Chalcone JAI‐51 improves efficacy of synchrotron microbeam radiation therapy of brain tumors

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.     

Comparison of phantom materials for use in quality assurance of microbeam radiation therapy

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%.     

Synchrotron X‐ray microbeam dosimetry with a 20 micrometre resolution scintillator fibre‐optic dosimeter

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.     

The first microbeam synchrotron X‐ray fluorescence beamline at the Siam Photon Laboratory

The first microbeam synchrotron X‐ray fluorescence (µ‐SXRF) beamline using continuous synchrotron radiation from Siam Photon Source has been constructed and commissioned as of August 2011. Utilizing an X‐ray capillary half‐lens allows synchrotron radiation from a 1.4 T bending magnet of the 1.2 GeV electron storage ring to be focused from a few millimeters‐sized beam to a micrometer‐sized beam. This beamline was originally designed for deep X‐ray lithography (DXL) and was one of the first two operational beamlines at this facility. A modification has been carried out to the beamline in order to additionally enable µ‐SXRF and synchrotron X‐ray powder diffraction (SXPD). Modifications included the installation of a new chamber housing a Si(111) crystal to extract 8 keV synchrotron radiation from the white X‐ray beam (for SXPD), a fixed aperture and three gate valves. Two end‐stations incorporating optics and detectors for µ‐SXRF and SXPD have then been installed immediately upstream of the DXL station, with the three techniques sharing available beam time. The µ‐SXRF station utilizes a polycapillary half‐lens for X‐ray focusing. This optic focuses X‐ray white beam from 5 mm × 2 mm (H × V) at the entrance of the lens down to a diameter of 100 µm FWHM measured at a sample position 22 mm (lens focal point) downstream of the lens exit. The end‐station also incorporates an XYZ motorized sample holder with 25 mm travel per axis, a 5× ZEISS microscope objective with 5 mm × 5 mm field of view coupled to a CCD camera looking to the sample, and an AMPTEK single‐element Si (PIN) solid‐state detector for fluorescence detection. A graphic user interface data acquisition program using the LabVIEW platform has also been developed in‐house to generate a series of single‐column data which are compatible with available XRF data‐processing software. Finally, to test the performance of the µ‐SXRF beamline, an elemental surface profile has been obtained for a piece of ancient pottery from the Ban Chiang archaeological site, a UNESCO heritage site. It was found that the newly constructed µ‐SXRF technique was able to clearly distinguish the distribution of different elements on the specimen.     

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

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

High‐flux hard X‐ray microbeam using a single‐bounce capillary with doubly focused undulator beam

A pre‐focused X‐ray beam at 12 keV and 9 keV has been used to illuminate a single‐bounce capillary in order to generate a high‐flux X‐ray microbeam. The BioCAT undulator X‐ray beamline 18ID at the Advanced Photon Source was used to generate the pre‐focused beam containing 1.2 × 10¹³ photons s^?1 using a sagittal‐focusing double‐crystal monochromator and a bimorph mirror. The capillary entrance was aligned with the focal point of the pre‐focused beam in order to accept the full flux of the undulator beam. Two alignment configurations were tested: (i) where the center of the capillary was aligned with the pre‐focused beam (`in‐line') and (ii) where one side of the capillary was aligned with the beam (`off‐line'). The latter arrangement delivered more flux (3.3 × 10¹² photons s^?1) and smaller spot sizes (≤10 µm FWHM in both directions) for a photon flux density of 4.2 × 10¹⁰ photons s^?1µm^?2. The combination of the beamline main optics with a large‐working‐distance (approximately 24 mm) capillary used in this experiment makes it suitable for many microprobe fluorescence applications that require a micrometer‐size X‐ray beam and high flux density. These features are advantageous for biological samples, where typical metal concentrations are in the range of a few ng cm^?2. Micro‐XANES experiments are also feasible using this combined optical arrangement.     

A curved image‐plate detector system for high‐resolution synchrotron X‐ray diffraction

The developed curved image plate (CIP) is a one‐dimensional detector which simultaneously records high‐resolution X‐ray diffraction (XRD) patterns over a 38.7° 2θ range. In addition, an on‐site reader enables rapid extraction, transfer and storage of X‐ray intensity information in ≤30 s, and further qualifies this detector to study kinetic processes in materials science. The CIP detector can detect and store X‐ray intensity information linearly proportional to the incident photon flux over a dynamical range of about five orders of magnitude. The linearity and uniformity of the CIP detector response is not compromised in the unsaturated regions of the image plate, regardless of saturation in another region. The speed of XRD data acquisition together with excellent resolution afforded by the CIP detector is unique and opens up wide possibilities in materials research accessible through X‐ray diffraction. This article presents details of the basic features, operation and performance of the CIP detector along with some examples of applications, including high‐temperature XRD.     

Image guidance protocol for synchrotron microbeam radiation therapy

The protocol for image‐guided microbeam radiotherapy (MRT) developed for the Australian Synchrotron's Imaging and Medical Beamline (IMBL) is described. The protocol has been designed for the small‐animal MRT station of IMBL to enable future preclinical trials on rodents. The image guidance procedure allows for low‐dose monochromatic imaging at 50 keV and subsequent semi‐automated sample alignment in 3D with sub‐100 µm accuracy. Following the alignment, a beamline operation mode change is performed and the relevant beamline components are automatically aligned for the treatment (pink) beam to be delivered on the sample. Here, the small‐animal MRT station, the parameters and procedures for the image guidance protocol, as well as the experimental imaging results using phantoms are described. Furthermore, the experimental validation of the protocol using 3D PRESAGE^® dosimeters is reported. It is demonstrated that the sample alignment is maintained after the mode change and the treatment can be delivered within the same spatial accuracy of 100 µm. The results indicate that the proposed approach is viable for preclinical trials of small‐animal MRT.     

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

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

Bone‐nanohydroxyapatite spheres interface evaluation by synchrotron radiation X‐ray microfluorescence

Hydroxyapatite (HA) is largely used as bone graft; it seems to be the most promising synthetic implant material, mainly because of its excellent biocompatibility. The crystallinity, particle and pore size of HA are important characteristics and can be modified by decreasing basic structural form below 100 nm and have evoked a great amount of attention for improving prevention, diagnosis, and disease treatment, besides improving bone repair through the biodegradation of the material. The aim of this study was to investigate bone mineral content in bone samples with nanohydroxyapatite and HA spheres, specially its spatial distribution on bone microarchitecture. Circular bone defects were made in both tibiae of 12 White New Zeland adult rabbits (Oryctolagus cuniculus) and were divided randomly into five groups – blood clot (control group), sintered HA, non‐sintered HA, sintered nanoHA and non‐sintered nanoHA – all materials in spherical shape, to smooth handling and accommodation of the surgical bed, and to minimize inflammatory response. The rabbits were euthanatized according to the experimental period of 1 and 4 weeks after surgery. The samples were evaluated by polarized microscopy as well as X‐ray microfluorescence in order to account the bone mineral content bone‐implant interfaces, through synchrotron radiation. Our results revealed greater newly formed bone area in the non‐sintered materials and control groups, and the used technique showed that the amount of calcium of new bone was consistent with both mature bone and HA spheres. In conclusion, the present findings suggest that HA‐based biomaterials are biocompatible, promote osteoconduction and favored bone repair. Copyright © 2011 John Wiley & Sons, Ltd.     

A new method of creating minibeam patterns for synchrotron radiation therapy: a feasibility study

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 µm with a separation between two adjacent minibeams of the same value, whilst in MRT the thickness is of the order of 25–50 µm with a distance between adjacent microbeams of the order of 200 µm. An original method has been developed and tested at the ESRF ID17 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.     

Single‐cell resolution in high‐resolution synchrotron X‐ray CT imaging with gold nanoparticles

Gold nanoparticles are excellent intracellular markers in X‐ray imaging. Having shown previously the suitability of gold nanoparticles to detect small groups of cells with the synchrotron‐based computed tomography (CT) technique both ex vivo and in vivo, it is now demonstrated that even single‐cell resolution can be obtained in the brain at least ex vivo. Working in a small animal model of malignant brain tumour, the image quality obtained with different imaging modalities was compared. To generate the brain tumour, 1 × 10⁵ C6 glioma cells were loaded with gold nanoparticles and implanted in the right cerebral hemisphere of an adult rat. Raw data were acquired with absorption X‐ray CT followed by a local tomography technique based on synchrotron X‐ray absorption yielding single‐cell resolution. The reconstructed synchrotron X‐ray images were compared with images obtained by small animal magnetic resonance imaging. The presence of gold nanoparticles in the tumour tissue was verified in histological sections.     

Sapphire hard X‐ray Fabry–Perot resonators for synchrotron experiments

Hard X‐ray Fabry–Perot resonators (FPRs) made from sapphire crystals were constructed and characterized. The FPRs consisted of two crystal plates, part of a monolithic crystal structure of Al₂O₃, acting as a pair of mirrors, for the backward reflection (0 0 0 30) of hard X‐rays at 14.3147 keV. The dimensional accuracy during manufacturing and the defect density in the crystal in relation to the resonance efficiency of sapphire FPRs were analyzed from a theoretical standpoint based on X‐ray cavity resonance and measurements using scanning electron microscopic and X‐ray topographic techniques for crystal defects. Well defined resonance spectra of sapphire FPRs were successfully obtained, and were comparable with the theoretical predictions.     

The contribution of synchrotron X‐ray computed microtomography to understanding volcanic processes

A series of computed microtomography experiments are reported which were performed by using a third‐generation synchrotron radiation source on volcanic rocks from various active hazardous volcanoes in Italy and other volcanic areas in the world. The applied technique allowed the internal structure of the investigated material to be accurately imaged at the micrometre scale and three‐dimensional views of the investigated samples to be produced as well as three‐dimensional quantitative measurements of textural features. The geometry of the vesicle (gas‐filled void) network in volcanic products of both basaltic and trachytic compositions were particularly focused on, as vesicle textures are directly linked to the dynamics of volcano degassing. This investigation provided novel insights into modes of gas exsolution, transport and loss in magmas that were not recognized in previous studies using solely conventional two‐dimensional imaging techniques. The results of this study are important to understanding the behaviour of volcanoes and can be combined with other geosciences disciplines to forecast their future activity.     

X‐ray analog pixel array detector for single synchrotron bunch time‐resolved imaging

Dynamic X‐ray studies can reach temporal resolutions limited by only the X‐ray pulse duration if the detector is fast enough to segregate synchrotron pulses. An analog integrating pixel array detector with in‐pixel storage and temporal resolution of around 150 ns, sufficient to isolate pulses, is presented. Analog integration minimizes count‐rate limitations and in‐pixel storage captures successive pulses. Fundamental tests of noise and linearity as well as high‐speed laser measurements are shown. The detector resolved individual bunch trains at the Cornell High Energy Synchrotron Source at levels of up to 3.7 × 10³ X‐rays per pixel per train. When applied to turn‐by‐turn X‐ray beam characterization, single‐shot intensity measurements were made with a repeatability of 0.4% and horizontal oscillations of the positron cloud were detected.     

Investigation of cadmium accumulation mechanism in hepatopancreas of Patinopecten yessoensis by synchrotron radiation X‐ray absorption fine structure and synchrotron radiation X‐ray fluorescence analyses

Chemical state of cadmium in a hepatopancreas of a scallop (Patinopecten yessoensis) was studied by means of synchrotron radiation‐based X‐ray analytical techniques. X‐ray absorption fine structure (XAFS) and X‐ray fluorescence (XRF) imaging were used to identify the chemical state and the distribution of cadmium in the hepatopancreas, respectively. The results of in vivo Cd K‐edge XAFS suggested that the neighboring atoms of the cadmium in the hepatopancreas are of sulfur. Therefore, we propose that cadmium was accumulated by a metalloprotein with sulfur. Micro XRF imaging of thin sections of the hepatopancreas showed that cadmium is distributed on the surface of intestinal epithelia and concentrated in the internal tissue of the hepatopancreas. These results indicated that scallops accumulate cadmium inside the hepatopancreas through the intestinal epithelium.     

Elemental and chemical state depth analysis by combined use of a polycapillary and a thin wire in a synchrotron X‐ray microprobe

A simple method is proposed to improve the depth resolution of a conventional X‐ray confocal microscopy system by adding a thin wire close to the sample surface and upstream of the polycapillary in the exit channel. A depth resolution of around 10 μm is easily obtained. The detection efficiency is improved by a factor of two to three times, compared with the thin wire technique previously proposed. It is also shown that not only the elemental distribution but also the X‐ray absorption near‐edge structure (XANES) spectrum from locations below the sample surface can be obtained. Copyright © 2017 John Wiley & Sons, Ltd.     

Microdistribution of lead in human teeth using microbeam synchrotron radiation X‐ray fluorescence (μ‐SRXRF)

Lead (Pb) exposure is known to be associated with adverse effects on human health, especially during the prenatal period and early childhood. The Pb content in teeth has been suggested as a useful biomarker for the evaluation of cumulative Pb exposure. This study was designed to employ the microbeam synchrotron radiation X‐ray fluorescence technique to determine the microdistribution of Pb within the tooth to evaluate the reliability of the technique and the effectiveness of tooth Pb as a biomarker of Pb exposure. The results showed that in the incisor sample, Pb primarily deposited in secondary dentine region close to the pulp and secondarily at enamel exterior. In addition, Pb colocalised with Zn, indicating a positive correlation between Pb and Zn. By contrast, in the two molar samples, Pb accumulated principally in the pulp, and secondarily in the enamel. At the same time, Pb in these two molar samples colocalised with Ca instead of Zn as was observed in the incisor sample. Several batches of line scans further confirmed the conclusions. The feasibility of using microbeam synchrotron radiation X‐ray fluorescence to determine the microdistribution of Pb in teeth and of using the tooth Pb, especially in dentine, as a biomarker was discussed. Copyright © 2016 John Wiley & Sons, Ltd.     

Investigation of GEM-Micromegas detector on X-ray beam of synchrotron radiation

To reduce the discharge of the standard bulk Micromegas and GEM detectors, a GEM-Micromegas detector was developed at the Institute of High Energy Physics. Taking into account the advantages of the two detectors, one GEM foil was set as a preamplifier on the mesh of Micromegas in the structure and the CEM pream- plification decreased the working voltage of Micromegas to significantly reduce the effect of the discharge. At the same gain, the spark probability of the GEM-Micromegas detector can be reduced to a factor 0.01 compared to the standard Micromegas detector, and an even higher gain could be obtained. This paper describes the performance of the X-ray beam detector that was studied at 1W2B Laboratory of Beijing Synchrotron Radiation Facility. Finally, the result of the energy resolution under various X-ray energies was given in different working gases. This indicates that the GEM-Micromegas detector has an energy response capability in an energy range from 6 keV to 20 keV and it could work better than the standard bulk-Micromegas.     

Investigation of GEM-Micromegas detector on X-ray beam of synchrotron radiation

To reduce the discharge of the standard bulk Micromegas and GEM detectors, a GEM-Micromegas detector was developed at the Institute of High Energy Physics. Taking into account the advantages of the two detectors, one GEM foil was set as a preamplifier on the mesh of Micromegas in the structure and the GEM preamplification decreased the working voltage of Micromegas to significantly reduce the effect of the discharge. At the same gain, the spark probability of the GEM-Micromegas detector can be reduced to a factor 0.01 compared to the standard Micromegas detector, and an even higher gain could be obtained. This paper describes the performance of the X-ray beam detector that was studied at 1W2B Laboratory of Beijing Synchrotron Radiation Facility. Finally, the result of the energy resolution under various X-ray energies was given in different working gases. This indicates that the GEM-Micromegas detector has an energy response capability in an energy range from 6 keV to 20 keV and it could work better than the standard bulk-Micromegas.