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Background: Use of a linear accelerator in ultra-high 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. Purpose: Failure Modes and Effects Analysis (FMEA) was carried out in a team that has been involved in converting a LINAC between clinical use and UHDR experimental mode for more than one year, following the proposed methods of TG100. Methods: 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 results. The team scored the categories of severity magnitude (S), occurrence likelihood (O), and detectability potential (D) in a scale of 1 to 10, so that a risk priority number (RPN=S*O*D) could be assessed for each. Results: A total of 46 potential failure modes were identified, including 5 with RPN>100. These failure modes involved 1) patient set up, 2) gating mechanisms in delivery, and 3) detector in the beam stop mechanism. Identified methods to mitigate errors included 1) use of a checklist post conversion, 2) use of robust radiation detectors, 3) automation of QA and beam consistency checks, and 4) implementation of surface guidance during beam delivery. Conclusions: The FMEA 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 towards expanded research access., 26 Pages, 6 Figures, 4 Tables

PurposeIn our experience treating locally advanced pancreatic cancer (PC) with magnetic resonance-guided radiation therapy (MRgRT), the true-fast imaging with steady-state free precession (TRUFI) sequences used to generate real-time 2D MRI (2D cine) impart differing intensities for relevant structures when compared to the pre-treatment high resolution 3D MRI (3D MRI). Since these variations can confound target tracking selection, we propose that an understanding of the differing contrast profiles could improve selection of tracking structures.Methods and MaterialsWe retrospectively reviewed both 2D cine and 3D MRI images for 20 patients with PC treated with MRgRT. At simulation, an appropriate tracking target was identified and contoured on a single 3mm sagittal slice of the 3D MRI. This sagittal slice was directly compared to the co-registered 7mm 2D cine to identify structures with notable discrepancies in signal intensity. The 3D MRI was then explored in additional planes to confirm structure identities. For quantitative verification of the clinically observed differences, the pixel intensity distributions of 2D cine and 3D MRI DICOM image datasets were statistically compared.ResultsIn all patients reviewed, arteries (aorta, celiac, SMA, HA) appeared mildly hyperintense on both scans. However, veins (PV, SMV) appeared hyperintense on 2D cine but isointense on 3D MRI. Biliary structures appeared mildly hyperintense on 2D cine but starkly hyperintense on 3D MRI. The pixel intensity distributions extracted from 2D cine and 3D MRI images were confirmed to differ significantly (two sample Kolmogorov-Smirnov test; test statistic =0.40; p ConclusionsThere are significant variations in image intensity between the immediate pre-treatment 2D cine when compared to the initial planning 3D MRI. Understanding variations of image intensity between the different MRI sequences used in MRgRT is valuable to radiation oncologists and may lead to improved target tracking and optimized treatment delivery.

The delivery of radiation at an ultra-high dose rate (FLASH) is an important new approach to radiotherapy (RT) that appears to be able to improve the therapeutic ratio by diminishing damage to normal tissues. While the mechanisms by which FLASH improves outcomes have not been established, a role involving molecular oxygen (O

PURPOSE Electron paramagnetic resonance oximetry using the OxyChip as an implantable oxygen sensor can directly and repeatedly measure tissue oxygen levels. A phase I, first-in-human clinical study has established the safety and feasibility of using OxyChip for reliable and repeated measurements of oxygen levels in a variety of tumors and treatment regimens. A limitation in these studies is the inability to easily locate and identify the implanted probes in the tissue, particularly in the long term, thus limiting spatial/anatomical registration of the implant for proper interpretation of the oxygen data. In this study, we have developed and evaluated an enhanced oxygen-sensing probe embedded with gold nanoparticles (GNP), called the OxyChip-GNP, to enable visualization of the sensor using routine clinical imaging modalities. METHODS In vitro characterization, imaging, and histopathology studies were carried out using tissue phantoms, excised tissues, and in vivo animal models (mice and rats). RESULTS The results demonstrated a substantial enhancement of ultrasound and CT contrast using the OxyChip-GNP without compromising its electron paramagnetic resonance and oxygen-sensing properties or biocompatibility. CONCLUSIONS The OxyChips embedded with gold nanoparticles (OxyChip-GNP) can be readily identified in soft tissues using standard clinical imaging modalities such as CT, cone beam-CT, or ultrasound imaging while maintaining its capability to make repeated in vivo measurements of tissue oxygen levels over the long term. This unique capability of the OxyChip-GNP facilitates precisely localized in vivo oxygen measurements in the clinical setting.

There is a strong need to enable accurate and convenient oxygen measurements in vivo for human subjects to improve treatments for cancer, peripheral vascular disease, and other diseases where tissue oxygen levels have a significant impact. While EPR spectroscopy has the potential to do this effectively, the full exploitation of these capabilities requires optimization of resonators for use with human subjects. Patient motion, and its effects on resonator coupling and positioning relative to the implanted oximetry probe, is a major source of noise and artifacts. Additionally, optimization of detection sensitivity to enable measurements from tissues at depths of several centimeters with clinically practical acquisition times is needed. To meet these needs, surface resonators with high sensitivity and flexible cables that allow the detection loop to be conveniently attached to the skin surface were developed for use with low frequency (L-Band, 1.15 GHz) continuous wave EPR. These resonators include a multi-segment sensing loop with a common capacitance. The light-weight segmented sensing loops, with diameters of 10–20 mm, can be connected to a commercial topical fixation applicator to conveniently and securely position them on patients’ skin surfaces. It was shown that a resonator of 20 mm in diameter makes it possible to obtain adequate EPR signals in tissue phantoms up to a depth of 20 mm with ~ 2 min of signal averaging. This novel lightweight resonator design, with sensitive multi-segment design and flexible cable with skin surface attachment, significantly reduced the impacts of subject motion enabling reliable EPR oximetry measurements in human subjects.

EPR spectrometers (and various sub-systems) have been designed and constructed to facilitate in vivo measurements with human subjects for dosimetry and oximetry. Most applications are primarily focused on surface tissue measurements; however, oximetric measurements utilizing implantable devices are also discussed. Given various specifications and considerations across these two primary applications, several embodiments and configurations of the associated sub-systems to the spectrometer have been realized and implemented. These embodiments and configurations have been developed and tested with a focus on the end-use and the end-users. This includes acknowledgement of the challenges and needs for making measurements in unanesthetized human patients, the nature of the data that are most likely to be useful for clinical decision-making, and the person who will be making the actual measurements. Significant developments in spectrometer automation and features to ensure the quality of recorded data are featured.

L-band electron paramagnetic resonance (EPR) in vivo dosimetry has the potential advantage of being able to accurately and sensitively measure the absorbed dose of ionizing radiation by measurements of teeth in situ. The equipment is transportable to the site where a radiation incident occurred and can be operated without specialized facilities. It, therefore, is very suitable for medical triage of victims in a large-scale radiation incident to quickly determine whether the dose was large enough to require urgent care. The measurements are made on the outer surfaces of the two upper incisor teeth. However, some in vitro studies of extracted teeth using higher frequency EPR have suggested that exposure to ultraviolet rays (UV) from sunlight might confound estimates of the dose of ionizing radiation made with EPR. Because the outer surfaces of incisors are likely to be exposed to UV/sunlight, it, therefore, is essential to determine the potential quantitative impact of UV on L-band EPR dosimetry measurements based on incisors. We, therefore, investigated the quantitative effect of UV on the EPR signal from ionizing irradiation of human teeth using the L-band spectrometer developed for field dosimetry. The UV-generated EPR signal was very small relative to the signals resulting from doses of ionizing radiation that are used for triage. For example, using our estimates of the effects of UV, for a lifetime of 50 years of exposure of these teeth (assuming an average exposure to sunlight of two hours/day), the expected average lifetime effect of UV-induced signal would be equivalent to 0.33 Gy; in contrast, triage criteria for accidental exposure to ionizing irradiation generally start at 2.0 Gy.

The objective of this study is to describe the oxygen profile obtained by electron paramagnetic resonance (EPR) oximetry of tissue after radiation, surgery, and hyperbaric oxygen therapy (HBOT) and its relationship to wound healing in a rodent model. The study design is rodent model for wound healing. A rodent model for wound healing was used for oxygen measurements before and after various treatments. EPR measurements and biopsies of normal vs irradiated and flap vs non-flap tissues were taken at 1–3-week intervals for 12 weeks. Wound healing was evaluated by gross photos, histology, and immunostaining. Student’s t test and a linear mixed model were used to compare oxygen levels and gross healing with radiation exposure. A Proportional Odds model was also used to calculate odds ratio toward better wound-healing rate with radiation exposure. In the rodent model, at 1–3 weeks after irradiation, the mean tissue oxygen measurement was significantly lower in irradiated versus non-irradiated leg tissue. There was a significant difference in oxygenation between flap and non-flap tissue in an irradiated bed at 1 and 3 weeks after surgery. On gross evaluation, wound healing from z-plasty flap was significantly worse in irradiated tissue compared to non-irradiated tissue. A rodent model for wound healing showed that radiation resulted in decreased tissue oxygenation at 1–3 weeks after irradiation. Wound healing was compromised in irradiated tissue at earlier time points when tissue oxygenation was lower. Oxygen profiling with EPR oximetry can be used to identify timing of oxygen interventions to improve wound healing. Level of evidence is NA, animal studies.

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.

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 cm2 ), and a 3D dose distribution was recovered for each pulse. Beam output was analyzed on a pulse by pulse basis. Results The Rp , Dmax and the R50 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%/2mm 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.

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 sur- face 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.

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.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.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.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.

Purpose The novel scintillator‐based system described in this study is capable of accurately and remotely measuring surface dose during Total Skin Electron Therapy (TSET); this dosimeter does not require post‐exposure processing or annealing and has been shown to be re‐usable, resistant to radiation damage, have minimal impact on surface dose, and reduce chances of operator error compared to existing technologies e.g. optically stimulated luminescence detector (OSLD). The purpose of this study was to quantitatively analyze the workflow required to measure surface dose using this new scintillator dosimeter and compare it to that of standard OSLDs. Methods Disc‐shaped scintillators were attached to a flat‐faced phantom and a patient undergoing TSET. Light emission from these plastic discs was captured using a time‐gated, intensified, camera during irradiation and converted to dose using an external calibration factor. Time required to complete each step (daily QA, dosimeter preparation, attachment, removal, registration, and readout) of the scintillator and OSLD surface dosimetry workflows was tracked. Results In phantoms, scintillators and OSLDs surface doses agreed within 3% for all data points. During patient imaging it was found that surface dose measured by OSLD and scintillator agreed within 5% and 3% for 35/35 and 32/35 dosimetry sites, respectively. The end‐to‐end time required to measure surface dose during phantom experiments for a single dosimeter was 78 and 202 sec for scintillator and OSL dosimeters, respectively. During patient treatment, surface dose was assessed at 7 different body locations by scintillator and OSL dosimeters in 386 and 754 sec, respectively. Conclusion Scintillators have been shown to report dose nearly twice as fast as OSLDs with substantially less manual work and reduced chances of human error. Scintillator dose measurements are automatically saved to an electronic patient file and images contain a permanent record of the dose delivered during treatment.

Minor splicing is a second splicing system required for the correct expression of ∼700 human minor intron-containing genes (MIGs). Many MIGs are expressed in vigorously proliferating cells and are frequently dysregulated in cancer including BRAF, ERK, JNK and p38. Minor splicing is carried out by the minor spliceosome which comprises several unique components, including a 65kDa protein encoded by RNPC3. We show that Rnpc3 heterozygosity reduces tumour burden in a broad spectrum of in vivo cancer settings, without harming normal tissues. Using the collective power of zebrafish, mouse and human cancer models, we reveal a sequence of events connecting Rnpc3 deficiency and impaired splicing of MIGs to DNA damage and activation of a Tp53-dependent transcriptional program that restricts tumour burden by inducing cell cycle arrest and apoptosis. Interrogation of human liver and lung cancer transcriptomes curated in TCGA revealed that the expression of many of the genes encoding protein components of the minor spliceosome is upregulated in these cancers. This is accompanied by upregulation of the expression of MIGs that are enriched in cell cycle and DNA damage pathways. These findings suggest that cancer cells can invoke mechanisms to increase the efficiency of minor splicing to support their high proliferation rates. Finally, Kaplan Meier survival analysis shows that highly expressed MIGs are frequently associated with poor patient survival. Taken together, these results indicate that the minor spliceosome offers a therapeutically viable target for the treatment of a broad spectrum of cancers.

OBJECTIVES: (1) Summarize revisions made to the implantable resonator (IR) design and results of testing to characterize biocompatibility; (2) Demonstrate safety of implantation and feasibility of deep tissue oxygenation measurement using electron paramagnetic resonance (EPR) oximetry. STUDY DESIGN: In vitro testing of the revised IR and in vivo implantation in rabbit brain and leg tissues. METHODS: Revised IRs were fabricated with 1–4 OxyChips with a thin wire encapsulated with two biocompatible coatings. Biocompatibility and chemical characterization tests were performed. Rabbits were implanted with either an IR with 2 oxygen sensors or a biocompatible-control sample in both the brain and hind leg. The rabbits were implanted with IRs using a catheter-based, minimally invasive surgical procedure. EPR oximetry was performed for rabbits with IRs. Cohorts of rabbits were euthanized and tissues were obtained at 1 week, 3 months, and 9 months after implantation and examined for tissue reaction. RESULTS: Biocompatibility and toxicity testing of the revised IRs demonstrated no abnormal reactions. EPR oximetry from brain and leg tissues were successfully executed. Blood work and histopathological evaluations showed no significant difference between the IR and control groups. CONCLUSIONS: IRs were functional for up to 9 months after implantation and provided deep tissue oxygen measurements using EPR oximetry. Tissues surrounding the IRs showed no more tissue reaction than tissues surrounding the control samples. This pre-clinical study demonstrates that the IRs can be safely implanted in brain and leg tissues and that repeated, non-invasive, deep-tissue oxygen measurements can be obtained using in vivo EPR oximetry.

Increased oxygen levels may enhance the radiosensitivity of brain metastases treated with stereotactic radiosurgery (SRS). This project administered hyperbaric oxygen (HBO) prior to SRS to assess feasibility, safety, and response.38 patients were studied, 19 with 25 brain metastases treated with HBO prior to SRS, and 19 historical controls with 27 metastases, matched for histology, GPA, resection status, and lesion size. Outcomes included time from HBO to SRS, quality-of-life (QOL) measures, local control, distant (brain) metastases, radionecrosis, and overall survival.The average time from HBO chamber to SRS beam-on was 8.3 ± 1.7 minutes. Solicited adverse events (AEs) were comparable between HBO and control patients; no grade III or IV serious AEs were observed. Radionecrosis-free survival (RNFS), radionecrosis-free survival before whole-brain radiation therapy (WBRT) (RNBWFS), local recurrence-free survival before WBRT (LRBWFS), distant recurrence-free survival before WBRT (DRBWFS), and overall survival (OS) were not significantly different for HBO patients and controls on Kaplan-Meier analysis, though at 1-year estimated survival rates trended in favor of SRS + HBO: RNFS - 83% vs 60%; RNBWFS - 78% vs 60%; LRBWFS - 95% vs 78%; DRBWFS - 61% vs 57%; and OS - 73% vs 56%. Multivariate Cox models indicated no significant association between HBO treatment and hazards of RN, local or distant recurrence, or mortality; however, these did show statistically significant associations (p 0.05) for: local recurrence with higher volume, radionecrosis with tumor resection, overall survival with resection, and overall survival with higher GPA.Addition of HBO to SRS for brain metastases is feasible without evident decrement in radiation necrosis and other clinical outcomes.

PURPOSE: We demonstrate the feasibility of optical imaging as a quality assurance tool for static small beamlets, and pre-treatment verification tool for radiosurgery and VMAT plans. METHODS: Small static beams and clinical Volumetric-modulated arc therapy (VMAT) plans were simulated in a treatment planning system (TPS) and delivered to a cylindrical tank filled with water-based liquid scintillator. Emission was imaged using a blue-sensitive, intensified CMOS camera time-gated to the linac pulses. For static beams, percentage depth and cross beam profiles of projected intensity distribution were compared to treatment planning system (TPS) data. 2D gamma analysis was performed on all clinical plans, and the technique was tested for sensitivity against common errors (multileaf collimator position, gantry angle) by inducing deliberate errors in the VMAT plans control points. The technique’s detection limits for spatial resolution and the smallest number of control points that could be imaged reliably was also tested. The sensitivity to common delivery errors was also compared against a commercial 2.5D diode array dosimeter. RESULTS: A spatial resolution of 1 mm was achieved with our imaging setup. The optical projected percentage depth intensity profiles agreed to within 2% relative to the TPS data for small static square beams (5, 10 and 50mm(2)). For projected cross beam profiles, a gamma pass rate >99% was achieved for a 3%/1mm criteria. All clinical plans passed the 3%/3mm criteria with >95% passing rate. A static 5 mm beam with 20 Monitor Units could be measured with an average percent difference of 5.5 ±3% relative to the TPS. The technique was sensitive to multileaf collimator errors down to 1 mm and gantry angle errors of 1°. CONCLUSIONS: Optical imaging provides ample spatial resolution for imaging small beams. The ability to faithfully image down to 20 MU of 5 mm, 6 MV beamlets prove the ability to perform quality assurance for each control point within dynamic plans. The technique is sensitive to small offsets errors in gantry angles and Multi-leaf collimator (MLC) leaf positions, and at certain scenario it exhibits higher sensitivity than a commercial 2.5D diode array.

Purpose A remote imaging system tracking Cherenkov emission was analyzed to verify that the linear accelerator (linac) beam shape could be quantitatively measured at the irradiation surface for Quality Audit (QA). Methods The Cherenkov camera recorded 2D dose images delivered on a solid acrylonitrile butadiene styrene (ABS) plastic phantom surface for a range of square beam sizes, and 6 MV photons. Imaging was done at source to surface distance (SSD) of 100 cm and compared to GaF film images and linac light fields of the same beam sizes, ranging over 5 × 5 cm2 up to 20 × 20 cm2 . Line profiles of each field were compared in both X and Y jaw directions. Each measurement was repeated on two different Clinac2100 machines. An interreader comparison of the beam width interpretation was completed using procedures commonly employed for beam to light field coincidence verification. Cherenkov measurements are also done for beams of complex treatment plan and isocenter QA. Results The Cherenkov image widths matched with the measured GaF images and light field images, with accuracy in the range of ±1 mm standard deviation. The differences between the measurements were minor and within tolerance of geometrical requirement of standard linac QA procedures conducted by human setup verification, which had a similar error range. The measurement made by the remote imaging system allowed for beam shape extraction of radiation fields at the SSD location of the beam. Conclusions The proposed Cherenkov image acquisition system provides a valid way to remotely confirm radiation field sizes and provides similar information to that obtained from the linac light field or GaF film estimates of the beam size. The major benefit of this approach is that with a fixed installation of the camera, testing could be done completely under software control with automated image analysis, potentially simplifying conventional QA procedures with appropriate calibration of boundary definitions, and the natural extension to capturing dynamic treatment beamlets at SSD could have future value, such as verification of beam plans with complex beam shapes, like IMRT or "star-shot" QA for the isocenter.

PURPOSE: Delivery of radiation at ultrahigh dose rates, known as FLASH, has recently been shown to preferentially spare normal tissues from radiation damage compared to tumor tissues. However, the underlying mechanism of this phenomenon remains unknown, with one of the most widely considered hypothesis 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 ultra-high dose rates (UHDR) reaching 300 Gy/s or conventional radiotherapy dose rates of 0.1 Gy/s. RESULTS: In vitro experiments with 5% BSA solutions at 23°C resulted in G-values for oxygen consumption of 0.19–0.21 mmHg/Gy (0.34–0.37 μM/Gy) for conventional irradiation and 0.16–0.17 mmHg/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 mmHg in normal tissue and 1.0±0.2 mmHg in tumor tissue with p-value < 0.00001, while 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.

During a first-in-humans clinical trial investigating electron paramagnetic resonance tumor oximetry, a patient injected with the particulate oxygen sensor Printex ink was found to have unexpected fluorodeoxyglucose (FDG) uptake in a dermal nodule via positron emission tomography (PET). This nodule co-localized with the Printex ink injection; biopsy of the area, due to concern for malignancy, revealed findings consistent with ink and an associated inflammatory reaction. Investigations were subsequently performed to assess the impact of oxygen sensors on FDG-PET/CT imaging. A retrospective analysis of three clinical tumor oximetry trials involving two oxygen sensors (charcoal particulates and LiNc-BuO microcrystals) in 22 patients was performed to evaluate FDG imaging characteristics. The impact of clinically used oxygen sensors (carbon black, charcoal particulates, LiNc-BuO microcrystals) on FDG-PET/CT imaging after implantation in rat muscle (n = 12) was investigated. The retrospective review revealed no other patients with FDG avidity associated with particulate sensors. The preclinical investigation found no injected oxygen sensor whose mean standard uptake values differed significantly from sham injections. The risk of a false-positive FDG-PET/CT scan due to oxygen sensors appears low. However, in the right clinical context the potential exists that an associated inflammatory reaction may confound interpretation.

Ultra-high dose rate electron sources require dose rate independent dosimeters and a calibrated dose control system for accurate delivery. In this study, we developed a single-pulse dose monitoring and a real-time dose-based control system for a converted clinical linear accelerator (LINAC). A point scintillator detector was coupled to a gated amplifier and a real-time controller for dose monitoring and feedback control loop. The controller was programmed to integrate dose and measure pulse width of each radiation pulse and gate the LINAC beam when the prescribed dose was delivered. The scintillator was mounted in solid water phantom and placed underneath mice skin for in vivo dose monitoring. Additionally, the scintillator was characterized in terms of its radiation stability, mean dose-rate, and dose per pulse dependence. Dose integration was performed for each radiation pulse and displayed in real-time. The scintillator was shown to be linear with mean dose-rate (40-380 Gy/s) and dose per pulse (0.3-1.3 Gy/Pulse) to within +/- 3%. However, the plastic scintillator was subject to significant radiation damage (16%/kGy) and would need to be calibrated frequently. Pulse-counting control was accurately implemented with direct 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 a ramp-up of 4-5 pulses was present during which the average dose per pulse was ~0.045 +/- 0.004 Gy/Pulse, whereas after the ramp-up it stabilized at 0.65 +/- 0.01 Gy/Pulse. 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., Comment: 30 Pages, 7 Figures

Clinical measurements of O2 in tissues will inevitably provide data that are at best aggregated and will not reflect the inherent heterogeneity of O2 in tissues over space and time. Additionally, the nature of all existing techniques to measure O2 results in complex sampling of the volume that is sensed by the technique. By recognizing these potential limitations of the measures, one can focus on the very important and useful information that can be obtained from these techniques, especially data about factors that can change levels of O2 and then exploit these changes diagnostically and therapeutically. The clinical utility of such data ultimately needs to be verified by careful studies of outcomes related to the measured changes in levels of O2.

Purpose: In this study, procedures were developed to achieve efficient reversible conversion of a clinical linear accelerator (LINAC) and deliver electron FLASH (eFLASH) or conventional beams to the treatment room isocenter. Material & Methods: The LINAC was converted to deliver eFLASH 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 per pulse and average dose rate were measured in a solid water phantom at different depths with Gafchromic film and OSLD. A pulse controller counted the pulses via scattered radiation signal and gated the delivery for preset pulse count. A fast photomultiplier tube-based Cherenkov detector measured per pulse beam output at 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: Dose per pulse of 0.86 +/- 0.01 Gy (310 +/- 7 Gy/s average dose rate) were achieved at isocenter. The dose from simultaneous irradiation of film and OSLD were within 1%. The PMT showed the LINAC required about 5 pulses before the output stabilized and its long-term stability was within 3% for measurements performed at 3 minutes intervals. The dose, flatness, symmetry, and photon energy were unchanged from baseline and within tolerance (1%, 3%, 2%, and 0.1% respectively) after reverting to conventional beams. Conclusion: 10 MeV FLASH beams were achieved at the isocenter of the treatment room. The beam output was reproducible but requires further investigation of the ramp up time in the first 5 pulses, equivalent to, Manuscript: 21 Pages, 1 Table, 8 Figures; Supplementary Material A: 2 Pages, 2 Figures; Appendix: Film Dosimetry: 2 Pages, 2 Tables

The aim of the paper is to discuss what currently is feasible clinically to measure the level of oxygen and how that measurement can be clinically useful. Because oxygen in tissues is quite heterogeneous and all methods of measurement can only provide an average across heterogeneities at some spatial and temporal resolution, the values that are obtained may have limitations on their clinical utility. However, even if such limitations are significant, if one utilizes repeated measurements and focuses on changes in the measured levels, rather than 'absolute levels', it may be possible to obtain very useful clinical information. While these considerations are especially pertinent in cancer, they also pertain to most other types of pathology.

The success of treatment for malignancies, especially those undergoing radiation therapy or chemotherapy, has long been recognized to depend on the degree of hypoxia in the tumor. In addition to the prognostic value of knowing the tumor’s initial level of hypoxia, assessing the tumor oxygenation during standard therapy or oxygen-related treatments (such as breathing oxygen-enriched gas mixtures or taking drugs that can increase oxygen supply to tissues) can provide valuable data to improve the efficacy of treatments. A series of early clinical studies of tumors in humans are ongoing at Dartmouth and Emory using electron paramagnetic resonance (EPR) oximetry to assess tumor oxygenation, initially and over time during either natural disease progression or treatment. This approach has the potential for reaching the long-sought goal of enhancing the effectiveness of cancer therapy. In order to effectively reach this goal, we consider the validity of the practical and statistical assumptions when interpreting the measurements made in vivo for patients undergoing treatment for cancer.

541 Background: MR-guided stereotactic body radiation therapy (MR-SBRT) is a novel method of treating mobile tumors with soft-tissue gating and on-table adaptive planning. In our experience using the ViewRay MRIdian system (VR) for treating locally advanced pancreatic cancer (PA) with MR-SBRT, the true-fast imaging with steady-state free precession (TRUFI) sequences on the VR impart differing intensities for relevant structures seen on the pre-treatment high resolution 3D MRI (3D MRI) versus the real-time 2D cine MRI (2D cine) used for target tracking. Since these variations can confound target tracking selection, we propose that an understanding of the differing contrast profiles could improve selection of tracking structures and optimize treatment delivery. Methods: We retrospectively reviewed both 3D MRI and 2D cine images for patients (pts) with PA (n =20) treated on the VR. At simulation, an appropriate tracking target was identified and contoured on a single 3mm sagittal slice of the 3D MRI. This sagittal slice was directly compared to the registered 7mm 2D cine to identify structures with notable discrepancies in signal intensity. The 3D MRI was then explored in additional planes to confirm structure identities. For quantitative verification of the clinically observed differences, the pixel intensity distributions of 3D MRI and 2D cine DICOM image datasets were statistically compared. Results: In all pts reviewed, arteries (aorta, celiac, SMA) appeared with similar contrast profiles on both images. However, veins (portal vein, SMV) appeared hypointense on 3D MRI but hyperintense on 2D cine. Biliary structures appeared hyperintense on 3D MRI but only mildly hyperintense on 2D cine. The pixel intensity distributions extracted from 3D MRI and 2D cine images were confirmed to differ significantly (two sample Kolmogorov-Smirnov test; test statistic =0.40; p < 0.001). Conclusions: There are significant variations in image intensity between the initial treatment planning 3D MRI and the immediate pre-treatment 2D cine obtained with the VR. Understanding these discrepancies can guide radiation oncologists in choosing optimal tracking targets. Future work will focus on identifying the particular causes and frequencies of target tracking failures and exploring alternative tracking algorithms using artificial intelligence which could ultimately allow for VMAT on the ViewRay system.

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 Gd2O2S: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-1quinine 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 (R2 = 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.

Hypoxic tumors are more resistant to radiotherapy and chemotherapy, which decreases the efficacy of these common forms of treatment. We have been developing implantable paramagnetic particulates to measure oxygen in vivo using electron paramagnetic resonance. Once implanted, oxygen can be measured repeatedly and non-invasively in superficial tissues (

Purpose To explore, in a dose-escalation study, the feasibility of hyperbaric oxygen (HBO) treatments immediately before intensity modulated radiation therapy in conjunction with cisplatinum chemotherapy for squamous cell carcinoma of the head and neck (SCCHN). Methods and Materials Eligible patients presented with SCCHN (stage III-IV [M0]), life expectancy >6 months, and Karnofsky performance status ≥70. Enrollees received intensity modulated radiation therapy, 70 Gy in 35 fractions over 7 weeks with weekly cisplatinum. Patients received HBO—100% oxygen, 2.4 atmospheres absolute (ATA) for 30 minutes—twice per week initially. Subsequent patients were escalated to 3 and then 5 times per week. Intensity modulated radiation therapy began within 15 minutes after HBO. Patients were followed for 2 years after RT with quality-of-life questionnaires (Performance Status Scale–Head and Neck Cancer and the Functional Assessment of Cancer Therapy–Head and Neck Cancer) and for 5+ years for local recurrence, distant metastases, disease-specific survival, and overall survival. Results Twelve subjects enrolled from 3 centers. Two withdrew during radiation therapy and 1 within 14 weeks after radiation therapy. The remaining 9 had primary oropharyngeal disease and were stage IVA (7) or IVB (2). No dose-limiting toxicities were observed with daily HBO. Two patients (22%) required pressure equalization tubes. The average time between HBO and radiation therapy was 8.5 minutes, with 2 of 231 administrations delivered beyond 15 minutes (0.5%). Per-protocol analysis showed a clinical complete response in 7 and a pathologic complete response without tumor in salvage neck dissections in 2. With minimum follow-up of 61 months, per-protocol 5-year overall survival was 100%, local recurrence 0%, and distant metastases 11%. Patient-reported outcomes for quality of life (Functional Assessment of Cancer Therapy–Head and Neck Cancer) were comparable to published results for chemoradiotherapy without HBO. Conclusions While acknowledging the study's small size and early attrition of 3 patients, our in-depth review of the acquired data indicates the feasibility of combining HBO with chemoradiation.

A new resonator for X-band electron paramagnetic resonance (EPR) spectroscopy, which utilizes the unique resonance properties of dielectric substrates, has been developed using a single crystal of titanium dioxide. As a result of the dielectric properties of the crystal(s) chosen, this novel resonator provides the ability to make in vivo EPR spectroscopy surface measurements in the presence of lossy tissues at X-band frequencies (up to 10 GHz). A double-loop coupling device is used to transmit and receive microwave power to/from the resonator. This coupler has been developed and optimized for coupling to the resonator in the presence of lossy tissues to further enable in vivo measurements, such as in vivo EPR spectroscopy of human fingernails or teeth to measure the dose of ionizing radiation that a given individual has been exposed to. An advantage of this resonator for surface measurements is that the magnetic fields generated by the resonator are inherently shallow, which is desirable for in vivo nail dosimetry.

Purpose Patients have reported sensations of seeing light flashes during radiation therapy, even with their eyes closed. These observations have been attributed to either direct excitation of retinal pigments or generation of Cherenkov light inside the eye. Both in vivo human and ex vivo animal eye imaging was used to confirm light intensity and spectra to determine its origin and overall observability. Methods and Materials A time-gated and intensified camera was used to capture light exiting the eye of a patient undergoing stereotactic radiosurgery in real time, thereby verifying the detectability of light through the pupil. These data were compared with follow-up mechanistic imaging of ex vivo animal eyes with thin radiation beams to evaluate emission spectra and signal intensity variation with anatomic depth. Angular dependency of light emission from the eye was also measured. Results Patient imaging showed that light generation in the eye during radiation therapy can be captured with a signal-to-noise ratio of 68. Irradiation of ex vivo eye samples confirmed that the spectrum matched that of Cherenkov emission and that signal intensity was largely homogeneous throughout the entire eye, from the cornea to the retina, with a slight maximum near 10 mm depth. Observation of the signal external to the eye was possible through the pupil from 0° to 90°, with a detected emission near 2500 photons per millisecond (during peak emission of the ON cycle of the pulsed delivery), which is over 2 orders of magnitude higher than the visible detection threshold. Conclusions By quantifying the spectra and magnitude of the signal, we now have direct experimental observations that Cherenkov light is generated in the eye during radiation therapy and can contribute to perceived light flashes. Furthermore, this technique can be used to further study and measure phosphenes in the radiation therapy clinic.

Surface dosimetry is required for ensuring effective administration of total skin electron therapy (TSET); however, its use is often reduced due to the time consuming and complex nature of acquisition. A new surface dose imaging technique was characterized in this study and found to provide accurate, rapid and remote measurement of surface doses without the need for post-exposure processing. Disc-shaped plastic scintillators (1 mm thick × 15 mm ) were chosen as optimal-sized samples and designed to attach to a flat-faced phantom for irradiation using electron beams. Scintillator dosimeter response to radiation damage, dose rate, and temperature were studied. The effect of varying scintillator diameter and thickness on light output was evaluated. Furthermore, the scintillator emission spectra and impact of dosimeter thickness on surface dose were also quantified. Since the scintillators were custom-machined, dosimeter-to-dosimeter variation was tested. Scintillator surface dose measurements were compared to those obtained by optically stimulated luminescence dosimeters (OSLD). Light output from scintillator dosimeters evaluated in this study was insensitive to radiation damage, temperature, and dose rate. Maximum wavelength of emission was found to be 422 nm. Dose reported by scintillators was linearly related to that from OSLDs. Build-up from placement of scintillators and OSLDs had a similar effect on surface dose (4.9% increase). Variation among scintillator dosimeters was found to be 0.3 ± 0.2%. Scintillator light output increased linearly with dosimeter thickness (~1.9 × /mm). All dosimeter diameters tested were able to accurately measure surface dose. Scintillator dosimeters can potentially improve surface dosimetry-associated workflow for TSET in the radiation oncology clinic. Since scintillator data output can be automatically recorded to a patient medical record, the chances of human error in reading out and recording surface dose are minimized.

Previous work has shown that capturing optical emission from plastic discs attached directly to the skin can be a viable means to accurately measure surface dose during total skin electron therapy. This method can provide accurate dosimetric information rapidly and remotely without the need for postprocessing. The objective of this study was to: (1) improve the robustness and usability of the scintillators and (2) enhance sensitivity of the optical imaging system to improve scintillator emission detection as related to tissue surface dose. Baseline measurements of scintillator optical output were obtained by attaching the plastic discs to a flat tissue phantom and simultaneously irradiating and imaging them. Impact on underlying surface dose was evaluated by placing the discs on-top of the active element of an ionization chamber. A protective coating and adhesive backing were added to allow easier logistical use, and they were also subjected to disinfection procedures, while verifying that these changes did not affect the linearity of response with dose. The camera was modified such that the peak of detector quantum efficiency better overlapped with the emission spectra of the scintillating discs. Patient imaging was carried out and surface dose measurements were captured by the updated camera and compared to those produced by optically stimulated luminescence detectors (OSLD). The updated camera was able to measure surface dose with3 % difference compared to OSLD–Cherenkov emission from the patient was suppressed and scintillation detection was enhanced by 25 × and 7 × , respectively. Improved scintillators increase underlying surface dose on average by 5.2 ± 0.1 % and light output decreased by 2.6 ± 0.3 % . Disinfection had0.02 % change on scintillator light output. The enhanced sensitivity of the imaging system to scintillator optical emission spectrum can now enable a reduction in physical dimensions of the dosimeters without loss in ability to detect light output.

Testing and verification are an integral part of any cycle to design, manufacture and improve a novel device intended for use in humans. In the case of testing Dartmouth's electron paramagnetic resonance (EPR) in vivo tooth dosimetry device, in vitro studies are needed throughout its development to test its performance, i.e. to verify its current capability for assessing dose in individuals potentially exposed to ionizing radiation. Since the EPR device uses the enamel of human teeth to assess dose, models that include human teeth have been an integral mechanism to carry out in vitro studies during development and testing its ability to meet performance standards for its ultimate intended in vivo use. As the instrument improves over time, new demands for in vitro studies change as well. This paper describes the tooth models used to perform in vitro studies and their evolution to meet the changing demands for testing in vivo EPR tooth dosimetry.

The aim of this study was to make direct measurements of the possible radiation-induced EPR signals in the teeth of volunteers who were residents in Fukushima within 80 km distance from the Fukushima Nuclear Power plant at the time of the disaster, and continued to live there for at least 3 month after the disaster. Thirty four volunteers were enrolled in this study. These measurements were made using a portable L-band EPR spectrometer, which was originally developed in the EPR Center at Dartmouth. All measurements were performed using surface loop resonators that have been specifically designed for the upper incisor teeth. Potentially these signals include not only radiation-induced signals induced by the incident but also background signals including those from prior radiation exposure from the environment and medical exposure. We demonstrated that it is feasible to transport the dosimeter to the measurement site and make valid measurements. The intensity of the signals that were obtained was not significantly above those seen in volunteers who had not had potential radiation exposures at Fukushima.