Immune Response following FLASH and Conventional Radiation in Diffuse Midline Glioma.

PURPOSE: Diffuse midline glioma (DMG) is a fatal tumor traditionally treated with radiation therapy (RT) and previously characterized as having a noninflammatory tumor immune microenvironment (TIME). FLASH is a novel RT technique using ultra-high dose rate that is associated with decreased toxicity and effective tumor control. However, the effect of FLASH and conventional (CONV) RT on the DMG TIME has not yet been explored. METHODS AND MATERIALS: Here, we performed single-cell RNA sequencing (scRNA-seq) and flow cytometry on immune cells isolated from an orthotopic syngeneic murine model of brainstem DMG after the use of FLASH (90 Gy/sec) or CONV (2 Gy/min) dose-rate RT and compared to unirradiated tumor (SHAM). RESULTS: At day 4 post-RT, FLASH exerted similar effects as CONV in the predominant microglial (MG) population, including the presence of two activated subtypes. However, at day 10 post-RT, we observed a significant increase in the type 1 interferon α/ß receptor (IFNAR+) in MG in CONV and SHAM compared to FLASH. In the non-resident myeloid clusters of macrophages (MACs) and dendritic cells (DCs), we found increased type 1 interferon (IFN1) pathway enrichment for CONV compared to FLASH and SHAM by scRNA-seq. We observed this trend by flow cytometry at day 4 post-RT in IFNAR+ MACs and DCs, which equalized by day 10 post-RT. DMG control and murine survival were equivalent between RT dose rates. CONCLUSIONS: Our work is the first to map CONV and FLASH immune alterations of the DMG TIME with single-cell resolution. Although DMG tumor control and survival were similar between CONV and FLASH, we found that changes in immune compartments differed over time. Importantly, although both RT modalities increased IFN1, we found that the timing of this response was cell-type and dose-rate dependent. These temporal differences, particularly in the context of tumor control, warrant further study.

Simulation study of a novel small animal FLASH irradiator (SAFI) with integrated inverse-geometry CT based on circularly distributed kV X-ray sources.

Ultra-high dose rate (UHDR) radiotherapy (RT) or FLASH-RT can potentially reduce normal tissue toxicity. A small animal irradiator that can deliver FLASH-RT treatments similar to clinical RT treatments is needed for pre-clinical studies of FLASH-RT. We designed and simulated a novel small animal FLASH irradiator (SAFI) based on distributed x-ray source technology. The SAFI system comprises a distributed x-ray source with 51 focal spots equally distributed on a 20 cm diameter ring, which are used for both FLASH-RT and onboard micro-CT imaging. Monte Carlo simulation was performed to estimate the dosimetric characteristics of the SAFI treatment beams. The maximum dose rate, which is limited by the power density of the tungsten target, was estimated based on finite-element analysis (FEA). The maximum DC electron beam current density is 2.6 mA/mm2, limited by the tungsten target's linear focal spot power density. At 160 kVp, 51 focal spots, each with a dimension of [Formula: see text] mm2 and 10° anode angle, can produce up to 120 Gy/s maximum DC irradiation at the center of a cylindrical water phantom. We further demonstrate forward and inverse FLASH-RT planning, as well as inverse-geometry micro-CT with circular source array imaging via numerical simulations.

Ultra-high dose rate FLASH irradiator at the radiological research accelerator facility.

The Radiological Research Accelerator Facility has modified a decommissioned Varian Clinac to deliver ultra-high dose rates: operating in 9 MeV electron mode (FLASH mode), samples can be irradiated at a Source-Surface Distance (SSD) of 20 cm at average dose rates of up to 600 Gy/s (3.3 Gy per 0.13 µs pulse, 180 pulses per second). In this mode multiple pulses are required for most irradiations. By modulating pulse repetition rate and irradiating at SSD = 171 cm, dose rates below 1 Gy/min can be achieved, allowing comparison of FLASH and conventional irradiations with the same beam. Operating in 6 MV photon mode, with the conversion target removed (SuperFLASH mode), samples are irradiated at higher dose rates (0.2-150 Gy per 5 µs pulse, 360 pulses per second) and most irradiations can be performed with a single very high dose rate pulse. In both modes we have seen the expected inverse relation between dose rate and irradiated area, with the highest dose rates obtained for beams with a FWHM of about 2 cm and ± 10% uniformity over 1 cm diameter. As an example of operation of the ultra-high dose rate FLASH irradiator, we present dose rate dependence of dicentric chromosome yields.

A multi-layer strip ionization chamber (MLSIC) device for proton pencil beam scan quality assurance.

Objective. Proton pencil beam scanning (PBS) treatment fields needs to be verified before treatment deliveries to ensure patient safety. In current practice, treatment beam quality assurance (QA) is measured at a few selected depths using film or a 2D detector array, which is insensitive and time-consuming. A QA device that can measure all key dosimetric characteristics of treatment beams spot-by-spot within a single beam delivery is highly desired.Approach. We developed a multi-layer strip ionization chamber (MLSIC) prototype device that comprises of two layers of strip ionization chambers (IC) plates for spot position measurement and 64 layers of plate IC for beam energy measurement. The 768-channel strip ion chamber signals are integrated and sampled at a speed of 3.125 kHz. It has a 25.6 cm × 25.6 cm maximum measurement field size and 2 mm spatial resolution for spot position measurement. The depth resolution and maximum depth were 2.91 mm and 18.6 cm for 1.6 mm thick IC plate, respectively. The relative weight of each spot was determined from total charge by all IC detector channels.Main results. The MLSIC is able to measure ionization currents spot-by-spot. The depth dose measurement has a good agreement with the ground truth measured using a water tank and commercial one-dimensional (1D) multi-layer plate chamber. It can verify the spot position, energy, and relative weight of clinical PBS beams and compared with the treatment plans.Significance. The MLSIC is a highly efficient QA device that can measure the key dosimetric characteristics of proton treatment beams spot-by-spot with a single beam delivery. It may improve the quality and efficiency of clinical proton treatments.

Design and optimization of thin-film tungsten (W)-diamond target for multi-pixel X-ray sources.

BACKGROUND: Emerging multi-pixel X-ray source technology enables new designs for X-ray imaging systems. The power of multi-pixel X-ray sources with a fixed anode is limited by focal spot power density. PURPOSE: The purpose of this study is to optimize the W-diamond target and predict its performance in multi-pixel X-ray sources. METHODS: X-ray intensity and energy deposition in the W-diamond target with different thicknesses of tungsten film and incident electron energies was calculated with the Geant4 Monte Carlo toolkit. COMSOL Multiphysics software was used to analyze the transient and stationary heat transfer in the thin-film W-diamond target. The maximum tube power and X-ray output intensity were predicted for both transmission and reflection target configurations. RESULTS: The maximum focal spot power density was limited by either the graphitization of the diamond substrate or the melting point of the W target. With optimal W-target thickness, the maximum transmission X-ray intensities are about 40%-50% higher than the maximum reflection intensities. Thin-film W-diamond targets allow four to five times more maximum power input and produce six to seven times higher transmission X-ray intensity in continuous mode compared with conventional reflection W thick targets. Depending on the focal spot size, reducing the X-ray pulse duration can further enhance the tube power. CONCLUSIONS: Multi-pixel X-ray sources using this W-diamond target design can produce significantly higher X-ray output than traditional thick tungsten targets without major modification of the tube design.

Tetrahedron beam imaging with a multi-pixel thermionic emission X-ray source and a photon-counting detector: A benchtop experimental study.

PURPOSE: A tetrahedron beam (TB) X-ray system with a linear X-ray source array and a linear detector array positioned orthogonal to each other may overcome the X-ray scattering problem of traditional cone-beam X-ray systems. We developed a TB imaging benchtop system using a linear array X-ray source to demonstrate the principle and benefits of TB imaging. METHODS: A multi-pixel thermionic emission X-ray (MPTEX) source with 48 focal spots in 4-mm spacing was developed in-house. The X-ray beams are collimated to a stack of fan beams that are converged to a 6-mm wide multi-row photon-counting detector (PCD). The data collected with a sequential scan of the sources at a fixed view angle were synthesized to a 2D radiography image by a shift-and-add algorithm. The data collected with a full rotation of the system were reconstructed into 3D TB CT (TBCT) images using an Feldkamp, Davis, and Kress (FDK)-based computed tomography (CT) algorithm modified for the TB geometry. RESULTS: With an 18.8-cm long source array and a 35-cm long detector array, the TB benchtop system provides a 25-cm cross-sectional and 8-cm axial field of view (FOV). The scatter-to-primary ratio (SPR) was approximately 17% for TB, as compared with 120% for cone beam geometry. The TBCT system enables reconstructions in two-dimensional radiography and three-dimensional volumetric CT. The TBCT images were free of "cupping" artifacts and have similar image quality as diagnostic helical CT. CONCLUSIONS: A TB imaging benchtop imaging system was successfully developed with MPTEX source and PCD. Phantom and animal cadaver imaging demonstrated that the TB system can produce satisfactory radiographic X-ray images and 3D CT images with image quality comparable to diagnostic helical CTs.

Dielectric resonator method for determining gap symmetry of superconductors through anisotropic nonlinear Meissner effect.

We present a new measurement method which can be used to image the gap nodal structure of superconductors whose pairing symmetry is under debate. This technique utilizes a high quality factor microwave resonance involving the sample of interest. While supporting a circularly symmetric standing wave current pattern, the sample is perturbed by a scanned laser beam, creating a photoresponse that was previously shown to reveal the superconducting gap anisotropy. Simulation and the measurement of the photoresponse of an unpatterned Nb film show less than 8% anisotropy, as expected for a superconductor with a nearly isotropic energy gap along with expected systematic uncertainty. On the other hand, measurement of a YBa2Cu3O7-δ thin film shows a clear 4-fold symmetric image with ∼12.5% anisotropy, indicating the well-known 4-fold symmetric dx2-y2 gap nodal structure in the ab-plane. The deduced gap nodal structure can be further cross-checked by low temperature surface impedance data, which are simultaneously measured. The important advantage of the presented method over the previous spiral resonator method is that it does not require a complicated lithographic patterning process which limits one from testing various kinds of materials due to photoresponse arising from patterning defects. This advantage of the presented technique, and the ability to measure unpatterned samples such as planar thin films and single crystals, enables one to survey the pairing symmetry of a wide variety of unconventional superconductors.

Design and numerical simulations of W-diamond transmission target for distributed x-ray sources.

Distributed x-ray sources enable novel designs of x-ray imaging systems. However, the x-ray power of such sources is limited by the focal spot power density of the fixed anode. To further improve x-ray output, we have designed and evaluated a diamond-W transmission target for multi-pixel x-ray sources. The target features a thin layer of tungsten deposited on a diamond substrate. The thickness of tungsten layer was optimized for maximum fluence through Monte Carlo simulations. Finite element thermal simulations were performed to evaluate focal spot temperature in the target under different power loadings and dwell duration. The results showed that the optimal thickness of the tungsten layer in the W-diamond transmission target is linearly proportional to the electron energy. A 5-6 µm tungsten thickness is suitable for the kVps ranges from 60 kVp to 140 kVp. A W-diamond transmission target produces up to 20% more x-ray fluence than a traditional W reflection target in the beam center depending on the kVp settings. The x-ray spectrum of the transmission target shows less characteristic x-rays than that of reflection target. The thermal performance of W-diamond targets for peak power is significantly better than that of reflection targets. The maximum focal spot power densities of W-diamond transmission and W reflection targets are both strongly dependent on the dwell duration. For longer pulse durations, the W-diamond target allows as much as a four-fold increase in power and an eight-fold increase in power density in comparison to a traditional W reflection target for the same temperature spikes. The stability of the W-diamond bond needs to be tested experimentally. Nevertheless, the W-diamond transmission target is an appealing target that can significantly simplify the design and improve the performance of distributed x-ray sources.