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Abstract DNA damage occurs in all living cells. γ-H2AX imaging by fluorescent microscopy is widely used across disciplines in the analysis of double-strand break (DSB) DNA damage. Here we demonstrate a method for the quantitative analysis of such DBSs. Ionising radiation, well known to induce DSBs, is used in this demonstration, and additional DBSs are induced if high-Z nanoparticles are present during irradiation. As a deliberate test of the methodology, cells are exposed to a spatially fractionated ionising radiation field, characterised by regions of high and low absorbed radiation dose that are only ever qualitatively verified biologically via γ-H2AX imaging. Here we validate our bio-dosimetric quantification method using γ-H2AX assays in the assessment of DSB enhancement. Our method reliably quantifies DSB enhancement in cells when exposed to either a spatially contiguous or fractionated irradiation fields. Using the γ-H2AX assay, we deduce the biological dose response, and for the first time, demonstrate equivalence to the independently measured physical absorbed dose. Using our novel method, we are also able quantify the nanoparticle DSB enhancement at the cellular level, which is not possible using physical dose measurement techniques. Our method therefore provides a new paradigm in γ-H2AX image quantification of DSBs, as well as an independently validated bio-dosimetry technique.

Simple Summary: Microbeam radiation therapy (MRT) is a novel, still pre-clinical form of radiation therapy for cancer treatment, where the dose is applied in spatial fractions. MRT was shown to be able to treat tumors effectively while causing reduced damage to normal tissue. Research on MRT nowadays requires large, expensive, and difficult-to-access facilities. In this study, we aim to develop an easily accessible MRT setup utilizing a conventional small animal irradiator. We developed a comprehensive treatment planning system with a dose calculation accuracy of 10%. We successfully applied microbeam radiation to a mouse in vivo and showed that the microbeam pattern is preserved by analyzing histological sections of a mouse brain. We demonstrated the feasibility of MRT using our developed setup. Microbeam radiation therapy (MRT) is a still pre-clinical form of spatially fractionated radiotherapy, which uses an array of micrometer-wide, planar beams of X-ray radiation. The dose modulation in MRT has proven effective in the treatment of tumors while being well tolerated by normal tissue. Research on understanding the underlying biological mechanisms mostly requires large third-generation synchrotrons. In this study, we aimed to develop a preclinical treatment environment that would allow MRT independent of synchrotrons. We built a compact microbeam setup for pre-clinical experiments within a small animal irradiator and present in vivo MRT application, including treatment planning, dosimetry, and animal positioning. The brain of an immobilized mouse was treated with MRT, excised, and immunohistochemically stained against γ H2AX for DNA double-strand breaks. We developed a comprehensive treatment planning system by adjusting an existing dose calculation algorithm to our setup and attaching it to the open-source software 3D-Slicer. Predicted doses in treatment planning agreed within 10% with film dosimetry readings. We demonstrated the feasibility of MRT exposures in vivo at a compact source and showed that the microbeam pattern is observable in histological sections of a mouse brain. The platform developed in this study will be used for pre-clinical research of MRT. [ABSTRACT FROM AUTHOR]

Synchrotron Microbeam Radiation Therapy (MRT) is an innovative technique that spatially segments the synchrotron radiation field for cancer treatment. A microbeam peak dose is often hundreds of times the dose in the valley (the sub-millimeter region between the peaks of the microbeams). Peak and valley doses vary with increasing depth in tissue which effects tumor dose coverage. It remains to be seen whether the peak or valley is the primary factor in MRT cancer control. This study investigates how unilateral MRT doses can be modulated using a bolus, and identifies the valley dose as a primary factor in MRT cancer control. Fischer rats bearing 9 L gliosarcoma tumors were irradiated with MRT at the Imaging and Medical Beam Line of the Australian Synchrotron. MRT valley doses of 8–15 Gy (250–1040 Gy peak doses) were used to treat tumors with and without a 5 mm dose-modulating bolus. Long-term survival depended on the valley dose primarily (92% correlation), and the use of the bolus reduced the variance in animal survival and improved to the mean survival of rats treated with MRT by 47% and 18% using 15 Gy and 8 Gy valley doses, respectively.

It has been shown lately that gold nanoparticles (AuNPs) and ionizing radiation (IR) have inhibitory effects on cancer cell migration while having promoting effects on normal cells' motility. Also, IR increases cancer cell adhesion with no significant effects on normal cells. In this study, synchrotron-based microbeam radiation therapy, as a novel pre-clinical radiotherapy protocol, is employed to investigate the effects of AuNPs on cell migration. Experiments were conducted utilizing synchrotron X-rays to investigate cancer and normal cell morphology and migration behaviour when they are exposed to synchrotron broad beams (SBB) and synchrotron microbeams (SMB). This in vitro study was conducted in two phases. In phase I two cancer cell lines – human prostate (DU145) and human lung (A549) – were exposed to various doses of SBB and SMB. Based on the phase I results, in phase II two normal cell lines were studied: human epidermal melanocytes (HEM) and human primary colon epithelial (CCD841), along with their respective cancerous counterparts, human primary melanoma (MM418-C1) and human colorectal adenocarcinoma (SW48). The results show that radiation-induced damage in cells' morphology becomes visible with SBB at doses greater than 50 Gy, and incorporating AuNPs increases this effect. Interestly, under the same conditions, no visible morphological changes were observed in the normal cell lines post-irradiation (HEM and CCD841). This can be attributed to the differences in cell metabolic and reactive oxygen species levels between normal and cancer cells. The outcome of this study highlights future applications of synchrotron-based radiotherapy, where it is possible to deliver extremely high doses to cancer tissues whilst preserving surrounding normal tissues from radiation-induced damage.

Simple Summary: This work describes the development of a fast and accurate machine learning (ML) 3D U-Net dose engine, trained with Monte Carlo (MC) radiation transport simulations, to calculate the dose in rat patients treated in Microbeam Radiation Therapy (MRT) preclinical studies at the Imaging and Medical Beamline at the Australian Synchrotron. Digital phantoms are created based on CT scans of sixteen rats and are augmented to obtain enough anatomical data. Augmented variations of the digital phantoms are then used to simulate with Geant4 the energy depositions of an MRT beam inside the phantoms with 15% (high-noise) and 2% (low-noise) statistical uncertainty. The high-noise MC simulations are used for ML model training and validation, while the low-noise ones for testing. The results show that the ML dose engine provides a satisfactory dose description in the tumor target and generates the dose maps in less than one second. Microbeam radiation therapy (MRT) utilizes coplanar synchrotron radiation beamlets and is a proposed treatment approach for several tumor diagnoses that currently have poor clinical treatment outcomes, such as gliosarcomas. Monte Carlo (MC) simulations are one of the most used methods at the Imaging and Medical Beamline, Australian Synchrotron to calculate the dose in MRT preclinical studies. The steep dose gradients associated with the 50 μ m-wide coplanar beamlets present a significant challenge for precise MC simulation of the dose deposition of an MRT irradiation treatment field in a short time frame. The long computation times inhibit the ability to perform dose optimization in treatment planning or apply online image-adaptive radiotherapy techniques to MRT. Much research has been conducted on fast dose estimation methods for clinically available treatments. However, such methods, including GPU Monte Carlo implementations and machine learning (ML) models, are unavailable for novel and emerging cancer radiotherapy options such as MRT. In this work, the successful application of a fast and accurate ML dose prediction model for a preclinical MRT rodent study is presented for the first time. The ML model predicts the peak doses in the path of the microbeams and the valley doses between them, delivered to the tumor target in rat patients. A CT imaging dataset is used to generate digital phantoms for each patient. Augmented variations of the digital phantoms are used to simulate with Geant4 the energy depositions of an MRT beam inside the phantoms with 15% (high-noise) and 2% (low-noise) statistical uncertainty. The high-noise MC simulation data are used to train the ML model to predict the energy depositions in the digital phantoms. The low-noise MC simulations data are used to test the predictive power of the ML model. The predictions of the ML model show an agreement within 3% with low-noise MC simulations for at least 77.6% of all predicted voxels (at least 95.9% of voxels containing tumor) in the case of the valley dose prediction and for at least 93.9% of all predicted voxels (100.0% of voxels containing tumor) in the case of the peak dose prediction. The successful use of high-noise MC simulations for the training, which are much faster to produce, accelerates the production of the training data of the ML model and encourages transfer of the ML model to different treatment modalities for other future applications in novel radiation cancer therapies. [ABSTRACT FROM AUTHOR]

It has been shown lately that gold nanoparticles (AuNPs) and ionizing radiation (IR) have inhibitory effects on cancer cell migration while having promoting effects on normal cells' motility. Also, IR increases cancer cell adhesion with no significant effects on normal cells. In this study, synchrotron-based microbeam radiation therapy, as a novel pre-clinical radiotherapy protocol, is employed to investigate the effects of AuNPs on cell migration. Experiments were conducted utilizing synchrotron X-rays to investigate cancer and normal cell morphology and migration behaviour when they are exposed to synchrotron broad beams (SBB) and synchrotron microbeams (SMB). This in vitro study was conducted in two phases. In phase I two cancer cell lines - human prostate (DU145) and human lung (A549) - were exposed to various doses of SBB and SMB. Based on the phase I results, in phase II two normal cell lines were studied: human epidermal melanocytes (HEM) and human primary colon epithelial (CCD841), along with their respective cancerous counterparts, human primary melanoma (MM418-C1) and human colorectal adenocarcinoma (SW48). The results show that radiation-induced damage in cells' morphology becomes visible with SBB at doses greater than 50 Gy, and incorporating AuNPs increases this effect. Interestly, under the same conditions, no visible morphological changes were observed in the normal cell lines post-irradiation (HEM and CCD841). This can be attributed to the differences in cell metabolic and reactive oxygen species levels between normal and cancer cells. The outcome of this study highlights future applications of synchrotron-based radiotherapy, where it is possible to deliver extremely high doses to cancer tissues whilst preserving surrounding normal tissues from radiation-induced damage. [ABSTRACT FROM AUTHOR]

Successful transition of synchrotron-based microbeam radiation therapy (MRT) from pre-clinical animal studies to human trials is dependent upon ensuring that there are sufficient and adequate measures in place for quality assurance purposes. Transmission detectors provide researchers and clinicians with a real-time quality assurance and beam-monitoring instrument to ensure safe and accurate dose delivery. In this work, the effect of transmission detectors of different thicknesses (10 and 375 µm) upon the photon energy spectra and dose deposition of spatially fractionated synchrotron radiation is quantified experimentally and by means of a dedicated Geant4 simulation study. The simulation and experimental results confirm that the presence of the 375 µm thick transmission detector results in an approximately 1–6% decrease in broad-beam and microbeam peak dose. The capability to account for the reduction in dose and change to the peak-to-valley dose ratio justifies the use of transmission detectors as thick as 375 µm in MRT provided that treatment planning systems are able to account for their presence. The simulation and experimental results confirm that the presence of the 10 µm thick transmission detector shows a negligible impact (

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. [ABSTRACT FROM AUTHOR]

Background: Microbeam and x‐ray FLASH radiation therapy are innovative concepts that promise reduced normal tissue toxicity in radiation oncology without compromising tumor control. However, currently only large third‐generation synchrotrons deliver acceptable x‐ray beam qualities and there is a need for compact, hospital‐based radiation sources to facilitate clinical translation of these novel treatment strategies. Purpose: We are currently setting up the first prototype of a line‐focus x‐ray tube (LFxT), a promising technology that may deliver ultra‐high dose rates (UHDRs) of more than 100 Gy/s from a table‐top source. The operation of the source in the heat capacity limit allows very high dose rates with micrometer‐sized focal spot widths. Here, we investigate concepts of effective heat management for the LFxT, a prerequisite for the performance of the source. Methods: For different focal spot widths, we investigated the temperature increase numerically with Monte Carlo simulations and finite element analysis (FEA). We benchmarked the temperature and thermal stresses at the focal spot against a commercial x‐ray tube with similar power characteristics. We assessed thermal loads at the vacuum chamber housing caused by scattering electrons in Monte Carlo simulations and FEA. Further, we discuss active cooling strategies and present a design of the rotating target. Results: Conventional focal spot widths led to a temperature increase dominated by heat conduction, while very narrow focal spots led to a temperature increase dominated by the heat capacity of the target material. Due to operation in the heat capacity limit, the temperature increase at the focal spot was lower than for the investigated commercial x‐ray tube. Hence, the thermal stress at the focal spot of the LFxT was considered uncritical. The target shaft and the vacuum chamber housing require active cooling to withstand the high heat loads. Conclusions: The heat capacity limit allows very high power densities at the focal spot of the LFxT and thus facilitates very high dose rates. Numerical simulations demonstrated that the heat load imparted by scattering electrons requires active cooling. [ABSTRACT FROM AUTHOR]

Successful transition of synchrotron‐based microbeam radiation therapy (MRT) from pre‐clinical animal studies to human trials is dependent upon ensuring that there are sufficient and adequate measures in place for quality assurance purposes. Transmission detectors provide researchers and clinicians with a real‐time quality assurance and beam‐monitoring instrument to ensure safe and accurate dose delivery. In this work, the effect of transmission detectors of different thicknesses (10 and 375 µm) upon the photon energy spectra and dose deposition of spatially fractionated synchrotron radiation is quantified experimentally and by means of a dedicated Geant4 simulation study. The simulation and experimental results confirm that the presence of the 375 µm thick transmission detector results in an approximately 1–6% decrease in broad‐beam and microbeam peak dose. The capability to account for the reduction in dose and change to the peak‐to‐valley dose ratio justifies the use of transmission detectors as thick as 375 µm in MRT provided that treatment planning systems are able to account for their presence. The simulation and experimental results confirm that the presence of the 10 µm thick transmission detector shows a negligible impact (<0.5%) on the photon energy spectra, dose delivery and microbeam structure for both broad‐beam and microbeam cases. Whilst the use of 375 µm thick detectors would certainly be appropriate, based upon the idea of best practice the authors recommend that 10 µm thick transmission detectors of this sort be utilized as a real‐time quality assurance and beam‐monitoring tool during MRT. [ABSTRACT FROM AUTHOR]

Background and purpose: Microbeam radiotherapy (MRT) is a preclinical concept in radiation oncology with arrays of alternating micrometer-wide high-dose peaks and low-dose valleys. Experiments demonstrated a superior normal tissue sparing at similar tumor control rates with MRT compared to conventional radiotherapy. Possible clinical applications are currently limited to large third-generation synchrotrons. Here, we investigated the line-focus X-ray tube as an alternative microbeam source. Materials and methods: We developed a concept for a high-voltage supply and an electron source. In Monte Carlo simulations, we assessed the influence of X-ray spectrum, focal spot size, electron incidence angle, and photon emission angle on the microbeam dose distribution. We further assessed the dose distribution of microbeam arc therapy and suggested to interpret this complex dose distribution by equivalent uniform dose. Results: An adapted modular multi-level converter can supply high-voltage powers in the megawatt range for a few seconds. The electron source with a thermionic cathode and a quadrupole can generate an eccentric, high-power electron beam of several 100 keV energy. Highest dose rates and peak-to-valley dose ratios (PVDRs) were achieved for an electron beam impinging perpendicular onto the target surface and a focal spot smaller than the microbeam cross-section. The line-focus X-ray tube simulations demonstrated PVDRs above 20. Conclusion: The line-focus X-ray tube is a suitable compact source for clinical MRT. We demonstrated its technical feasibility based on state-of-the-art high-voltage and electron-beam technology. Microbeam arc therapy is an effective concept to increase the target-to-entrance dose ratio of orthovoltage microbeams.

Objective. Detectors that can provide accurate dosimetry for microbeam radiation therapy (MRT) must possess intrinsic radiation hardness, a high dynamic range, and a micron-scale spatial resolution. In this work we characterize hydrogenated amorphous silicon detectors for MRT dosimetry, presenting a novel combination of flexible, ultra-thin and radiation-hard features. Approach. Two detectors are explored: an n-type/intrinsic/p-type planar diode (NIP) and an NIP with an additional charge selective layer (NIP + CSC). Results. The sensitivity of the NIP + CSC detector was greater than the NIP detector for all measurement conditions. At 1 V and 0 kGy under the 3T Cu-Cu synchrotron broadbeam, the NIP + CSC detector sensitivity of (7.76 ± 0.01) pC cGy -1 outperformed the NIP detector sensitivity of (3.55 ± 0.23) pC cGy -1 by 219%. The energy dependence of both detectors matches closely to the attenuation coefficient ratio of silicon against water. Radiation damage measurements of both detectors out to 40 kGy revealed a higher radiation tolerance in the NIP detector compared to the NIP + CSC (17.2% and 33.5% degradations, respectively). Percentage depth dose profiles matched the PTW microDiamond detector's performance to within ±6% for all beam filtrations except in 3T Al-Al due to energy dependence. The 3T Cu-Cu microbeam field profile was reconstructed and returned microbeam width and peak-to-peak values of (51 ± 1) μ m and (405 ± 5) μ m, respectively. The peak-to-valley dose ratio was measured as a function of depth and agrees within error to the values obtained with the PTW microDiamond. X-ray beam induced charge mapping of the detector revealed minimal dose perturbations from extra-cameral materials. Significance. The detectors are comparable to commercially available dosimeters for quality assurance in MRT. With added benefits of being micron-sized and possessing a flexible water-equivalent substrate, these detectors are attractive candidates for quality assurance, in-vivo dosimetry and in-line beam monitoring for MRT and FLASH therapy., (Creative Commons Attribution license.)

Synchrotron microbeam radiation therapy is a promising pre-clinical radiation treatment modality; however, it comes with many technical challenges. This study describes the image guidance protocol used for Australia's first long-term pre-clinical MRT treatment of rats bearing 9L gliosarcoma tumours. The protocol utilises existing infrastructure available at the Australian Synchrotron and the adjoining Monash Biomedical Imaging facility. The protocol is designed and optimised to treat small animals utilising high-resolution clinical CT for patient specific tumour identification, coupled with conventional radiography, using the recently developed SyncMRT program for image guidance. Dosimetry performed in small animal phantoms shows patient dose is comparable to standard clinical doses, with a CT associated dose of less than 1.39 c Gy and a planar radiograh dose of less than 0.03 c Gy. Experimental validation of alignment accuracy with radiographic film demonstrates end to end accuracy of less than ± 0.34 m m in anatomical phantoms. Histological analysis of tumour-bearing rats treated with microbeam radiation therapy verifies that tumours are targeted well within applied treatment margins. To date, this technique has been used to treat 35 tumour-bearing rats. [ABSTRACT FROM AUTHOR]

Spatially fractionated ultra‐high‐dose‐rate beams used during microbeam radiation therapy (MRT) have been shown to increase the differential response between normal and tumour tissue. Quality assurance of MRT requires a dosimeter that possesses tissue equivalence, high radiation tolerance and spatial resolution. This is currently an unsolved challenge. This work explored the use of a 500 nm thick organic semiconductor for MRT dosimetry on the Imaging and Medical Beamline at the Australian Synchrotron. Three beam filters were used to irradiate the device with peak energies of 48, 76 and 88 keV with respective dose rates of 3668, 500 and 209 Gy s−1. The response of the device stabilized to 30% efficiency after an irradiation dose of 30 kGy, with a 0.5% variation at doses of 35 kGy and higher. The calibration factor after pre‐irradiation was determined to be 1.02 ± 0.005 µGy per count across all three X‐ray energy spectra, demonstrating the unique advantage of using tissue‐equivalent materials for dosimetry. The percentage depth dose curve was within ±5% of the PTW microDiamond detector. The broad beam was fractionated into 50 microbeams (50 µm FHWM and 400 µm centre‐to‐centre distance). For each beam filter, the FWHMs of all 50 microbeams were measured to be 51 ± 1.4, 53 ± 1.4 and 69 ± 1.9 µm, for the highest to lowest dose rate, respectively. The variation in response suggested the photodetector possessed dose‐rate dependence. However, its ability to reconstruct the microbeam profile was affected by the presence of additional dose peaks adjacent to the one generated by the X‐ray microbeam. Geant4 simulations proved that the additional peaks were due to optical photons generated in the barrier film coupled to the sensitive volume. The simulations also confirmed that the amplitude of the additional peak in comparison with the microbeam decreased for spectra with lower peak energies, as observed in the experimental data. The material packaging can be optimized during fabrication by solution processing onto a flexible substrate with a non‐fluorescent barrier film. With these improvements, organic photodetectors show promising prospects as a cost‐effective high spatial resolution tissue‐equivalent flexible dosimeter for synchrotron radiation fields. [ABSTRACT FROM AUTHOR]

γH2AX biodosimetry has been proposed as an alternative dosimetry method for microbeam radiation therapy (MRT) because conventional dosimeters, such as ionization chambers, lack the spatial resolution required to accurately measure the MRT valley dose. Here we investigated whether γH2AX biodosimetry should be used to measure the biological valley dose of MRT-irradiated mammalian cells. We irradiated human skin fibroblasts and mouse skin flaps with synchrotron MRT and broad beam (BB) radiation. BB doses of 1–5 Gy were used to generate a calibration curve in order to estimate the biological MRT valley dose using the γH2AX assay. Our key finding was that MRT induced a non-linear dose response compared to BB, where doses 2–3 times greater showed the same level of DNA DSB damage in the valley in cell and tissue studies. This indicates that γH2AX may not be an appropriate biodosimeter to estimate the biological valley doses of MRT-irradiated samples. We also established foci yields of 5.9 ± 0. 04 and 27.4 ± 2. 5 foci/cell/Gy in mouse skin tissue and human fibroblasts respectively, induced by BB. Using Monte Carlo simulations, a linear dose response was seen in cell and tissue studies and produced predicted peak-to-valley dose ratios (PVDRs) of ∼30 and ∼107 for human fibroblasts and mouse skin tissue respectively. Our report highlights novel MRT radiobiology, attempts to explain why γH2AX may not be an appropriate biodosimeter and suggests further studies aimed at revealing the biological and cellular communication mechanisms that drive the normal tissue sparing effect, which is characteristic of MRT. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Resistance to radiotherapy is frequently encountered in patients with glioblastoma multiforme. It is caused at least partially by the high glutathione content in the tumour tissue. Therefore, the administration of the glutathione synthesis inhibitor Buthionine-SR-Sulfoximine (BSO) should increase survival time. Methods BSO was tested in combination with an experimental synchrotron-based treatment, microbeam radiation therapy (MRT), characterized by spatially and periodically alternating microscopic dose distribution. One hundred thousand F98 glioma cells were injected into the right cerebral hemisphere of adult male Fischer rats to generate an orthotopic small animal model of a highly malignant brain tumour in a very advanced stage. Therapy was scheduled for day 13 after tumour cell implantation. At this time, 12.5% of the animals had already died from their disease. The surviving 24 tumour-bearing animals were randomly distributed in three experimental groups: subjected to MRT alone (Group A), to MRT plus BSO (Group B) and tumour-bearing untreated controls (Group C). Thus, half of the irradiated animals received an injection of 100 μM BSO into the tumour two hours before radiotherapy. Additional tumour-free animals, mirroring the treatment of the tumour-bearing animals, were included in the experiment. MRT was administered in bi-directional mode with arrays of quasi-parallel beams crossing at the tumour location. The width of the microbeams was ≈28 μm with a center-to-center distance of ≈400 μm, a peak dose of 350 Gy, and a valley dose of 9 Gy in the normal tissue and 18 Gy at the tumour location; thus, the peak to valley dose ratio (PVDR) was 31. Results After tumour-cell implantation, otherwise untreated rats had a mean survival time of 15 days. Twenty days after implantation, 62.5% of the animals receiving MRT alone (group A) and 75% of the rats given MRT + BSO (group B) were still alive. Thirty days after implantation, survival was 12.5% in Group A and 62.5% in Group B. There were no survivors on or beyond day 35 in Group A, but 25% were still alive in Group B. Thus, rats which underwent MRT with adjuvant BSO injection experienced the largest survival gain. Conclusions In this pilot project using an orthotopic small animal model of advanced malignant brain tumour, the injection of the glutathione inhibitor BSO with MRT significantly increased mean survival time.

Purpose: X‐ray microbeam radiation therapy is a preclinical concept for tumor treatment promising tissue sparing and enhanced tumor control. With its spatially separated, periodic micrometer‐sized pattern, this method requires a high dose rate and a collimated beam typically available at large synchrotron radiation facilities. To treat small animals with microbeams in a laboratory‐sized environment, we developed a dedicated irradiation system at the Munich Compact Light Source (MuCLS). Methods: A specially made beam collimation optic allows to increase x‐ray fluence rate at the position of the target. Monte Carlo simulations and measurements were conducted for accurate microbeam dosimetry. The dose during irradiation is determined by a calibrated flux monitoring system. Moreover, a positioning system including mouse monitoring was built. Results: We successfully commissioned the in vivo microbeam irradiation system for an exemplary xenograft tumor model in the mouse ear. By beam collimation, a dose rate of up to 5.3 Gy/min at 25 keV was achieved. Microbeam irradiations using a tungsten collimator with 50 μm slit size and 350 μm center‐to‐center spacing were performed at a mean dose rate of 0.6 Gy/min showing a high peak‐to‐valley dose ratio of about 200 in the mouse ear. The maximum circular field size of 3.5 mm in diameter can be enlarged using field patching. Conclusions: This study shows that we can perform in vivo microbeam experiments at the MuCLS with a dedicated dosimetry and positioning system to advance this promising radiation therapy method at commercially available compact microbeam sources. Peak doses of up to 100 Gy per treatment seem feasible considering a recent upgrade for higher photon flux. The system can be adapted for tumor treatment in different animal models, for example, in the hind leg. [ABSTRACT FROM AUTHOR]

Purpose: Current techniques and procedures for dosimetry in microbeams typically rely on radiochromic film or small volume ionization chambers for validation and quality assurance in 2D and 1D, respectively. Whilst well characterized for clinical and preclinical radiotherapy, these methods are noninstantaneous and do not provide real time profile information. The objective of this work is to determine the suitability of the newly developed vM1212 detector, a pixelated CMOS (complementary metal‐oxide‐semiconductor) imaging sensor, for in situ and in vivo verification of x‐ray microbeams. Methods: Experiments were carried out on the vM1212 detector using a 220 kVp small animal radiation research platform (SARRP) at the Helmholtz Centre Munich. A 3 x 3 cm2 square piece of EBT3 film was placed on top of a marked nonfibrous card overlaying the sensitive silicon of the sensor. One centimeter of water equivalent bolus material was placed on top of the film for build‐up. The response of the detector was compared to an Epson Expression 10000XL flatbed scanner using FilmQA Pro with triple channel dosimetry. This was also compared to a separate exposure using 450 µm of silicon as a surrogate for the detector and a Zeiss Axio Imager 2 microscope using an optical microscopy method of dosimetry. Microbeam collimator slits with range of nominal widths of 25, 50, 75, and 100 µm were used to compare beam profiles and determine sensitivity of the detector and both film measurements to different microbeams. Results: The detector was able to measure peak and valley profiles in real‐time, a significant reduction from the 24 hr self‐development required by the EBT3 film. Observed full width at half maximum (FWHM) values were larger than the nominal slit widths, ranging from 130 to 190 µm due to divergence. Agreement between the methods was found for peak‐to‐valley dose ratio (PVDR), peak to peak separation and FWHM, but a difference in relative intensity of the microbeams was observed between the detectors. Conclusions: The investigation demonstrated that pixelated CMOS sensors could be applied to microbeam radiotherapy for real‐time dosimetry in the future, however the relatively large pixel pitch of the vM1212 detector limit the immediate application of the results. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Synchrotron microbeam radiation therapy is a promising pre-clinical radiation treatment modality; however, it comes with many technical challenges. This study describes the image guidance protocol used for Australia’s first long-term pre-clinical MRT treatment of rats bearing 9L gliosarcoma tumours. The protocol utilises existing infrastructure available at the Australian Synchrotron and the adjoining Monash Biomedical Imaging facility. The protocol is designed and optimised to treat small animals utilising high-resolution clinical CT for patient specific tumour identification, coupled with conventional radiography, using the recently developed SyncMRT program for image guidance. Dosimetry performed in small animal phantoms shows patient dose is comparable to standard clinical doses, with a CT associated dose of less than 1.39cGy and a planar radiograh dose of less than 0.03cGy. Experimental validation of alignment accuracy with radiographic film demonstrates end to end accuracy of less than ±0.34mm in anatomical phantoms. Histological analysis of tumour-bearing rats treated with microbeam radiation therapy verifies that tumours are targeted well within applied treatment margins. To date, this technique has been used to treat 35 tumour-bearing rats.

Abstract Background Normal tissue toxicity is the dose-limiting side effect of radiotherapy. Spatial fractionation irradiation techniques, like microbeam radiotherapy (MRT), have shown promising results in sparing the normal brain tissue. Most MRT studies have been conducted at synchrotron facilities. With the aim to make this promising treatment more available, we have built the first desktop image-guided MRT device based on carbon nanotube x-ray technology. In the current study, our purpose was to evaluate the effects of MRT on the rodent normal brain tissue using our device and compare it with the effect of the integrated equivalent homogenous dose. Methods Twenty-four, 8-week-old male C57BL/6 J mice were randomly assigned to three groups: MRT, broad-beam (BB) and sham. The hippocampal region was irradiated with two parallel microbeams in the MRT group (beam width = 300 μm, center-to-center = 900 μm, 160 kVp). The BB group received the equivalent integral dose in the same area of their brain. Rotarod, marble burying and open-field activity tests were done pre- and every month post-irradiation up until 8 months to evaluate the cognitive changes and potential irradiation side effects on normal brain tissue. The open-field activity test was substituted by Barnes maze test at 8th month. A multilevel model, random coefficients approach was used to evaluate the longitudinal and temporal differences among treatment groups. Results We found significant differences between BB group as compared to the microbeam-treated and sham mice in the number of buried marble and duration of the locomotion around the open-field arena than shams. Barnes maze revealed that BB mice had a lower capacity for spatial learning than MRT and shams. Mice in the BB group tend to gain weight at the slower pace than shams. No meaningful differences were found between MRT and sham up until 8-month follow-up using our measurements. Conclusions Applying MRT with our newly developed prototype compact CNT-based image-guided MRT system utilizing the current irradiation protocol can better preserve the integrity of normal brain tissue. Consequently, it enables applying higher irradiation dose that promises better tumor control. Further studies are required to evaluate the full extent effects of this novel modality.

• Microbeam radiation therapy is an innovative radiotherapy technique. • Radiocromic film dosimetry at micrometric scale is fundamental. • Comparison between a microdensitometer and an optical microscope for film dosimetry. • Definition of film dosimetry protocol for microbeam dose analysis. • The microscope allows more precise, accurate and reliable dose evaluation. 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. 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). 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. 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. [ABSTRACT FROM AUTHOR]

Purpose: The removal of Cherenkov light in an optical dosimetry system is an important process to ensure accurate dosimetry without compromising spatial resolution. Many solutions have been presented in the literature, each with advantages and disadvantages. We present a methodology to remove Cherenkov light from a scintillator fiber optic dosimeter in a pulsed megavoltage x‐ray beam using the temporal waveform across the pulse. Methods: A sample waveform of Cherenkov light can be measured by exposing only the fiber to the beam. By assuming that the Cherenkov waveform closely matches the intensity of incident radiation, this waveform can be convoluted with the instantaneous scintillation response function to generate an expected scintillation signal. By finding the least‐squares fit between these two functions and the experimental data, the estimated Cherenkov contribution can be subtracted off the net signal. This can be applied for arbitrarily complex Cherenkov waveforms (within the 2 ns timing resolution of the data acquisition), and in fact, the results suggest more fluctuations in the waveforms provide a better fit to data. Results: Four beam profiles for different field sizes and energies were found with this method. They closely matched references data measured with ionization chamber with average differences across the beam no more than 4%. Noisy waveforms are assumed to be the primary cause of differences between the analyzed scintillator and IC results. We propose methods for improving the results and optimizing the data acquisition and analysis processes. Conclusions: These results demonstrate that it is possible and effective with a single probe to use function fitting of expected data to experimental to remove a complicated Cherenkov signal from the net light signal in pulsed‐beam optical dosimetry. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of death worldwide. External beam radiation therapy is one of the most important modalities for the treatment of cancers. Synchrotron microbeam radiation therapy (MRT) is a novel pre‐clinical therapy that uses highly spatially fractionated X‐ray beams to target tumours, allowing doses much higher than conventional radiotherapies to be delivered. A dosimeter with a high spatial resolution is required to provide the appropriate quality assurance for MRT. This work presents a plastic scintillator fibre optic dosimeter with a one‐dimensional spatial resolution of 20 µm, an improvement on the dosimeter with a resolution of 50 µm that was demonstrated in previous work. The ability of this probe to resolve microbeams of width 50 µm has been demonstrated. The major limitations of this method were identified, most notably the low‐light signal resulting from the small sensitive volume, which made valley dose measurements very challenging. A titanium‐based reflective paint was used as a coating on the probe to improve the light collection, but a possible effect of the high‐Z material on the probes water‐equivalence has been identified. The effect of the reflective paint was a 28.5 ± 4.6% increase in the total light collected; it did not affect the shape of the depth‐dose profile, nor did it explain an over‐response observed when used to probe at low depths, when compared with an ionization chamber. With improvements to the data acquisition, this probe design has the potential to provide a water‐equivalent, inexpensive dosimetry tool for MRT. [ABSTRACT FROM AUTHOR]

Microbeam radiation therapy has demonstrated superior normal tissue sparing properties compared to broadbeam radiation fields. The ratio of the microbeam peak dose to the valley dose (PVDR), which is dependent on the X-ray energy/spectrum and geometry, should be maximised for an optimal therapeutic ratio. Simulation studies in the literature report the optimal energy for MRT based on the PVDR. However, most of these studies have considered different microbeam geometries to that at the Imaging and Medical Beamline (50 μm beam width with a spacing of 400 μm). We present the first fully experimental investigation of the energy dependence of PVDR and microbeam penumbra. Using monochromatic X-ray energies in the range 40–120 keV the PVDR was shown to increase with increasing energy up to 100 keV before plateauing. PVDRs measured for pink beams were consistently higher than those for monochromatic energies similar or equivalent to the average energy of the spectrum. The highest PVDR was found for a pink beam average energy of 124 keV. Conversely, the microbeam penumbra decreased with increasing energy before plateauing for energies above 90 keV. The effect of bone on the PVDR was investigated at energies 60, 95 and 120 keV. At depths greater than 20 mm beyond the bone/water interface there was almost no effect on the PVDR. In conclusion, the optimal energy range for MRT at IMBL is 90–120 keV, however when considering the IMBL flux at different energies, a spectrum with 95 keV weighted average energy was found to be the best compromise. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the influence of energy spectra, mesh sizes, high Z element on dose and PVDR in Microbeam Radiation Therapy (MRT) based on 1-D analogy-mouse-head-model (1-D MHM) and 3-D voxel-mouse-head-phantom (3-D VMHP) by Monte Carlo simulation. Methods A Microbeam-Array-Source-Model was implemented into EGSnrc/DOSXYZnrc. The microbeam size is assumed to be 25 μm, 50 μm or 75 μm in thickness and fixed 1 mm in height with 200 μm c-t-c. The influence of the energy spectra of ID17@ESRF and BMIT@CLS were investigated. The mesh size was optimized. PVDR in 1-D MHM and 3-D VMHP was compared with the homogeneous water phantom. The arc influence of 3-D VMHP filled with water (3-D VMHWP) was compared with the rectangle phantom. Results PVDR of the lower BMIT@CLS spectrum is 2.4 times that of ID17@ESRF for lower valley dose. The optimized mesh is 5 µm for 25 µm, and 10 µm for 50 µm and 75 µm microbeams with 200 µm c-t-c. A 500 μm skull layer could make PVDR difference up to 62.5% for 1-D MHM. However this influence is limited (<5%) for the farther homogeneous media (e.g. 600 µm). The peak dose uniformity of 3-D VMHP at the same depth could be up to 8% for 1.85 mm × 1 mm irradiation field, whereas that of 3-D VMHWP is <1%. The high Z element makes the dose uniformity enhance in target. The surface arc could affect the superficial PVDR (from 44% to 21% in 0.2 mm depth), whereas this influence is limited for the more depth (<1%). Conclusion An accurate MRT dose calculation algorithm should include the influence of 3-D heterogeneous media. [ABSTRACT FROM AUTHOR]

Preclinical investigations of thick microbeams show these to be feasible for use in radiotherapeutic dose delivery. To create the beams we access a radiotherapy x-ray tube that is familiarly used within a conventional clinical environment, coupling this with beam-defining grids. Beam characterisation, both single and in the form of arrays, has been by use of both MCNP simulation and direct Gafchromic EBT film dosimetry. As a first step in defining optimal exit-beam profiles over a range of beam energies, simulation has been made of the x-ray tube and numbers of beam-defining parallel geometry grids, the latter being made to vary in thickness, slit separation and material composition. For a grid positioned after the treatment applicator, and of similar design to those used in the first part of the study, MCNP simulation and Gafchromic EBT film were then applied in examining the resultant radiation profiles. MCNP simulations and direct dosimetry both show useful thick microbeams to be produced from the x-ray tube, with peak-to-valley dose ratios (PVDRs) in the approximate range 8.8–13.9. Although the potential to create thick microbeams using radiotherapy x-ray tubes and a grid has been demonstrated, Microbeam Radiation Therapy (MRT) would still need to be approved outside of the preclinical setting, a viable treatment technique of clinical interest needing to benefit for instance from substantially improved x-ray tube dose rates. [ABSTRACT FROM AUTHOR]

Background: Normal tissue toxicity is the dose-limiting side effect of radiotherapy. Spatial fractionation irradiation techniques, like microbeam radiotherapy (MRT), have shown promising results in sparing the normal brain tissue. Most MRT studies have been conducted at synchrotron facilities. With the aim to make this promising treatment more available, we have built the first desktop image-guided MRT device based on carbon nanotube x-ray technology. In the current study, our purpose was to evaluate the effects of MRT on the rodent normal brain tissue using our device and compare it with the effect of the integrated equivalent homogenous dose.Methods: Twenty-four, 8-week-old male C57BL/6 J mice were randomly assigned to three groups: MRT, broad-beam (BB) and sham. The hippocampal region was irradiated with two parallel microbeams in the MRT group (beam width = 300 μm, center-to-center = 900 μm, 160 kVp). The BB group received the equivalent integral dose in the same area of their brain. Rotarod, marble burying and open-field activity tests were done pre- and every month post-irradiation up until 8 months to evaluate the cognitive changes and potential irradiation side effects on normal brain tissue. The open-field activity test was substituted by Barnes maze test at 8th month. A multilevel model, random coefficients approach was used to evaluate the longitudinal and temporal differences among treatment groups.Results: We found significant differences between BB group as compared to the microbeam-treated and sham mice in the number of buried marble and duration of the locomotion around the open-field arena than shams. Barnes maze revealed that BB mice had a lower capacity for spatial learning than MRT and shams. Mice in the BB group tend to gain weight at the slower pace than shams. No meaningful differences were found between MRT and sham up until 8-month follow-up using our measurements.Conclusions: Applying MRT with our newly developed prototype compact CNT-based image-guided MRT system utilizing the current irradiation protocol can better preserve the integrity of normal brain tissue. Consequently, it enables applying higher irradiation dose that promises better tumor control. Further studies are required to evaluate the full extent effects of this novel modality. [ABSTRACT FROM AUTHOR]

Microbeam radiation therapy (MRT) is a promising radiotherapy modality that uses arrays of spatially fractionated micrometre-sized beams of synchrotron radiation to irradiate tumours. Routine dosimetry quality assurance (QA) prior to treatment is necessary to identify any changes in beam condition from the treatment plan, and is undertaken using solid homogeneous phantoms. Solid phantoms are designed for, and routinely used in, megavoltage X-ray beam radiation therapy. These solid phantoms are not necessarily designed to be water-equivalent at low X-ray energies, and therefore may not be suitable for MRT QA. This work quantitatively determines the most appropriate solid phantom to use in dosimetric MRT QA. Simulated dose profiles of various phantom materials were compared with those calculated in water under the same conditions. The phantoms under consideration were RMI457 Solid Water (Gammex-RMI, Middleton, WI, USA), Plastic Water (CIRS, Norfolk, VA, USA), Plastic Water DT (CIRS, Norfolk, VA, USA), PAGAT (CIRS, Norfolk, VA, USA), RW3 Solid Phantom (PTW Freiburg, Freiburg, Germany), PMMA, Virtual Water (Med-Cal, Verona, WI, USA) and Perspex. RMI457 Solid Water and Virtual Water were found to be the best approximations for water in MRT dosimetry (within ±3% deviation in peak and 6% in valley). RW3 and Plastic Water DT approximate the relative dose distribution in water (within ±3% deviation in the peak and 5% in the valley). PAGAT, PMMA, Perspex and Plastic Water are not recommended to be used as phantoms for MRT QA, due to dosimetric discrepancies greater than 5%. [ABSTRACT FROM AUTHOR]

Purpose A high resolution, water equivalent, optical and passive x-ray dosimeter has been constructed using plastic scintillator and optical fiber. This dosimeter has a peak edge-on spatial resolution of 100 μm in one dimension, with a 10 μm resolution dosimeter under investigation. The dosimeter design has a potential application in synchrotron x-ray microbeam radiation therapy where a high resolution is vital for accurate dose measurements and quality assurance. Methods BC-400 plastic scintillator, of thickness 100 μm, was optically coupled to an optical fiber with core diameter 1 mm. The end was coated in optical paint to improve sensitivity. An identical fiber was made without the scintillator to measure the background Cherenkov radiation induced in the fiber, to allow background signal subtraction. The light captured by the fibers was measured by PMTs. The probe system was exposed to a 6 MV, 10 × 10 cm2 LINAC x-ray field and the beam profile was measured at 100 cm, as well as the depth dose profile. Results The measured profiles matched well with ionisation chamber data. Important beam parameters such as penumbra width and percent depth dose at various depths matched the ionisation chamber data, within uncertainty. Conclusions This work demonstrates that high resolutions can be achieved with a scintillation and optical fiber system. The probe is water-equivalent, passive, energy independent, radiation hard and inexpensive, making it ideal for further improvements for use with microbeam radiation therapy. [ABSTRACT FROM AUTHOR]

Microbeam radiotherapy (MRT) is a novel concept in radiation oncology with arrays of alternating micrometer-wide high-dose peaks and low-dose valleys. Preclinical experiments have shown a lower normal tissue toxicity for MRT with similar tumor control rates compared to conventional radiotherapy. A promising candidate for the demanded compact radiation source is the line-focus x-ray tube. Here, we present the setup of a prototype for an electron accelerator being able to provide a suitable x-ray beam for the tube. Several beam dynamic calculations and simulations were performed concerning particle tracking, thermal and electrostatic properties of the electron source, resulting in a proper beamline, including the cathode, the pierce electrode (PE) and the focusing magnets. These parts are discussed separately. The simulations showed that a rectangular cathode with a small width of 0.4 mm is mandatory. To quickly shut down the electron beam, an additional voltage of -600 V must be applied to the PE. Moreover, the electric field inside the vacuum chamber stays below 10 MV m−1 to minimize the risk of field emission. The thermal simulation validates a small displacement of 0.1 mm of the heated cathode with respect to the PE, which must be considered during manufacturing of the cathode-PE assembly. The simulations lead to an adequate choice of cathode, electrodes and beamline to achieve the required focal spot of 0. 05 × 20 mm 2 with a beam current of 0.3 A and an electron energy of 300 keV. With this setup first MRT experiments with high dose rates up to 10 Gy s−1 can be executed. • Line-focus x-ray tubes are suitable for clinical microbeam radiation therapy (MRT) with very high dose rates. • With tracking simulations, a suitable setup for an electron source and beamline was found. • Additional electrostatic simulations ensure fields sufficiently low to avoid a field breakdown. • Thermal simulations identified mechanical displacements after heating up the cathode, which must be compensated. [ABSTRACT FROM AUTHOR]

Purpose: Microbeam radiation therapy is an innovative treatment approach in radiation therapy that uses arrays of a few tens of micrometer wide and a few hundreds of micrometer spaced planar x-ray beams as treatment fields. In preclinical studies these fields efficiently eradicated tumors while normal tissue could effectively be spared. However, development and clinical application of microbeam radiation therapy is impeded by a lack of suitable small scale sources. Until now, only large synchrotrons provide appropriate beam properties for the production of microbeams. Methods: In this work, a conventional x-ray tube with a small focal spot and a specially designed collimator are used to produce microbeams for preclinical research. The applicability of the developed source is demonstrated in a pilot in vitro experiment. The properties of the produced radiation field are characterized by radiochromic film dosimetry. Results: 50 μm wide and 400 µm spaced microbeams were produced in a 20×20 mm² sized microbeam field. The peak to valley dose ratio ranged from 15.5 to 30, which is comparable to values obtained at synchrotrons. A dose rate of up to 300 mGy/s was achieved in the microbeam peaks. Analysis of DNA double strand repair and cell cycle distribution after in vitro exposures of pancreatic cancer cells (Panc1) at the x-ray tube and the European Synchrotron leads to similar results. In particular, a reduced G2 cell cycle arrest is observed in cells in the microbeam peak region. Conclusions: At its current stage, the source is restricted to in vitro applications. However, moderate modifications of the setup may soon allow in vivo research in mice and rats. [ABSTRACT FROM AUTHOR]

Microbeam Radiation Therapy (MRT) exploits tumour selectivity and normal tissue sparing with spatially fractionated kilovoltage X-ray microbeams through the dose volume effect. Experimental measurements with Ta 2 O 5 nanoparticles (NPs) in 9L gliosarcoma treated with MRT at the Australian Synchrotron, increased the treatment efficiency. Ta 2 O 5 NPs were observed to form shells around cell nuclei which may be the reason for their efficiency in MRT. In this article, our experimental observation of NP shell formation is the basis of a Geant4 radiation transport study to characterise dose enhancement by Ta 2 O 5 NPs in MRT. Our study showed that NP shells enhance the physical dose depending microbeam energy and their location relative to a single microbeam. For monochromatic microbeam energies below ∼70 keV, NP shells show highly localised dose enhancement due to the short range of associated secondary electrons. Low microbeam energies indicate better targeted treatment by allowing higher microbeam doses to be administered to tumours and better exploit the spatial fractionation related selectivity observed with MRT. For microbeam energies above ∼100 keV, NP shells extend the physical dose enhancement due to longer-range secondary electrons. Again, with NPs selectively internalised, the local effectiveness of MRT is expected to increase in the tumour. Dose enhancement produced by the shell aggregate varied more significantly in the cell population, depending on its location, when compared to a homogeneous NP distribution. These combined simulation and experimental data provide first evidence for optimising MRT through the incorporation of newly observed Ta 2 O 5 NP distributions within 9L cancer cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 imageguided MRT from multiple ports to large animals during future veterinary trials. [ABSTRACT FROM AUTHOR]