A prototype scintillator real-time beam monitor for ultra-high dose rate radiotherapy.

BACKGROUND: FLASH Radiotherapy (RT) is an emergent cancer RT modality where an entire therapeutic dose is delivered at more than 1000 times higher dose rate than conventional RT. For clinical trials to be conducted safely, a precise and fast beam monitor that can generate out-of-tolerance beam interrupts is required. This paper describes the overall concept and provides results from a prototype ultra-fast, scintillator-based beam monitor for both proton and electron beam FLASH applications. PURPOSE: A FLASH Beam Scintillator Monitor (FBSM) is being developed that employs a novel proprietary scintillator material. The FBSM has capabilities that conventional RT detector technologies are unable to simultaneously provide: (1) large area coverage; (2) a low mass profile; (3) a linear response over a broad dynamic range; (4) radiation hardness; (5) real-time analysis to provide an IEC-compliant fast beam-interrupt signal based on true two-dimensional beam imaging, radiation dosimetry and excellent spatial resolution. METHODS: The FBSM uses a proprietary low mass, less than 0.5 mm water equivalent, non-hygroscopic, radiation tolerant scintillator material (designated HM: hybrid material) that is viewed by high frame rate CMOS cameras. Folded optics using mirrors enable a thin monitor profile of ∼10 cm. A field programmable gate array (FPGA) data acquisition system generates real-time analysis on a time scale appropriate to the FLASH RT beam modality: 100-1000 Hz for pulsed electrons and 10-20 kHz for quasi-continuous scanning proton pencil beams. An ion beam monitor served as the initial development platform for this work and was tested in low energy heavy-ion beams (86Kr+26 and protons). A prototype FBSM was fabricated and then tested in various radiation beams that included FLASH level dose per pulse electron beams, and a hospital RT clinic with electron beams. RESULTS: Results presented in this report include image quality, response linearity, radiation hardness, spatial resolution, and real-time data processing. The HM scintillator was found to be highly radiation damage resistant. It exhibited a small 0.025%/kGy signal decrease from a 216 kGy cumulative dose resulting from continuous exposure for 15 min at a FLASH compatible dose rate of 237 Gy/s. Measurements of the signal amplitude versus beam fluence demonstrate linear response of the FBSM at FLASH compatible dose rates of >40 Gy/s. Comparison with commercial Gafchromic film indicates that the FBSM produces a high resolution 2D beam image and can reproduce a nearly identical beam profile, including primary beam tails. The spatial resolution was measured at 35-40 µm. Tests of the firmware beta version show successful operation at 20 000 Hz frame rate or 50 µs/frame, where the real-time analysis of the beam parameters is achieved in less than 1 µs. CONCLUSIONS: The FBSM is designed to provide real-time beam profile monitoring over a large active area without significantly degrading the beam quality. A prototype device has been staged in particle beams at currents of single particles up to FLASH level dose rates, using both continuous ion beams and pulsed electron beams. Using a novel scintillator, beam profiling has been demonstrated for currents extending from single particles to 10 nA currents. Radiation damage is minimal and even under FLASH conditions would require ≥50 kGy of accumulated exposure in a single spot to result in a 1% decrease in signal output. Beam imaging is comparable to radiochromic films, and provides immediate images without hours of processing. Real-time data processing, taking less than 50 µs (combined data transfer and analysis times), has been implemented in firmware for 20 kHz frame rates for continuous proton beams.

A Prototype Scintillator Real-Time Beam Monitor for Ultra-high Dose Rate Radiotherapy.

Background: FLASH Radiotherapy (RT) is an emergent cancer radiotherapy modality where an entire therapeutic dose is delivered at more than 1000 times higher dose rate than conventional RT. For clinical trials to be conducted safely, a precise and fast beam monitor that can generate out-of-tolerance beam interrupts is required. This paper describes the overall concept and provides results from a prototype ultra-fast, scintillator-based beam monitor for both proton and electron beam FLASH applications. Purpose: A FLASH Beam Scintillator Monitor (FBSM) is being developed that employs a novel proprietary scintillator material. The FBSM has capabilities that conventional RT detector technologies are unable to simultaneously provide: 1) large area coverage; 2) a low mass profile; 3) a linear response over a broad dynamic range; 4) radiation hardness; 5) real-time analysis to provide an IEC-compliant fast beam-interrupt signal based on true two-dimensional beam imaging, radiation do-simetry and excellent spatial resolution. Methods: The FBSM uses a proprietary low mass, less than 0.5 mm water equivalent, non-hygroscopic, radiation tolerant scintillator material (designated HM: hybrid material) that is viewed by high frame rate CMOS cameras. Folded optics using mirrors enable a thin monitor profile of ~10 cm. A field programmable gate array (FPGA) data acquisition system (DAQ) generates real-time analysis on a time scale appropriate to the FLASH RT beam modality: 100-1000 Hz for pulsed electrons and 10-20 kHz for quasi-continuous scanning proton pencil beams. An ion beam monitor served as the initial development platform for this work and was tested in low energy heavy-ion beams (86Kr+26 and protons). A prototype FBSM was fabricated and then tested in various radiation beams that included FLASH level dose per pulse electron beams, and a hospital radiotherapy clinic with electron beams. Results: Results presented in this report include image quality, response linearity, radiation hardness, spatial resolution, and real-time data processing. The HM scintillator was found to be highly radiation damage resistant. It exhibited a small 0.025%/kGy signal decrease from a 216 kGy cumulative dose resulting from continuous exposure for 15 minutes at a FLASH compatible dose rate of 237 Gy/s. Measurements of the signal amplitude vs beam fluence demonstrate linear response of the FBSM at FLASH compatible dose rates of > 40 Gy/s. Comparison with commercial Gafchromic film indicates that the FBSM produces a high resolution 2D beam image and can reproduce a nearly identical beam profile, including primary beam tails. The spatial resolution was measured at 35-40 µm. Tests of the firmware beta version show successful operation at 20,000 Hz frame rate or 50 µs/frame, where the real-time analysis of the beam parameters is achieved in less than 1 µs. Conclusions: The FBSM is designed to provide real-time beam profile monitoring over a large active area without significantly degrading the beam quality. A prototype device has been staged in particle beams at currents of single particles up to FLASH level dose rates, using both continuous ion beams and pulsed electron beams. Using a novel scintillator, beam profiling has been demonstrated for currents extending from single particles to 10 nA currents. Radiation damage is minimal and even under FLASH conditions would require ≥ 50 kGy of accumulated exposure in a single spot to result in a 1% decrease in signal output. Beam imaging is comparable to radiochromic films, and provides immediate images without hours of processing. Real-time data processing, taking less than 50 µs (combined data transfer and analysis times), has been implemented in firmware for 20 kHz frame rates for continuous proton beams.

Current status of the preclinical evaluation of alternating electric fields as a form of cancer therapy.

Exposing cancer cells to alternating electric fields of 100-300 kHz frequency and 1-4 V/cm strength has been shown to significantly reduce cancer growth in cell culture and in human patients. This form of anti-cancer therapy is more commonly referred to as tumor treating fields (TTFields), a novel treatment modality that has been approved by the U.S. Food and Drug Administration for use in patients with glioblastoma and malignant pleural mesothelioma. Pivotal trials in other solid organ cancer trials are underway. In regards to overall survival, TTFields alone is comparable to chemotherapy alone in recurrent glioblastoma. However, when combined with adjuvant chemotherapy, TTFields prolong median survival by 4.9 months in newly-diagnosed glioblastoma. TTFields hold promise as a therapeutic approach to numerous solid organ cancers. This review summarizes the current status of TTFields research at the preclinical level, highlighting recent aspects of a relatively complex working hypothesis. In addition, we point out the gaps between limited preclinical in vivo studies and the available clinical data. To date, no customized system for TTFields delivery in rodent models of glioblastoma has been presented. We aim to motivate the expansion of TTFields preclinical research and facilitate the availability of suitable hardware, to ultimately improve outcomes in patients with cancer.

Comparative accuracy and resolution assessment of two prototype proton computed tomography scanners.

BACKGROUND: Improving the accuracy of relative stopping power (RSP) in proton therapy may allow reducing range margins. Proton computed tomography (pCT) has been shown to provide state-of-the-art RSP accuracy estimation, and various scanner prototypes have recently been built. The different approaches used in scanner design are expected to impact spatial resolution and RSP accuracy. PURPOSE: The goal of this study was to perform the first direct comparison, in terms of spatial resolution and RSP accuracy, of two pCT prototype scanners installed at the same facility and by using the same image reconstruction algorithm. METHODS: A phantom containing cylindrical inserts of known RSP was scanned at the phase-II pCT prototype of the U.S. pCT collaboration and at the commercially oriented ProtonVDA scanner. Following distance-driven binning filtered backprojection reconstruction, the radial edge spread function of high-density inserts was used to estimate the spatial resolution. RSP accuracy was evaluated by the mean absolute percent error (MAPE) over the inserts. No direct imaging dose estimation was possible, which prevented a comparison of the two scanners in terms of RSP noise. RESULTS: In terms of RSP accuracy, both scanners achieved the same MAPE of 0.72% when excluding the porous sinus insert from the evaluation. The ProtonVDA scanner reached a better overall MAPE when all inserts and the body of the phantom were accounted for (0.81%), compared to the phase-II scanner (1.14%). The spatial resolution with the phase-II scanner was found to be 0.61 lp/mm, while for the ProtonVDA scanner somewhat lower at 0.46 lp/mm. CONCLUSIONS: The comparison between two prototype pCT scanners operated in the same clinical facility showed that they both fulfill the requirement of an RSP accuracy of about 1%. Their spatial resolution performance reflects the different design choices of either a scanner with full tracking capabilities (phase-II) or of a more compact tracker system, which only provides the positions of protons but not their directions (ProtonVDA).

The role of Monte Carlo simulation in understanding the performance of proton computed tomography.

Proton computed tomography (pCT) is a promising tomographic imaging modality allowing direct reconstruction of proton relative stopping power (RSP) required for proton therapy dose calculation. In this review article, we aim at highlighting the role of Monte Carlo (MC) simulation in pCT studies. After describing the requirements for performing proton computed tomography and the various pCT scanners actively used in recent research projects, we present an overview of available MC simulation platforms. The use of MC simulations in the scope of investigations of image reconstruction, and for the evaluation of optimal RSP accuracy, precision and spatial resolution omitting detector effects is then described. In the final sections of the review article, we present specific applications of realistic MC simulations of an existing pCT scanner prototype, which we describe in detail.

Particle-Tracking Proton Computed Tomography-Data Acquisition, Preprocessing, and Preconditioning.

Proton CT (pCT) is a promising new imaging technique that can reconstruct relative stopping power (RSP) more accurately than x-ray CT in each cubic millimeter voxel of the patient. This, in turn, will result in better proton range accuracy and, therefore, smaller planned tumor volumes (PTV). The hardware description and some reconstructed images have previously been reported. In a series of two contributions, we focus on presenting the software algorithms that convert pCT detector data to the final reconstructed pCT images for application in proton treatment planning. There were several options on how to accomplish this, and we will describe our solutions at each stage of the data processing chain. In the first paper of this series, we present the data acquisition with the pCT tracking and energy-range detectors and how the data are preprocessed, including the conversion to the well-formatted track information from tracking data and water-equivalent path length from the data of a calibrated multi-stage energy-range detector. These preprocessed data are then used for the initial image formation with an FDK cone-beam CT algorithm. The output of data acquisition, preprocessing, and FDK reconstruction is presented along with illustrative imaging results for two phantoms, including a pediatric head phantom. The second paper in this series will demonstrate the use of iterative solvers in conjunction with the superiorization methodology to further improve the images resulting from the upfront FDK image reconstruction and the implementation of these algorithms on a hybrid CPU/GPU computer cluster.

Experimental comparison of proton CT and dual energy x-ray CT for relative stopping power estimation in proton therapy.

Proton computed tomography (pCT) has been proposed as an alternative to x-ray computed tomography (CT) for acquiring relative to water stopping power (RSP) maps used for proton treatment planning dose calculations. In parallel, it has been shown that dual energy x-ray CT (DECT) improves RSP accuracy when compared to conventional single energy x-ray CT. This study aimed at directly comparing the RSP accuracy of both modalities using phantoms scanned at an advanced prototype pCT scanner and a state-of-the-art DECT scanner. Two phantoms containing 13 tissue-mimicking inserts of known RSP were scanned at the pCT phase II prototype and a latest generation dual-source DECT scanner (Siemens SOMATOM Definition FORCE). RSP accuracy was compared by mean absolute percent error (MAPE) over all inserts. A highly realistic Monte Carlo (MC) simulation was used to gain insight on pCT image artifacts which degraded MAPE. MAPE was 0.55% for pCT and 0.67% for DECT. The realistic MC simulation agreed well with pCT measurements ([Formula: see text]). Both simulation and experimental results showed ring artifacts in pCT images which degraded the MAPE compared to an ideal pCT simulation ([Formula: see text]). Using the realistic simulation, we could identify sources of artifacts, which are attributed to the interfaces in the five-stage plastic scintillator energy detector and calibration curve interpolation regions. Secondary artifacts stemming from the proton tracker geometry were also identified. The pCT prototype scanner outperformed a state-of-the-art DECT scanner in terms of RSP accuracy (MAPE) for plastic tissue mimicking inserts. Since artifacts tended to concentrate in the inserts, their mitigation may lead to further improvements in the reported pCT accuracy.

Software platform for simulation of a prototype proton CT scanner.

PURPOSE: Proton computed tomography (pCT) is a promising imaging technique to substitute or at least complement x-ray CT for more accurate proton therapy treatment planning as it allows calculating directly proton relative stopping power from proton energy loss measurements. A proton CT scanner with a silicon-based particle tracking system and a five-stage scintillating energy detector has been completed. In parallel a modular software platform was developed to characterize the performance of the proposed pCT. METHOD: The modular pCT software platform consists of (1) a Geant4-based simulation modeling the Loma Linda proton therapy beam line and the prototype proton CT scanner, (2) water equivalent path length (WEPL) calibration of the scintillating energy detector, and (3) image reconstruction algorithm for the reconstruction of the relative stopping power (RSP) of the scanned object. In this work, each component of the modular pCT software platform is described and validated with respect to experimental data and benchmarked against theoretical predictions. In particular, the RSP reconstruction was validated with both experimental scans, water column measurements, and theoretical calculations. RESULTS: The results show that the pCT software platform accurately reproduces the performance of the existing prototype pCT scanner with a RSP agreement between experimental and simulated values to better than 1.5%. CONCLUSIONS: The validated platform is a versatile tool for clinical proton CT performance and application studies in a virtual setting. The platform is flexible and can be modified to simulate not yet existing versions of pCT scanners and higher proton energies than those currently clinically available.

A Fast Experimental Scanner for Proton CT: Technical Performance and First Experience with Phantom Scans.

We report on the design, fabrication, and first tests of a tomographic scanner developed for proton computed tomography (pCT) of head-sized objects. After extensive preclinical testing, pCT is intended to be employed in support of proton therapy treatment planning and pre-treatment verification in patients undergoing particle-beam therapy. The scanner consists of two silicon-strip telescopes that track individual protons before and after the phantom, and a novel multistage scintillation detector that measures a combination of the residual energy and range of the proton, from which we derive the water equivalent path length (WEPL) of the protons in the scanned object. The set of WEPL values and the associated paths of protons passing through the object over a 360° angular scan are processed by an iterative, parallelizable reconstruction algorithm that runs on modern GP-GPU hardware. In order to assess the performance of the scanner, we have performed tests with 200 MeV protons from the synchrotron of the Loma Linda University Medical Center and the IBA cyclotron of the Northwestern Medicine Chicago Proton Center. Our first objective was calibration of the instrument, including tracker channel maps and alignment as well as the WEPL calibration. Then we performed the first CT scans on a series of phantoms. The very high sustained rate of data acquisition, exceeding one million protons per second, allowed a full 360° scan to be completed in less than 10 minutes, and reconstruction of a CATPHAN 404 phantom verified accurate reconstruction of the proton relative stopping power in a variety of materials.

Development of proton computed tomography detectors for applications in hadron therapy.

Radiation therapy with protons and heavier ions is an attractive form of cancer treatment that could enhance local control and survival of cancers that are currently difficult to cure and lead to less side effects due to sparing of normal tissues. However, particle therapy faces a significant technical challenge because one cannot accurately predict the particle range in the patient using data provided by existing imaging technologies. Proton computed tomography (pCT) is an emerging imaging modality capable of improving the accuracy of range prediction. In this paper, we describe the successive pCT scanners designed and built by our group with the goal to support particle therapy treatment planning and image guidance by reconstructing an accurate 3D map of the stopping power relative to water in patient tissues. The pCT scanners we have built to date consist of silicon telescopes, which track the proton before and after the object to be reconstructed, and an energy or range detector, which measures the residual energy and/or range of the protons used to evaluate the water equivalent path length (WEPL) of each proton in the object. An overview of a decade-long evolution of the conceptual design of pCT scanners and their calibration is given. Results of scanner performance tests are presented, which demonstrate that the latest pCT scanner approaches readiness for clinical applications in hadron therapy.

Nanodosimetry-based quality factors for radiation protection in space.

Evaluation and monitoring of the cancer risk from space radiation exposure is a crucial requirement for the success of long-term space missions. One important task in the risk calculation is to properly weigh the various components of space radiation dose according to their assumed contribution to the cancer risk relative to the risk associated with radiation of low ionization density. Currently, quality factors of radiation both on the ground and in space are defined by national and international commissions based on existing radiobiological data and presumed knowledge of the ionization density distribution of the radiation field at a given point of interest. This approach makes the determination of the average quality factor ofa given radiation field a rather complex task. In this contribution, we investigate the possibility to define quality factors of space radiation exposure based on nanodosimetric data. The underlying formalism of the determination of quality factors on the basis of nanodosimetric data is described, and quality factors for protons and ions (helium and carbon) of different energies based on simulated nanodosimetric data are presented. The value and limitations of this approach are discussed.

Phosphorylation of Rad55 on serines 2, 8, and 14 is required for efficient homologous recombination in the recovery of stalled replication forks.

DNA damage checkpoints coordinate the cellular response to genotoxic stress and arrest the cell cycle in response to DNA damage and replication fork stalling. Homologous recombination is a ubiquitous pathway for the repair of DNA double-stranded breaks and other checkpoint-inducing lesions. Moreover, homologous recombination is involved in postreplicative tolerance of DNA damage and the recovery of DNA replication after replication fork stalling. Here, we show that the phosphorylation on serines 2, 8, and 14 (S2,8,14) of the Rad55 protein is specifically required for survival as well as for normal growth under genome-wide genotoxic stress. Rad55 is a Rad51 paralog in Saccharomyces cerevisiae and functions in the assembly of the Rad51 filament, a central intermediate in recombinational DNA repair. Phosphorylation-defective rad55-S2,8,14A mutants display a very slow traversal of S phase under DNA-damaging conditions, which is likely due to the slower recovery of stalled replication forks or the slower repair of replication-associated DNA damage. These results suggest that Rad55-S2,8,14 phosphorylation activates recombinational repair, allowing for faster recovery after genotoxic stress.

Constitutive expression of the human peroxiredoxin V gene contributes to protection of the genome from oxidative DNA lesions and to suppression of transcription of noncoding DNA.

Peroxiredoxins belong to a family of antioxidant proteins that neutralize reactive oxygen species. One member of this family, peroxiredoxin I (PRDX1), suppresses DNA oxidation. Peroxiredoxin V (PRDX5) has been cloned as a transcriptional corepressor, as a peroxisomal/mitochondrial antioxidant protein, and as an inhibitor of p53-dependent apoptosis. Promoters of mammalian PRDX5 genes contain clusters of antioxidant response elements, which can bind the transcription factor NRF2. However, we found that expression of the human PRDX5 gene in situ was not stimulated by the oxidative agent menadione. Silencing of the NRF2 gene in the absence of oxidative stress by specific siRNA did not decrease PRDX5 protein concentration. We also constructed clones of human lung epithelial cells A549 with siRNA-mediated knockdown of the PRDX5 gene. This led to a significant increase in 8-oxoguanine formation in cell DNA. In the PRDX5 knockdown clone, an increase in transcripts containing sequences of alpha-satellite and satellite III DNAs was also detected, suggesting that this protein may be required for silencing of heterochromatin. Together, these results suggest that constitutively expressed PRDX5 gene plays an important role in protecting the genome against oxidation and may also be involved in the control of transcription of noncoding DNA.

Esc4/Rtt107 and the control of recombination during replication.

When replication forks stall during DNA synthesis, cells respond by assembling multi-protein complexes to control the various pathways that stabilize the replication machinery, repair the replication fork, and facilitate the reinitiation of processive DNA synthesis. Increasing evidence suggests that cells have evolved scaffolding proteins to orchestrate and control the assembly of these repair complexes, typified in mammalian cells by several BRCT-motif containing proteins, such as Brca1, Xrcc1, and 53BP1. In Saccharomyces cerevisiae, Esc4 contains six such BRCT domains and is required for the most efficient response to a variety of agents that damage DNA. We show that Esc4 interacts with several proteins involved in the repair and processing of stalled or collapsed replication forks, including the recombination protein Rad55. However, the function of Esc4 does not appear to be restricted to a Rad55-dependent process, as we observed an increase in sensitivity to the DNA alkylating agent methane methylsulfonate (MMS) in a esc4Deltarad55Delta mutant, as well as in double mutants of esc4Delta and other recombination genes, compared to the corresponding single mutants. In addition, we show that Esc4 forms multiple nuclear foci in response to treatment with MMS. Similar behavior is also observed in the absence of damage when either of the S-phase checkpoint proteins, Tof1 or Mrc1, is deleted. Thus, we propose that Esc4 associates with ssDNA of stalled forks and acts as a scaffolding protein to recruit and/or modulate the function of other proteins required to reinitiate DNA synthesis.

Density resolution of proton computed tomography.

Conformal proton radiation therapy requires accurate prediction of the Bragg peak position. Protons may be more suitable than conventional x-rays for this task since the relative electron density distribution can be measured directly with proton computed tomography (CT). However, proton CT has its own limitations, which need to be carefully studied before this technique can be introduced into routine clinical practice. In this work, we have used analytical relationships as well as the Monte Carlo simulation tool GEANT4 to study the principal resolution limits of proton CT. The noise level observed in proton CT images of a cylindrical water phantom with embedded tissue-equivalent density inhomogeneities, which were generated based on GEANT4 simulations, compared well with predictions based on Tschalar's theory of energy loss straggling. The relationship between phantom thickness, initial energy, and the relative electron density resolution was systematically investigated to estimate the proton dose needed to obtain a given density resolution. We show that a reasonable density resolution can be achieved with a relatively small dose, which is comparable to or even lower than that of x-ray CT.

Identification and characterization of the rlp1+, the novel Rad51 paralog in the fission yeast Schizosaccharomyces pombe.

A new DNA repair gene from fission yeast Schizosaccharomyces pombe rlp1+ (RecA-like protein) has been identified. Rlp1 shows homology to RecA-like proteins, and is the third S. pombe Rad51 paralog besides Rhp55 and Rhp57. The new gene encodes a 363 aa protein with predicted Mr of 41,700 and has NTP-binding motif. The rlp1Delta mutant is sensitive to methyl methanesulfonate (MMS), ionizing radiation (IR), and camptothecin (CPT), although to a lesser extent than the deletion mutants of rhp55+ and rhp51+ genes. In contrast to other recombinational repair mutants, the rlp1Delta mutant does not exhibit sensitivity to UV light and mitomycin C (MMC). Mitotic recombination is moderately reduced in rlp1 mutant. Epistatic analysis of MMS and IR-sensitivity of rlp1Delta mutant indicates that rlp1+ acts in the recombinational pathway of double-strand break (DSB) repair together with rhp51+, rhp55+, and rad22+ genes. Yeast two-hybrid analysis suggests that Rlp1 may interact with Rhp57 protein. We propose that Rlp1 have an accessory role in repair of a subset of DNA damage induced by MMS and IR, and is required for the full extent of DNA recombination and cell survival under condition of a replication fork collapse.