm region, a phenomenon that may be attributed to a lack of charged particle equilibrium. The effect that the detector has on a traversing beam’s macroscopic dose deposition was determined as being a mean reduction in dose of (1.44 ± 0.15) % for depths in water between 5 and 35 mm. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Purpose: To explore the effects of microbeam radiation (MR) on vascular biology, we used the chick chorioallantoic membrane (CAM) model of an almost pure vascular system with immature vessels (lacking periendothelial coverage) at Day 8 and mature vessels (with coverage) at Day 12 of development. Methods and Materials: CAMs were irradiated with microplanar beams (width, ∼25 μm; interbeam spacing, ∼200 μm) at entrance doses of 200 or 300 Gy and, for comparison, with a broad beam (seamless radiation [SLR]), with entrance doses of 5 to 40 Gy. Results: In vivo monitoring of Day-8 CAM vasculature 6 h after 200 Gy MR revealed a near total destruction of the immature capillary plexus. Conversely, 200 Gy MR barely affected Day-12 CAM mature microvasculature. Morphological evaluation of Day-12 CAMs after the dose was increased to 300 Gy revealed opened interendothelial junctions, which could explain the transient mesenchymal edema immediately after irradiation. Electron micrographs revealed cytoplasmic vacuolization of endothelial cells in the beam path, with disrupted luminal surfaces; often the lumen was engorged with erythrocytes and leukocytes. After 30 min, the capillary plexus adopted a striated metronomic pattern, with alternating destroyed and intact zones, corresponding to the beam and the interbeam paths within the array. SLR at a dose of 10 Gy caused growth retardation, resulting in a remarkable reduction in the vascular endpoint density 24 h postirradiation. A dose of 40 Gy damaged the entire CAM vasculature. Conclusions: The effects of MR are mediated by capillary damage, with tissue injury caused by insufficient blood supply. Vascular toxicity and physiological effects of MR depend on the stage of capillary maturation and appear in the first 15 to 60 min after irradiation. Conversely, the effects of SLR, due to the arrest of cell proliferation, persist for a longer time. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluated suppression of tumor growth in human glioma cells embedded in mice with the use of microbeams. The tumor growth ratio was equated and acute cell death was histologically studied. Immunohistochemistry with the use of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining revealed no growth in TUNEL-positive cells.

Since its advent during the mid-twentieth century, radiosurgery has undergone a steady evolution. Gamma Knife and linear accelerator based systems using rigid frames preceded the development of frameless devices. The present report describes the development of microbeam radiosurgery, a technique which uses submillimetric beams of radiation to treat disease. Typically, the technique is employed using parallel arrays of beams delivered via a high-fluence synchrotron source. Beam widths between 20 and 950 μm have been used with the majority of studies utilizing beam widths less than 100 μm. In addition to its high precision, the technique allows users to take advantage of two unique properties of microbeams. The first is a remarkable tolerance of healthy tissue to microbeams delivered at doses up to several hundred grays, while at the same time, tumors are highly susceptible to the lethal effects of microbeams. Together, these findings allow for a 'preferential tumoricidal effect' beyond the typical dose-volume relationship. Although only used in animal experiments so far, we explore the hypothetical clinical role of microbeam radiosurgery which may be feasible in the near future. In addition to the treatment of traditional radiosurgery targets such as malignancies and vascular malformations, microbeams may allow the non-invasive treatment of functional disease such as movement disorders, epilepsy, and mental illness. [ABSTRACT FROM AUTHOR]

Purpose: High-dose synchrotron microbeam radiation therapy (MRT) can be effective at destroying tumors in animal models while causing very little damage to normal tissues. The aim of this study was to investigate the cellular processes behind this observation of potential clinical importance. Methods and Materials: MRT was performed using a lattice of 25 μm-wide, planar, polychromatic, kilovoltage X-ray microbeams, with 200-μm peak separation. Inoculated EMT-6.5 tumor and normal mouse skin tissues were harvested at defined intervals post-MRT. Immunohistochemical detection of γ-H2AX allowed precise localization of irradiated cells, which were also assessed for proliferation and apoptosis. Results: MRT significantly reduced tumor cell proliferation by 24 h post-irradiation (p = 0.002). An unexpected finding was that within 24 h of MRT, peak and valley irradiated zones were indistinguishable in tumors because of extensive cell migration between the zones. This was not seen in MRT-treated normal skin, which appeared to undergo a coordinated repair response. MRT elicited an increase in median survival times of EMT-6.5 and 67NR tumor-inoculated mice similar to that achieved with conventional radiotherapy, while causing markedly less normal tissue damage. Conclusions: This study provides evidence of a differential response at a cellular level between normal and tumor tissues after synchrotron MRT. [Copyright &y& Elsevier]

Abstract: Microbeam radiation therapy (MRT) is currently being considered for the treatment of glioblastoma multiforme. A high degree of dosimetric accuracy (around 5%) is known to be required for a successful outcome in conventional radiation therapy, Modelling of MRT beams, measurements and treatments have been performed with Monte Carlo methods using the code EGS5, which features improved physics models for low energy scattering processes including linear polarisation. Polarisation of the X-ray source leads to distortions in beam profiles that exceed the usual clinical tolerances. Changes in the energy spectrum also effect the response of many dosimetry systems. Anatomical (CT) data has been used in the dose calculations and the manipulation of dose data with the open-source software treatment planning system, PlanUNC, is demonstrated, in order that the therapeutic effects of the different components, e.g. the microbeam and scattered photons, can examined separately in relation to relevant anatomy. [Copyright &y& Elsevier]

Abstract: In radiation cancer therapy, the aim is to destroy the tumour cells in the treated area while minimizing damage to the surrounding normal tissue. Synchrotron microbeam radiation therapy offers considerable promise in this respect, based on knowledge that normal tissue can tolerate high doses of radiation over small volumes. At the ESRF microbeam radiation therapy facility, one of the several aspects being investigated is measurement of very high dose gradients (changing by hundreds of Gy over ∼10μm), as there is no established physical dosimetric system simultaneously providing accurate measurements of the doses in the microbeam peaks and valleys. Monte Carlo simulations have been obtained but these have yet to be validated by measurements. One possible means of obtaining micro dosimetric evaluations is use of the thermoluminescence (TL) produced by optical fibres. Previous studies at conventional electron linac radiotherapy facilities have shown that germanium-doped silica fibres offer useful sensitivity to radiotherapy doses it is being further established that commercially produced Ge-doped optical fibres can provide a TL-yield reproducibility of better than 4% (1 SD). Present experiments have investigated the thermoluminescence response of such fibres at incident energies of several tens of keV, for a wide range of doses, from 1Gy to 10kGy, revealing a linear correlation of r 2≥0.998 up to a dose of 2kGy, encompassing the dosimetric needs of both conventional and synchrotron microbeam radiotherapy. [Copyright &y& Elsevier]

Abstract: Microbeam radiation therapy (MRT) uses highly collimated, quasi-parallel arrays of X-ray microbeams of 50–600keV, produced by third generation synchrotron sources, such as the European Synchrotron Radiation Facility (ESRF), in France. The main advantages of highly brilliant synchrotron sources are an extremely high dose rate and very small beam divergence. High dose rates are necessary to deliver therapeutic doses in microscopic volumes, to avoid spreading of the microbeams by cardiosynchronous movement of the tissues. The minimal beam divergence results in the advantage of steeper dose gradients delivered to a tumor target, thus achieving a higher dose deposition in the target volume in fractions of seconds, with a sharper penumbra than that produced in conventional radiotherapy. MRT research over the past 20 years has yielded many results from preclinical trials based on different animal models, including mice, rats, piglets and rabbits. Typically, MRT uses arrays of narrow (∼25–100μm wide) microplanar beams separated by wider (100–400μm centre-to-centre) microplanar spaces. The height of these microbeams typically varies from 1 to 100mm, depending on the target and the desired preselected field size to be irradiated. Peak entrance doses of several hundreds of Gy are surprisingly well tolerated by normal tissues, up to ∼2yr after irradiation, and at the same time show a preferential damage of malignant tumor tissues; these effects of MRT have now been extensively studied over nearly two decades. More recently, some biological in vivo effects of synchrotron X-ray beams in the millimeter range (0.68–0.95mm, centre-to-centre distances 1.2–4mm), which may differ to some extent from those of microscopic beams, have been followed up to ∼7 months after irradiation. Comparisons between broad-beam irradiation and MRT indicate a higher tumor control for the same sparing of normal tissue in the latter, even if a substantial fraction of tumor cells are not receiving a radiotoxic level of radiation. The hypothesis of a selective radiovulnerability of the tumor vasculature versus normal blood vessels by MRT, and of the cellular and molecular mechanisms involved remains under investigation. The paper highlights the history of MRT including salient biological findings after microbeam irradiation with emphasis on the vascular components and the tolerance of the central nervous system. Details on experimental and theoretical dosimetry of microbeams, core issues and possible therapeutic applications of MRT are presented. [Copyright &y& Elsevier]

Microbeam radiation therapy (MRT) is an innovative technique to treat brain tumors. The synchrotron generated x-ray beam, used for the treatment, is collimated and delivered in an array of narrow micrometer-sized planar rectangular fields. Several preclinical experiments performed at the Brookhaven National Laboratory (BNL) and at the European Synchrotron Radiation Facility (ESRF) have shown the sparing effect of the healthy tissue and the ablation of tumors in several animal models. It has also been determined that MRT yields a higher therapeutic index than nonsegmented beams of the same energy. This therapeutic index could be greatly improved by loading the tumor with high atomic number (Z) contrast agents. In this work, the dose enhancement factors and the peak to valley dose ratios (PVDRs) are assessed for different gadolinium (Z=64) concentrations in the tumor and different microbeam energies by using Monte Carlo simulations (PENELOPE 2006 code). A significant decrease in the PVDR values in the tumor, and therefore a relevant increase in the dose deposition, is found in the presence of gadolinium. The optimum energy for the dose deposition in the tumor while keeping a high PVDR in the healthy tissues, which guaranties their sparing, has been investigated. [ABSTRACT FROM AUTHOR]

Several synchrotrons around the world are currently developing innovative radiotherapy techniques with the aim of palliating and possibly curing human brain tumors. Amongst them, microbeam radiation therapy (MRT) and, more recently, minibeam radiation therapy (MBRT) have shown promising results. In MBRT the beam thickness ranges from 500 to 700 urn with a separation between two adjacent minibeams of the same value, whilst in MRT the thickness is of the order of 25-50 urn with a distance between adjacent microbeams of the order of 200 tim. An original method has been developed and tested at the ESRF 1D17 biomedical beamline to produce the minibeam patterns. It utilizes a specially developed high-energy white-beam chopper whose action is synchronized with the vertical motion of the target moving at constant speed. Each opening of the chopper generates a horizontal beam print. The method described here has the advantage of being simple and reliable, and it allows for an easy control of the patient safety in future clinical trials. To study the feasibility of the method, dosimetric measurements have been performed using Gafchromic HD-810 films and compared with Monte Carlo simulations. The results of this comparison are discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: Half of all cancer patients receive radiation therapy during their course of treatment. The destructive effects of radiation on normal tissue causes side effects that significantly affect the patient's quality of life. Microplanar radiation therapy (MRT) is a novel, promising method that, in animal models, has shown fewer effects on normal tissue and better therapeutic efficacy. MRT does not expose the entire tissue to intense radiation, but has micron-scale "valleys" between the peaks of radiation. We have previously developed an accessible method to apply MRT. Using our approach, here, we show that MRT greatly enhanced the response of the immune system to the tumor by stimulating specific signaling molecules. Moreover, we show that combining MRT with immune checkpoint therapy was even more effective in reducing the treated tumors, possibly pointing towards using similar approaches in the clinic. Spatially fractionated radiotherapy has been shown to have effects on the immune system that differ from conventional radiotherapy (CRT). We compared several aspects of the immune response to CRT relative to a model of spatially fractionated radiotherapy (RT), termed microplanar radiotherapy (MRT). MRT delivers hundreds of grays of radiation in submillimeter beams (peak), separated by non-radiated volumes (valley). We have developed a preclinical method to apply MRT by a commercial small animal irradiator. Using a B16-F10 murine melanoma model, we first evaluated the in vitro and in vivo effect of MRT, which demonstrated significant treatment superiority relative to CRT. Interestingly, we observed insignificant treatment responses when MRT was applied to Rag−/− and CD8-depleted mice. An immuno-histological analysis showed that MRT recruited cytotoxic lymphocytes (CD8), while suppressing the number of regulatory T cells (Tregs). Using RT-qPCR, we observed that, compared to CRT, MRT, up to the dose that we applied, significantly increased and did not saturate CXCL9 expression, a cytokine that plays a crucial role in the attraction of activated T cells. Finally, MRT combined with anti-CTLA-4 ablated the tumor in half of the cases, and induced prolonged systemic antitumor immunity. [ABSTRACT FROM AUTHOR]

Abstract: The radiotherapy clinical trials projects, both aiming at treating aggressive brain tumors, require several major modifications and new constructions at the ESRF ID17 Biomedical beamline. The application of the Stereotactic Synchrotron Radiation Therapy (SSRT) technique mainly necessitates an upgrade of the existing patient positioning system, which was formerly used for the angiography program. It will allow for accurate positioning, translation and rotation of the patient during the treatment. For the Microbeam Radiation Therapy (MRT) clinical trials project, a new white beam hutch will be constructed to accommodate a dedicated patient positioning system. Consequently, the existing control hutches and the related installations will also be completely refurbished. Furthermore, the foreseen installation of a second X-ray source, which will allow doubling the currently available photon flux at high energies, requires a redesign of most optical components to handle the increased power and power densities. Starting from the current ID17 Biomedical beamline layout, the paper will present an update of the different modification/construction projects, including the general organization and planning. [Copyright &y& Elsevier]

Abstract: Background: Disturbances of memory function are frequently observed in patients with malignant brain tumours and as adverse effects after radiotherapy to the brain. Experiments in small animal models of malignant brain tumour using synchrotron-based microbeam radiation therapy (MRT) have shown a promising prolongation of survival times. Materials and methods: Two animal models of malignant brain tumour were used to study survival and memory development after MRT. Thirteen days after implantation of tumour cells, animals were submitted to MRT either with or without adjuvant therapy (buthionine-SR-sulfoximine=BSO or glutamine). We used two orthogonal 1-cm wide arrays of 50microplanar quasiparallel microbeams of 25μm width and a center-to-center distance of about 200μm, created by a multislit collimator, with a skin entrance dose of 350Gy for each direction. Object recognition tests were performed at day 13 after tumour cell implantation and in monthly intervals up to 1 year after tumour cell implantation. Results: In both animal models, MRT with and without adjuvant therapy significantly increased survival times. BSO had detrimental effects on memory function early after therapy, while administration of glutamine resulted in improved memory. [Copyright &y& Elsevier]

Abstract: Microbeam radiation therapy (MRT) is a form of radiosurgery first dedicated to the treatment of brain tumors. It uses arrays of synchrotron generated X-rays microbeams of very high doses (typically 625Gy). Microbeams are typically few micrometers large (25μm) and few hundred micrometers spaced (200μm). Previous experiments have shown that despite a good tumor eradication rate (5/11), a 100-μm spacing unidirectional irradiation (skin dose 625Gy, width 25μm) was too invasive for normal tissue. On the contrary, a 200-μm spacing unidirectional irradiation preserved healthy tissue with a low tumor eradication rate (2/32). The purpose of this study was to enhance the potential of the 200μm spacing irradiation protocol. After diagnosis of the tumor by MRI, 9L tumor-bearing rats were laterally irradiated with 51 microbeams (625Gy, 25μm, 200μm) 14 days after implantation. Three drugs (Gd-DTPA, CisPt, temozolomide) were tested, after intratumoral injection at the theoretical center of the tumor. Control rats displayed a median survival time of 19 days. There was no significant difference between drug-treated rats and control group. Irradiated animals showed an increase in life span (ILS) of 60.5%. Interestingly, the ILS increased to 131.6% and 1/6 rat survived more than 1 year in case of MRT combined with gadolinium injection. These results showed that the synergy between gadolinium injection (acting as a dose enhancer) and MRT improved significantly the life span of tumor bearing rats (more than a factor 2). [Copyright &y& Elsevier]

Purpose: The purpose of this study was to assess the early effects of microbeam irradiation on the vascular permeability and volume in the parietal cortex of normal nude mice using two-photon microscopy and immunohistochemistry. Methods and Materials: The upper part of the left hemisphere of 55 mice was irradiated anteroposteriorly using 18 vertically oriented beams (width 25 μm, interdistance 211 μm; peak entrance doses: 312 or 1000 Gy). At different times after microbeam exposure, the microvasculature in the cortex was analyzed using intravital two-photon microscopy after intravascular injection of fluorescein isothiocyanate (FITC)-dextrans and sulforhodamine B (SRB). Changes of the vascular volume were observed at the FITC wavelength over a maximum depth of 650 μm from the dura. The vascular permeability was detected as extravasations of SRB. Results: For all times (12 h to 1 month) after microbeam irradiation and for both doses, the FITC-dextran remained in the vessels. No significant change in vascular volume was observed between 12 h and 3 months after irradiation. Diffusion of SRB was observed in microbeam irradiated regions from 12 h until 12 days only after a 1000 Gy exposure. Conclusion: No radiation damage to the microvasculature was detected in normal brain tissue after a 312 Gy microbeam irradiation. This dose would be more appropriate than 1000 Gy for the treatment of brain tumors using crossfired microbeams. [Copyright &y& Elsevier]

Abstract: Radiotherapy is among the most useful treatments of cancer. Penetrating radiation (ionizing particles or bremsstrahlung photons) is aimed toward the tumor-bearing target, gradually delivering as high radiation to it as is usefully suppressive of tumor growth, yet tolerated by normal vital tissues inevitably irradiated with the tumor. The high collimation and dose rate of synchrotron X-ray beams, even when monochromatized, favor radiotherapy. Photon activation therapy, tomotherapy, microbeam radiation therapy, and radiosurgery mediated by synchrotron wigglers are conceptually promising for difficult tumors. Radiotherapy of malignant brain tumors in rats has been encouraging, but suitable beam lines exist at only a few research facilities and much basic work must be done before the promise of synchrotron-based radiotherapy can be realized clinically. [Copyright &y& Elsevier]

: BackgroundParallel, thin (<100 μm) planes of synchrotron-generated X rays, have been shown to spare normal tissues and preferentially damage tumors in animal models. The aim of the present study was to assess the effect of such microbeams directed unidirectionally on angioplasted rat carotid arteries.: Methods and materialsThree groups of Sprague–Dawley rats were studied: (a) rats with normal, untreated arteries, (b) rats treated by balloon angioplasty, but not irradiated, and (c) rats treated with balloon angioplasty and exposed to single fraction, unidirectional, parallel, microbeams an hour after angioplasty. The microbeam array, 15 mm wide×7.6 mm high, consisting of 27-μm-wide beam slices, spaced 200 μm center-to-center laterally traversed the damaged artery. The in-depth in-beam dose was 150 Gy, the “valley” dose (dose midway between microbeams resulting mainly from X-ray scattering) was 4.5 Gy on average, and the “integrated” (averaged) dose was 26 Gy.: ResultsMicrobeam irradiation, as given in the present study, was tolerated, but was insufficient to significantly suppress the neointimal hyperplasia.: DiscussionThe microbeam dose used is considered low. Dose escalation would be necessary to reach conclusive results regarding the X-ray microbeam efficacy to control restenosis. [Copyright &y& Elsevier]