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Purpose: This study investigates scintillation dosimetry coupled with Cherenkov imaging for in vivo dose monitoring during whole breast radiation therapy (WBRT). Given recent observations of excess dose to the contralateral breast (CB), in vivo dosimetry (IVD) could help ensure accurate dose delivery and decrease risks of secondary cancer. This work presents a rapid, streamlined alternative to traditional IVD, providing direct visualization of measurement location relative to the treatment field on the patient., Methods and Materials: Ten WBRT patients consented under an institutional review board-approved protocol were monitored with scintillation dosimetry and always-on Cherenkov imaging, on both their treated and CB for 1 to 3 fractions. Scintillator dosimeters, small plastic discs 1 mm thick and 15 mm in diameter, were calibrated against optically stimulated luminescent dosimeters (OSLDs) to generate an integral output-to-dose conversion, where integral output is measured in postprocessing through a custom fitting algorithm. The discs have been extensively characterized in a previous study for various treatment conditions including beam energy and treatment geometry., Results: A total of 44 dosimetry measurements were evaluated, including 22 treated breast and 22 CB measurements. After integral output-to-dose calibration, in vivo scintillator dosimeters exhibited high linearity (R 2 = 0.99) with paired OSLD readings across all patients. The difference between scintillation and OSLD dose measurements averaged 2.8% of the prescribed dose, or an absolute dose difference of approximately 7 cGy., Conclusions: Integration of scintillation dosimetry with Cherenkov imaging offers an accurate, rapid alternative for in vivo dose verification in WBRT, circumventing the limitations of conventional point dosimeters. The additional benefit of visualizing measurement locations relative to the treatment field provides users an enhanced understanding of results and allows for detection of high dose gradients. Future work will explore the applicability of this technique across a broader range of radiation therapy treatments, aiming to streamline IVD practices., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To retrospectively validate the dose and dose rates delivered in FAST-01 clinical trial fields via submillimeter spatial and <0.25 ms temporal resolution scintillation imaging., Methods and Materials: An ultrafast intensified CMOS camera (4.5-12 kHz sampling rate) imaged the light response of a scintillator sheet at the treatment isocenter and irradiated by pencil beam scanning proton fields, including FAST-01 clinical fields. Dose and dose rate linearity studies were performed, followed by camera calibration via gafchromic (external beam therapy 3) film. An EDGE diode detector was placed directly under the scintillator at the surface and at a 5 cm depth for comparison with the imaging data and log files. Frame-by-frame analysis of image stacks yielded dose and dose rate maps for each delivery at the surface. Using the percent depth dose curves and 3-dimensional spot profiles, the surface images were projected to a 5 cm depth for comparison with a secondary diode and log file recordings., Results: Camera response was linear with dose (R 2 = 0.9998) and beam current (R 2 = 0.9883) from 2 to 12 Gy and 20 to 210 nA, respectively. Gamma analysis of the cumulative dose maps at 3%/2 mm indicated a mean passing rate of 100% compared with film. Total irradiation time agreed with the log file recordings with an average deviation of 0.20 ± 0.07 ms. At the surface, the average imaged dose rate across the 7 fields was 114 ± 1 Gy/s, agreeing with the diode within 1% ± 1%. The dose at a 5 cm depth from the projected images (mean, 8.4 Gy) agreed with the reported dose (log files) within 0.13 ± 0.03 Gy (2% ± 1%). The average dose rate from projected images at a 5 cm depth was 62 ± 1 Gy/s, which agreed with the reported and diode values within 2% ± 3%., Conclusions: This study provides the first independent validation of dose and dose rate for clinical proton FAST-01 fields at unprecedented spatiotemporal resolution. Owing to the nontrivial dose rate distributions in pencil beam scanning fields, such direct 2-dimensional dose rate mapping will be important in future pretreatment plan quality assurance., (Published by Elsevier Inc.)

Objective . To develop a robust method for non-contact surface dosimetry during Total Body Irradiation (TBI) that uses an optimally paired choice of scintillator material with camera photocathode and can work insensitively to the normal ambient room lighting conditions (∼500 Lux). Approach . This goal was approached by assessing the emission contrast of scintillator signal to background room ratio (SBR) detected by the camera, in the challening conditions of low dose rate TBI with high room lights. A total of 9 fast-response scintillators, 3 wavelength shifters, and 2 camera photocathodes were systematically tested to determine the optimal combination. The effects of room lights on the scintillator signal and the background signal were assessed to avoid signal saturation while retaining accurate dose measurement. A bandpass wavelength filter was then applied to reduce the effects on room lights and scintillator signal. Main Results . One scintillator (EJ262) combined with a blue-green sensitive photocathode camera and a 500 nm band pass filter produced the greatest available scintillator SBR of 95 with maximal room lights on. The caveat is that this design rejects all patient Cherenkov light, which can be useful for visualizing the patient treatment. Another option which retained the Cherenkov signal but produced less available scintillator signal was found with another scintillator (EJ-260) and a red photocathode camera with SBR of 35, but a narrow bandpass filter is required to make it work in ambient room lights, which addition will also remove most of the Cherenkov signal. Significance . Non-contact scintillator imaging can be used for surface dosimetry in TBI with appropriate pairing of scintillator emission spectrum and camera photocathode sensitivity or optical filtering range., (Creative Commons Attribution license.)

Purpose. Cherenkov imaging during radiotherapy provides a real time visualization of beam delivery on patient tissue, which can be used dynamically for incident detection or to review a summary of the delivered surface signal for treatment verification. Very few photons form the images, and one limitation is that the noise level per frame can be quite high, and mottle in the cumulative processed images can cause mild overall noise. This work focused on removing or suppressing noise via image postprocessing. Approach. Images were analyzed for peak-signal-to-noise and spatial frequencies present, and several established noise/mottle reduction algorithms were chosen based upon these observations. These included total variation minimization (TV-L1), non-local means filter (NLM), block-matching 3D (BM3D), alpha (adaptive) trimmed mean (ATM), and bilateral filtering. Each were applied to images acquired using a BeamSite camera (DoseOptics) imaged signal from 6x photons from a TrueBeam linac delivering dose at 600 MU min -1 incident on an anthropomorphic phantom and tissue slab phantom in various configurations and beam angles. The standard denoised images were tested for PSNR, noise power spectrum (NPS) and image sharpness. Results. The average peak-signal-to-noise ratio (PSNR) increase was 17.4% for TV-L1. NLM denoising increased the average PSNR by 19.1%, BM3D processing increased it by12.1% and the bilateral filter increased the average PSNR by 19.0%. Lastly, the ATM filter resulted in the lowest average PSNR increase of 10.9%. Of all of these, the NLM and bilateral filters produced improved edge sharpness with, generally, the lowest NPS curve. Conclusion. For cumulative image Cherenkov data, NLM and the bilateral filter yielded optimal denoising with the TV-L1 algorithm giving comparable results. Single video frame Cherenkov images exhibit much higher noise levels compared to cumulative images. Noise suppression algorithms for these frame rates will likely be a different processing pipeline involving these filters incorporated with machine learning., (Creative Commons Attribution license.)

Purpose: Large, rapid extracellular oxygen transients (ΔpO 2 ) have been measured in vivo during ultra-high dose rate radiation therapy; however, it has been unclear if they match intracellular oxygen levels. Here, the endogenously produced protoporphyrin IX (PpIX) delayed fluorescence signal was measured as an intracellular in-vivo oxygen sensor to quantify these transients, with direct comparison to extracellular pO 2 . Intracellular ΔpO 2 is closer to the cellular DNA, the site of major radiobiological damage, and therefore should help elucidate radiochemical mechanisms of the FLASH effect and potentially be translated to human tissue measurement., Methods and Materials: PpIX was induced in mouse skin through intraperitoneal injection of 250 mg/kg of aminolevulinic acid. The animals were also administered a 50 µL intradermal injection of 10 µM oxyphor G4 (PdG4) for phosphorescence lifetime pO 2 measurement. Paired oxygen transients were quantified in leg or flank tissues while delivering 10 MeV electrons in 3 µs pulses at 360 Hz for a total dose of 10 to 28 Gy., Results: Transient reductions in pO 2 were quantifiable in both PpIX delayed fluorescence and oxyphor phosphorescence, corresponding to intracellular and extracellular pO 2 values, respectively. Reponses were quantified for 10, 22, and 28 Gy doses, with ΔpO 2 found to be proportional to the dose on average. The ΔpO 2 values were dependent on initial pO 2 in a logistic function. The average and standard deviations in ΔpO 2 per dose were 0.56 ± 0.18 mm Hg/Gy and 0.43 ± 0.06 mm Hg/Gy for PpIX and oxyphor, respectively, for initial pO 2 > 20 mm Hg. Although there was large variability in the individual animal measurements of ΔpO 2 , the average values demonstrated a direct and proportional correlation between intracellular and extracellular pO 2 changes, following a linear 1:1 relationship., Conclusions: A fundamentally new approach to measuring intracellular oxygen depletion in living tissue showed that ΔpO 2 transients seen during ultra-high dose rate radiation therapy matched those quantified using extracellular oxygen measurement. This approach could be translated to humans to quantify intracellular ΔpO 2 . The measurement of these transients could potentially allow the estimation of intracellular reactive oxygen species production., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cherenkov imaging enables real-time visualization of megavoltage X-ray or electron beam delivery to the patient during Radiation Therapy (RT). Bio-morphological features, such as vasculature, seen in these images are patient-specific signatures that can be used for verification of positioning and motion management that are essential to precise RT treatment. However until now, no concerted analysis of this biological feature-based tracking was utilized because of the slow speed and accuracy of conventional image processing for feature segmentation. This study demonstrated the first deep learning framework for such an application, achieving video frame rate processing. To address the challenge of limited annotation of these features in Cherenkov images, a transfer learning strategy was applied. A fundus photography dataset including 20,529 patch retina images with ground-truth vessel annotation was used to pre-train a ResNet segmentation framework. Subsequently, a small Cherenkov dataset (1,483 images from 212 treatment fractions of 19 breast cancer patients) with known annotated vasculature masks was used to fine-tune the model for accurate segmentation prediction. This deep learning framework achieved consistent and rapid segmentation of Cherenkov-imaged bio-morphological features on another 19 patients, including subcutaneous veins, scars, and pigmented skin. Average segmentation by the model achieved Dice score of 0.85 and required less than 0.7 milliseconds processing time per instance. The model demonstrated outstanding consistency against input image variances and speed compared to conventional manual segmentation methods, laying the foundation for online segmentation in real-time monitoring in a prospective setting.

Background: Ultra-high dose rate radiotherapy (UHDR-RT) has demonstrated normal tissue sparing capabilities, termed the FLASH effect; however, available dosimetry tools make it challenging to characterize the UHDR beams with sufficiently high concurrent spatial and temporal resolution. Novel dosimeters are needed for safe clinical implementation and improved understanding of the effect of UHDR-RT., Purpose: Ultra-fast scintillation imaging has been shown to provide a unique tool for spatio-temporal dosimetry of conventional cyclotron pencil beam scanning (PBS) deliveries, indicating the potential use for characterization of UHDR PBS proton beams. The goal of this work is to introduce this novel concept and demonstrate its capabilities in recording high-resolution dose rate maps at FLASH-capable proton beam currents, as compared to log-based dose rate calculation, internally developed UHDR beam simulation, and a fast point detector (EDGE diode)., Methods: The light response of a scintillator sheet located at isocenter and irradiated by PBS proton fields (40-210 nA, 250 MeV) was imaged by an ultra-fast iCMOS camera at 4.5-12 kHz sampling frequency. Camera sensor and image intensifier gain were optimized to maximize the dynamic range; the camera acquisition rate was also varied to evaluate the optimal sampling frequency. Large field delivery enabled flat field acquisition for evaluation of system response homogeneity. Image intensity was calibrated to dose with film and the recorded spatio-temporal data was compared to a PPC05 ion chamber, log-based reconstruction, and EDGE diode. Dose and dose rate linearity studies were performed to evaluate agreement under various beam conditions. Calculation of full-field mean and PBS dose rate maps were calculated to highlight the importance of high resolution, full-field information in UHDR studies., Results: Camera response was linear with dose (R 2 = 0.997) and current (R2 2 = 0.98) in the range from 2-22 Gy and 40-210 nA, respectively, when compared to ion chamber readings. The deviation of total irradiation time calculated with the imaging system from the log file recordings decreased from 0.07% to 0.03% when imaging at 12 kfps versus 4.5 kfps. Planned and delivered spot positions agreed within 0.2 ± $\pm$ 0.1 mm and total irradiation time agreed within 0.2 ± $\pm$ 0.2 ms when compared with the log files, indicating the high concurrent spatial and temporal resolution. For all deliveries, the PBS dose rate measured at the diode location agreed between the imaging and the diode within 3% ± $\pm$ 2% and with the simulation within 5% ± $\pm$ 3% CONCLUSIONS: Full-field mapping of dose and dose rate is imperative for complete understanding of UHDR PBS proton dose delivery. The high linearity and various spatiotemporal metric reporting capabilities confirm the continued use of this camera system for UHDR beam characterization, especially for spatially resolved dose rate information., (© 2024 American Association of Physicists in Medicine.)

Tissue oxygenation is well understood to impact radiosensitivity, with reports demonstrating a significant effect of breathing condition and anesthesia type on tissue oxygenation levels and radiobiological response. However, the temporal kinetics of intracellular and extracellular oxygenation have never been quantified, on the timescale that may affect radiotherapy studies. C57BL/6 mice were anesthetized using isoflurane at various percentages or ketamine/xylazine (ket/xyl: 100/10 mg/kg) (N = 48). Skin pO 2 was measured using Oxyphor PdG4 and tracked after anesthetization began. Oxyphor data was validated with relative measurements of intracellular oxygen via protoporphyrin IX (PpIX) delayed fluorescence (DF) imaging. Ex vivo localization of both PdG4 Oxyphor and PpIX were quantified. Under all isoflurane anesthesia conditions, leg skin pO2 levels significantly increased from 12-15 mmHg at the start of anesthesia induction (4-6 minutes) to 24-27 mmHg after 10 minutes (p < 0.05). Ketamine/xylazine anesthesia led to skin pO2 maintained at 15-16 mmHg throughout the 10-minute study period (p < 0.01). An increase of pO2 in mice breathing isoflurane was demonstrated with Oxyphor and PpIX DF, indicating similar intracellular and extracellular oxygenation. These findings demonstrate the importance of routine anesthesia administration, where consistency in the timing between induction and irradiation may be crucial to minimizing variability in radiation response., Competing Interests: Declarations Additional Declarations: No competing interests reported.

Fluorescence guidance is routinely used in surgery to enhance perfusion contrast in multiple types of diseases. Pressure-enhanced sensing of tissue oxygenation (PRESTO) via fluorescence is a technique extensively analyzed here, that uses an FDA-approved human precursor molecule, 5-aminolevulinic acid (ALA), to stimulate a unique delayed fluorescence signal that is representative of tissue hypoxia. The ALA precontrast agent is metabolized in most tissues into a red fluorescent molecule, protoporphyrin IX (PpIX), which has both prompt fluorescence, indicative of the concentration, and a delayed fluorescence, that is amplified in low tissue oxygen situations. Applied pressure from palpation induces transient capillary stasis and a resulting transient PRESTO contrast, dominant when there is near hypoxia. This study examined the kinetics and behavior of this effect in both normal and tumor tissues, with a prolonged high PRESTO contrast (contrast to background of 7.3) across 5 tumor models, due to sluggish capillaries and inhibited vasodynamics. This tissue function imaging approach is a fundamentally unique tool for real-time palpation-induced tissue response in vivo, relevant for chronic hypoxia, such as vascular diseases or oncologic surgery., Competing Interests: Competing interests statement:A.F.P., P.B., and B.W.P. declare financial involvement with DoseOptics LLC outside of the scope of this work. DoseOptics LLC develops camera systems and software for radiotherapy imaging of Cherenkov light for dosimetry. P.B., B.W.P., and A.F.P. were named inventors on a patent describing the technology used for PRESTO imaging as protected by patent PCT/US23/10825 B.W.P., P.B., and A.F.P. 2023.

Objective . The FLASH effect can potentially be used to improve the therapeutic ratio of radiotherapy (RT) through delivery of Ultra-high-dose-rate (UHDR) irradiation. Research is actively being conducted to translate UHDR-RT and for this purpose the Mobetron is capable of producing electron beams at both UHDR and conventional dose rates for FLASH research and translation. This work presents commissioning of an UHDR Mobetron with end-to-end tests developed for preclinical research. Approach . UHDR electron beams were commissioned with an efficient approach utilizing a 3D-printed water tank and film to fully characterize beam characteristics and dependences on field size, pulse width (PW) and pulse repetition frequency (PRF). This commissioning data was used to implement a beam model using the GAMOS Monte Carlo toolkit for the preclinical research. Then, the workflow for preclinical FLASH irradiation was validated with end-to-end tests delivered to a 3D-printed mouse phantom with internal inhomogeneities. Main results. PDDs, profiles and output factors acquired with radiochromic films were precisely measured, with a PRF that showed little effect on the UHDR beam energy and spatial characteristics. Increasing PW reduced the D max and R 50 by 2.08 mm µ s -1 and 1.28 mm µ s -1 respectively. An end-to-end test of the preclinical research workflow showed that both profiles in head-foot and lateral directions were in good agreement with the MC calculations for the heterogeneous 3D printed mouse phantom with Gamma index above 93% for 2 mm/2% criteria, and 99% for 3 mm/3%. Significance . The UHDR Mobetron is a versatile tool for FLASH preclinical research and this comprehensive beam model and workflow was validated to meet the requirements for conducting translational FLASH research., (© 2024 Institute of Physics and Engineering in Medicine.)

Background: While careful planning and pre-treatment checks are performed to ensure patient safety during external beam radiation therapy (EBRT), inevitable daily variations mean that in vivo dosimetry (IVD) is the only way to attain the true delivered dose. Several countries outside the US require daily IVD for quality assurance. However, elsewhere, the manual labor and time considerations of traditional in vivo dosimeters may be preventing frequent use of IVD in the clinic., Purpose: This study expands upon previous research using plastic scintillator discs for optical dosimetry for electron therapy treatments. We present the characterization of scintillator discs for in vivo x-ray dosimetry and describe additional considerations due to geometric complexities., Methods: Plastic scintillator discs were coated with reflective white paint on all sides but the front surface. An anti-reflective, matte coating was applied to the transparent face to minimize specular reflection. A time-gated iCMOS camera imaged the discs under various irradiation conditions. In post-processing, background-subtracted images of the scintillators were fit with Gaussian-convolved ellipses to extract several parameters, including integral output, and observation angle., Results: Dose linearity and x-ray energy independence were observed, consistent with ideal characteristics for a dosimeter. Dose measurements exhibited less than 5% variation for incident beam angles between 0° and 75° at the anterior surface and 0-60 ∘ $^\circ $ at the posterior surface for exit beam dosimetry. Varying the angle between the disc surface and the camera lens did not impact the integral output for the same dose up to 55°. Past this point, up to 75°, there is a sharp falloff in response; however, a correction can be used based on the detected width of the disc. The reproducibility of the integral output for a single disc is 2%, and combined with variations from the gantry angle, we report the accuracy of the proposed scintillator disc dosimeters as ±5.4%., Conclusions: Plastic scintillator discs have characteristics that are well-suited for in vivo optical dosimetry for x-ray radiotherapy treatments. Unlike typical point dosimeters, there is no inherent readout time delay, and an optical recording of the measurement is saved after treatment for future reference. While several factors influence the integral output for the same dose, they have been quantified here and may be corrected in post-processing., (© 2024 American Association of Physicists in Medicine.)

Background: Ultra-high-dose-rate (UHDR) electron beams have been commonly utilized in FLASH studies and the translation of FLASH Radiotherapy (RT) to the clinic. The EDGE diode detector has potential use for UHDR dosimetry albeit with a beam energy dependency observed., Purpose: The purpose is to present the electron beam response for an EDGE detector in dependence on beam energy, to characterize the EDGE detector's response under UHDR conditions, and to validate correction factors derived from the first detailed Monte Carlo model of the EDGE diode against measurements, particularly under UHDR conditions., Methods: Percentage depth doses (PDDs) for the UHDR Mobetron were measured with both EDGE detectors and films. A detailed Monte Carlo (MC) model of the EDGE detector has been configured according to the blueprint provided by the manufacturer under an NDA agreement. Water/silicon dose ratios of EDGE detector for a series of mono-energetic electron beams have been calculated. The dependence of the water/silicon dose ratio on depth for a FLASH relevant electron beam was also studied. An analytical approach for the correction of PDD measured with EDGE detectors was established., Results: Water/silicon dose ratio decreased with decreasing electron beam energy. For the Mobetron 9 MeV UHDR electron beam, the ratio decreased from 1.09 to 1.03 in the build-up region, maintained in range of 0.98-1.02 at the fall-off region and raised to a plateau in value of 1.08 at the tail. By applying the corrections, good agreement between the PDDs measured by the EDGE detector and those measured with film was achieved., Conclusions: Electron beam response of an UHDR capable EDGE detector was derived from first principles utilizing a sophisticated MC model. An analytical approach was validated for the PDDs of UHDR electron beams. The results demonstrated the capability of EDGE detector in measuring PDDs of UHDR electron beams., (© 2024 American Association of Physicists in Medicine.)

Purpose: In this study, a C-series linear accelerator was configured to enable rapid and reliable conversion between the production of conventional electron beams and an ultrahigh-dose-rate (UHDR) electron beamline to the treatment room isocenter for FLASH radiation therapy. Efforts to tune the beam resulted in a consistent, stable UHDR beamline., Methods and Materials: The linear accelerator was configured to allow for efficient switching between conventional and modified electron output modes within 2 minutes. Additions to the air system allow for retraction of the x-ray target from the beamline when the 10 MV photon mode is selected. With the carousel set to an empty port, this grants access to the higher current pristine electron beam normally used to produce clinical photon fields. Monitoring signals related to the automatic frequency control system allows for tuning of the waveguide while the machine is in a hold state so a stable beam is produced from the initial pulse. A pulse counting system implemented on an field-programmable gate array-based controller platform controls the delivery to a desired number of pulses. Beam profiles were measured with Gafchromic film. Pulse-by-pulse dosimetry was measured using a custom electrometer designed around the EDGE diode., Results: This method reliably produces a stable UHDR electron beam. Open-field measurements of the 16-cm full-width, half-maximum gaussian beam saw average dose rates of 432 Gy/s at treatment isocenter. Pulse overshoots were limited and ramp up was eliminated. Over the last year, there have been no recorded incidents that resulted in machine downtime due to the UHDR conversions., Conclusions: Stable 10 MeV UHDR beams were generated to produce an average dose rate of 432 Gy/s at the treatment room isocenter. With a reliable pulse-counting beam control system, consistent doses can be delivered for FLASH experiments with the ability to accommodate a wide range of field sizes, source-to-surface distances, and other experimental apparatus that may be relevant for future clinical translation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: FLASH radiotherapy based on ultra-high dose rate (UHDR) is actively being studied by the radiotherapy community. Dedicated UHDR electron devices are currently a mainstay for FLASH studies., Purpose: To present the first Monte Carlo (MC) electron beam model for the UHDR capable Mobetron (FLASH-IQ) as a dose calculation and treatment planning platform for preclinical research and FLASH-radiotherapy (RT) clinical trials., Methods: The initial beamline geometry of the Mobetron was provided by the manufacturer, with the first-principal implementation realized in the Geant4-based GAMOS MC toolkit. The geometry and electron source characteristics, such as energy spectrum and beamline parameters, were tuned to match the central-axis percentage depth dose (PDD) and lateral profiles for the pristine beam measured during machine commissioning. The thickness of the small foil in secondary scatter affected the beam model dominantly and was fine tuned to achieve the best agreement with commissioning data. Validation of the MC beam modeling was performed by comparing the calculated PDDs and profiles with EBT-XD radiochromic film measurements for various combinations of applicators and inserts., Results: The nominal 9 MeV electron FLASH beams were best represented by a Gaussian energy spectrum with mean energy of 9.9 MeV and variance (σ) of 0.2 MeV. Good agreement between the MC beam model and commissioning data were demonstrated with maximal discrepancy < 3% for PDDs and profiles. Hundred percent gamma pass rate was achieved for all PDDs and profiles with the criteria of 2 mm/3%. With the criteria of 2 mm/2%, maximum, minimum and mean gamma pass rates were (100.0%, 93.8%, 98.7%) for PDDs and (100.0%, 96.7%, 99.4%) for profiles, respectively., Conclusions: A validated MC beam model for the UHDR capable Mobetron is presented for the first time. The MC model can be utilized for direct dose calculation or to generate beam modeling input required for treatment planning systems for FLASH-RT planning. The beam model presented in this work should facilitate translational and clinical FLASH-RT for trials conducted on the Mobetron FLASH-IQ platform., (© 2024 American Association of Physicists in Medicine.)

Background: Dosimetry in pre-clinical FLASH studies is essential for understanding the beam delivery conditions that trigger the FLASH effect. Resolving the spatial and temporal characteristics of proton pencil beam scanning (PBS) irradiations with ultra-high dose rates (UHDR) requires a detector with high spatial and temporal resolution., Purpose: To implement a novel camera-based system for time-resolved two-dimensional (2D) monitoring and apply it in vivo during pre-clinical proton PBS mouse irradiations., Methods: Time-resolved 2D beam monitoring was performed with a scintillation imaging system consisting of a 1 mm thick transparent scintillating sheet, imaged by a CMOS camera. The sheet was placed in a water bath perpendicular to a horizontal PBS proton beam axis. The scintillation light was reflected through a system of mirrors and captured by the camera with 500 frames per second (fps) for UHDR and 4 fps for conventional dose rates. The raw images were background subtracted, geometrically transformed, flat field corrected, and spatially filtered. The system was used for 2D spot and field profile measurements and compared to radiochromic films. Furthermore, spot positions were measured for UHDR irradiations. The measured spot positions were compared to the planned positions and the relative instantaneous dose rate to equivalent fiber-coupled point scintillator measurements. For in vivo application, the scintillating sheet was placed 1 cm upstream the right hind leg of non-anaesthetized mice submerged in the water bath. The mouse leg and sheet were both placed in a 5 cm wide spread-out Bragg peak formed from the mono-energetic proton beam by a 2D range modulator. The mouse leg position within the field was identified for both conventional and FLASH irradiations. For the conventional irradiations, the mouse foot position was tracked throughout the beam delivery, which took place through repainting. For FLASH irradiations, the delivered spot positions and relative instantaneous dose rate were measured., Results: The pixel size was 0.1 mm for all measurements. The spot and field profiles measured with the scintillating sheet agreed with radiochromic films within 0.4 mm. The standard deviation between measured and planned spot positions was 0.26 mm and 0.35 mm in the horizontal and vertical direction, respectively. The measured relative instantaneous dose rate showed a linear relation with the fiber-coupled scintillator measurements. For in vivo use, the leg position within the field varied between mice, and leg movement up to 3 mm was detected during the prolonged conventional irradiations., Conclusions: The scintillation imaging system allowed for monitoring of UHDR proton PBS delivery in vivo with 0.1 mm pixel size and 2 ms temporal resolution. The feasibility of instantaneous dose rate measurements was demonstrated, and the system was used for validation of the mouse leg position within the field., (© 2024 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Objective . Imaging of optical photons emitted from tissue during radiotherapy is a promising technique for real-time visualization of treatment delivery, offering applications in dose verification, treatment monitoring, and retrospective treatment plan comparison. This research aims to explore the feasibility of intensified imaging of tissue luminescence during proton therapy (PT), under both conventional and ultra-high dose rate (UHDR) conditions. Approach . Conventional and UHDR pencil beam scanning (PBS) PT irradiation of fresh ex vivo porcine tissue and tissue-mimicking plastic phantom was imaged using intensified complementary metal-oxide-semiconductor(CMOS) cameras. The optical emission from tissue was characterized during conventional irradiation using both blue and red-sensitive intensifiers to ensure adequate spectral coverage. Spectral characterization was performed using bandpass filters between the lens and sensor. Imaging of conventional proton fields (240 MeV, 10 nA) was performed at 100 Hz frame rate, while UHDR PBS proton delivery (250 MeV, 99 nA) was recorded at 1 kHz frame rate. Dependence of optical emission yield on proton energy was studied using an optical tissue-mimicking plastic phantom and a range shifter. Finally, we demonstrated fast beam tracking capability of fast camera towards in vivo monitoring of FLASH PT. Main results . Under conventional treatment dose rates optical emission was imaged with single spot resolution. Spot profiles were found to agree with the treatment planning system calculation within >90% for all spectral bands and spot intensity was found to vary with spectral filtration. The resultant polychromatic emission presented a maximum intensity at 650 nm and decreasing signal at lower wavelengths, which is consistent with expected attenuation patterns of high fat and muscle tissue. For UHDR beam imaging, optical yield increased with higher proton energy. Imaging at 1 kHz allowed continuous monitoring of delivery during porcine tissue irradiation, with clear identification of individual dwell positions. The number of dwell positions matched the treatment plan in total and per row showing adequate temporal capability of iCMOS imaging. Significance . For the first time, this study characterizes optical emission from tissue during PT and demonstrates our capability of fast optical tracking of pencil proton beam on the tissue anatomy in both conventional and UHDR setting. Similar to the Cherenkov imaging in radiotherapy, this imaging modality could enable a seamless, independent validation of PT treatments., (Creative Commons Attribution license.)

Significance: Fluorescence guidance is used clinically by surgeons to visualize anatomical and/or physiological phenomena in the surgical field that are difficult or impossible to detect by the naked eye. Such phenomena include tissue perfusion or molecular phenotypic information about the disease being resected. Conventional fluorescence-guided surgery relies on long, microsecond scale laser pulses to excite fluorescent probes. However, this technique only provides two-dimensional information; crucial depth information, such as the location of malignancy below the tissue surface, is not provided., Aim: We developed a depth sensing imaging technique using light detection and ranging (LiDAR) time-of-flight (TOF) technology to sense the depth of target tissue while overcoming the influence of tissue optical properties and fluorescent probe concentration., Approach: The technology is based on a large-format ( 512 × 512   pixel ), binary, gated, single-photon avalanche diode (SPAD) sensor with an 18 ps time-gate step, synchronized with a picosecond pulsed laser. The fast response of the sensor was developed and tested for its ability to quantify fluorescent inclusions at depth and optical properties in tissue-like phantoms through analytical model fitting of the fast temporal remission data., Results: After calibration and algorithmic extraction of the data, the SPAD LiDAR technique allowed for sub-mm resolution depth sensing of fluorescent inclusions embedded in tissue-like phantoms, up to a maximum of 5 mm in depth. The approach provides robust depth sensing even in the presence of variable tissue optical properties and separates the effects of fluorescence depth from absorption and scattering variations., Conclusions: LiDAR TOF fluorescence imaging using an SPAD camera provides both fluorescence intensity images and the temporal profile of fluorescence, which can be used to determine the depth at which the signal is emitted over a wide field of view. The proposed tool enables fluorescence imaging at a higher depth in tissue and with higher spatial precision than standard, steady-state fluorescence imaging tools, such as intensity-based near-infrared fluorescence imaging, optical coherence tomography, Raman spectroscopy, or confocal microscopy. Integration of this technique into a standard surgical tool could enable rapid, more accurate estimation of resection boundaries, thereby improving the surgeon's efficacy and efficiency, and ultimately improving patient outcomes., (© 2024 The Authors.)

Objective . With the introduction of Cherenkov imaging technology on the Halcyon O-ring linear accelerator platform, we seek to demonstrate the imaging feasibility and optimize camera placement. Approach . Imaging parameters were probed by acquiring triggering data Cherenkov image frames for simplistic beams on the Halcyon and comparing the analyzed metrics with those from the TrueBeam platform. Camera position was analyzed by performing 3D rendering of patient treatment plans for various sites and iterating over camera positions to assess treatment area visibility. Main results . Commercial Cherenkov imaging systems are compatible with the pulse timing of the Halcyon, and this platform design favorably impacts signal to noise in Cherenkov image frames. Additionally, ideal camera placement is treatment site dependent and is always within a biconical zone of visibility centered on the isocenter. Visibility data is provided for four treatment sites, with suggestions for camera placement based on room dimensions. Median visibility values were highest for right breast plans, with values of 80.33% and 68.49% for the front and rear views respectively. Head and neck plans presented with the lowest values at 26.44% and 38.18% respectively. Significance . This work presents the first formal camera positional analysis for Cherenkov imaging on any platform and serves as a template for performing similar work for other irradiation platforms. Additionally, this study confirms the Cherenkov imaging parameters do not need to be changed for optimal imaging on the Halcyon. Lastly, the presented methodology provides a framework which could be further expanded to other optical imaging systems which rely on line of sight visibility to the patient., (© 2023 Institute of Physics and Engineering in Medicine.)

This exploratory study investigates a human agent's evolving judgements of reliability when interacting with an AI system. Two aims drove this investigation: (1) compare the predictive performance of quantum vs. Markov random walk models regarding human reliability judgements of an AI system and (2) identify a neural correlate of the perturbation of a human agent's judgement of the AI's reliability. As AI becomes more prevalent, it is important to understand how humans trust these technologies and how trust evolves when interacting with them. A mixed-methods experiment was developed for exploring reliability calibration in human-AI interactions. The behavioural data collected were used as a baseline to assess the predictive performance of the quantum and Markov models. We found the quantum model to better predict the evolving reliability ratings than the Markov model. This may be due to the quantum model being more amenable to represent the sometimes pronounced within-subject variability of reliability ratings. Additionally, a clear event-related potential response was found in the electroencephalographic (EEG) data, which is attributed to the expectations of reliability being perturbed. The identification of a trust-related EEG-based measure opens the door to explore how it could be used to adapt the parameters of the quantum model in real time.

Recent studies suggest ultra-high dose rate radiation treatment (UHDR-RT) reduces normal tissue damage compared to conventional radiation treatment (CONV-RT) at the same dose. In this study, we compared first, the kinetics and degree of skin damage in wild-type C57BL/6 mice, and second, tumor treatment efficacy in GL261 and B16F10 dermal tumor models, at the same UHDR-RT and CONV-RT doses. Flank skin of wild-type mice received UHDR-RT or CONV-RT at 25 Gy and 30 Gy. Normal skin damage was tracked by clinical observation to determine the time to moist desquamation, an endpoint which was verified by histopathology. Tumors were inoculated on the right flank of the mice, then received UHDR-RT or CONV-RT at 1 × 11 Gy, 1 × 15, 1 × 25, 3 × 6 and 3 × 8 Gy, and time to tumor tripling volume was determined. Tumors also received 1 × 11, 1 × 15, 3 × 6 and 3 × 8 Gy doses for assessment of CD8+/CD4+ tumor infiltrate and genetic expression 96 h postirradiation. All irradiations of the mouse tumor or flank skin were performed with megavoltage electron beams (10 MeV, 270 Gy/s for UHDR-RT and 9 MeV, 0.12 Gy/s for CONV-RT) delivered via a clinical linear accelerator. Tumor control was statistically equal for similar doses of UHDR-RT and CONV-RT in B16F10 and GL261 murine tumors. There were variable qualitative differences in genetic expression of immune and cell damage-associated pathways between UHDR and CONV irradiated B16F10 tumors. Compared to CONV-RT, UHDR-RT resulted in an increased latent period to skin desquamation after a single 25 Gy dose (7 days longer). Time to moist skin desquamation did not significantly differ between UHDR-RT and CONV-RT after a 30 Gy dose. The histomorphological characteristics of skin damage were similar for UHDR-RT and CONV-RT. These studies demonstrated similar tumor control responses for equivalent single and fractionated radiation doses, with variable difference in expression of tumor progression and immune related gene pathways. There was a modest UHDR-RT skin sparing effect after a 1 × 25 Gy dose but not after a 1 × 30 Gy dose., (©2023 by Radiation Research Society. All rights of reproduction in any form reserved.)

Background: Ultra-high dose rate (UHDR) FLASH beams typically deliver dose at rates of  >40 Gy/sec. Characterization of these beams with respect to dose, mean dose rate, and dose per pulse requires dosimeters which exhibit high temporal resolution and fast readout capabilities., Purpose: A diode EDGE Detector with a newly designed electrometer has been characterized for use in an UHDR electron beam and demonstrated appropriateness for UHDR FLASH radiotherapy dosimetry., Methods: Dose linearity, mean dose rate, and dose per pulse dependencies of the EDGE Detector were quantified and compared with dosimeters including a W1 scintillator detector, radiochromic film, and ionization chamber that were irradiated with a 10 MeV UHDR beam. The dose, dose rate, and dose per pulse were controlled via an in-house developed scintillation-based feedback mechanism, repetition rate of the linear accelerator, and source-to-surface distance, respectively. Depth-dose profiles and temporal profiles at individual pulse resolution were compared to the film and scintillation measurements, respectively. The radiation-induced change in response sensitivity was quantified via irradiation of ∼5kGy., Results: The EDGE Detector agreed with film measurements in the measured range with varying dose (up to 70 Gy), dose rate (nearly 200 Gy/s), and dose per pulse (up to 0.63 Gy/pulse) on average to within 2%, 5%, and 1%, respectively. The detector also agreed with W1 scintillation detector on average to within 2% for dose per pulse (up to 0.78 Gy/pulse). The EDGE Detector signal was proportional to ion chamber (IC) measured dose, and mean dose rate in the bremsstrahlung tail to within 0.4% and 0.2% respectively. The EDGE Detector measured percent depth dose (PDD) agreed with film to within 3% and per pulse output agreed with W1 scintillator to within -6% to +5%. The radiation-induced response decrease was 0.4% per kGy., Conclusions: The EDGE Detector demonstrated dose linearity, mean dose rate independence, and dose per pulse independence for UHDR electron beams. It can quantify the beam spatially, and temporally at sub millisecond resolution. It's robustness and individual pulse detectability of treatment deliveries can potentially lead to its implementation for in vivo FLASH dosimetry, and dose monitoring., (© 2023 American Association of Physicists in Medicine.)

Significance: High-energy x-ray delivery from a linear accelerator results in the production of spectrally continuous broadband Cherenkov light inside tissue. In the absence of attenuation, there is a linear relationship between Cherenkov emission and deposited dose; however, scattering and absorption result in the distortion of this linear relationship. As Cherenkov emission exits the absorption by tissue dominates the observed Cherenkov emission spectrum. Spectroscopic interpretation of this effects may help to better relate Cherenkov emission to ionizing radiation dose delivered during radiotherapy., Aim: In this study, we examined how color Cherenkov imaging intensity variations are caused by absorption from both melanin and hemoglobin level variations, so that future Cherenkov emission imaging might be corrected for linearity to delivered dose., Approach: A custom, time-gated, three-channel intensified camera was used to image the red, green, and blue wavelengths of Cherenkov emission from tissue phantoms with synthetic melanin layers and varying blood concentrations. Our hypothesis was that spectroscopic separation of Cherenkov emission would allow for the identification of attenuated signals that varied in response to changes in blood content versus melanin content, because of their different characteristic absorption spectra., Results: Cherenkov emission scaled with dose linearly in all channels. Absorption in the blue and green channels increased with increasing oxy-hemoglobin in the blood to a greater extent than in the red channel. Melanin was found to absorb with only slight differences between all channels. These spectral differences can be used to derive dose from measured Cherenkov emission., Conclusions: Color Cherenkov emission imaging may be used to improve the optical measurement and determination of dose delivered in tissues. Calibration for these factors to minimize the influence of the tissue types and skin tones may be possible using color camera system information based upon the linearity of the observed signals., (© 2023 The Authors.)

Purpose: The use of a linear accelerator (LINAC) in ultrahigh-dose-rate (UHDR) mode can provide a conduit for wider access to UHDR FLASH effects, sparing normal tissue, but care needs to be taken in the use of such systems to ensure errors are minimized. The failure mode and effects analysis was carried out in a team that has been involved in converting a LINAC between clinical use and UHDR experimental mode for more than 1 year after the proposed methods of TG100., Methods and Materials: A team of 9 professionals with extensive experience were polled to outline the process map and workflow for analysis, and developed fault trees for potential errors, as well as failure modes that would result. The team scored the categories of severity magnitude, occurrence likelihood, and detectability potential in a scale of 1 to 10, so that a risk priority number (RPN = severity×occurrence×detectability) could be assessed for each., Results: A total of 46 potential failure modes were identified, including 5 with an RPN >100. These failure modes involved (1) patient set up, (2) gating mechanisms in delivery, and (3) detector in the beam stop mechanism. The identified methods to mitigate errors included the (1) use of a checklist post conversion, (2) use of robust radiation detectors, (3) automation of quality assurance and beam consistency checks, and (4) implementation of surface guidance during beam delivery., Conclusions: The failure mode and effects analysis process was considered critically important in this setting of a new use of a LINAC, and the expert team developed a higher level of confidence in the ability to safely move UHDR LINAC use toward expanded research access., (Copyright © 2022. Published by Elsevier Inc.)

Objective. To demonstrates the ability of an ultra-fast imaging system to measure high resolution spatial and temporal beam characteristics of a synchrocyclotron proton pencil beam scanning (PBS) system. Approach. An ultra-fast (1 kHz frame rate), intensified CMOS camera was triggered by a scintillation sheet coupled to a remote trigger unit for beam on detection. The camera was calibrated using the linear ( R 2 > 0.9922) dose response of a single spot beam to varying currents. Film taken for the single spot beam was used to produce a scintillation intensity to absolute dose calibration. Main results . Spatial alignment was confirmed with the film, where the x and y -profiles of the single spot cumulative image agreed within 1 mm. A sample brain patient plan was analyzed to demonstrate dose and temporal accuracy for a clinically-relevant plan, through agreement within 1 mm to the planned and delivered spot locations. The cumulative dose agreed with the planned dose with a gamma passing rate of 97.5% (2 mm/3%, 10% dose threshold). Significance . This is the first system able to capture single-pulse spatial and temporal information for the unique pulse structure of a synchrocyclotron PBS systems at conventional dose rates, enabled by the ultra-fast sampling frame rate of this camera. This study indicates that, with continued camera development and testing, target applications in clinical and FLASH proton beam characterization and validation are possible., (Creative Commons Attribution license.)

The context-sensitivity of cognition has been demonstrated across a wide range of cognitive functions such as perception, memory, judgement and decision making. A related term, 'contextuality', has appeared from the field of quantum cognition, with mounting empirical evidence demonstrating that cognitive phenomena are sometimes contextual. Contextuality is a subtle notion that influences how we must view the properties of the cognitive phenomenon being studied. This article addresses the questions: What does it mean for a cognitive phenomenon to be contextual? What are the implications of contextuality for probabilistic models of cognition? How does contextuality differ from context-sensitivity? Starting from George Boole's "conditions of possible experience", we argue that a probabilistic model of a cognitive phenomenon is necessarily subject to an assumption of realism. By this we mean that the phenomenon being studied is assumed to have cognitive properties with a definite value independent of observation. In contrast, quantum cognition holds that a cognitive property maybe indeterminate, i.e., its properties do not have well established values prior to observation. We argue that indeterminacy is sufficient for incompatibility between cognitive properties. In turn, incompatibility is necessary for their contextuality. The significance of this argument for cognitive psychology is the following:if a cognitive phenomenon is found to be contextual, then there is reason to believe it may be indeterminate. We illustrate by means of two crowdsourced experiments how context-sensitivity and contextuality of cognitive properties in the form of facial trait judgements can be characterized from empirical data. Finally, we conceptually and formally contrast contextuality with context-sensitivity. We propose that both involve a form of context dependence, with causality being the differentiating factor: the context dependence in context-sensitivity has a causal basis, whereas the context dependence in contextuality is acausal. The resulting implications for probabilistic models of cognition are discussed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Cherenkov imaging is clinically available as a radiation therapy treatment verification tool. The aim of this work was to discover the benefits of always-on Cherenkov imaging as a novel incident detection and quality improvement system through review of all imaging at our center., Methods and Materials: Multicamera Cherenkov imaging systems were permanently installed in 3 treatment bunkers, imaging continuously over a year. Images were acquired as part of normal treatment procedures and reviewed for potential treatment delivery anomalies., Results: In total, 622 unique patients were evaluated for this study. We identified 9 patients with treatment anomalies occurring over their course of treatment, which were only detected with Cherenkov imaging. Categorizing each event indicated issues arising in simulation, planning, pretreatment review, and treatment delivery, and none of the incidents were detected before this review by conventional measures. The incidents identified in this study included dose to unintended areas in planning, dose to unintended areas due to positioning at treatment, and nonideal bolus placement during setup., Conclusions: Cherenkov imaging was shown to provide a unique method of detecting radiation therapy incidents that would have otherwise gone undetected. Although none of the events detected in this study reached the threshold of reporting, they identified opportunities for practice improvement and demonstrated added value of Cherenkov imaging in quality assurance programs., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Introduction/background: The goal of Total Skin Electron Therapy (TSET) is to achieve a uniform surface dose, although assessment of this is never really done and typically limited points are sampled. A computational treatment simulation approach was developed to estimate dose distributions over the body surface, to compare uniformity of (i) the 6 pose Stanford technique and (ii) the rotational technique., Methods: The relative angular dose distributions from electron beam irradiation was calculated by Monte Carlo simulation for cylinders with a range of diameters, approximating body part curvatures. These were used to project dose onto a 3D body model of the TSET patient's skin surfaces. Computer animation methods were used to accumulate the dose values, for display and analysis of the homogeneity of coverage., Results: The rotational technique provided more uniform coverage than the Stanford technique. Anomalies of under dose were observed in lateral abdominal regions, above the shoulders and in the perineum. The Stanford technique had larger areas of low dose laterally. In the rotational technique, 90% of the patient's skin was within ±10% of the prescribed dose, while this percentage decreased to 60% or 85% for the Stanford technique, varying with patient body mass. Interestingly, the highest discrepancy was most apparent in high body mass patients, which can be attributed to the loss of tangent dose at low angles of curvature., Discussion/conclusion: This simulation and visualization approach is a practical means to analyze TSET dose, requiring only optical surface body topography scans. Under- and over-exposed body regions can be found, and irradiation could be customized to each patient. Dose Area Histogram (DAH) distribution analysis showed the rotational technique to have better uniformity, with most areas within 10% of the umbilicus value. Future use of this approach to analyze dose coverage is possible as a routine planning tool., (Copyright © 2022. Published by Elsevier Inc.)

Significance: Hypoxia imaging for surgical guidance has never been possible, yet it is well known that most tumors have microregional chronic and/or cycling hypoxia present as well as chaotic blood flow. The ability to image oxygen partial pressure (pO2) is therefore a unique control of tissue metabolism and can be used in a range of disease applications to understand the complex biochemistry of oxygen supply and consumption., Aim: Delayed fluorescence (DF) from the endogenous molecule protoporphyrin IX (PpIX) has been shown to be a truly unique reporter of the local oxygen partial pressure in tissue. PpIX is endogenously synthesized by mitochondria in most tissues, and the particular property of DF emission is directly related to low microenvironmental oxygen concentration. Here, it is shown that PpIX has a unique emission in hypoxic tumor tissue regions, which is measured as a DF signal in the red to near-infrared spectrum., Approach: A time-gated imaging system was used for PpIX DF for wide field direct mapping of pO2 changes. Acquiring both prompt and DF in a rapid sequential cycle allowed for imaging oxygenation in a way that was insensitive to the PpIX concentration. By choosing adequate parameters, the video rate acquisition of pO2 images could be achieved, providing real-time tissue metabolic information., Results: In this report, we show the first demonstration of imaging hypoxia signals from PpIX in a pancreatic cancer model, exhibiting >5X contrast relative to surrounding normal oxygenated tissues. Additionally, tissue palpation amplifies the signal and provides intuitive temporal contrast based upon neoangiogenic blood flow differences., Conclusions: PpIX DF provides a mechanism for tumor contrast that could easily be translated to human use as an intrinsic contrast mechanism for oncologic surgical guidance.

Purpose: To document experiences with one year of clinical implementation of the first Cherenkov imaging system and share the methods that we developed to utilize Cherenkov imaging to improve treatment delivery accuracy in real-time., Methods: A Cherenkov imaging system was installed commissioned and calibrated for clinical use. The optimal room lighting conditions and imaging setup protocols were developed to optimize both image quality and patient experience. The Cherenkov images were analyzed for treatment setup and beam delivery verification., Results: We have successfully implemented a clinical Cherenkov imaging system in a community-based hospital. Several radiation therapy patient setup anomalies were found in 1) exit dose to the contralateral breast, 2) dose to the chin due to head rotation for a supraclavicular field, 3) intrafractional patient motion during beam delivery, and 4) large variability (0.5 cm to 5 cm) in arm position between fractions. The system was used to deliver deep inspiration breath hold (DIBH) treatment delivery of an electron treatment beam. Clinical process and procedures were improved to mitigate the identified issues to ensure treatment delivery safety and to improve treatment accuracy., Conclusion: The Cherenkov imaging system has proven to be a valuable clinical tool for the improvement of treatment delivery safety and accuracy at our hospital. With only minimal training the therapists were able to adjust or correct treatment positions during treatment delivery as needed. With future Cherenkov software developments Cherenkov imaging systems could provide daily surface guided radiotherapy (SGRT) and real time treatment delivery quality control for all 3D and clinical setup patients without adding additional radiation image dose as in standard kV, MV and CBCT image verifications. Cherenkov imaging can greatly improve clinical efficiency and accuracy, making real time dose delivery consistency verification and SGRT a reality., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier B.V. on behalf of European Society for Radiotherapy & Oncology.)

Objectives: Examine the responses of multiple image similarity metrics to detect patient positioning errors in radiotherapy observed through Cherenkov imaging, which may be used to optimize automated incident detection., Methods: An anthropomorphic phantom mimicking patient vasculature, a biological marker seen in Cherenkov images, was simulated for a breast radiotherapy treatment. The phantom was systematically shifted in each translational direction, and Cherenkov images were captured during treatment delivery at each step. The responses of mutual information (MI) and the γ passing rate (%GP) were compared to that of existing field-shape matching image metrics, the Dice coefficient, and mean distance to conformity (MDC). Patient images containing other incidents were analyzed to verify the best detection algorithm for different incident types., Results: Positional shifts in all directions were registered by both MI and %GP, degrading monotonically as the shifts increased. Shifts in intensity, which may result from erythema or bolus-tissue air gaps, were detected most by %GP. However, neither metric detected beam-shape misalignment, such as that caused by dose to unintended areas, as well as currently employed metrics (Dice and MDC)., Conclusions: This study indicates that different radiotherapy incidents may be detected by comparing both inter- and intrafractional Cherenkov images with a corresponding image similarity metric, varying with the type of incident. Future work will involve determining appropriate thresholds per metric for automatic flagging., Advances in Knowledge: Classifying different algorithms for the detection of various radiotherapy incidents allows for the development of an automatic flagging system, eliminating the burden of manual review of Cherenkov images.

This article extends the combinatorial approach to support the determination of contextuality amidst causal influences. Contextuality is an active field of study in Quantum Cognition, in systems relating to mental phenomena, such as concepts in human memory. In the cognitive field of study, a contemporary challenge facing the determination of whether a phenomenon is contextual has been the identification and management of disturbances. Whether or not said disturbances are identified through the modeling approach, constitute causal influences, or are disregardableas as noise is important, as contextuality cannot be adequately determined in the presence of causal influences. To address this challenge, we first provide a formalization of necessary elements of the combinatorial approach within the language of canonical causal models. Through this formalization, we extend the combinatorial approach to support a measurement and treatment of disturbance, and offer techniques to separately distinguish noise and causal influences. Thereafter, we develop a protocol through which these elements may be represented within a cognitive experiment. As human cognition seems rife with causal influences, cognitive modelers may apply the extended combinatorial approach to practically determine the contextuality of cognitive phenomena., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Obeid, Bruza, Moreira, Bruns and Angus.)

Objective. Existing ultra-high dose rate (UHDR) electron sources lack dose rate independent dosimeters and a calibrated dose control system for accurate delivery. In this study, we aim to develop a custom single-pulse dose monitoring and a real-time dose-based control system for a FLASH enabled clinical linear accelerator (Linac). Approach. A commercially available point scintillator detector was coupled to a gated integrating amplifier and a real-time controller for dose monitoring and feedback control loop. The controller was programmed to integrate dose for each radiation pulse and stop the radiation beam when the prescribed dose was delivered. Additionally, the scintillator was mounted in a solid water phantom and placed underneath mice skin for in vivo dose monitoring. The scintillator was characterized in terms of its radiation stability, mean dose-rate (Ḋm), and dose per pulse ( D p ) dependence. Main results. The D p exhibited a consistent ramp-up period across ∼4-5 pulse. The plastic scintillator was shown to be linear withḊm(40-380 Gy s -1 ) and D p (0.3-1.3 Gy Pulse -1 ) to within +/- 3%. However, the plastic scintillator was subject to significant radiation damage (16%/kGy) for the initial 1 kGy and would need to be calibrated frequently. Pulse-counting control was accurately implemented with one-to-one correspondence between the intended and the actual delivered pulses. The dose-based control was sufficient to gate on any pulse of the Linac. In vivo dosimetry monitoring with a 1 cm circular cut-out revealed that during the ramp-up period, the average D p was ∼0.045 ± 0.004 Gy Pulse -1 , whereas after the ramp-up it stabilized at 0.65 ± 0.01 Gy Pulse -1 . Significance. The tools presented in this study can be used to determine the beam parameter space pertinent to the FLASH effect. Additionally, this study is the first instance of real-time dose-based control for a modified Linac at ultra-high dose rates, which provides insight into the tool required for future clinical translation of FLASH-RT., (© 2022 Institute of Physics and Engineering in Medicine.)

Purpose: To present a Monte Carlo (MC) beam model and its implementation in a clinical treatment planning system (TPS, Varian Eclipse) for a modified ultrahigh dose-rate electron FLASH radiation therapy (eFLASH-RT) linear accelerator (LINAC) using clinical accessories and geometry., Methods and Materials: The gantry head without scattering foils or targets, representative of the LINAC modifications, was modeled in the Geant4-based GAMOS MC toolkit. The energy spectrum (σ E ) and beam source emittance cone angle (θ cone ) were varied to match the calculated open-field central-axis percent depth dose (PDD) and lateral profiles with Gafchromic film measurements. The beam model and its Eclipse configuration were validated with measured profiles of the open field and nominal fields for clinical applicators. An MC forward dose calculation was conducted for a mouse whole-brain treatment, and an eFLASH-RT plan was compared with a conventional (Conv-) RT electron plan in Eclipse for a human patient with metastatic renal cell carcinoma., Results: The eFLASH beam model agreed best with measurements at σ E  = 0.5 MeV and θ cone  = 3.9° ± 0.2°. The model and its Eclipse configuration were validated to clinically acceptable accuracy (the absolute average error was within 1.5% for in-water lateral, 3% for in-air lateral, and 2% for PDDs). The forward calculation showed adequate dose delivery to the entire mouse brain while sparing the organ at risk (lung). The human patient case demonstrated the planning capability with routine accessories to achieve an acceptable plan (90% of the tumor volume receiving 95% and 90% of the prescribed dose for eFLASH and Conv-RT, respectively)., Conclusions: To our knowledge, this is the first functional beam model commissioned in a clinical TPS for eFLASH-RT enabling planning and evaluation with minimal deviation from the Conv-RT workflow. It facilitates the clinical translation because eFLASH-RT and Conv-RT plan quality were comparable for a human patient involving complex geometries and tissue heterogeneity. The methods can be expanded to model other eFLASH irradiators with different beam characteristics., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Color vision is used throughout medicine to interpret the health and status of tissue. Ionizing radiation used in radiation therapy produces broadband white light inside tissue through the Cherenkov effect, and this light is attenuated by tissue features as it leaves the body. In this study, a novel time-gated three-channel camera was developed for the first time and was used to image color Cherenkov emission coming from patients during treatment. The spectral content was interpreted by comparison with imaging calibrated tissue phantoms. Color shades of Cherenkov emission in radiotherapy can be used to interpret tissue blood volume, oxygen saturation and major vessels within the body., (© 2021. The Author(s).)

Significance: The Cherenkov emission spectrum overlaps with that of ambient room light sources. Choice of room lighting devices dramatically affects the efficient detection of Cherenkov emission during patient treatment., Aim: To determine optimal room light sources allowing Cherenkov emission imaging in normally lit radiotherapy treatment delivery rooms., Approach: A variety of commercial light sources and long-pass (LP) filters were surveyed for spectral band separation from the red to near-infrared Cherenkov light emitted by tissue. Their effects on signal-to-noise ratio (SNR), Cherenkov to background signal ratio, and image artifacts were quantified by imaging irradiated tissue equivalent phantoms with an intensified time-gated CMOS camera., Results: Because Cherenkov emission from tissue lies largely in the near-infrared spectrum, a controlled choice of ambient light that avoids this spectral band is ideal, along with a camera that is maximally sensitive to it. An RGB LED light source produced the best SNR out of all sources that mimic room light temperature. A 675-nm LP filter on the camera input further reduced ambient light detected (optical density > 3), achieving maximal SNR for Cherenkov emission near 40. Reduction of the room light signal reduced artifacts from specular reflection on the tissue surface and also minimized spurious Cherenkov signals from non-tissue features such as bolus., Conclusions: LP filtering during image acquisition for near-infrared light in tandem with narrow band LED illuminated rooms improves image quality, trading off the loss of red wavelengths for better removal of room light in the image. This spectral filtering is also critically important to remove specular reflection in the images and allow for imaging of Cherenkov emission through clear bolus. Beyond time-gated external beam therapy systems, the spectral separation methods can be utilized for background removal for continuous treatment delivery methods including proton pencil beam scanning systems and brachytherapy.

X-ray induced molecular luminescence (XML) is a phenomenon that can be utilized for clinical, deep-tissue functional imaging of tailored molecular probes. In this study, a survey of common or clinically approved fluorophores was carried out for their megavoltage X-ray induced excitation and emission characteristics. We find that direct scintillation effects and Cherenkov generation are two possible ways to cause these molecules' excitation. To distinguish the contributions of each excitation mechanism, we exploited the dependency of Cherenkov radiation yield on X-ray energy. The probes were irradiated by constant dose of 6 MV and 18 MV X-ray radiation, and their relative emission intensities and spectra were quantified for each X-ray energy pair. From the ratios of XML, yield for 6 MV and 18 MV irradiation we found that the Cherenkov radiation dominated as an excitation mechanism, except for aluminum phthalocyanine, which exhibited substantial scintillation. The highest emission yields were detected from fluorescein, proflavin and aluminum phthalocyanine, in that order. XML yield was found to be affected by the emission quantum yield, overlap of the fluorescence excitation and Cherenkov emission spectra, scintillation yield. Considering all these factors and XML emission spectrum respective to tissue optical window, aluminum phthalocyanine offers the best XML yield for deep tissue use, while fluorescein and proflavine are most useful for subcutaneous or superficial use., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: Delivery of radiation at ultrahigh dose rates (UHDRs), known as FLASH, has recently been shown to preferentially spare normal tissues from radiation damage compared with tumor tissues. However, the underlying mechanism of this phenomenon remains unknown, with one of the most widely considered hypotheses being that the effect is related to substantial oxygen depletion upon FLASH, thereby altering the radiochemical damage during irradiation, leading to different radiation responses of normal and tumor cells. Testing of this hypothesis would be advanced by direct measurement of tissue oxygen in vivo during and after FLASH irradiation., Methods and Materials: Oxygen measurements were performed in vitro and in vivo using the phosphorescence quenching method and a water-soluble molecular probe Oxyphor 2P. The changes in oxygen per unit dose (G-values) were quantified in response to irradiation by 10 MeV electron beam at either UHDR reaching 300 Gy/s or conventional radiation therapy dose rates of 0.1 Gy/s., Results: In vitro experiments with 5% bovine serum albumin solutions at 23°C resulted in G-values for oxygen consumption of 0.19 to 0.21 mm Hg/Gy (0.34-0.37 μM/Gy) for conventional irradiation and 0.16 to 0.17 mm Hg/Gy (0.28-0.30 μM/Gy) for UHDR irradiation. In vivo, the total decrease in oxygen after a single fraction of 20 Gy FLASH irradiation was 2.3 ± 0.3 mm Hg in normal tissue and 1.0 ± 0.2 mm Hg in tumor tissue (P < .00001), whereas no decrease in oxygen was observed from a single fraction of 20 Gy applied in conventional mode., Conclusions: Our observations suggest that oxygen depletion to radiologically relevant levels of hypoxia is unlikely to occur in bulk tissue under FLASH irradiation. For the same dose, FLASH irradiation induces less oxygen consumption than conventional irradiation in vitro, which may be related to the FLASH sparing effect. However, the difference in oxygen depletion between FLASH and conventional irradiation could not be quantified in vivo because measurements of oxygen depletion under conventional irradiation are hampered by resupply of oxygen from the blood., (Published by Elsevier Inc.)

Significance: Optical imaging of Cherenkov emission during radiation therapy could be used to verify dose delivery in real-time if a more comprehensive quantitative understanding of the factors affecting emission intensity could be developed., Aim: This study aims to explore the change in diffuse Cherenkov emission intensity with x-ray beam energy from irradiated tissue, both theoretically and experimentally., Approach: Derivation of the emitted Cherenkov signal was achieved using diffusion theory, and experimental studies with 6 to 18 MV energy x-rays were performed in tissue phantoms to confirm the model predictions as related to the radiation build-up factor with depth into tissue., Results: Irradiation at lower x-ray energies results in a greater surface dose and higher build-up slope, which results in a ∼46  %   greater diffusely emitted Cherenkov signal per unit dose at 6 MV relative to 18 MV x-rays. However, this phenomenon competes with a decrease in signal from less Cherenkov photons being generated at lower energies, a ∼44  %   reduction at 6 versus 18 MV. The result is an emitted Cherenkov signal that is nearly constant with beam energy., Conclusions: This study explains why the observed Cherenkov emission from tissue is not a strong function of beam energy, despite the known strong correlation between Cherenkov intensity and particle energy in the absence of build-up and scattering effects.

Purpose: In this study, procedures were developed to achieve efficient reversible conversion of a clinical linear accelerator (LINAC) and deliver ultrahigh-dose-rate (UHDR) electron or conventional beams to the treatment room isocenter for FLASH radiation therapy., Methods and Materials: The LINAC was converted to deliver UHDR beam within 20 minutes by retracting the x-ray target from the beam's path, positioning the carousel on an empty port, and selecting 10 MV photon beam energy in the treatment console. Dose rate surface and depth dose profiles were measured in solid water phantom at different field sizes with Gafchromic film and an optically stimulated luminescent dosimeter (OSLD). A pulse controller counted the pulses via scattered radiation signal and gated the delivery for a preset pulse count. A fast photomultiplier tube-based Cherenkov detector measured the per pulse beam output at a 2-ns sampling rate. After conversion back to clinical mode, conventional beam output, flatness, symmetry, field size, and energy were measured for all clinically commissioned energies., Results: The surface average dose rates at the isocenter for 1-cm diameter and 1.5-in diameter circular fields and for a jaws-wide-open field were 238 ± 5 Gy/s, 262 ± 5 Gy/s, and 290 ± 5 Gy/s, respectively. The radial symmetry of the beams was within 2.4%, 0.5%, and 0.2%, respectively. The doses from simultaneous irradiation of film and OSLD were within 1%. The photomultiplier tube showed the LINAC required ramp up time in the first 4 to 6 pulses before the output stabilized, after which its stability was within 3%., Conclusions: At the isocenter of the treatment room, 10 MeV UHDR beams were achieved. The beam output was reproducible but requires further investigation of the ramp up time, equivalent to ∼1 Gy, requiring dose monitoring. The UHDR beam can irradiate both small and large subjects to investigate potential FLASH radiobiological effects in minimally modified clinical settings, and the dose rate can be further increased by reducing the source-to-surface distance., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: In mono-isocentric radiation therapy treatment plans designed to treat the whole breast and supraclavicular lymph nodes, the fields meet at isocenter, forming the match line. Insufficient coverage at the match line can lead to recurrence, and overlap over weeks of treatment can lead to increased risk of healthy tissue toxicity. Cherenkov imaging was used to assess the accuracy of delivery at the match line and identify potential incidents during patient treatments., Methods and Materials: A controlled calibration was constructed from the deconvolved Cherenkov images from the delivery of a modified patient treatment plan to an anthropomorphic phantom with introduced separation and overlap. The trend from this calibration was then used to evaluate the field match line for accuracy and inter-fraction consistency for two patients., Results: The intersection point between matching field profiles was directly correlated to the distance (gap/overlap) between the fields (anthropomorphic phantom R 2 = 0.994 "breath hold" and R 2 = 0.990 "free breathing"). The profile intersection points from two patients' imaging sessions yielded an average of +1.40 mm offset (overlap) and -1.32 mm offset (gap), thereby introducing roughly a 25.0% over-dose and a -23.6% under-dose (R 2 = 0.994)., Conclusions: This study shows that field match regions can be detected and quantified by taking deconvolved Cherenkov images and using their product image to create steep intensity gradients, causing match lines to stand out. These regions can then be quantitatively translated into a dose consequence. This approach offers a high sensitivity detection method which can quantify match line variability and errors in vivo., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose. In this study, spatio-temporal beam profiling for electron ultra-high dose rate (UHDR; >40 Gy s -1 ) radiation via Cherenkov emission and radioluminescence imaging was investigated using intensified complementary metal-oxide-semiconductor cameras. Methods. The cameras, gated to FLASH optimized linear accelerator pulses, imaged radioluminescence and Cherenkov emission incited by single pulses of a UHDR (>40 Gy s -1 ) 10 MeV electron beam delivered to the isocenter. Surface dosimetry was investigated via imaging Cherenkov emission or scintillation from a solid water phantom or Gd 2 O 2 S:Tb screen positioned on top of the phantom, respectively. Projected depth-dose profiles were imaged from a tank filled with water (Cherenkov emission) and a 1 g l -1 quinine sulfate solution (scintillation). These optical results were compared with projected lateral dose profiles measured by Gafchromic film at different depths, including the surface. Results. The per-pulse beam output from Cherenkov imaging agreed with the photomultiplier tube Cherenkov output to within 3% after about the first five to seven ramp-up pulses. Cherenkov emission and scintillation were linear with dose ( R 2  = 0.987 and 0.995, respectively) and independent of dose rate from ∼50 to 300 Gy s -1 (0.18-0.91 Gy/pulse). The surface dose distribution from film agreed better with scintillation than with Cherenkov emission imaging (3%/3 mm gamma pass rates of 98.9% and 88.8%, respectively). Using a 450 nm bandpass filter, the quinine sulfate-based water imaging of the projected depth optical profiles agreed with the projected film dose to within 5%. Conclusion. The agreement of surface dosimetry using scintillation screen imaging and Gafchromic film suggests it can verify the consistency of daily beam quality assurance parameters with an accuracy of around 2% or 2 mm. Cherenkov-based surface dosimetry was affected by the target's optical properties, prompting additional calibration. In projected depth-dose profiling, scintillation imaging via spectral suppression of Cherenkov emission provided the best match to film. Both camera-based imaging modalities resolved dose from single UHDR beam pulses of up to 60 Hz repetition rate and 1 mm spatial resolution., (© 2021 Institute of Physics and Engineering in Medicine.)

Purpose: This study demonstrates a robust Cherenkov imaging-based solution to MR-Linac daily QA, including mechanical-imaging-radiation isocenter coincidence verification., Methods: A fully enclosed acrylic cylindrical phantom was designed to be mountable to the existing jig, indexable to the treatment couch. An ABS plastic conical structure was fixed inside the phantom, held in place with 3D-printed spacers, and filled with water allowing for high edge contrast on MR imaging scans. Both a star shot plan and a four-angle sheet beam plan were delivered to the phantom; the former allowed for radiation isocenter localization in the x-z plane (A/P and L/R directions) relative to physical landmarks on the phantom, and the latter allowed for the longitudinal position of the sheet beam to be encoded as a ring of Cherenkov radiation emitted from the phantom, allowing for isocenter localization on the y-axis (S/I directions). A custom software application was developed to perform near-real-time analysis of the data by any clinical user., Results: Calibration procedures show that linearity between longitudinal position and optical ring diameter is high (R 2  > 0.99), and that RMSE is low (0.184 mm). The star shot analysis showed a minimum circle radius of 0.34 mm. The final isocenter coincidence measurements in the lateral, longitudinal, and vertical directions were -0.61 mm, 0.55 mm, and -0.14 mm, respectively, and the total 3D distance coincidence was 0.83 mm, with each of these being below 2 mm tolerance., Conclusion: This novel system provided an efficient, MR safe, all-in-one method for acquisition and near-real-time analysis of isocenter coincidence data. This represents a direct measurement of the 3D isocentricity. The combination of this phantom and the custom analysis application makes this solution readily clinically deployable after the longitudinal analysis of performance consistency., (© 2021 American Association of Physicists in Medicine.)

Purpose: High dose rate conditions, coupled with problems related to small field dosimetry, make dose characterization for FLASH-RT challenging. Most conventional dosimeters show significant dependence on dose rate at ultra-high dose rate conditions or fail to provide sufficiently fast temporal data for pulse to pulse dosimetry. Here fast 2D imaging of radioluminescence from a water and quinine phantom was tested for dosimetry of individual 4 μs linac pulses., Methods: A modified clinical linac delivered an electron FLASH beam of >50 Gy/s to clinical isocenter. This modification removed the x-ray target and flattening filter, leading to a beam that was symmetric and gaussian, as verified with GafChromic EBT-XD film. Lateral projected 2D dose distributions for each linac pulse were imaged in a quinine-doped water tank using a gated intensified camera, and an inverse Abel transform reconstruction provided 3D images for on-axis depth dose values. A total of 20 pulses were delivered with a 10 MeV, 1.5 cm circular beam, and beam with jaws wide open (40 × 40 cm 2 ), and a 3D dose distribution was recovered for each pulse. Beam output was analyzed on a pulse by pulse basis., Results: The R p , D max , and the R 50 measured with film and optical methods agreed to within 1 mm for the 1.5 cm circular beam and the beam with jaws wide open. Cross beam profiles for both beams agreed with film data with >95% passing rate (2%/2 mm gamma criteria). The optical central axis depth dose agreed with film data, except for near the surface. A temporal pulse analysis revealed a ramp-up period where the dose per pulse increased for the first few pulses and then stabilized., Conclusions: Optical imaging of radioluminescence was presented as a valuable tool for establishing a baseline for the recently initiated electron FLASH beam at our institution., (© 2021 American Association of Physicists in Medicine.)

Purpose: The value of Cherenkov imaging as an on-patient, real-time, treatment delivery verification system was examined in a 64-patient cohort during routine radiation treatments in a single-center study., Methods and Materials: Cherenkov cameras were mounted in treatment rooms and used to image patients during their standard radiation therapy regimen for various sites, predominantly for whole breast and total skin electron therapy. For most patients, multiple fractions were imaged, with some involving bolus or scintillators on the skin. Measures of repeatability were calculated with a mean distance to conformity (MDC) for breast irradiation images., Results: In breast treatments, Cherenkov images identified fractions when treatment delivery resulted in dose on the contralateral breast, the arm, or the chin and found nonideal bolus positioning. In sarcoma treatments, safe positioning of the contralateral leg was monitored. For all 199 imaged breast treatment fields, the interfraction MDC was within 7 mm compared with the first day of treatment (with only 7.5% of treatments exceeding 3 mm), and all but 1 fell within 7 mm relative to the treatment plan. The value of imaging dose through clear bolus or quantifying surface dose with scintillator dots was examined. Cherenkov imaging also was able to assess field match lines in cerebral-spinal and breast irradiation with nodes. Treatment imaging of other anatomic sites confirmed the value of surface dose imaging more broadly., Conclusions: Daily radiation therapy can be imaged routinely via Cherenkov emissions. Both the real-time images and the posttreatment, cumulative images provide surrogate maps of surface dose delivery that can be used for incident discovery and/or continuous improvement in many delivery techniques. In this initial 64-patient cohort, we discovered 6 minor incidents using Cherenkov imaging; these otherwise would have gone undetected. In addition, imaging provides automated, quantitative metrics useful for determining the quality of radiation therapy delivery., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Total Skin Electron Therapy (TSET) utilizes high-energy electrons to treat cancers on the entire body surface. The otherwise invisible radiation beam can be observed via the optical Cherenkov photons emitted from interaction between the high-energy electron beam and tissue. Cherenkov emission can be used to evaluate the dose uniformity on the surface of the patient in real-time using a time-gated intensified camera system. Each patient was monitored during TSET by in-vivo detectors (IVD) as well as Scintillators. Patients undergoing TSET in various conditions (whole body and half body) were imaged and analyzed. A rigorous methodology for converting Cherenkov intensity to surface dose as products of correction factors, including camera vignette correction factor, incident radiation correction factor, and tissue optical properties correction factor. A comprehensive study has been carried out by inspecting various positions on the patients such as vertex, chest, perineum, shins, and foot relative to the umbilicus point (the prescription point).

Significance: Deep-tissue penetration by x-rays to induce optical responses of specific molecular reporters is a new way to sense and image features of tissue function in vivo. Advances in this field are emerging, as biocompatible probes are invented along with innovations in how to optimally utilize x-ray sources., Aim: A comprehensive review is provided of the many tools and techniques developed for x-ray-induced optical molecular sensing, covering topics ranging from foundations of x-ray fluorescence imaging and x-ray tomography to the adaptation of these methods for sensing and imaging in vivo., Approach: The ways in which x-rays can interact with molecules and lead to their optical luminescence are reviewed, including temporal methods based on gated acquisition and multipoint scanning for improved lateral or axial resolution., Results: While some known probes can generate light upon x-ray scintillation, there has been an emergent recognition that excitation of molecular probes by x-ray-induced Cherenkov light is also possible. Emission of Cherenkov radiation requires a threshold energy of x-rays in the high kV or MV range, but has the advantage of being able to excite a broad range of optical molecular probes. In comparison, most scintillating agents are more readily activated by lower keV x-ray energies but are composed of crystalline inorganic constituents, although some organic biocompatible agents have been designed as well. Methods to create high-resolution structured x-ray-optical images are now available, based upon unique scanning approaches and/or a priori knowledge of the scanned x-ray beam geometry. Further improvements in spatial resolution can be achieved by careful system design and algorithm optimization. Current applications of these hybrid x-ray-optical approaches include imaging of tissue oxygenation and pH as well as of certain fluorescent proteins., Conclusions: Discovery of x-ray-excited reporters combined with optimized x-ray scan sequences can improve imaging resolution and sensitivity.

Significance: The study has confirmed the feasibility of using ultraviolet (UV) excitation to visualize and quantify desmoplasia in fresh tumor tissue of pancreatic adenocarcinoma (PDAC) in an orthotopic xenograft mouse model, which provides a useful imaging platform to evaluate acute therapeutic responses., Aim: Stromal network of collagen prominent in PDAC tumors is examined by imaging fresh tissue samples stained with histological dyes. Fluorescence signals are color-transferred to mimic Masson's trichrome staining., Approach: Murine tumor samples were stained with Hoechst, eosin, and rhodamine B and excited at 275-nm. Fluorescence signals in the visible spectrum were captured by a CMOS color camera with high contrast and resolution at whole-tumor slice field of view., Results: Fluorescence imaging using UV excitation is capable of visualizing collagen deposition in PDAC tumors. Both fluorescence and histology data showed collagen content of up to 30%. The collagen modulation effect due to photodynamic priming treatment was observed showing 13% of collagen reduction. Necrosis area is visible and perfusion imaging using Texas Red dextran is feasible., Conclusions: The study demonstrates collagen visualization in fresh PDAC tumor samples using UV excitation. This imaging platform also provides quantitative stromal information from fiber analysis and visibility of necrosis and perfusion, suitable for therapeutic response assessment of photodynamic therapy.

Purpose: A Geant4-based TOPAS Monte Carlo toolkit was utilized to model a Varian ProBeam proton therapy system, with the aim of providing an independent computational platform for validating advanced dosimetric methods., Materials and Methods: The model was tested for accuracy of dose and linear energy transfer (LET) prediction relative to the commissioning data, which included integral depth dose (IDD) in water and spot profiles in air measured at varying depths (for energies of 70 to 240 MeV in increments of 10 MeV, and 242 MeV), and absolute dose calibration. Emittance was defined based on depth-dependent spot profiles and Courant-Snyder's particle transport theory, which provided spot size and angular divergence along the inline and crossline plane. Energy spectra were defined as Gaussian distributions that best matched the range and maximum dose of the IDD. The validity of the model was assessed based on measurements of range, dose to peak difference, mean point to point difference, spot sizes at different depths, and spread-out Bragg peak (SOBP) IDD and was compared to the current treatment planning software (TPS)., Results: Simulated and commissioned spot sizes agreed within 2.5%. The single spot IDD range, maximum dose, and mean point to point difference of each commissioned energy agreed with the simulated profiles generally within 0.07 mm, 0.4%, and 0.6%, respectively. A simulated SOBP plan agreed with the measured dose within 2% for the plateau region. The protons/MU and absolute dose agreed with the current TPS to within 1.6% and exhibited the greatest discrepancy at higher energies., Conclusions: The TOPAS model agreed well with the commissioning data and included inline and crossline asymmetry of the beam profiles. The discrepancy between the measured and TOPAS-simulated SOBP plan may be due to beam modeling simplifications of the current TPS and the nuclear halo effect. The model can compute LET, and motivates future studies in understanding equivalent dose prediction in treatment planning, and investigating scintillation quenching., (© 2020 American Association of Physicists in Medicine.)

This article proposes a novel and comprehensive framework on how to describe the probabilistic nature of decision-making process. We suggest extending the quantum-like Bayesian network formalism to incorporate the notion of maximum expected utility to model human paradoxical, sub-optimal and irrational decisions. What distinguishes this work is that we take advantage of the quantum interference effects produced in quantum-like Bayesian Networks during the inference process to influence the probabilities used to compute the maximum expected utility of some decision. The proposed quantum-like decision model is able to (1) predict the probability distributions found in different experiments reported in the literature by modelling uncertainty through quantum interference, (2) to identify decisions that the decision-makers perceive to be optimal within their belief space, but that are actually irrational with respect to expected utility theory, (3) gain an understanding of how the decision-maker's beliefs evolve within a decision-making scenario. The proposed model has the potential to provide new insights in decision science, as well as having direct implications for decision support systems that deal with human data, such as in the fields of economics, finance, psychology, etc., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)