OxyChip embedded with radio-opaque gold nanoparticles for anatomic registration and oximetry in tissues.

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.

A Radiation Biological Analysis of the Oxygen Effect as a Possible Mechanism in FLASH.

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 (O2) is frequently mentioned. In order to effectively determine if the protective effect of FLASH RT occurs via a differential direct depletion of O2 (compared to conventional radiation), it is essential to consider the known role of O2 in modifying the response of cells and tissues to ionising radiation (known as 'the oxygen effect'). Considerations include: (1) The pertinent reaction involves an unstable intermediate of radiation-damaged DNA, which either undergoes chemical repair to restore the DNA or reacts with O2, resulting in an unrepairable lesion in the DNA, (2) These reactions occur in the nuclear DNA, which can be used to estimate the distance needed for O2 to diffuse through the cell to reach the intermediates, (3) The longest lifetime that the reactive site of the DNA is available to react with O2 is 1-10 µsec, (4) Using these lifetime estimates and known diffusion rates in different cell media, the maximal distance that O2 could travel in the cytosol to reach the site of the DNA (i.e., the nucleus) in time to react are 60-185 nm. This calculation defines the volume of oxygen that is pertinent for the direct oxygen effect, (5) Therefore, direct measurements of oxygen to determine if FLASH RT operates through differential radiochemical depletion of oxygen will require the ability to measure oxygen selectively in a sphere of <200 nm, with a time resolution of the duration of the delivery of FLASH, (6) It also is possible that alterations of oxygen levels by FLASH could occur more indirectly by affecting oxygen-dependent cell signalling and/or cellular repair.

What Is the Meaning of an Oxygen Measurement? : Analysis of Methods Purporting to Measure Oxygen in Targeted Tissues.

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.

Evaluation of a Refined Implantable Resonator for Deep-Tissue EPR Oximetry in the Clinic.

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.

Guidance to Transfer 'Bench-Ready' Medical Technology into Usual Clinical Practice: Case Study - Sensors and Spectrometer Used in EPR Oximetry.

This paper considers the critical role that academics can have in the development of clinical innovations and especially how their impact can be optimized. The focus should be on establishing the safety and efficacy of new approaches while also incorporating human factors and human use considerations into the inventions. It is very advantageous to work in concert with the end-users (operators and clinicians) to help ensure that the innovation will be useful and feasible to be incorporated into actual clinical practice as intended. This strategy enables developments to tackle real clinical needs by providing novel strategies to improve patient care while using solutions that fit into clinical practice and that are welcomed by patients and clinical staff. These principles are illustrated by a case study of the development of clinical in vivo EPR oximetry.

EPR Oximetry for Investigation of Hyperbaric O2 Pre-treatment for Tumor Radiosensitization.

A number of studies have reported benefits associated with the application of hyperbaric oxygen treatment (HBO) delivered immediately prior to radiation therapy. While these studies provide evidence that pre-treatment with HBO may be beneficial, no measurements of intratumoral pO2 were carried out and they do not directly link the apparent benefits to decreased hypoxic fractions at the time of radiation therapy. While there is empirical evidence and some theoretical basis for HBO to enhance radiation therapy, without direct and repeated measurements of its effects on pO2, it is unlikely that the use of HBO can be understood and optimized for clinical applications. In vivo EPR oximetry is a technique uniquely capable of providing repeated direct measurements of pO2 through a non-invasive procedure in both animal models and human patients. In order to evaluate the ability of pretreatment with HBO to elevate tumor pO2, a novel small animal hyperbaric chamber system was constructed that allows simultaneous in vivo EPR oximetry. This chamber can be placed within the EPR magnet and is equipped with a variety of ports for multiplace gas delivery, thermoregulation, delivery of anesthesia, physiologic monitoring, and EPR detection. Initial measurements were performed in a subcutaneous RIF-1 tumor model in C3H/HeJ mice. The mean baseline pO2 value was 6.0 ± 1.2 mmHg (N = 7) and responses to two atmospheres absolute pressure HBO varied considerably across subjects, within tumors, and over time. When an increase in pO2 was observed, the effect was transient in all but one case, with durations lasting from 5 min to over 20 min, and returned to baseline levels during HBO administration. These results indicate that without direct measurements of pO2 in the tissue of interest, it is likely to be difficult to know the effects of HBO on actual tissue pO2.

Direct and Repeated Clinical Measurements of pO2 for Enhancing Cancer Therapy and Other Applications.

The first systematic multi-center study of the clinical use of EPR oximetry has begun, with funding as a PPG from the NCI. Using particulate oxygen sensitive EPR, materials in three complementary forms (India Ink, "OxyChips", and implantable resonators) the clinical value of the technique will be evaluated. The aims include using repeated measurement of tumor pO2 to monitor the effects of treatments on tumor pO2, to use the measurements to select suitable subjects for the type of treatment including the use of hyperoxic techniques, and to provide data that will enable existing clinical techniques which provide data relevant to tumor pO2 but which cannot directly measure it to be enhanced by determining circumstances where they can give dependable information about tumor pO2.

Advances in probes and methods for clinical EPR oximetry.

EPR oximetry, which enables reliable, accurate, and repeated measurements of the partial pressure of oxygen in tissues, provides a unique opportunity to investigate the role of oxygen in the pathogenesis and treatment of several diseases including cancer, stroke, and heart failure. Building on significant advances in the in vivo application of EPR oximetry for small animal models of disease, we are developing suitable probes and instrumentation required for use in human subjects. Our laboratory has established the feasibility of clinical EPR oximetry in cancer patients using India ink, the only material presently approved for clinical use. We now are developing the next generation of probes, which are both superior in terms of oxygen sensitivity and biocompatibility including an excellent safety profile for use in humans. Further advances include the development of implantable oxygen sensors linked to an external coupling loop for measurements of deep-tissue oxygenations at any depth, overcoming the current limitation of 10 mm. This paper presents an overview of recent developments in our ability to make meaningful measurements of oxygen partial pressures in human subjects under clinical settings.

Skeletal muscle and glioma oxygenation by carbogen inhalation in rats: a longitudinal study by EPR oximetry using single-probe implantable oxygen sensors.

The feasibility of EPR oximetry using a single-probe implantable oxygen sensor (ImOS) was tested for repeated measurement of pO2 in skeletal muscle and ectopic 9L tumors in rats. The ImOS (50 mm length) were constructed using nickel-chromium alloy wires, with lithium phthalocyanine (LiPc, oximetry probe) crystals loaded in the sensor loop and coated with AF 2400(®) Teflon. These ImOS were implanted into the skeletal muscle in the thigh and subcutaneous 9L tumors. Dynamic changes in tissue pO2 were assessed by EPR oximetry at baseline, during tumor growth, and repeated hyperoxygenation with carbogen breathing. The mean skeletal muscle pO2 of normal rats was stable and significantly increased during carbogen inhalation in experiments repeated for 12 weeks. The 9L tumors were hypoxic with a tissue pO2 of 12.8 ± 6.4 mmHg on day 1; however, the response to carbogen inhalation varied among the animals. A significant increase in the glioma pO2 was observed during carbogen inhalation on day 9 and day 14 only. In summary, EPR oximetry with ImOS allowed direct and longitudinal oxygen measurements in deep muscle tissue and tumors. The heterogeneity of 9L tumors in response to carbogen highlights the need to repeatedly monitor pO2 to confirm tumor oxygenation so that such changes can be taken into account in planning therapies and interpreting results.

Overview of the principles and practice of biodosimetry.

The principle of biodosimetry is to utilize changes induced in the individual by ionizing radiation to estimate the dose and, if possible, to predict or reflect the clinically relevant response, i.e., the biological consequences of the dose. Ideally, the changes should be specific for ionizing radiation, and the response should be unaffected by prior medical or physiological variations among subjects, including changes that might be caused by the stress and trauma from a radiation event. There are two basic types of biodosimetry with different and often complementary characteristics: those based on changes in biological parameters such as gene activation or chromosomal abnormalities and those based on physical changes in tissues (detected by techniques such as EPR). In this paper, we consider the applicability of the various techniques for different scenarios: small- and large-scale exposures to levels of radiation that could lead to the acute radiation syndrome and exposures with lower doses that do not need immediate care, but should be followed for evidence of long-term consequences. The development of biodosimetry has been especially stimulated by the needs after a large-scale event where it is essential to have a means to identify those individuals who would benefit from being brought into the medical care system. Analyses of the conventional methods officially recommended for responding to such events indicate that these methods are unlikely to achieve the results needed for timely triage of thousands of victims. Emerging biodosimetric methods can fill this critically important gap.

In vivo EPR tooth dosimetry for triage after a radiation event involving large populations.

The management of radiation injuries following a catastrophic event where large numbers of people may have been exposed to life-threatening doses of ionizing radiation will rely critically on the availability and use of suitable biodosimetry methods. In vivo electron paramagnetic resonance (EPR) tooth dosimetry has a number of valuable and unique characteristics and capabilities that may help enable effective triage. We have produced a prototype of a deployable EPR tooth dosimeter and tested it in several in vitro and in vivo studies to characterize the performance and utility at the state of the art. This report focuses on recent advances in the technology, which strengthen the evidence that in vivo EPR tooth dosimetry can provide practical, accurate, and rapid measurements in the context of its intended use to help triage victims in the event of an improvised nuclear device. These advances provide evidence that the signal is stable, accurate to within 0.5 Gy, and can be successfully carried out in vivo. The stability over time of the radiation-induced EPR signal from whole teeth was measured to confirm its long-term stability and better characterize signal behavior in the hours following irradiation. Dosimetry measurements were taken for five pairs of natural human upper central incisors mounted within a simple anatomic mouth model that demonstrates the ability to achieve 0.5 Gy standard error of inverse dose prediction. An assessment of the use of intact upper incisors for dose estimation and screening was performed with volunteer subjects who have not been exposed to significant levels of ionizing radiation and patients who have undergone total body irradiation as part of bone marrow transplant procedures. Based on these and previous evaluations of the performance and use of the in vivo tooth dosimetry system, it is concluded that this system could be a very valuable resource to aid in the management of a massive radiological event.

Initial Observation of Contrast Profiles for 2-Dimensional and 3-Dimensional Magnetic Resonance Imaging Sequences in Magnetic Resonance-Guided Radiation Therapy for Locally Advanced Pancreatic Cancer.

Purpose: In our experience treating locally advanced pancreatic cancer with magnetic resonance-guided radiation therapy (MRgRT), the true-fast imaging with steady-state free precession sequences used to generate both the real-time 2-dimensional (2D) magnetic resonance images (MRI; 2D cine) and the pretreatment high-resolution 3-dimensional (3D) MRI impart differing intensities for relevant structures between the 2 scans. 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 Materials: We retrospectively reviewed both 2D cine and 3D MRI images for 20 patients with pancreatic cancer treated with MRgRT. At simulation, an appropriate tracking target was identified and contoured on a single 3-mm sagittal slice of the 3D MRI. This sagittal slice was directly compared with the coregistered 7-mm 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 digital imaging and communications in medicine data sets were statistically compared. Results: In all patients reviewed, arteries (aorta, celiac, superior mesenteric artery, hepatic artery) appeared mildly hyperintense on both scans. However, veins (portal vein, superior mesenteric vein) 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 (2 sample Kolmogorov-Smirnov test; test statistic, 0.40; P < .001). Conclusions: There are significant variations in image intensity between the immediate pretreatment 2D cine compared with 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.

Technical note: Visual, rapid, scintillation point dosimetry for in vivo MV photon beam radiotherapy treatments.

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.

In Vivo Verification of Electron Paramagnetic Resonance Biodosimetry Using Patients Undergoing Radiation Therapy Treatment.

PURPOSE: Electron paramagnetic resonance (EPR) biodosimetry, used to triage large numbers of individuals incidentally exposed to unknown doses of ionizing radiation, is based on detecting a stable physical response in the body that is subject to quantifiable variation after exposure. In vivo measurement is essential to fully characterize the radiation response relevant to a living tooth measured in situ. The purpose of this study was to verify EPR spectroscopy in vivo by estimating the radiation dose received in participants' teeth. METHODS AND MATERIALS: A continuous wave L-band spectrometer was used for EPR measurements. Participants included healthy volunteers and patients undergoing head and neck and total body irradiation treatments. Healthy volunteers completed 1 measurement each, and patients underwent measurement before starting treatment and between subsequent fractions. Optically stimulated luminescent dosimeters and diodes were used to determine the dose delivered to the teeth to validate EPR measurements. RESULTS: Seventy measurements were acquired from 4 total body irradiation and 6 head and neck patients over 15 months. Patient data showed a linear increase of EPR signal with delivered dose across the dose range tested. A linear least-squares weighted fit of the data gave a statistically significant correlation between EPR signal and absorbed dose (P < .0001). The standard error of inverse prediction (SEIP), used to assess the usefulness of fits, was 1.92 Gy for the dose range most relevant for immediate triage (≤7 Gy). Correcting for natural background radiation based on patient age reduced the SEIP to 1.51 Gy. CONCLUSIONS: This study demonstrated the feasibility of using spectroscopic measurements from radiation therapy patients to validate in vivo EPR biodosimetry. The data illustrated a statistically significant correlation between the magnitude of EPR signals and absorbed dose. The SEIP of 1.51 Gy, obtained under clinical conditions, indicates the potential value of this technique in response to large radiation events.

Standard error of inverse prediction for dose-response relationship: approximate and exact statistical inference.

This paper develops a new metric, the standard error of inverse prediction (SEIP), for a dose-response relationship (calibration curve) when dose is estimated from response via inverse regression. SEIP can be viewed as a generalization of the coefficient of variation to regression problem when x is predicted using y-value. We employ nonstandard statistical methods to treat the inverse prediction, which has an infinite mean and variance due to the presence of a normally distributed variable in the denominator. We develop confidence intervals and hypothesis testing for SEIP on the basis of the normal approximation and using the exact statistical inference based on the noncentral t-distribution. We derive the power functions for both approaches and test them via statistical simulations. The theoretical SEIP, as the ratio of the regression standard error to the slope, is viewed as reciprocal of the signal-to-noise ratio, a popular measure of signal processing. The SEIP, as a figure of merit for inverse prediction, can be used for comparison of calibration curves with different dependent variables and slopes. We illustrate our theory with electron paramagnetic resonance tooth dosimetry for a rapid estimation of the radiation dose received in the event of nuclear terrorism.

Failure Mode and Effects Analysis for Experimental Use of FLASH on a Clinical Accelerator.

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.

One Year of Clinic-Wide Cherenkov Imaging for Discovery of Quality Improvement Opportunities in Radiation Therapy.

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.

Comparison of Tumor Control and Skin Damage in a Mouse Model after Ultra-High Dose Rate Irradiation and Conventional Irradiation.

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.

Computational dose visualization & comparison in total skin electron treatment suggests superior coverage by the rotational versus the Stanford technique.

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.

Individual pulse monitoring and dose control system for pre-clinical implementation of FLASH-RT.

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 forin vivodose monitoring. The scintillator was characterized in terms of its radiation stability, mean dose-rate (Dm), and dose per pulse (Dp) dependence.Main results.TheDpexhibited a consistent ramp-up period across ∼4-5 pulse. The plastic scintillator was shown to be linear withDm(40-380 Gy s-1) andDp(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 vivodosimetry monitoring with a 1 cm circular cut-out revealed that during the ramp-up period, the averageDpwas ∼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.